PHARMACOLOGY - came from the Greek word "Pharmakon" which means "Drug" and "Logos" which means "Discourse" / "Logia" (Latin) - "Study". - it is a science that deals with the chemical and physical properties of drugs, their sources, effects, biotransformation and excretion. - it is the study of the effects of chemical substances upon living tissues.

HISTORY OF PHARMACOLOGY Pharmacologic thought had its beginning when early humans began to wonder why the chewing of certain plant roots or leaves altered their awareness or functions. As experience in root and leaf chewing progressed into therapeutic berry picking and smoke smelling, the experiences were spread and shared. As time progressed, some individuals became more astute in observing and remembering that plant products produced predictable effects. Thus, the first pharmacologist was born. Clearly this humble beginning has evolved through the years into a huge industrial and academic community that is concerned with the study and development of drugs. Drugs that evolved are then prescribed and dispensed through the practice of medicine, dentistry, and pharmacy. (for continuation - refer to Holroyd) The history of pharmacology can be divided into 2 periods: the early period dates back to antiquity and is characterized by empirical observations in the use of crude drugs. It is interesting that even primitive people could discover relationships between drugs and disease. The use of drugs has been so prevalent throughout history that Sir William Osler stated (1894) with some justification that man has an inborn craving for medicine. In contrast to this ancient period, modern pharmacology is based on experimental investigations concerning the site and mode of action of drugs. The application of the scientific method to studies on drugs was initiated in France by Francois Magendie and was expanded by Claude Bernard (1813-1878). The name of Oswald Schiemie Debug (1838 1921) is commonly associated with the development of Experimental Pharmacology - in Germany and John Jacob Abel (1857-1938) played a similar role in the U.S. The growth of pharmacology was greatly stimulated by the rise of synthetic organic chemistry which provided new tools and new therapeutic agents. More recently, pharmacology has benefited from developments of other basic sciences and in turn has contributed to their growth. Some of the greatest changes in medicine that have occurred during the last few decades are directly attributable to the discovery of new drugs.

Claude Bernard - expanded application in scientific method. Alexander Fleming - discovered penicillin. Hippocrates - father of medicine John Jacob Abel - development of experiments in pharmacology Oswald Schieme Debug - development of experimental pharmacology Joseph Lister - antiseptic technique

BRANCHES OF PHARMACOLOGY1. Pharmacokinetics - concerned with the absorption, distribution, biotransformation, and excretion of drugs. - movement of drugs in the body. "How the body handles the drug?"

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2. Pharmacodynamics - deals with the effects of drugs in the body; deals with the mechanism of action/effect of a drug in living organisms and their corresponding responses and the physiologic and biochemical effects of the drug. "How the drug produces its effect?" "What the drug does to the body?" 3. Pharmacognosy - identification and procurement of crude and naturally occurring drugs. Former name: "Materia Medica"4. Pharmacy - procurement, preparation and dispensing of drugs.5. Pharmacogenetics - effects of drug on people with congenital abnormalities of metabolism. e.q. Eskimos - hydrolyze isoniazid = faster than other races. barbiturates - geriatrics = stimulation instead of depression6. Posology - study of dosage of drugs.7. Toxicology - study of the adverse effects of drugs.8. Biochemorphology - alteration of the chemical structure of drugs to produce a different effect. 9. Developmental pharmacology - effects of drugs in fetal development. e.q. Thalidomide babies - teratogenic.10. Pharmacotherapeutics - "clinical pharmacology' - the uses/application of drugs in the treatment of disease; the art and science of using drugs in the diagnosis, treatment, and prevention of disease.11. Descriptive pharmacology - qualitative effects of drugs in man.12. Clinical Pharmacology – the study of the effects of drugs in man.13. Molecular pharmacology – the study of drug effects at the molecular level.

IMPORTANCE OF PHARMACOLOGY TO DENTISTRY1. To be able to cure diseases2. To be able to prescribe drugs to the patient appropriate for his condition.3. To be able to communicate with the medical staff and practitioners.

***The dentist should be able to obtain the maximal advantage while producing the minimal disadvantages.***The prescriber should be aware of how drugs may modify the physiology of the patient.

DRUGS - any chemical substance that affects / modifies the biologic system. - chemical necessary for the maintenance of life processes by their ability to act selectively in biologic systems to accomplish a desired effect. - a single entity that may be one of the constituent of medicine.

Medicine - may contain one or more active constituents (drugs) together with additives to facilitate administration.

*** "All medicines are drugs, but not all drugs are medicine."

SOURCES OF DRUGS1. Natural a. Animals - glandular products are the chief medicinal currently obtained form animal sources. e.q. thyroid hormone, insulin from pancreas of cattle and pigs, epinephrine and ACTH.

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b. Plants - crude drugs maybe obtained from any part of various plants used medicinally. E.q Leaves - Pito-pito, Alagaw, Banaba, etc.; digitalis from foxglove plant. c. Minerals - iron, commonly used in the form of ferrous sulphate2. Synthetic/Chemical Substances - done in the laboratory by chemists. a. Pure drugs and other simple substances b. Products of complex synthesis (antibiotics, sulfonamides and adrenocorticosteroids).

STAGES IN THE DEVELOPMENT OF A DRUGEvolution of a New DrugDrug development StrategiesExperimental PharmacologyToxicological AssessmentClinical EvaluationMarketing and Promotion

STRATEGIES* Serendipity (luck and intuition)* Molecular Roulette (random clinical synthesis)* Program Basic Research with Synthesis of Specific Chemicals.* Clinical Observation of Drug Action in the Practice.

PRINCIPAL INDIVIDUAL(S) STAGES IN THE DEVELOPMENT OF A DRUG CONCERNED

Various IdeasChemist Natural or synthetic chemical compoundsPharmacologists Pharmacological TestsBiochemists Performs "biologic assays"Toxicologists Acute toxicity Chronic toxicity tests Mutagenicity Teratogenesis CarcinogenecityPharmacists Pharmaceutical formulation / Clinical trialsClinical Pharmacologists Phase 1: A pilot investigation made in a small numberNormal Volunteers of normal volunteersDentist/Doctor/Patients Phase 2: An open clinical trial carried out in a small Clinical Pharmacologists number of patientsNurse Patients Statistician Phase 3: Large scale clinical trial Practicing Dentists/Doctors Phase 4: Monitored release and post- marketing and their patients surveillance of new drug Accepted drug

CLINICAL EVALUATIONPhase I* A pilot study that uses small numbers of human volunteers* Initially, low doses of drug that are gradually increased are used and the toxic or exaggerated effects are monitoredPhase II* The drug is tested in limited numbers of hospitalized patients with the disease the drug is

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intended to treat* The test drug is compared to established drugs and placeboPhase III* Testing is intended to large group of outpatients to permit evaluation of the drug under conditions that may exist if the drug is marketed.* If the drug is safe and effective for its intended use, the FDA may approve the drug for marketing.Phase IV* A new drug is usually marketed only after a few hundreds, or at most few thousand patients have been exposed to it for a relatively short period of time.* Post-marketing surveillance is necessary to assess efficacy and toxicity of a new drug on a larger scale.

* 3 MAJOR PHASES IN A PRE-CLINICAL TESTS1. Acute Toxicity Test2. Sub-acute (prolonged) Toxicity Test3. Chronic Toxicity Test

PRINCIPLES OF DRUG ACTION1. Cure disease2. Alleviate symptoms3. Replace deficiencies

FUNDAMENTAL ACTION OF DRUGS1. STIMULATION - drugs that increases the overall activity of specialized organs, tissue, or cell. e.q. caffeine (coffee - CNS stimulant; can cause tachycardia (inc. heart activity).2. DEPRESSION - drugs that decreases the overall functional activity of cells, tissues, or organs. e.q. alcohol, barbiturates.3. IRRITATION - either inc. or dec. but it is said that stimulation is pushed too far to the point of injuring the cell.; manifested as nausea, vomiting, itchiness, redness.4. REPLACEMENT / SUPPLEMENT - drugs that can be used as substitutes for what is lacking in the body. e.q. vitamins.5. ANTIMICROBIAL / ANTIBACTERIAL - when the action of the drug is directed towards the invading microorganism in the body. e.q. antibiotics.6. ANESTHETIC - a solution that tends to produce a temporary block or nerve conduction.7. PROPHYLACTIC - to prevent any untoward occurrences/illnesses in the body. e.q. DPT, polio vaccines, etc.

*All drugs exert some effect on a biologic system* In most instances, a given effect can be related to drug dosage in a quantitative fashion.*Two important expressions of drug action can be demonstrated: POTENCY and EFFICACY.

Potency - amount/strength of a drug required to produce the desired effect or action - is a measure of drug activity in terms of the amount required to produce an effect of given intensity.Efficacy - ability of the drug to elicit its maximum inherent physiologic effect. - the "Maximum Intensity of Effect" of a certain drug.

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* For example, one drug (drug A) produces complete eradication of premature ventricular contractions (PVCs) at a dose of 10 mg. A second drug (drug B) produces complete eradication of PVCs at a dose of 20 mg. Therefore, both drugs have the same efficacy (complete eradication of PVCs), but drug A is more potent than drug B. It takes less of drug A to produce the same effect. A third drug (drug C) can reduce the PVCs by only 60%, and it takes a dose of 50 mg. to achieve the effect. Therefore, drug C has less efficacy and less potency in the reduction of PVCs compared with both drug A and drug B.

CHARACTERISTICS OF DRUG ACTION 1. According to Biochemical Action E.q. Hypoglycemic agents; Hemostatic agents2. According to Physiologic Effects E.q. Muscle relaxants; Anti-hypertensive agents3. According to the Organ System on which they exert their Therapeutic Action E.q. CNS stimulants

USES OF DRUGS1. Diagnosis - e.q. barium enema2. Prevention - e.q. DPT vaccine3. Contraception - e.q. pills, deprovera, etc.4. Treatment - e.q. analgesics, antibiotics

MECHANISM OF DRUG ACTION1. Action on a Receptor2. Action on an Enzyme3. Action on Membrane Ionic Channels4. Cytotoxic action

I. ACTION ON A RECEPTOR Receptor - a specific macromolecule usually a protein to which a specific group of drug or naturally occurring substances such as neurotransmitter or hormone can bind.

RECEPTORS INVOLVED IN THE ACTION OF COMMONLY USED DRUGS

RECEPTOR MAIN ACTION OF NATURAL AGONISTS

ADRENOCEPTOR 1 Vasoconstriction 2 Hypotension ; Sedation B 1 Heart Rate B 2 Bronchodilation Vasodilation Uterine Relaxation CHOLINERGIC Muscarinic Heart Rate Secretion

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Gut Motility Bronchoconstriction Nicotinic Contraction of Striated Muscle

HISTAMINE H1 Bronchoconstriction Capillary Dilation H2 Increased Gastric Acid

DOPAMINE CNS Neurotransmitter OPIOD CNS Neurotransmitter

II. ACTION ON ENZYME Enzyme - protein macromolecule with which substances interact to produce “activation” or “inhibition”. *Drugs in clinical use which exert their effect thru enzyme action generally do so by “inhibition”. E.q. Aspirin inhibits platelet cyclo-oxygenase; Allopurinol inhibits xanthene oxidase.

III. ACTION ON MEMBRANE IONIC CHANNELS The conduction of impulse in nerve tissues and electrochemical coupling in muscles depends on the movement of ions particularly sodium, calcium, and potasium through membrane channels. *Several group of drugs that interfere with these processess: Antiarrythmic drugs, General and local anesthesia, Anticonvulsant.

IV. CYTOTOXIC ACTIONS This mechanism have been defined in terms of effects on specific receptors or enzymes. But in other cases, chemical action (Alkylation) damages DNA or other macromolecules and results in cell death or failure of cell division. E.q. Drugs used in cancer or in treatment of infection may kill malignant cells or Microorganisms.

PUBLICATIONS IN PHARMACOLOGY

U.S.P. United States Pharmacopoeia- Representatives from school of medicine and pharmacy- American medical Association- American Pharmaceutical Association- State Medical Societies- American Chemical Society- Other scientific organization and federal agencies

Purpose of U.S.P. : It sets the official chemical and physical standards that relate essentially to strength and purity of drug.

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N.F. National Formulary - issued every 5 years - establishes official standards for drugs not described in the U.S.P. - described extent of drugs' use and therapeutic value

British Pharmacopoeia - English equivalent of U.S.P. (Great Britain and Canada)

Pharmacopoeia Internationalis - issued by W.H.O.

A.D.T. Accepted Dental Therapeutics A.D.R. Accepted Dental Remedies - biennial publication of the Council on Dental Therapeutics (CDT) of the American Dental Association - drugs of recognized value that are labeled and advertised in accordance with CDT are included. - Primarily a handbook of dental pharmacotherapeutics and intended to assist the dental practitioner in the selection of drugs.

P.D.R. Physician's Desk Reference - a handbook published annually by some 200 manufacturers Special Value: 1. Published annually and therefore includes relatively up to date information 2. It is cross-indexed to include the use of proprietary names Disadvantages: 1. Products or drugs are arranged by manufacturers rather than by pharmacologic class 2. Information may be "biased".

* REPUBLIC ACT 6675 - known as the GENERIC ACT OF 1988 - an act to Promote, Require and Ensure the production of an adequate supply, distribution, use and acceptance of drugs and medicines identified by their generic names.

AIM: 1. To promote, encourage and require the use of generic terminology in the importation, manufacturing, distribution, marketing, advertising and promotion, prescription and dispensing of drugs.2. To ensure the adequate supply of drug with generic names through a rational system of procurement and distribution.3. To encourage the extensive use of drug with generic names through a national system of procurement and distribution.

Importance of R.A. 66751. For health professionals to become more aware and cognizant of their therapeutic effectiveness.2. To provide drugs to indigent patients at the lowest possible cost.3. To have healthy competition among drug manufacturers

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Who Shall Use Generic Terms?All government health agenciesAll medical, Dental and Veterinary practitionersAll drug establishmentsAll drug outlets

Penalty for NOT complying to R.A. 6675First Offense Reprimand which will be recorded in the Professional Regulation Commission Book.Second Offense Fine : Not less than P2,000.00 but not greater than P5,000.00.Third Offense Fine : Not less than P5,000.00 but not greater than P10,000.00.Fourth and Succeeding Fine : Not less than P10,000.00 and suspension of license to practice for one year.

DRUG NOMENCLATURE

1. CHEMICAL NAME "FIRST NAME" given to compound of known composition - conveys the chemical structure of the compound. E.q. N-Acetyl p-aminophenol

CODE DESIGNATION - convenient means of referring to the compound before it has been assigned either a generic or trade name.

2 Types of Code Designation 1. A letter and number combination e.q. SH 567 letter/s - research laboratory involved number/s - arbitrarily assigned 2. Letter combination e.q. AZT - Azothymidine TPA - Tissue Plasminogen Activator ASA - Acetyl Salicylic Acid

2. TRADE NAME (Commercial Name; Proprietary Name; Brand Name) - name of the company who manufactured the drug - gives no or little information about the drug itself

BRAND NAME - name of the company marketing the product - distinguishes its product from others. - E.q. Biogesic, Ponstan, Flanax, Amoxil,

Two Important Disadvantages of Trade Name: 1. Makes the problem of drug identification more complex 2. Deprive the patient to avail of a less expensive generic preparations.

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Advantages of Trade Names: 1. They are convenient and saves time when writing prescriptions for multiple-entity drugs 2. Trade names are usually shorter and easier to remember than generic names. 3. The use of trade names demands the product of a specific manufacturer in whose manufacturing practices the practitioner may have special confidence.

3. GENERIC NAME - "Official" name of the drug; "Non-Proprietary name.

Advantages of using Generic Names1. Healthy competition among drug manufacturers2. Provides a wide selection of drugs3. It is universally accepted.

Disadvantages of using Generic Names

1. Not all preparations are prepared as they should be.2. It is hard to remember.3. It is inconvenient when written.

E.g. Chemical : 2-diethylamino 2,6 acetoxylidide : N-acetyl p-aminophenol Generic : Lidocaine : Acetaminophen Trade Name : Xylocaine : Tylenol Dolicaine : Tempra Octocaine : Valadol L-caine : Datril

*** How to use the PIMS / MIMS

PIMS - Philippine Index for Medical SpecialtiesMIMS - Monthly Index for Medical Specialties. It is a global term for a therapeutic index.

Brand Name /Manufacturer / Distributor Contents ( C ) Indication/s ( I ) Dosage ( D ) Contraindications ( C/I ) Special Precautions ( SP ) Adverse Reactions ( AR ) Drug Interactions ( DI ) Presentation / Price ( P/P )

Example: (Based from MIMS Dental Phils. 2002 page 68)

ATMOSE Morishita-Seggs Rx (Atmose is the proprietary name of the (Metro Drug) drug; C. Mefenamic Acid Morishita-Seggs is the name of the I. Relief of mild to moderate pain including company who manufactured the drug

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headache, dental pain, post-op and postpartum Metro Drug is the name of the pain, dysmenorrhea, osteoarthritis and RA. company marketing the product D. Adult and children > 14 yr. Initially 500 mg. Rx means this drug needs prescription then 250 mg 6 hrly. P/P. Atmose is available in capsule CI. Peptic ulceration or inflammatory bowel disease. form at a dosage of 500 mg.; SP. Hepatic or renal impairment; epilepsy. X100 means in one box there are AR. GI disturbances; peptic ulceration, GI bleeding; 100 capsules that costs drowsiness; dizziness; nervousness; visual Php357.63 disturbances; skin rash; urticaria; blood dyscrasias.DI. Enhances the effects of the coumarin anticoagulants.P/P. Cap 500 mg X 100’s (P357.63)

PHARMACOLOGICAL CLASSIFICATION INDEXPharmacological Classes and Sub-classes(based on MIMS Dental Phils 2002) I. ALIMENTARY SYSTEM

1. Antacids and Antiulcerants2. GIT regulators, Antiflatulents and Anti-Inflammatories3. Antispasmodics4. Antidiarrheals5. Laxatives, Purgatives6. Digestives7. Cholagogues, Cholelitholytics and Hepatic Protectors

II. CARDIOVASCULAR AND HEMATOPOIETIC SYSTEM1. Cardiac Drugs2. Anti-anginal Drugs3. ACE Inhibitors4. Beta Blockers5. Calcium Antagonists6. Diuretics7. Antidiuretics8. Peripheral Vasodilators and Cerebral Activators9. Vasoconstrictors10. Migraine Drugs11. Haemostatics12. Anticoagulants, Antithrombotics and Fibrinolytics13. Haemorrhoidal, Phlebitis and Varicose Preparations14. Haemorrheologicals15. Haematopoetic Agents16. Other Cardiovascular Drugs

III. RESPIRATORY SYSTEM1. Respiratory Stimulants2. Antiasthmatic Preparations

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3. Cough and Cold Remedies4. Decongestants and other Nasal Preparations5. Other drugs acting on Respiratory System

IV. NEUROMUSCULAR SYSTEM1. Anti-inflammatory Enzymes2. Analgesics and Antipyretics3. Antirheumatic, Anti-inflammatory Analgesics4. Gout Preparations5. Minor Tranquilisers6. Major Tranquilisers7. Hypnotics and Sedatives8. Anticonvulsants9. Antidepressants10. CNS Stimulants 11. Nootropics and Neurotonics12. Antiemetics and Antivertigo Drugs13. Neurodegenerative Disease Drugs14. Antiparkinsonism Preparations15. Neuromuscular Disorder Drugs16. Muscle Relaxants

V. HORMONES1. Androgens and Related Synthetic Drugs2. Oestrogens and Progesterones and Related Synthetic Drugs3. Combined Sex Hormones4. Corticosteroid Hormones5. Trophic Hormones and Related Synthetic drugs6. Anabolic Agents7. Other Hormone Related Drugs

VI. CONTRACEPTIVE AGENTS1. Depot Contraceptives2. Oral Contraceptives3. Other Contraceptives

VII. ANTIBIOTICS1. Aminoglycosides 2. Cephalosphorins 3. Chloramphenicols 4. Macrolides5. Penicillins6. Quinolones7. Tetracyclines8. Antifungals9. Antibacterial Combinations10. Other Antibiotics

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VIII. OTHER CHEMOTHERAPEUTICS1. Antituberculous Agents2. Sulphonamides3. Antiamoebics4. Anthelmintics5. Antileprotics6. Antivirals7. Antineoplastics8. Antimalarials9. Leishmaniacides, Trypanocides10. Filaricides

IX. GENITO-URINARY SYSTEM1. Preparations for Vaginal Conditions2. Urinary Antiseptics3. Drug acting on Uterus4. Other Drugs Acting on Genito-Urinary System

X. METABOLISM1. Insulins2. Oral Antidiabetic Agents3. Thyroid Preparations4. Antithyroids5. Antihyperlipidaemic Agents6. Other Agents Affecting Metabolism

XI. VITAMINS AND MINERALS1. Vitamins A, D, E2. Vitamin B’s / with C3. Vitamin C4. Calcium / with Vitamins5. Multivitamins / with Minerals6. Vitamins with Hormones / Geriatric Preparations7. Pediatric Vitamins and Minerals8. Electrolytes and Minerals9. Antianemics / Pre and Post Natal Vitamins

XII. NUTRITION1. Infant / Follow-On Formulae2. Enteral / Nutritional Products3. Parenteral Nutrition4. Tonics5. Appetite Stimulants6. Antiobesity Agents

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XIII. EYE, EAR, MOUTH / THROAT

*EYE1. Eye Anti-infectives and Antiseptics2. Eye corticosteroids3. Eye Antiseptics with Corticosteroids4. Mydriatic Drugs5. Miotic Drugs6. Glaucoma Preparations7. Other Eye Preparations

*EAR1. Ear Anti-infectives and Antiseptics2. Ear Corticosteroids3. Ear Antiseptics with corticosteroids4. Other Ear Preparations

*Mouth / Throat1. Mouth / Throat Preparations

XIV. DERMATOLOGICALS1. Topical Anti-infectives2. Topical Anti-infectives with Corticosteroids3. Topical Corticosteroids4. Acne Treatment Preparations5. Antiseptics and Disinfectants6. Medicated Surgical Dressings7. Topical Fungicides and Antiparasites8. Psoriasis, Seborrhea and Ichthyosis Preparations9. Topical Antivirals10. Keratolytics11. Skin Protectives12. Topical Antihistamines / Antipruritics13. Topical Analgesics and Anti-inflammatories14. Other Dermatologicals

XV. ANAESTHETICS1. Local Anesthetics2. General Anesthetics

XVI. DIAGNOSTIC AGENTS

1. Urinalysis Agents

XVII. ALLERGY AND IMMUNE SYSTEM1. Antihistamines and Antiallergies2. Vaccines, Antisera and Immunologicals3. Immunosuppressants

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XVIII. ANTIDOTES AND DETOXIFYING AGENTS

XIX. INTRAVENOUS AND OTHER STERILE SOLUTIONS

XX. MISCELLANEOUS

Different Factors Affecting Response: Routes of Drug Administration Passage of Drug Across Body Membranes Molecular Mechanism of Action

Absorption Distribution FATE of a DRUG Metabolism Excretion

ROUTES OF DRUG ADMINISTRATION

ENTERAL Oral Rectal

PARENTERAL Hypodermic Routes Intravenous Intramuscular Subcutaneous Intradermal Intrathecal Intraperitoneal Additional Routes Topical Inhalation Sublingual Transdermal

LOCAL ROUTE Topical Intradermal Intrathecal Intranasal Intraconjuctival Intra-oral Intra-articular Intra-arterial Other special routes

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SYSTEMIC ROUTES Enteral Parenteral

*** Locally administered drugs may be absorbed at a rate and to an extent sufficient to result in the production of systemic effects.

ENTERAL ROUTES - drug is placed directly into the GIT from where absorption occurs. A. ORAL ROUTE - simplest and most convenient for self administration.

Contraindication for Oral Route 1. Patients with gastrointestinal intolerance 2. Patients preparing for anesthesia 3. Patients with gastrointestinal surgery 4. Precluded in coma

Disadvantages of Oral Route1. Irritant drugs cannot always be given by mouth for it may cause sickness. 2. It is not feasible to give drugs by this route to patients who are vomiting or moribund.3. Many drugs are destroyed by the action of the digestive ferments before they can be

absorbed.4. Intestinal absorption may be irregular due to other substances in the git.5. Intestinal absorption may be affected by changes in gastric emptying which may

increase or decrease the rate of absorption.

"First Pass Effect" - refers to the metabolism of a drug en route from the gut lumen to the systemic circulation. - a process that rapidly deactivate some drugs in the liver that was given orally and was initially perfused into the hepatic portal circulation. Some drugs do not go directly into the systemic circulation following absorption but pass from the intestinal lumen to the liver, by the portal vein. In the liver, most of the drug is metabolized to an inactive drug form for excretion, reducing the amount of active drug.

Importance of First Pass Metabolism 1. It is one of the reasons for the apparent differences in drug absorption between individuals. 2. In patients with severe liver disease, first-pass metabolism may be dramatically reduced leading to the absorption of greater amounts of parent drug.

Drugs with High First Pass Metabolism Analgesics Aspirin Morphine Paracetamol Pentazocine

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Pethidine Respiratory Drugs Salbutamol Terbutaline Drugs Acting on Central Nervous System Chlormethiazole Chlorpromazine Imipramine Levodopa Nortriptyline Oral Contraceptives Cardiovascular Drugs Glyceryl Trinitrate Isoprenaline Nifedipine Prazosin Propanolol Verapamil Lignocaine Metropolol RECTAL ROUTE - drugs are given via the rectum. E.q. solid form – suppositories; liquid form – enemata. - used when oral administration is impossible. - avoids the acidity and enzymes of the gastric juice and first pass metabolism. - Both local and systemic effects are obtained but absorption of many drugs are often irregular and incomplete. Indications: Pediatrics / Geriatrics

PARENTERAL ROUTES - generally chosen when speed or reliability are specially desired. A. Injection – essential if the drug is to be absorbed in active form. - absorption is usually more predictable and more rapid - requires special skill; drugs cannot be withdrawn easily. Disadvantages

1. Difficult for the patients to perform the injection by themselves.2. Strict asepsis must be maintained to avoid infection3. Usually more costly and less safe.4. Can cause pain.

TYPES OF INJECTION

Intravenous (IV) - route of choice for emergency cases - Most rapid route / method to elicit drug response. Advantages

1. Rapid action2. Can be used for drugs which are irritant by IM injection.3. Useful for ill, hospitalized patients when a slow IV infusion provides a steady flow

without disturbing the patient

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Disadvantages1. Tend to produce more immediate adverse reactions.2. Too high concentration of the drug is readily obtained when injected rapidly.3. The chance of penetration into an artery instead of a vein is a possibility.

Complications: 1. Drug Shock 2. Acute, serious, allergic responses 3. Phlebitis 4. Necrosis around the injection site.

Intradermal (cutaneous) - E.q. skin testing. Action:

- local effect- small amount is injected into the epidermis of the skin so that volume does not interfere

with wheal formation or cause a systemic reaction.- used for observation of an inflammatory (allergic) reaction to foreign proteins.

- rarely employed except in certain Diagnostic and test procedures (screening for allergic or local irritant responses).- takes the longest time for drug absorption.

Sites:- Locations are chosen so that inflammatory reaction can be observed. Preferred areas

are lightly pigmented, thinly keratinized, and hairless such as ventral mid-forearm, clavicular area of chest, scapula area of back, and medial aspect of thighs.

Equipment: Needle: 26 – 27 gauge Syringe: 1 ml. calibrated in 0.01 ml. increments Usually 0.01 – 0.1 ml. injected.

Technique: Cleanse area using circular motion; observe sterile technique. Hold skin taut. Insert needle, bevel up, at a 15 degree angle; outline of needle under the skin should be visible. Inject medication slowly to form a wheal (blister or bleb). Remove needle slowly. Make a mark or encircle the bleb with a pen. Do not massage area; instruct client not to do so. Assess for allergic reaction in 24 – 72 hours; measure diameter of local reaction.

Subcutaneous - for drugs which are not irritant to tissues. E.q. morphine sulphate, adrenaline, and insulin. - volume is usually 1 ml. or less; seldom exceeds 2 ml. - cutaneous blood flow is slower compared to IM - sustained effect can be obtained by placing a pellet of drug subcutaneously; e.q.

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Estradiol plants. - drug is injected in the subcutaneous layer into the alveolar connective tissue just below the skin.

Action:- Systemic effect- Sustained effect; absorbed mainly through capillaries; usually slower in onset than with

intramuscular route.- Used for small doses of non-irritating water-soluble drugs.

Sites:

- Locations for subcutaneous injection are chosen for adequate fat pad size and include the abdomen, upper hips, upper back, lateral upper arms, and lateral hips.

Equipment: Needle: 25 – 27 gauge ½ - 5/8 in. in length Syringe: 1 – 3 ml. Usually 0.5 – 1.5 ml. injected. Insulin syringe measured in units for use with insulin only.

Technique: Cleanse area with circular motion using sterile technique Pinch the skin. Insert needle at angle appropriate to body size. 45 to 90 degrees. Release skin. Aspirate, except with heparin. Inject medication slowly. Remove needle quickly. Gently massage area, unless contraindicated with heparin. Apply plaster if needed. Advantages:

1. Spread the action out over a number of hours.2. Avoid too intense or too short response3. Avoid frequent injections.

Layer of skin and site of injections:

Epidermis Cutaneous Dermis Membrane Fascia Subcutaneous Muscle

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Intramuscular (IM) - more dangerous than IV; better for irritant tissues.

Action:- systemic effect.- Usually more rapid effect of drug than with subcutaneous.- Used for irritating drugs, aqueous suspensions, and solutions in oils.- indicated when an immediate effect is not required but a prompt effect is desirable.- 10 –

30 minutes absorption.

Sites: Locations are chosen for adequate muscle size and minimal major nerves and blood vessels in the area. Preferred locations include ventrogluteal, dorsogluteal, deltoid, and vastus lateralis.

Equipment: Needle: 18 – 21 gauge 1 – 1.5 in. in length Syringe: 1 –3 ml. Usually 0.5 – 1.5 ml. injected

Technique: Same as for subcutaneous injection except that needle is inserted at 90 degree angle into the muscle.

Figure: Angles for injections. (A) IM 90 (B) (C) (D) SC 90 , 60 , 45 (E) ID 10=15 .

Intraperitoneal – injected into the peritoneal cavity by absorption of messenteric veins

Intrapleural - introduce into the pleural cavity; for aspiration of fluids.

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Intrathecal / Intraspinal - for spinal analgesia into the spinal subarachnoid space. - administered into the cerebrospinal fluid at any level of the cerebrospinal axis.

Intraneural - used in trigeminal neuralgia.

Intrasternal - drugs which normally do not cross the blood brain barrier.

BUCCAL and SUBLINGUAL route- an enteral route infrequently used but useful in drugs with first pass hepatic metabolism.

E.q. glyceryl trinitrate for angina attack but ineffective when swallowed as its first pass metabolism approaches 100 per cent

- drugs that are susceptible to degradation by the GIT and even the liver are safely administered sublingually.

INHALATION - E.q. inhalation anesthetics, aerosol inhalation for asthma.- inhalation is via the mouth; absorption occurs in the small bronchioles. E.q. disodium

cromoglycate via a “Spinhaler”.- drug is absorbed through the pulmonary endothelium at the alveoli to gain rapid access

to the general circulation.

Reasons for rapid absorption1. Alveolar and vascular epithelial membranes of the lungs are quite permeable.2. Blood flow is abundant.3. There is al large surface for absorption.

Particle Size1. Particles greater than I um in diameter - tend to settle in the bronchi.2. Particles less than 0.5 um - fail to settle; mainly are exhaled.

TOPICAL - least effective.

- drug is applied to the skin and other epithelial surfaces with glove, tongue blade, or cotton-tipped applicator.

- utilized for local drug effect.- Use appropriate technique to remove medication form container and apply to clean, dry

skin, when possible. Do not contaminate medication in container, use gloves or an applicator.

Methods of enhancing drug absorption via the Topical route1. Ionotophresis - uses galvanic current2. Inunction - mechanical rubbing of drug into the skin.

TRANSDERMAL- stored in a patch placed on the skin and absorbed through skin, having systemic effect- Transdermal drugs provide more consistent blood levels and avoid GI absorption

associated with oral products.

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PHARMACEUTICAL PREPARATIONS AND DOSAGE FORMS Pharmaceutical preparations are the forms in which drugs are prepared by the pharmacist or pharmaceutical chemist for administration in the treatment of the sick.

SOLID PREPARATIONSAerosols - packed with compressed gas under pressure for topical application. Upon release, the aerosol takes the form of a fine mist, foam, semisolid fluid or solid.Ampules - are hermetically sealed glass containers for medicinal substances containing a sterile solution for parenteral use.Capsules - small gelatin receptacles of various sizes for oral administration. Generally dissolve in the stomach except the enteric capsules which dissolves in the intestines. They maybe of firm or flexible consistency.Carpules - are glass tubes enclosed on both ends with rubber stoppers, one acting as a plunger, the other as a diaphragm. Contain a drug in solution and designed for parenteral medicationConfections - medicinal substances formed into a mass with sugar, honey, and water as confection of rose.Effervescent Salts - powdered drug which give off CO2 gas and go into solution when added to water.Konseals - (rice flour capsules) or wafers (thin sheets of dried flour paste) – sometimes used to enclose drug powders.Papers - paper impregnated with medicinal substances. E.q. mustard paperPills - small spherical masses of drugs intended for swallowing covered with various substances as gelatin, salol, sugar, chocolate, etc. and generally colored; powdered drugs mixed with adhesive substances like glucose or honey and molded in spherical or ovoid forms.Suppositories - solid bodies of various weights and shapes adapted for introduction into orifices (vagina, rectum, urethra, etc.) of the human body and usually melting, softening, or dissolving at body temperature. For urethral use, they are called bougies. Rectal Suppositories - conical or bullet-shaped, usually weigh about 2 grams. Used to produce local and systemic effects and to produce catharsis. Vaginal Suppositories - conical or spherical in shape and weigh from 4 – 10 grams. Used to confer antisepsis, to combat various infections, and as spermatocides. Urethral Suppositories - pencil-shaped and weigh for 2 – 4 grams. Used mainly for local treatment of the female urethraTablets - solid dosage forms containing granulated or powdered drugs that are compressed or molded into round or discoid shapes.contains medicinal substances with or without suitable diluents. They vary in shape, size and weight. It may be classed according to the method of manufacture, as molded tablets or compressed tablets. Troches - lozenges intended to be dissolved in the mouth for local effect on the mucous membrane of the mouth and throat.

SEMI-SOLID PREPARATIONSCerates - unctuous preparations having for their bases the simple cerate. Similar to ointments in consistency but do not melt at body temperature. E.q. Cantharides cerate.Creams - semi-solid emulsions of either the oil-water or the water in oil type for topical

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application.Extracts - concentrated preparation of vegetable or animal drugs. Made in 3 forms: 1) Semi liquids or liquids of syrupy consistency 2) Plastic masses (pilular or solid extracts) and 3) Dry powders (powdered extracts.Ointments - for external application. Medicinal substances are combined with a base of sufficient softness which tend to fall into two groups: hydrophilic such as the lanolin and the lipophilic, such as the petrolatum. E.q. ZOE ointmentPastes - comprise two classes of ointment-like preparations intended for external application: 1)Hydrogels – such as hydrated pectin; and 2) Fatty pastes – such as ZOE paste, which consist of thick, stiff ointments which do not ordinarily flow at body temperature and therefore serve as protective coatings over the areas they are applied.Plasters - adhesive, fatty or resinous compounds spread on textile fibers, leather, muslin, etc., Either soft or dry and intended for local application. E.q. Belladone plaster, etc..Poultices (Cataplasma) - semi-liquid mixtures of such substances as flaxseed, elm bark, or bread, etc., with hot water or milk, spread upon cloth and used as a means for applying heat and moisture or stimulation to the body surfaces. E.q. Cataplasma Kaolini.Triturations - powders consisting of an active remedy triturated with sugar or milk, usually of 10% strength. E.q. Triturations of Elaterin.

LIQUID PREPARATIONSAromatic waters - saturated (0.2%) aqueous solutions of volatile substances, usually volatile oils. Generally used as vehicle for water-soluble drugs. E.q. peppermint water.Collodions - liquid preparations having for their base a solution of guncotton (pyroxylin) in a mixture of ether and alcohol. E.q. Flexible collodion.Collyria - Medicinal eyewashes.Decoctions - solutions of vegetable substances prepared by boiling with water in a closed container for 15 minutes and strained – as decoction of coffee and sarsaparilla.Elixirs - clear, sweetened, hydroalcoholic liquids intended for oral use. Contains flavoring substances. Because of alcoholic content, they are miscible with tinctures. Two types:

1. Aromatic elixir - used mainly for diluting other liquid preparations2. Medicated elixirs - include Phenobarbital elixir, Diphenhydramine Hydrochloride

Elixir, and Terpin Hydrate and Codeine elixir. Emulsions - aqueous preparations in which oils, oleoresins, balsams, resins, or other substances which are insoluble in water are suspended by means of gum or other viscid excipients. E.q. Cod liver oil emulsion, milk and eggyolk.Fluid extracts - liquid extractions of drugs prepared by percolation. Concentrated tinctures in which 1 g. of the drug corresponds to 1 ml. of the finished product. E.q. Ergot fluid extract. Gargles - mixtures or hydroalcoholic solutions for application to the pharynx and mouth.Gels - suspension in a water medium, of insoluble drugs in hydrated form wherein particle size approaches or attains colloidal dimensions.Glycerites - mixtures or solutions of medicinal substances with or in glycerin. E.q. Tannic acid glycerite.Honeys - solutions of drug in clarified honey. E.q. Honey of rose.Injections - sterile preparations for parenteral use. Comprise of 1) Solutions for injection 2) Dry solids, which upon the addition of suitable solvents yield solutions conforming

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in all respects to the requirements for injections 3) Solids suspended in a suitable fluid medium which are not to be injected IV or into the spinal canal 4) dry solids, which upon the addition of suitable vehicles, yield preparations conforming to the requirements for sterile suspensions and 5) emulsions of fluids in fluid media, suitable for parenteral administration, but are not to be injected in the spinal canal.Liniments - liquid ointments applied with friction to the skin. Lotions - mixtures or solutions of medicinal agents intended for external application with soothing and protective effect.Milks - suspension of poorly soluble drugs in water medium and distinguished from gels mainly in that the suspended particles are larger. They tend to separate on standing and must be shaken well before use. E.q. Milk of magnesia.Mixtures - suspension of drugs in an aqueous vehicle. E.q. Brown mixture.Oleates - solutions of metallic salts or alkaloids in oleic acid. E.q. Oleate of Mercury.Solutions - liquid preparations that contain one or several soluble chemical substances (non volatile) in water.Spirits or Essences - volatile substances dissolved in alcoholic solution. Many are flavoring agents. E.q. Peppermint spirit –also used as a carminative. Aromatic Ammonia Spirit – a medicated spirit used as a reflex stimulant.Suspensions - finely divided drugs either intended for suspension in some suitable liquid vehicle prior to use or already in suspension in a liquid vehicle.Syrups - highly concentrated solutions of sugar such as sucrose in water, carrying flavors or medicinal substances – as syrup of Orange, Syrup of Wild cherry. Syrups serves as vehicle or preservatives. Some contain active therapeutic agents. 2 Classes of Syrups: 1. Flavored syrups - employed to mask the taste of unpleasant tasting drugs and to add stability to preparations. E.q Acacia syrup, Cocoa syrup. 2. Medicated syrups - E.q Ipecac syrup (emetic, expectorant); Chloral Hydrate syrup (hypnotic), contain some added medicinal substances.Tinctures - hydroalcoholic solutions of medicinal substances usually obtained by extractin of vegetable drugs; generally alcoholic extracts of vegetable or animal drugs obtained by percolation. E.q. Belladona tincture; Vanilla tincture (used as flavoring agents); Iodine tincture (used as antiseptic).Waters - may be a natural product, as tap water, or distilled and de-ionized to form a more purified and sterile product. E.q. Water for injection.

SYSTEMS OF MEASUREMENT Three systems of measurement (metric, apothecary, and household) are used in measuring drugs and solutions. The metric system developed in the late eighteenth century, is the internationally accepted system of measure. It is replacing the apothecary system, which dates back to the middle ages and had been used in England since the 17th century. It is proposed that the apothecary system will phase out by the end of this century. Household measurement is commonly used in community and home settings.

I. METRIC - to measure based on decimals and Arabic numbers; the official system used in the USP.

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Units: Meter (m) = for length Liter (l) = for capacity Gram (gm.) = for weight

Metric Tables:Table of Length Table of Capacity Table of Weight

1 km. = 1,000 m. 1 kl. = 1,000 l. 1 kg. = 1,000 gm.1 hm. = 100 m. 1 hl. = 100 l. 1 hg. = 100 gm.1 dkm = 10 m. 1 dkl = 10 l. 1 dkg = 10 gm.1 dm. = 0.1 m. 1 dl. = 0.1 l. 1 dg. = 0.1 gm.1 cm. = 0.01 m. 1 cl. = 0.01 l. 1 cg. = 0.01 gm.1mm. = 0.001 m. 1ml. = 0.001 l. 1mg. = 0.001 gm.

Procedure for Conversion Between Units of the Metric System: 1. To change milligrams to grams, milliliters to liters, or grams to kilograms, divide by 1000. 2. To change liters to milliliters, grams to milligrams, kilograms to grams, multiply by 1000.

Examples: a. 64 mg. = ? gm. 1000 mg. : 1 gm. = 64 mg. : x gm. 1000 x = 64 x = . 64 . 1000

= 0.064 gm.

b. 325 ml. = ?L 1000 ml. : 1L. = 325 ml. : x L. 1000 x = 325 x = . 325 . 1000

= 0.325 L II. APOTHECARIE’S OR ENGLISH SYSTEM - In this older system, Roman numerals and common fractions are used to designate units. Also, the units of measure precede the numeral in correct form. e.q the correct way to signify 20 grains would be “gr.xx.” A line is often written above the numerals, and a dot is placed above the numeral I to distinguish more clearly between the two I’s and a V or X hastily written. When using the apothecary system in calculations, however, the Arabic numbers are used.

Procedure for Conversion Within the apothecary System1. Write the equivalent between the terms to be converted as the first two terms of the

proportion.

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2. Being careful to keep the units in the last two terms in the same order as they occur in the first, write the known quantity and the unknown equivalent as the third and fourth terms of the proportion.

Examples: a. 6 drams = ? ounces 8 drams : 1 ounce = 6 drams : X ounces 8 x = 6

x = . 6 . = . 3 . ounce 8 4

b. 2 drams = ? minims 60 minims : 1 dram = x minims : 2 drams 1 x = 120

x = 120 minims

TABLE OF WEIGHT 60 grains = 1 dram 8 drams = 1 ounce 12 ounces = 1 lb.

TABLE OF CAPACITY 60 minims = 1 fluidram 480 minims or 8 fluidrams = 1 fluid ounce 7680 minims or 16 fluid ounces = 1 pint 2 pints = 1 quart 4 quarts = 1 gallon

III. HOUSEHOLD SYSTEM - The household system of measurement is not as accurate as the metric system because of the lack of standardization of spoons, cups, and glasses. The measurements are approximate.

HOUSEHOLD UNITS OF MEASUREMENT 60 drops (gtt) = 1 teaspoon 3 teaspoon = 1 tablespoon (tbs) 6 teaspoon = 1 ounce 2 tbs = 1 oz.

6 oz. = 1 tea cup 8 oz. = 1 glass 8 oz. = 1 measuring cup

OTHER EQUIVALENTS 1,000 cc. = 1 L = 1 quart 500 cc. = 1 pint 30 cc. = 1 fluidounce = 2 tbsp. 5 cc. = 1 fluidram = 60 minims = 1 tsp. 1 cc. = 15 minims 1 kg. = 1000 gms. = 2.2. lbs.

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4 gms. = 1 dram = 60 grains

TEMPERATURE CONVERSION Celsius to Farenheit: ( C ) (9/5) + 32 Farenheit to Celsius: ( F – 32 ) (5/9)

METRIC DOSES with APPROXIMATE APOTHECARY EQUIVALENTS( by Musser/O’Neil * reprinted from USP XVI)

LIQUID MEASURE Approximate METRIC APOTHECARY equivalents

Approximate METRIC APOTHECARY equivalents

1000 ml. 1 quart 3 ml. 45 minims750 ml. 1 ½ pints 2 ml. 30 minims500 ml. 1 pint 1 ml. 15 minims250 ml. 8 fluid ounces 0.75 ml. 12 minims200 ml. 7 fluid ounces 0.6 ml. 10 minims100 ml. 3 ½ fluid ounces 0.5 ml. 8 minims50 ml. 1 ¾ fluid ounces 0.3 ml. 5 minims30 ml. 1 fluid ounce 0.25 ml. 4 minims15 ml. 4 fluid drams 0.2 ml. 3 minims10 ml. 2 ½ fluid drams 0.1 ml. 1 ½ minims8 ml. 2 fluid drams 0.06 ml. 1 minim5 ml. 1 ¼ fluid drams 0.05 ml. ¾ minim4 ml. 1 fluid drams 0.03 ml. ½ minim

WEIGHT Approximate METRIC APOTHECARY Equivalents

Approximate METRIC APOTHECARY equivalents

30 Gm. 1 ounce 30 mg. ½ grain15 Gm. 4 drams 25 mg. 3/8 grain10 Gm. 2 ½ drams 20 mg. 1/3 grain7.5 Gm. 2 drams 15 mg. ¼ grain6 Gm. 90 grains 12 mg. 1/5 grain5 Gm. 75 grains 10 mg. 1/6 grain4 Gm. 60 grains (1 dram) 8 mg. 1/8 grain 3 Gm. 45 grains 6 mg. 1/10 grain2 Gm. 30 grains 5 mg. 1/12 grain1.5 Gm. 22 grains 4 mg. 1/15 grain1 Gm. 15 grains 3 mg. 1/20 grain0.75 Gm. 12 grains 2 mg. 1/30 grain0.6 Gm. 10 grains 1.5 mg. 1/40 grain0.5 Gm. 7 ½ grains 1.2 mg. 1/50 grain

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0.4 Gm. 6 grains 1 mg. 1/60 grain0.3 Gm. 5 grains 0.8 mg. 1/80 grain0.25 Gm. 4 grains 0.6 mg. 1/100 grain0.2 Gm. 3 grains 0.5 mg. 1/120 grain0.15 Gm. 2 ½ grains 0.4 mg. 1/150 grain0.12 Gm. 2 grains 0.3 mg. 1/200 grain0.1 Gm. 1 ½ grains 0.25 mg. 1/250 grain75 mg. 1 ¼ grains 0.2 mg. 1/300 grain50 mg. 1 grains 0.15 mg. 1/400 grain60 mg. ¾ grain 0.12 mg. 1/500 grain40 mg. 2/3 grains 0.1 mg. 1/600 grain

APPROXIMATE HOUSEHOLD EQUIVALENTS HOUSEHOLD APOTHECARY METRIC1 drop (gt) 1 minim (m or min) 0.06 milliliter (ml.)15 drops (gtt) 15 min 1 ml. (cc.)1 teaspoon (tsp) 1 fluidram (60 minims) 5 or 4 ml. *1 tablespoon (tbsp) 4 fluid dram 15 ml.2 Tbs. 1 fluid ounce 30 ml.1 ounce 1 fluid ounce 30 ml.1 tea cup 6 fluid ounce 180 ml.1 glass 8 fluid ounce 240 ml.1 measuring cup 8 fluid ounce 240 ml.2 measuring cups 1 pint (pt) 500 ml.

DOSE CALCULATIONS

Children are not able to tolerate adult doses of drugs. There are several formulas for graduating dosage according to age and weight. The recommended dosage for kg. or lb. of body weight is more accurate than calculating dosage according to age. Other factors beside age and weight enter into dosage for children. For this reason, some physicians, use the :body surface area” method to estimate the dosage for children. Charts are available to determine the body surface area in square meters according to height and weight.

For Infants and Preschool children

Clark’s Rule

Weight (lbs.) X Adult dose ---------------------------------- = Infant dose 150

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Fried’s Rule - sometimes used in calculating dosages for infants less than 2 years old.

Age (mos.) X Adult dose --------------------------------- = Infant dose 15

For Preschool to Adolescent years:

Young’s Rule - not valid after 12 years of age. If the child is small enough to warrant a reduced dose after 12 years of age, the reduction should be calculated on the basis of Clark’s rule.

Age (yr.) X Adult dose ---------------------------------- = Child dose Age (yr.) + 12

Cowling’s Rule

Age (at next b-day) X Adult dose ------------------------------------------- = Child dose 24

Calculation based on Body Surface Area (BSA) : - considered to be the most accurate way to calculate the drug dose for infants, children, older adults, and clients who are on antineoplastic agents or whose body weight is low. The BSA, in square meters is determined by where the person’s height and weight intersect the nomogram scale.

Surface area X Adult dose ----------------------------------- = Child dose 2.00

OR

Multiply the drug dose ordered by the number of square meters.

Example: Order: Cyclophosphamide (Cytoxan) 100 mg. / m2 / day, PO Patient is 5 ft. 10 in. (70 in.) tall and weighs 160 lbs.

a. 70 in. and 160 lbs. intersect the nomogram at 1.97 m2 (BSA)b. 100 mg. x 1.97 = 197 mg.

Answer: Administer Cyclophosphamide 197 mg. or 200 mg./day.

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PRESENTLY USED DOSE CALCULATION:

Weight: (Ideal Body Weight)

At Birth: 3000 Grams

Less than 6 months: Weight In Grams Age in Months X 600 + Birth Weight

6 – 12 Months: Weight in Grams Age in Months X 500 + Birth Weight

1 – 6 Years: Weight in Kilograms Age in Years X 2 + 8

7 – 12 Years: Weight in Kilograms Age in Years X 7 - 5 2 Suggested Dose: Age 13 – 18 years = 250 mg. 19 – above = 500 mg.

Example: Given: Age of child = 2 years old Recommended dose = 10 mg. Available dose: 250mg./5ml. x 30 ml.

Formula: Age in years X 2 + 8 Solution: 2 X 2 + 8 = 12 kg.

10 mg. X 12 Kg. = 120 mg. (dose needed by a 2-year old child)

What part of 250 mg. is 120 mg.? To compute for the exact dose/ml., multiply 120 mg. to 5ml. and 250mg. to X(ml.) then divide to 250mg.

250mg. / 5ml. = 120mg / X(ml.)

5ml. X 120mg. = 600mg./ml. 250mg. X ?ml = 250mg. Then divide: 600mg./ml. 250 mg. = 2.4 ml.

*120mg. computed dose of the child is 2.4ml. in a 250mg./5ml. preparation of the drug.

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DOSE CALCULATION ACCORDING TO KEE AND HAYES Basic Formula: D ------ X V = A H

Where: D = is the desired dose; drug dose ordered by the physician H = is the on hand dose; drug dose on label of container (bottle, vial). V = is the vehicle; drug form in which the drug comes (tablet, capsule, liquid) A = is the amount calculated to be given to the client.

Example: Order: Ampicillin (Polycillin) 0.5 g., PO, bid Available (drug label): Polycilin 250 mg./capsule

Solution: The unit of measure that is ordered, grams, and the unit on the bottle, milligrams, are from the same system of measurement, the metric system. Conversion to the same unit is necessary to work the problem. Since the bottles is in milligrams, convert grams to milligrams. To convert grams (large value) to milligrams (small value), move the decimal point three spaces to the right.

0.5 G. = 0.500 mg. or 500 mg.

D 500 mg. 500 ------ x V = --------- x 1 capsule = ------- = 2 capsules H 250 mg. 250

RATIO AND PROPORTION: - the oldest method currently used in calculating drug dosage. Known Desired H : V : : D : x means

extremes

x = Example: Order: Ampicillin 100 mg., PO, qid Available: Ampicillin (Polycillin) 250 mg./5ml.

Solution: Conversion is not needed since both are expressed in the same unit of measure.

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H : V : : D : x 250 mg. : 5 ml. : : 100 mg. : x ml.

means

extremes

250x = 500 x = 2 ml.

Answer: Ampicillin 100 mg. = 2 ml.

DRUG LIST:

NARCOTIC ANALGESICS 1. MEPERIDINE HCL (DEMEROL) Elixir: 50mg/5ml. Tablet 50,100 mg. Injection 100 mg./ml. Dose: 6mg./kg./Day or 0.5 – 1.0 mg./Kg./Dose

2. NALBUPHINE (NUBAIN) Injection 10 mg./ml.

Dose: 0.1 – 0.2 mg./Kg./Dose

NON-NARCOTIC ANALGESIC 1. ASA (ASPIRIN) 60, 81, 200, 300, 600, mg. Tablet Dose: 6.5 mg./Kg./Day

2. ACETAMINOPHEN Afebrin, Tempra, Tylenol, Calpol, Rexidol, Naprex, Panadol 100 mg./5ml., 120mg./5ml., 250mg./5ml. Syrup 60mg./0.6 ml. Drops Dose: 10 – 20 mg./Kg./Dose

3. MEFENAMIC ACID Ponstan, Dolfenal 50 mg./5ml. Suspension 250, 500 mg. Tablet, Capsule Dose: 6.5 mg./Kg./Dose (Pedia)

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BETA-LACTAM ANTIBIOTICS PENICILLIN G 1. PENICILLIN G BENZATHINE Usual Dose: Newborn(NB), Infants (IN): 50,000 – units/kg/single dose IM Children (CH) (>60 lbs.) and Adults (A): 600000-1200000 units IM q 3 weeks for rheumatic fever prophylaxis 2.4 million units IM once (divided into 2 injection sites at one visit) for three treatment of early syphilis, weekly X 3 doses for syphilis of more than one year duration. Preparation: (Penadur L-A): 1.2 M units and 2.4 M units/vial.

2. CRYSTALLINE PEN G (BENZYLPENICILLIN) Usual dose: NB - 25,000 U/Kg. q 6, 8, 12 IN, CH - 100,000 – 250,000 U/Kg. div. q4h. Preparation: Pen G: 1 M units/vial and 5 M units/vial

3. PHENOXYMETHYLPENICILLIN (PENICILLIN V) Usual Dose: IN, CH - 25-50 mg./Kg./Day or 25,000-100,000 U/Kg./Day div.q6-8 h, PO 1-2 g/d or 1.6-3.2 million u/d div.q6h, PO Preparation: Oral - 250, 500, 625 mg. capsule 125 mg./5ml; 25mg./5ml, suspension 60 ml. Note: Administer on empty stomach (1-2 hours after meal)

BROAD SPECTRUM PENICILLINS 1. AMOXICILLIN Usual Dose: IN, CH- 20-40 mg./kg./day div.by 3 doses (q8h) PO Adults- 750-1500 mg./day div. q8h, PO Preparations: Drops - 100mg./ml. Granules/Powder for suspension, 10ml. drops 125, 250 mg./5ml. 60-70 ml. Capsule- 250, 500 mg. Injection- 250,500mg./vial

2. AMPICILLIN Usual Dose: NB- 25-50 mg./kg. Q6-12 IV IN, CH- 100-200 mg./kg./day div.q4-6 h. A- 2-12 Grams infusion div. q6h. (Ampicin, Amopen drops: 100 mg/ml.; suspension 125, 250 mg./5ml.; capsule- 250,500mg.; Injection- 100, 250, 500 mg./vial)

COMBINATION OF A PENICILLIN AND BETA-LACTAMASE INHIBITOR 1. BACAMPICILLIN Usual Dose: IN, CH - 25-50 mg./kg./day div.by 2 doses (q12) PO A- 800-1600 mg. bid (Penglobe susp. 200mg./5ml.; Tablet- 200, 400, 800 mg.

2. CO-AMOXICLAV

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Usual Dose: NB- not recommended IN, CH- 40 mg./kg./day div. q8h PO and IV. A- 750 – 1.5 Grams/d div.q8 PO and IV. Preparations: 156.25 mg./5ml (30-60 ml) 375, 625 mg. tablet 600,1200 mg./vial

PENICILLINASE RESISTANT PENICILLIN 1. CLOXACILLIN Usual Dose: IN, CH - 50-100 mg./kg./day div.q6h (4 doses) PO Adults - 2-4 Grams/day div.q6 PO Preparations: Suspension - 125 mg./5ml x 60 ml. Capsule - 250 mg., 500 mg. Injection - 250, 500 mg./ vial

CEPHALOSPORINS First Generation A. CEPHALEXIN Usual Dose: IN, CH - 25-50 mg./kg./day div.q6h, PO Adults - 1-4 Grams/day div.q6h, PO Preparations: 125 mg./ 5ml. Granules/Powder for Suspension (50-70 ml). 100 mg./ 5 ml. Granules/Powder for drops (10 ml.) Capsule - 250, 500 mg.

B. CEPHAZOLIN Usual Dose: NB - 20 mg./kg. q12h IN, CH - 50-100 mg./kg./day div. q8h, IM or IV Adults - 1-6 Grams/day div.q8h, IM or IV. Preparation: 1 Gram vial

Second Generation A. CEFACLOR Usual Dose: IN, CH - 20-40 mg./kg./day q8-12h, PO Adults - 750 – 1500 mg./day div.q8-12 h, PO Preparations: Suspension 125mg./5ml. Granules/ Powder for suspension Puvule 250, 500 mg. 50 mg./ml. Granules/Powder for drops (20ml.)

B. CEFUROXIME Usual dose - 30-50 mg./kg./day Injection 250-750 mg./vial

Third Generation A. CEFTRIAZONE Usual Dose: 50-100 mg./kg./day Injection 250, 500 mg., 1 G / vial

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B. CEFTAZIDIME Usual Dose: 30-50 mg./kg./day Injection 250, 500 mg., 1 G./ vial

AMINOGLYCOSIDES 1. GENTAMYCIN SULFATE Usual Dose: IN, CH, A - 3.5-8 mg./kg./day div.q8 IM or IV Preparation: Injection - 20, 40, 80 mg./ml. (vial) 2. AMIKACIN SULFATE Usual Dose: IN,CH,A - 15mg./kg./day loading, 10mg./kg./day maintenance Preparation: Injection - 50, 125, 250 mg./ml. (vial)

DRUGS THAT ACT ON 30 S RIBOSOMAL SUBUNIT TETRACYCLINE Usual Dose: CH(>8years) - 25-50 mg./kg./day div. q6h, PO Adults - 1-2 Grams / day div.q6h, PO Preparations: Oral - 250, 500 mg. capsules Other preparations: Doxycycline - 2-4 mg./kg./day Doxin capsule - 100 mg. Minocycline (Minocin) - capsule: 50 mg., 100 mg.

DRUGS THAT ACT ON 50 S SUBUNIT CHLORAMPHENICOL Usual Dose: IN, CH - 50-100 mg./kg./day div.q6h, PO, IM, IV Adults - 50-100 mg./kg./day div.q6h, PO, IM, IV Preparations: Oral - 125 mg./5 ml., 60 ml. suspension 250, 500 mg. capsules Injection - 1 Gram vials

ERYTHROMYCIN Usual Dose: IN, CH - 30-50 mg./kg./day, div. q6h PO, IV Adults - 1-2 Grams/day div. q6 PO, IV Preparations: 250, 500 mg. tablet; 500 mg. capsules; 100mg./2.5 ml. (30 ml. drops); 200, 400 mg./5ml. (60 ml. suspension)

CLINDAMYCIN Usual Dose: IN, CH - 10-25 mg./kg./day, div. q6h PO, IV Adults - 600-1800 mg./day div. q6 PO Preparations: Oral - 150, 300 mg. capsule; 75 mg./5 ml. x 30 ml. suspension

TRIMETHOPRIM - SULFAMETHOXAZOLE (COTRIMOXAZOLE) Usual Dose: IN, CH - 8 mg. TMP and 40 mg. SMX/kg./d div.q12h PO Adults - 320 mg. TMP and 1600 SMX/d div.q12h PO Preparations: Oral - 100,000 units/ml. 30 ml. suspension; 500,000 units per tablet Vaginal - 100,000 units tablets

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KETOCONAZOLE Usual Dose: CH - 5-10 mg./kg./day div. q12-24 h, PO Adults - 200 – 400 mg. qd PO Preparations: Oral - 200 mg. tablets

ISONIAZID Usual Dose: 10-20 mg./kg./day Preparation: Syrup - 150 mg./5ml. Tablet - 400 mg.

METRONIDAZOLE Usual Dose: For amoebiasis and Anaerobic Infections: IN, CH - 35-50 mg./kg./d div. q8h, PO Adults - 750 mg. tid, PO Preparations: Oral - 250, 500 mg. tablets; 125 mg./5ml. (60 ml. suspension) Injection - 5mg./ml. 100 ml. vial Rectal - 1 G Suppository

QUINOLONES Usual Dose: Adults - 400-800 mg./day divq12h, PO, IV Preparations: Ofloxacin (Inoflax), Ciprofloxacin (Coprobay) - 200, 400 mg. tablets

RIFAMPICIN Usual Dose: 10-20 mg./kg./day PO Preparations: Syrup - 100 mg./ml. and 200 mg./5ml. (50-60 ml. suspension) Capsule - 150, 300, 450, 600 mg.

ANTIFUNGALS AMPHOTERECIN B Usual Dose: IN, CH - 0.1-0.25 mg./kg./day (single IV dose) Adults - 0.25-1 mg./kg./day Preparation: Injection - 5 mg./ml. (10 ml. vial)

NYSTATIN Usual Dose: NB - 400,000 units/day div.q4-6 h PO IN, CH - 400,000-800,000 units / day div.q4-6 h PO Adults - 800,000 – 2,000000 units/day div. q4-6 h PO

PRINCIPLES OF PRESCRIPTION ORDER WRITING

Prescription - a written order for medicines written by a qualified Medical, Dental or Veterinary practitioner to the pharmacist for a patient.

“Simple” - if containing only one ingredient. “Compound” - if containing more than one ingredient.

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Drugs may be combined in prescriptions for the following reasons:1. To obtain the conjoint effect of two or more active substances.2. To diminish or annul undesirable effects produced by one or more of the active

ingredients.3. To increase the solubility or aid in the dispensing of the active substances.4. Occasionally, to produce a new compound.

PARTS OF AN IDEAL PRESCRIPTION

________Doctor’s Name______________________Address______________

________Tel. No.________

----------------------------------------------------------------------------------------------------------------------

Patient’s name: __________________________________ Date:_____________Address:________________________________________________________________________Tel. No. __________________ Age: ______ Sex: ______

Rx Generic name of drug, dosage form and amount . (Brand name of drug)

Direction to the pharmacist .

Direction to the patient .

__________________ D.M.D. Prescriber’s Signature

PRC License Number

P.T.R. Number .Narcotic License Number ( S-2)T.I.N. Tax Identification Number

____________________

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Refill Information

Parts of the Prescription Superscription : Patient’s name, address, and age; date and the symbol Rx. Inscription : Name of drug, dosage form, and amount. Subscription : Directions to the pharmacist Transcription / Signature : Direction to the patient

HEADING Name, address and phone number of the prescriber. Name, address, age, and phone number of the patient, and date

BODY The symbol Rx Name and dosage unit or concentration (liquids) of the drug. Amount to be dispensed Directions to the patient

CLOSING Prescriber’s signature Space for DEA number Refill instructions “Please place name of drug on label”

Importance of placing the name of the drug on label:1. In case of overdose or adverse reactions, the drugs’ identity can be quickly obtained.2. Other practitioners can identify drugs the patient is taking.3. In most cases, the patient has the right to know what drug he or she is taking.

Hints for Prescription Writing1. Write legibly in ink or have it typewritten2. Use the metric system3. Avoid abbreviations4. Keep a copy of each prescription or transcribe the information to the patient’s record.5. Include complete information for the patient.

a. Never use “take as directed” unless a written instruction sheet is provided.b. Include the intended purpose.c. Use precautions to remind a patient of a drug’s side effects. E.q. “Caution: Sedation

or drowsiness.”d. Add reminder phrases to increase the patient’s compliance. E.q. “Take until all are

gone.” 6. It must contain the following particulars:

a. The address and usual signature of the practitioner giving it.b. The date on which it was signed by the practitioner.c. An indication of whether the practitioner is a dentist, doctor, or veterinary surgeon.d. The name, address, age (if under 12) of the person whose treatment is given.

7. The prescription shall not be dispensed not later than six months after the date of signature.

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Considerations in Drug Administration / Prescribing1. Tolerance – the ability of a client to respond to a particular dose of a certain drug may

diminish after days or weeks of repeated administration. A combination of drugs may be given to decrease or delay the development of tolerance for a specific drug.

2. Pathologic State / Pre-existing Disease State - Liver, kidney, heart, circulatory and gastrointestinal disorders are examples of preexisting states that can affect a response to a drug. For instance, diabetics should not be given elixirs or syrups than contain sugar.

3. Age - The age of a patient will affect his or her response to drugs. Children and elderly persons are more sensitive to drugs; they require less than the usual adult dose.

4. Weight - the more a person weighs, the more dilute the drug will become and a smaller amount will accumulate in the tissues. On the other hand, the less a person weighs, the greater accumulation in the tissues and a more powerful drug effect is produced.

5. Sex - Women are more susceptible to the action of certain drugs and are usually given smaller doses.

6. Drug-Drug Interaction - the effects of a combination of drugs may be greater then, equal to, or less than the effects of a single drug. Some drugs may compete for the same receptor sites. An adverse reaction may lead to toxicity or complication such as anaphylaxis.

7. Psychological factors / Emotional factors - A person’s personality often plays an important part in his response to drugs; comments about the drug and its side effects may influence its effects.

8. Genetic factors - drug idiosyncrasy is an abnormal susceptibility of some individuals that causes them to react differently than most people. This intolerance to small amounts of some drugs is thought to be due to genetic factors. If your mother or father has an adverse reaction to a drug, you may also.

9. Environmental factors - the setting in which the drugs are given and the attitude of the person giving the medication may influence the effects of drugs.

10. Method of administration - generally, larger doses are ordered when a medication is given by mouth or by rectum and smaller doses when the parenteral route is used.

11. Blood level curves and dosing regimens 12. Pregnant and breastfeeding mothers - Administration of medication in the early weeks of

pregnancy may cause damage to the fetus. During the third trimester, there is the possibility of premature labor caused by drugs that may stimulate muscular contractions.

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LATIN PHRASES and ABBREVIATIONSU sed in PRESCRIPTION WRITING

Abbreviations L a t i n E n g l i s h

a. ante beforeaa ana of eacha.c. ante cibum before mealsad ad to, up toass. adde, addantur add, let them be addedad lib. ad libitum at pleasureacq. acqualis equalagit. agita shakeaq. aqua wateraq. dest. aqua distilata distilled wateramp. --- ampuleb. bis twicebene bene wellb.i.d. bis in die twice a dayc cibum mealc. cum withcap. capsula capsuleco. ; comp. compositus compoundcoch. mag. cochleare magnum a tablespoonfulcoch. med. cochleare medium a dessertspoonfulcoch. parv. cochleare parvum a teaspoonfulcong. congium a gallond. dies a dayda da gived. in p. acq. dividatur in partes acquales let it be divided into equal partsd.t.d. dentus tales doses give such dosesdieb alt. diebus alternis every other daydil dilitus dilutedisp. dispensa, dispensetur dispensediv. divide dividedos. dosis a doseE.C. --- enteric coatedelix. elixir elixirEt et andEx ex out ofExt extractum extractex aq. ex aqua with watere.m.p. ex modo prescripto after the manner prescribedf. fiat, fiant make, let be madeFac face makefl. or fld. fluidus fluidFt. fiat makegm. --- gramgr. --- graingtt. gutta, guttae a drop, dropsh hora hourh.s. hora somni at bedtime(hour of sleep)hypo --- hypodermically

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DRUG THERAPY

Pharmaceutical ProcessPharmacokinetics ProcessPharmacodynamics ProcessTherapeutic Process

PHARMACEUTICAL PROCESS Is the drug getting into the patient? Approximately 80% of drugs are taken by mouth; therefore, the pharmaceutic phase is the first phase of drug action. In the gastrointestinal tract, drugs need to be in solution to be absorbed. A drug in solid form (tablet or pill) must disintegrate into smaller particles in order for it to dissolve into a liquid.

Disintegration is the breakdown of the tablet or pill into smaller particles. Dissolution is the dissolving of smaller particles in gastrointestinal fluid for absorption. Rate Limiting is the time it takes for the drug to disintegrate and become available for the body to absorb it.

Factors to consider1. Particle size - the smaller the particle size, the faster it can be absorbed in the body.2. Excipients of drug - fillers and inert substances are used in drug preparation to allow the

drug to take on a particular size and shape and to enhance dissolution of the drug. Some additives such as K and Na in penicillin K and penicillin Na, increase the absorbability of the drug.

3. Coating material - Enteric-coated (EC) drugs resist disintegration in the gastric acid in the stomach, so disintegration does not occur until the drug reaches the alkaline environment in the small intestine.

PHARMACOKINETIC PROCESS Is the drug getting into its site of action? - is the process of drug movement to achieve drug action. - concerned with the absorption, distribution and elimination (metabolism and excretion) of drugs.

ABSORPTION - process by which drug molecules are transferred form the site of administration in the body to the circulating fluids

Factors Affecting Absorption 1. Physico-chemical factors 2. Site of absorption / Blood flow at the site 3. Drug Solubility 4. Effects of food a. Blood flow b. Gastric emptying

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the non-ionized portion behaves as a non-polar lipid soluble compound which readily traverses body membranes.

The amount of ionization that any weak electrolytes undergoes depend on the pH at the drug site in the tissues and its dissociation characteristics.

Increase pH (weak acids) - the greater the degree of ionizationDecrease pH (weak bases) – the greater the degree of ionization.

Oral absorption – depends on the dosage form of drugs. Absorption on injection sites - depends on the solubility of drug and the blood flow at the site; also affected by dosage form. E.q. drugs in suspension are absorbed much ore slowly than those in solution.

Effects of food on drug absorption - by affecting the blood flow and gastric emptying. E.q. liquid glucose meal decreases flow and a meal rich in protein increases flow. - some drugs are irritating to the stomach mucosa, so fluids or food are necessary to dilute drug concentration - there are drugs that are absorbed easily in the presence of food.

Factors that Modify the Rate of Absorption 1. Drug Concentration at the Site 2. Circulation to the Site of Absorption 3. Area of Absorptive surface

FACTORS GOVERNING THE FATE OF A DRUG1. Molecular Weight

- substances with high molecular weight are not usually absorbed intact except in minute quantities.

- they are absorbed by enzymatic actions. E.q. insulin is a protein – it undergoes enzymatic breakdown in the git and is not absorbed.

2. Chemical Stability- unstable drugs maybe inactivated in the git. E.q. Benzylpenicillin in unstable in acid medium and cannot be effective if given by mouth. Phenoxymethylpenicillin is more stable in acid medium.

3. Lipid Solubility- if the drug is lipid soluble, it can easily pass through the membrane.

4. Degree of Ionization- the unionized portion of a drug is lipid soluble and so is readily absorbed; ionized portion is lipid insoluble.

THE CELL MEMBRANE Composition: Lipids (40%) phospholipids - makes membrane relatively impermeable to ions and polar molecules Proteins (50-60%) - make up the structural components of the membrane - acts as enzyme during transport

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Carbohydrates (remainder) Oligosaccharide - linked covalently to form complexes of glycoproteins and glycolipids

*PRINCIPAL MECHANISMS INVOLVED IN THE PASSAGE OF DRUGS ACROSS CELL MEMBRANE

1. Lipid Diffusion (Simple Diffusion) - drug molecules dissolves in the membrane to penetrate through the other side.

Can take place either via: Lipoprotein membrane

Paracellular spaces2. Aqueous Diffusion (Filtration through Pores)

- the size of the drug molecule is relative to the size of the pores.- water soluble drugs with molecular weight less than 100 Daltons are able to cross the cell membrane by passing through the polar pores. E.q. Ethanol (46); Urea (60)

3. Specific Carrier Mediated Transport System Active Transport - process by which a substance is transported against a concentration gradient. Drug molecules are mediated by transport “carrier” that furnish energy for the transportation of drug from lower concentration through higher concentrations. E.q. Na, K, Ca, Fe, amino acids, and glucose.

3 Features1. Ability to work against concentration gradient, osmotic, electrical, or

hydrostatic gradient2. Specificity – ability to concentrate a selected substance on one side of the cell

membrane.3. Each system require an energy source (ATP), to which it is directly coupled.

Facilitated Diffusion - a passive process whereby drugs can move across cell membranes more rapidly than simple diffusion. - involves the action of a specific but saturable carrier system - can only work in the presence of an appropriate concentration gradient.

DISTRIBUTION - the passage of drug into various body fluids compartments such as plasma, intestinal fluids and intracellular fluids; process by which the drug becomes available to body fluids and body tissues.

Factors affecting Distribution1. Blood flow2. Affinity to the tissue3. Protein binding

Forms of Drug inside the Body 1. Free / Unbound state - free active drug

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2. Bound - inactive drug Binding to Plasma Proteins - e.q. salicylic acid and warfarin bind to Albumin Basic drugs bind to acid glycoproteins and lipoproteins Binding to Cells - drugs become bound onto the surface or inside the cells.

*Only free drugs or drugs not bound to protein are active and can cause a pharmacologic response. As the free drug in the tissues decreases, more bound drug is released from the protein to maintain the balance of free drug. Checking the protein-binding percentage of all drugs administered is important in order to avoid possible drug toxicity. E.q. Drug accumulation and toxicity can result if two highly protein-bound drugs are given concurrently because they will compete for protein binding sites causing more free drug to be released into the circulation; Also, a low protein level decreases the number of protein binding sites, causing an increase in the amount of free drug in the plasma. Drug overdose may result because drug dosage is prescribed according to the percentage in which the drug binds to protein.

STORAGE DEPOT (Non-specific Site) - helps prevent prolong the action or areas for transient storage.

AFFINITY TISSUES - maybe sites of action or areas for transient storage; some drugs accumulate in particular tissues such as fat, bone, liver, eye, and muscle. E.g. Guanethidine - binds to heart and skeletal muscle Quinacrine - binds to liver and skeletal muscles Tetracycline - bone and enamel Thiopental - adipose tissue

METABOLISM - Liver – main organ of metabolism - most drugs are inactivated by liver enzymes and are then converted by hepatic enzymes to an inactive metabolite or water soluble substance for excretion. However, some drugs are transformed into active metabolites causing an increased pharmacologic response. Example of liver disease that affects metabolism - cirrhosis and hepatitis.

1. Excretion in the original form e.q. Hexamethonium – a highly ionized antihypertensive compound excreted in the urine unchanged.

2. Transformation into one or more MetabolitesOther organs: G.I.T., Lung, kidney, skin and placenta.

BIOTRANSFORMATION - a process wherein parent drug is converted by enzymes into drug metabolites ready to perform its action.

Biotransformation of Drugs has Two Effects1. It alters the pharmacological activity, usually decreasing it but sometimes converting

the drug to a compound similar or greater activity (potency) than the original.2. Results in metabolites that are more water-soluble and less lipid soluble than the parent

compounds and therefore more readily excreted in the urine.

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* Two General Types of Chemical Reaction Phase 1 (Non-Synthetic reaction)

1. Oxidation - Diazepam2. Reduction - Nitrazepam, Cortisone3. Hydrolysis - Suxamethonium, Amethocaine

Phase 2 (Synthetic (Conjugation) Reaction) -It involves conjugation to form one or more of the following:

1. Glucoronide e.g. Morphine, Paracetamol2. Sulphate e.g. Isoprenaline3. Acetate e.g. Isoniazid, Hydralazine4. Glutathione e.g. Paracetamol

BIOLOGIC HALF-LIFE (t1/2) - is the time it takes for one half of the drug concentration to be eliminated. - a drug goes through several half-lives before more than 90% is eliminated.

Example: 650 mg. of Aspirin t1/2 = 3 hours

Number (t1/2) Time of Elimination(h) Dosage Remaining (mg) %left 1 3 325 50 2 6 162 25 3 9 81 12.5 4 12 40.5 6.25 5 15 20 3.1 6 18 10 1.55

- it takes three hours for the first half-life to eliminate 325 mg and the second half-life (6h) for an additional 162 mg. to be eliminated, and so until the 6th half-life (18h) when 10 mg. of aspirin is left in the body. - a short half-life is 4-8 hours. - a long half-life is 24 hours or longer (e.q Digoxin 36 hours); it takes several days until the body completely eliminates the drug.

Factors Affecting Drug Metabolism1. Age2. Sex3. Liver Disease4. Environmental Factors5. Genetic Factors6. Route of Administration

MICROSOMAL DRUG METABOLIZING SYSTEM - the most important of the many biochemical system in the body involved in biotransformation. - located primarily in the smooth Endoplasmic Reticulum of hepatic cells.

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CYTOCHROME P450 - the most important enzyme in the microsomal enzyme system involved in the oxidative transport processes.

EXCRETION - major way by which the activity of the drug is terminated - mainly in the Kidney; some via the (Extra Renal Route) .Bile, Skin (sweat), Lungs (expired air), Saliva, Feces and Breast Milk - expressed in terms of “Renal Plasma Clearance” – the volume of plasma effectively cleared of the drug by the kidney in unit time.

RENAL EXCRETION - most important route of drug elimination *3 Processes Implicated in Renal Excretion 1. Glomerular Filtration - depends upon the plasma concentration of drugs and molecular weight. - 125 ml./min. 2. Tubular Reabsorption / Active Secretion in the Proximal tubule 3. Tubular Secretion / Passive Re-absorption in the distal tubule

PHARMACODYNAMICS Is the Drug producing the required Pharmacological Effect? - study of a drug’s effect on cellular physiology and biocehmistry and the drug’s mechanism of action.

I. Drugs which act via Pharmacological Receptors:1. Act at low concentration2. React with specific receptors3. Show structure activity relation4. Can be antagonized by specific antagonist

e.q. acetylcholine; adrenaline; noraduraline and histamine

II. Drugs which DO NOT act via Pharmacological Receptors: 1. Act at higher concentrations 2. Do not react with specific receptors 3. Tend to show structure-activity relationships 4. Do not have specific antagonists e.q. General anesthetics and non-specific destructants of cell membranes such as detergents.

DRUG-RECEPTOR INTERACTION Receptor - a macromolecule with special sites to which specific substances binds. (Drug/Ligands – Receptor).

SITES OF RECEPTORS1. On or within Cell Membranes2. Inside Cells

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Most receptors, protein in structure, are found on cell membranes. Drugs act through receptors by binding to the receptor to produce (initiate) a response or block (prevent) a response. The activity of many drug is determined by the ability of the drug to bind to a specific receptor. The better the drug fits at the receptor site, the more biologically active the drug is. It is similar to the fit of the right key in a lock.

Figure: Two drug agonists attach to the receptor site. The drug agonist that has an exact fit is a strong agonist and is more biologically active than the weak agonist.

Agonist - a drug (hormone or neurotransmitter) which combines with its specific receptor, activates it and initiates a sequence of effects. E.q. Isoproterenol stimulates the beta1 receptor. Antagonist - a drug which interferes with the action of an agonist but does not have any effect itself unless it possess partial agonist activity. E.q. Cimetidine blocks the H2 receptor thus preventing excessive gastric secretion. Partial Agonist - a drug that act on a receptor with an intrinsic activity or efficacy of < 1.

Mixed Agonist-Antagonist - a drug that act simultaneously on a mixed group of receptor with an agonist action on one set and an antagonist action on another.

***DRUG ANTAGONISM - occurs when their biological effect is less than the expected sum of their individual effects. Pharmacological Antagonism:

1. Reversible Competitive / Equilibrium Antagonism - substances are competing dynamically for the same pharmacological receptor 2. Irreversible Competitive / Non-Equilibrium Antagonism

- drugs form very strong bonds Non-Competitive Antagonism - block action of an agonist not at the receptor level but at some point between receptor and effector that leads to the action of the agonist. Physiological Antagonism - occurs when two drugs that act on different receptors produce opposite effects. E.q. Adrenaline antagonizes the effects of histamine on bronchial smooth muscle. Chemical Antagonism - occurs when one drug combines chemically with another to produce inactive product.

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Pharmacokinetic Antagonism - occurs when one drug effectively reduces the concentration of another at its site of action by altering its absorption, distribution or elimination.

***Relationship Between the Dose of Drug and the Effect it produces: Two Types of Relationship:

1. Quantitative (Graded) responses or effects - the effect increases as the dose is increased until the maximum is reached. Beyond this point, any increase in the dose is not accompanied by an increase in effect or response.

Graded - refers to that characteristic of an effect which begins at some low level and increase through progressive stages until it reaches some higher level.

2. Quantal responses or effects- “All or None” response. E.q. In toxicity test, a dose could either kill or not.

Definition of Terms:Onset of Action - begins when the drug enters the plasma and lasts until it reaches minimum effective concentration (MEC).Peak Action - occurs when the drug reaches its highest blood or plasma concentration.Duration of Action - is the length of time the drug has a pharmacologic effect.Time-response-curve - evaluates three parameters of drug action: the onset of drug, peak action, and duration of action.Biologic Variation - connotes the sum total of all the sources of variation that combine to cause one biologic unit to vary from one another.Threshold Dose - lowest case of a drug that will produce a measurable response.Plateau - endpoint/terminal point in a graded dose response curve.Therapeutic Index - the difference between the dose which will produce the desired effect and that which will cause adverse effect. - estimates the margin of safety of a drug by using a ration that measures the effective therapeutic dose in 50% of animals (ED50) and lethal dose in 50% of animals (LD50). The closer the ratio is to 1, the greater the danger of toxicity.

- a figure that gives measure as to the amount by which therapeutic dose made exceeded before eliciting a toxic effect. For clinical situation, a better measure would be adverse effect dose ED50 in which a specific adverse effect is considered, rather than the lethal median dose.

Median Effective Dose (ED 50) - smallest dose causing the given pharmacologic effect in 50% of the individuals of a sample.Relative Safety - dose of the drug required to produce the desired therapeutic effect relative to the dose of the drug required to produce toxic or lethal effects.Therapeutic Effects - desirable clinical action of a drug."Risk - Benefit Ratio" - toxicity taken into consideration --- "the risk of treatment weighed against the risk of disease" e.q. the use of known highly toxic drugs such as those used in the treatment of cancer applies this principle.

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THERAPEUTIC PROCESS Is the Pharmacological effect being translated into a desired therapeutic effect?

Factors which Determine the Relationship Between Prescribed Drug Dosage and DRUG Effect

Dosage Pathway Influences on Drug Effect

Prescribed dose Patient compliance Medication errorsAdministered dose Rate and extent of absorption Body size and composition Distribution in body fluids Binding in plasma and tissues Rate of eliminationConcentration at locus of action Physiological variables Pathological factors Genetic factors Interaction with other drugs Development of toleranceIntensity of effect Drug receptor interaction Functional state Placebo effects

PHARMACOLOGY OF INFLAMMATION - a reaction of the vascular and supporting elements of a tissue to injury which results in a protein-rich exudate, provided the injury has not been so severe as to destroy the area.

CLINICAL SIGNS OF INFLAMMATION1 Rubor - Redness 2. Tumor - Swelling 3. Calor - Hotness 4. Dolor - Pain 5. Functio Laesa - Loss of function

CLINICAL MEDIATORSHISTAMINE

- a vasoactive amine found in most tissues of the body- formed by the decarboxylation of the amino acid histidine.

PHARMACOLOGICAL PROPERTIES OF HISTAMINE - relaxation of the vascular smooth muscle - contraction of the bronchi and gut wall - secretion of exocrine glands - production of pain and itch - acts as neurotransmitter in the CNS (control of thirst, secretion of antidiuretic hormone, control of blood pressure, and pain perception).

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TYPES OF HISTAMINE RECEPTORS H1 = primarily related to smooth m. activity H2 = primarily involved with the stimulation of gastric secretions H3 = mediates CNS effects of histamine on histaminergic nerve terminals

Effects of Histamine: Heart - increase heart rate & force of contraction which results in an increase in cardiac output - increase histamine may cause arrhytmias due to slowing of A-V conduction - dilation of small b.v leads to flushing, lowered peripheral resistance, and a drop in blood pressure.

Smooth muscles - “Bronchial muscle’ - activation of H1 receptor results to bronchoconstriction. - Patients who suffer from asthma are particularly sensitive to the action of histamine on the bronchial musculature however, antihistamines are of no value in the treatment of asthma.

Gastric secretion - even a slow concentration can cause copious secretion of the gastric juices mediated by H2 receptor. Pain and Itch - caused by direct stimulation of free nerve endings when injected. - Subcutaneous injection of histamine causes sharp pain of short duration like a wasp’s sting but when injected into a more superficial layer of the skin, causes itching.

ANAPHYLAXIS AND ALLERGY Anaphylactic reaction – most dangerous acute allergic reaction occurring hour after drug administration. - histamine will be released due to an antigen combining with specific antibody attached to the surface of mast cells (DEGRANULATION) causing the extrusion of histamine from the secretory granules in the mast cells. - e.q. of substances that can cause anaphylaxis and allergy: Penicillin, animal fur, pollen.

Adverse Effects - undesirable clinical action of a drug; a range of untoward effects (unintended and occurring at normal doses) of drugs that cause mild to severe side effects, including anaphylaxis; Always undesirable. Side Effects - are physiologic effect not related to desired rug effects; Maybe desirable or undesirable and are predicted. Toxic Effects - adverse effects of an unexpected nature resulting from the direct action of a drug. Allergy - altered capacity of the body to react to various antigens. Idiosyncracies - covers unusual or bizarre drug effects that cannot readily be explained in an individual recipient.

AUTOCOIDS – derived from the Greek word “autos” (self) and ‘akas” (remedy). It refers

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substances which have local hormone-like activity at or near the site of production.

EICOSANOIDS – a term that denotes the metabolites of certain 20-carbon polyunsaturated fatty acids, mainly arachidonic acid. - products of arachidonic acid metabolism are divided into two main groups on the basis that they are ultimately derived from the action of one of the two enzymes systems (cyclo-oxygenase or lipoxygenase) on arachidonic acid.

ARACHIDONIC ACID - a 20 - polyunsaturated fatty acid Two sources :

1. Metabolic pool - endogenous synthesis of arachidonic acid2. Cell membrane pool - stimulated synthesis such as trauma; major source of the

eicosanoid precursor in inflammation.

Arachidonic acid -----metabolized------ results to metabolites (eicosanoids - a term…) by the action of the 2 enzyme (cyclo-oxygenase and lipoxygenase)

*In most cells and tissues, phospolipids are thought to be the major source of arachidonic acid. 1. The first step in eicosanoid synthesis: liberation of the Arach. Acid from cell membrane phospolipids by the action of a group of enzymes known as the phospolipases particularly phospolipase A2 responsible for its bulk. 2. The second step : formation of cyclo-oxygenase on free arachidonic acid ( results in the insertion of 2 oxygen molecules into the fatty acid carbon chain to form PGG2 which is rapidly transformed by the peroxydase-like activity of cyclo-oxygenase into the hydroxyperoxide, PGH2). This is followed by the formation of one of the three groups depending on the particular cell and circumstances involved, the prostaglandins, thromboxane, and prostacyclin.

CYCLO-OXYGENASE PRODUCTS:

PROSTAGLANDIN - 1st identified in 1930 but their structure and function were elucidated until 1960. - occur in every tissue and body fluid. – vasodilators = fall in blood pressure 2 Types: PGE and PGF series

THROMBOXANE AND PROSTACYCLIN THROMBOXANE A2 - Main synthesis in platelets plays an important role in platelet aggregation PROSTACYCLIN - a potent vasodilator and acts as an antagonist of platelet aggregation; main synthesis in vessel walls. *T and P are biologically opposite poles of the mechanism for regulating the platelet vessel wall interaction and the formation of hemostatic plug. Both are unstable, with very short half lives.

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LIPOXYGENASE PRODUCTS:

LEUKOTRIENES - has potent chemotactic properties; probably involved in the process of cellular infiltration that accompanies inflammation. Types: LTA4; LTB4; LTC4; LTD4; LTE4

PLATELET ACTIVATING FACTOR - a lipid autocoid synthesized mainly by platelets, leukocytes, and endothelial cells. - action includes vasodilation, inc. in vascular permeability, white blood chemotaxis, and the release of lysosomal enzymes. - a potent stimulator of platelet aggregation. - may also be important in the pathogenesis of asthma.

Arachidonic Acid Metabolism Product

Cyclo-oxygenase product Lipoxygenase product

Prostaglandins Leukotrienes Thromboxanes Compounds based on Prostacyclin eicosatetraenoic acid

BRADYKININ AND KALLIDIN - Polypeptides formed from the plasma alpha globulins by a complex series of proteolytic reactions. - Potent vasodilators - Increase capillary permeability = oedema - Cause bronchoconstriction - Bradykinin: 10X active than histamine; effects are brought by: Kinin Receptors : B1 and B2

5-HYDROXYTRYPTAMINE (5-HT) - amine formed by the hydroxylation of tryptophan stored in gastric mucosa - dilatation of arteries and constriction of veins via receptors 5HT1 ; 5HT2 ; 5HT3 - high concentrations are found in platelets. - pharmacologic properties: role in inflammation is uncertain and maybe insignificant; dilation of arteries and constriction of veins.

CYTOKINES - Proteins secreted by cells that have effects on other cells

LYMPHOKINES - cytokines produced by sensitized T lymphocytes and to a lesser extent by B lymphocytes in response to antigenic challenge

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Actions of Lymphokines:1. Chemotactic for macrophages2. Macrophage activation3. Macrophage inhibition4. Chemotactic for other mononuclear WBC5. Mutagenic for other lymphocytes6. Increased vascular permeability7. Activation of osteoclasts.

INTERLEUKINS - cytokines from macrophages and lymphocytes during inflammation and immune response. - exerts a number of inflammatory actions which include the stimulation of PG and collagenase production, chemoattraction for WBC and enhancement of the hepatic synthesis of acute phase proteins. - Has 8 types: Interleukins 1 – 8.

COMPLEMENT - consist of a series of protein that react in a cascade fashion ANTIHISTAMINES - antagonize histamine at the receptor sites; do not alter the formation or release of histamine from tissues or mast cells. - classified as H1 or H2 receptor blockers (antagonists)

H1 Receptor Antagonists - interact with H1 receptor on cell membranes - results in a decrease in the availability of these receptors for the action of histamine; well absorbed from the git; therapeutic effects can be observed within 15-30 min. after dosage; widely distributed in the body and broken down in the liver. - Therapeutic uses: Treatment and prevention of a variety of allergic conditions (e.q. rhinitis, hay fever, and certain allergic dermatoses such as acute urticaria). Topical application is useful in relieving the itching associated with insect bites; widely used as common cold remedies usually combined with decongestants (e.q. Actifed). - no effect on bronchospasm or severe hypotension associated with anaphylactic shock; no value in the treatment of asthma. Unwanted effects: Sedation; may cause stimulation; dryness of the mouth; variety of g.i disturbances.

*** Alcohol should be avoided while taking H1 blockers as it enhances the sedative effect.

H2 R eceptor Antagonists - antagonizes the action of histamine at H2 receptor. - commonly used are Cimetidine and Ranitidine. - reduce gastric secretion; Treatment of duodenal ulcers and gastric hypersecretion. Unwanted effects: slight such as headache, dizziness, constipation or diarrhea, and skin rashes

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5-HT ANTAGONISTS - Ergot alkaloids are a group of compounds that are antagonists for 5-HT, Ergotamine.

CORTICOSTEROIDS - have potent anti-inflammatory properties; widely used in the treatment of recurrent oral ulceration and other oral mucosal lesion such as erosive lichen planus, erythema multiforme, and pemphigus. E.q. 0.1% Triamcinolone (topical) ; hydrocortisone sodium succinate 2.5 mg. ; Bethamethasone 17-valerate (topical spray) ; etc. - pulpal inflammation; TMJ pain; Bell’s palsy; post-operative pain and swelling after dental surgery; Anaphylactic and allergic reactions.

PHARMACOLOGY OF PAINPain - an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.Analgesia - absence of pain in response to stimulation which would normally be painful.Hyperalgesia - an increased response to a stimulus which is normally painfulNeuralgia - pain in the distribution of a nerve.Neuritis - inflammation of a nerve or nerves.Nociception - activity in a nerve fiber which arises as the result of stimulation of nociceptors. If nociception reaches consciousness, it is perceived as pain.Nociceptor - a receptor preferentially sensitive to a noxious stimulus or to a stimulus which would become noxious if prolonged.Pain threshold - the least stimulus intensity at which a subject perceives pain.Pain tolerance level - the greatest stimulus intensity causing pain that a subject is prepared to tolerate.Allodynia - pain due to a stimulus which does not normally provoke pain.Causalgia - a syndrome of sustained burning pain, allodynia and hyperpathia after a traumatic nerve lesion, often combined with vasomotor dysfunction and later trophic changes.Hyperaesthesia - increased sensitivity to stimulation excluding special senses.Hyperpathia - a painful syndrome characterized by increased reaction to a stimulus, especially repetitive stimulus, as well as an increased threshold.Neuropathy - a disturbance of function or pathological change in a nerve; in one nerve, mononeuropathy; in several nerves, mononeuropathy multiplex; if diffuse and bilateral, polyneuropathy.

Two Main Types of NOCICEPTORS1. High Threshold Mechanoreceptor2. Polymodal Nociceptor

THEORIES OF PAIN1. SPECIFICITY Theory - concerned primarily with the sensory discriminative aspects of

pain and its quality, location on the skin, intensity and duration.2. CENTRAL SUMMATION (PATTERN) Theory – pain is not a separate entity, but

results from over stimulation of other primary sensations.3. SENSORY INTERACTION Theory – stresses inhibition as an important physiological

mechanism in pain transmission.

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4. GATE CONTROL Theory - stressed the importance of both descending control mechanism and activity in large sensory fiber in modulating the pain experience.

PERIPHERAL MEDIATORS OF PAIN1. BRADYKININ2. HISTAMINE3. EICOSANOIDS

Four Main Groups of Eicosanoids1. Prostaglandin2. Prostacyclin3. Thromboxane4. Leukotrienes

CENTRAL MEDIATORS OF PAIN1. Amino Acids2. Peptides

METHODS TO RELIEVE PAIN1. Remove peripheral stimulus2. Interrupt nociceptive input3. Stimulate nociceptive inhibitory mechanism4. Modulate central appreciation of pain and/or emotional concomitants5. Block or remove secondary factors maintaining pain.

I. NON – NARCOTIC ANALGESICS General Characteristics

1. Relieves pain without altering consciousness.2. Safer than narcotics.3. Produce fewer side effects.4. Not addicting.5. Act principally on peripheral nerve endings.6. Inhibits the synthesis of prostaglandins.

PharmacologicAction1. Analgesia2. Antipyresis3. Antiinflammatory

SALICYLATES – extracts of willow bark containing the bitter glycoside salicin. Therapeutically Useful SALICYLATES

1. Salicylic Acid - parent compound., toxic internally, topical fungicide, keratolytic agent.

2. Sodium Salicylate - internal use as an analgesic, less effective than aspirin, may be used in patients allergic to aspirin.

3. Methyl Salicylate (oil of wintergreen) – external use as a counterirritant, flavoring in cooking.

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4. Acetylsalicylic acid - widespread use as an analgesic, antipyretic and antirheumatic5. Salicylamide – internal use as an analgesic; less effective than aspirin; less G.I.

irritation.6. Difflunisal – an investigational salicylate; possibly better tolerated , effective at lower

doses; apparent therapeutic advantage over aspirin and perhaps other inflammatory agents.

ASPIRIN - absorbed from the git; partly from stomach but mainly in the upper small intestine Pharmacological Properties - Analgesic (mild analgesic) – due to inhibition of the synthesis of PGE. Suitable regimen: 600-1200mg. every 4-6 hours. - Anti-inflammatory – inhibit synthesis of eicosanoids; High concentrations can inhibit the function and activity of PMN leukocytes - Antipyretic – lowers an elevated body temp. (pyrexia) due to infection, tissue damage, malignancy or other disease states; due to inhibition of prostaglandin production in the hypothalamus. - Antithrombotic effect

Unwanted effects - Gastrointestinal – epigastric pain, nausea, gastric erosions leading to blood loss - Haemostatic effects – prolongs bleeding time; inhibiting the synthesis of platelet thromboxane. - Tinnitus – hearing loss due to rise in labyrinth pressure - Uricosuric effect – increase plasma uric acid. Should Not be given to patients with gout(a disorder of uric acid metabolism). - Effects on kidney – decrease renal blood flow; also enhances sodium and water retention.

Aspirin Hypersensitivity – from rhinitis to life threatening laryngeal edema. Aspirin Overdose – 10-30 gm. can be fatal. Aspirin and Reye”s Syndrome – an acute encephalopathic illness and fatty degeneration of the viscera, especially the liver that arises after an infectious illness such as chickenpox or influenza. - interaction between aspirin and the viral infection leads to damage of cell mitochondria in genetically susceptible individuals.

PARA-AMINOPHENOLSA. Acetaminophen (paracetamol, N-acetyl)B. Phenacetin (acetophenetidin)

ACETAMINOPHEN Pharmacologic Properties

1. Analgesic2. Antipyretic3. Antiinflammatory (not clinically significant)4. Do not produce gastric bleeding

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5. Do not affect platelet adhesiveness6. Do not affect uric acid excretion7. Enhances water transport in the kidney.8. Peak plasma concentration usually occur 30 minutes. After dosage, and the half life

is usually 2 hours. 9. Conjugated in the liver and excreted in the urine.

Adverse Effect:1. Methemoglobinemia (Phenacetin)

- condition that results from conversion of the iron in hemoglobin to an oxidized state that cannot effectively carry oxygen.Signs: 1. Cyanosis 2. Dyspnea on exertion 3. Anemia

2. Hemolytic Anemia- Hemolysis is caused by minor metabolites that oxidize glutathione in the RBC and thereby labilize the erythrocyte membrane to oxidative destruction.Signs: 1. Abdominal or lower back pain 2. Jaundice 3. Hemoglobinuria 4. Anemia

3. Hepatic Necrosis- may occur after ingestion of a single dose of 10 to 15 Grams.

4. NephrotoxicityAdult dose: 325 to 500 mg. or 2 tablets or capsules; not more than 4 Grams in 24 hours.

Unwanted effects: few; most serious is hepatoxicity Paracetamol Overdose: 10-15 gm. – acute liver damage – manifests between 2-6 days after overdose 25 gm. – fatal Treatment: Gastric lavage provided it is in the first hour after dosage; <12 hrs. – N acetylcysteine; after 24 hrs. – the success of treatment depends on the magnitude of the initial dose. (px will suffer a slow and distressing death). - In postoperative dental pain, efficacy is NOT dose-related.

NON-STEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDS) - share many of aspirin’s pharmacological properties. - anti-inflammatory and analgesic because they can inhibit the synthesis of eicosanoids. - produce unwanted effects similar to those of aspirin.

A. PHENYLPROPIONIC ACID DERIVATIVES – Ibuprofen, Naproxen, Flurbiprofen and FenoprofenPharmacologic Properties

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1. The mechanism of action appears to be related to inhibition of prostaglandin synthetase.

2. Analgesic, antipyretic, and anti-inflammatory.3. Indicated for the symptomatic treatment of rheumatoid arthritis.

Adverse Reaction1. Gastointestinal upset2. CNS effects such as dizziness, headaches, drowsiness and tinnitus.

Naproxen: t1/2 13 hours. Ibuprofen – peak plasma concentration – 1.5 hrs. after dosage and the plasma half life is 2 hours; broken down in the liver; excreted in the urine; has similar unwanted effects as aspirin.

B. INDOLEACETIC ACID1. Indomethacin

- most potent inhibitors of cycloxygenase - analgesic, antipyretic, powerful anti-inflammatory agent.- used in rheumatoid arthritis.- first drug of choice to treat gout.Adverse reaction: - GI complaints - CNS - dizziness, headache, tinnitus, vertigo, confusion – unknown, but may be due to PG inhibition

2. Sulindac- has analgesic, antipyretic effect.- treatment of rheumatoid arthritis.

C. PYRROLACETIC ACIDTolmentinZomepirac

D. FENAMIC ACID DERVIATIVES (FENAMATES) 1. Mefenamic acid

- treatment of pain, dysmenorrhea- sedation can occur- absorbed after oral dose; peak plasma concentrations – after 2 hrs.; half-life is 3-4 hours.- metabolized in liver, half of metabolites excreted in the urine, half in the feces.

- Diarrhea occurs in 25% of patients - as active as aspirin; - incidence of unwanted effects esp. GI disturbance is high.

2. Meclofenamate - treatment of arthritis - dose: initial – 500 mg. followed by 250 mg. every six hours.

E. PYRAZOLONES

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Phenylbutazone Oxyphenbutazone

F. DIFFLUNISAL - a difluorophenyl derivative of salicylic acid; has similar pharmacologic properties as aspirin - long plasma half-life – 8 hrs. (only b.i.d.)

II. NARCOTIC ANALGESIC Similarities: They all produce:

1. Potent analgesia2. Addiction3. Respiratory depression4. Sedation5. Emesis6. Constipation

CLASSIFICATION1. OPIUM ALKALOIDS2. SEMISYNTHETIC DERIVATIVES3. SYNTHETIC DERIVATIVES

I. OPIUM ALKALOIDS - opium is the dried juice obtained from the unripe seed capsules of the poppy plant (Papaver somniferum)

A. Morphine– most potent analgesic in use– named after Morpheus (Greek God of Dreams)– undergoes extensive first pass metabolism in the liver.– Parenteral solutions of morphine sulfate and oral preparations are available.– t1/2 = 3 hours– Dosage: Adult – 10 to 15 mg. subcutaneously every 4-6 hours.

Children – 0.1 to 0.2 mg/kg/dose Maximum dose: 15 mg.

Pharmacological Properties1. Analgesia - effective against continuous dull pain.2. GIT – used to treat diarrhea and dysentery; produce degree a degree of

constipation.3. Cough suppression - effective antitussive.4. Cardiovascular - cause the release of histamine.

Unwanted Effects1. Respiratory depression2. Dependence3. Nausea and Emetic effect

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4. Cause constriction of the pupil (MIOSIS)5. Actions on the bladder.

B. Codeine or Methyl Morphine

- Dose: Adult – 15-60 mg (1/4 to 1 grain)

Pharmacological Properties1. Effective when taken by mouth2. Use in treating mild to moderate pain3. Very effective antitussive.

Unwanted Effects1. Nausea, vomiting, sedation, dizziness2. Can depress respiration3. Can cause constipation

C. Heroin- produced by acetylation of morphine- 2 to 5X as potent as morphine as an analgesic.- highly euphoric and addicting drug

II. SEMISYNTHETIC DERIVATIVE OF MORPHINE OR CODEINE A. Hydromorphone - more potent than morphine. - principal use is for acute pain.

B. Hydrocodone (Codone, Dicodid)

C. Oxymorphone - extremely addicting and a potent respiratory depressant. - Dose: Adult - 1mg. subcutaneously. - Available only for parenteral use. III. SYNTHETIC NARCOTICS

A. Meperidine (Demerol) - most common narcotic abused by professionals.

- Dose: Adult – 50 to 100 mg. orally, subcutaneously, or intramuscularly. - Preparation: Tablets, elixir, and solutions for injections. - available in combination with acetaminophen or promethazine.

Adverse Effect1. Sedation2. Respiratory depression3. Increased tone and secretions of GIT4. Produces addiction5. Tolerance develops.

B. Alpaprodine

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C.

D. Anileridine - Dose: usual Adult dose – 25 to 50 mg. every six hours. - can be give orally, intramuscularly or subcutaneously. - available in tablets and injection.

OPIOID ANTAGONIST Naloxone - mainly used to treat opioid overdose, particularly the effects on respiration. - must be given intravenously. - 0.4 to 0.8 mg for immediate effect - t1/2 1 hour

COMPREHENSIVE DRUG ABUSE PREVENTION and CONTROL ACT OF 1970

SCHEDULE 1 SUBSTANCES Drugs with a high potential for abuse and no currently accepted medical use. Not for prescription use but may be obtained for research purposes. E.q. Heroin Ketobemidone Marijuana Benzylmorphine Peyote Nicomorphine Mescaline Methaqualone LSD Dihydromorphine Nicodeine Racemoramide Morphine methylsulfonate Levomoramide SCHEDULE II SUBSTANCES Drugs with a high potential for abuse with severe liability to cause psychic or physical

dependence. Consists of certain opioid drugs and drug containing amphetamines or metaamphetamines as

the single active ingredient or in combination with each other. Categorized as “Class A Narcotic Drugs.” E.g. Opium Morphine Codeine Hydromorphone Amobarbital Methadone Meperidine Cocaine Oxycodone Pentobarbital Diphenoxylate Phemetrazine Methylphenidate Secobarbital Methamphetamine Dextroamphetamine Etorphine hydrochloride

SCHEDULE III SUBSTANCES Drugs with a potential for abuse that is less than those in schedules I and II substances.

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Their abuse may lead to moderate or low physical dependence or high psychological dependence.

Drugs included was formerly known as “Class B Narcotic drugs” plus a number of non-narcotic agents.

E.q. Chlorhexadol Gluthethimide Methylprylon Sulfodiethylmethane Sulfonmethane Nalorphine Benzphetamine Chlorphentermine Phendimetrazine Certain barbiturates except those listed in another schedule.

SCHEDULE IV SUBSTANCES Drugs with low potential for abuse that leads only to limited physical or psychological

dependence relative to drugs in Schedule III. E.q. Barbital Phenobarbital Ethinamate Paraldehyde Phentermine Methohexital Fenfluramine Methylphenobarbital Chloral betaine Chloral hydrate Meprobamate Propoxyphene Benzodiazepines Mebutamate Ethchlorvynol

SCHEDULE V SUBSTANCES Drugs have a lower potential for abuse than those in Schedule IV for which there is currently

accepted medical use in the U.S. Drugs are categorized as “Exempt Narcotics.”

HEMOSTATICS Locally applied substances that are employed to arrest excessive bleeding or hemorrhage.

Sympathomimetics - reduce bleeding by local vasoconstriction. E.q. Epinephrine

Styptics and Astringents - precipitates the tissue proteins in the immediate area. E.q. Zinc Chloride, Aluminum Chloride, Ferric Sulfate

Mechanical Agents - acts as matrices in which blood cells / fibrin can be entrapped. E.q. Gel foam, Oxidized Cellulose, Oxidized Regenerated Cellulose.

Thrombin - normal constituent of the blood coagulation scheme, combines with fibrinogen.

HEMOSTASIS AND HEMOSTATIC AGENTS

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Factors in the Arrest of Hemorrhage 1. Vessel wall contraction - of short duration (5-20 minutes) - can be prolonged by topical or local infiltration of Adrenaline. 2. Adhesion and Aggregation of Platelets - Platelets are non-nuclear cells with a cytoplasm rich in granules. - normal count: 150,000 – 4000,000 cells/ml. - half life is 7 to 10 days - releases Adenosine Diphosphate (ADP) and Thromboxane A2

- forms Platelet PLUG

3. Ability of blood to coagulate Stage I - Activation of Factor X --- Xa Stage II – Prothrombin (II) --- Thrombin Stage III - Fibrinogen (I) --- Fibrin --- Clot Stage IV - Fibrin Clot - Lysed fibrin and fibrin peptides. 4. Fibrinolysis (The breakdown of blood clot) - can be influenced by age, sex, diet, smoking, altitude, exercise.

VITAMIN K - fat soluble vitamin that is essential for the normal hepatic biosynthesis of several factors required for blood clotting. (II, VII, IX, X)

ANTICOAGULANTS - they directly or indirectly interfere with the normal clotting mechanism of blood. - patients receiving are those with a history of myocardial infarction, cerebrovascular thrombosis, venous thrombosis, and pulmonary embolism.

A. Heparin - enhances the activity of antithrombin III (neutralizes several of the activated clotting factors Ixa, Xa, Xia, and XIIa. It also inactivates prothrombin by forming an irreversible complex with it). - must be administered parenterally. - half life is between 1 to 5 hours (the higher the dose, the higher the half life) - Unwanted effects: Heamorrhage and Thrombocytopenia. - the effect can be reversed by the specific antagonist (Protamine Sulphate) at eh dose regimen of 1 mg. of protamine for every 100 units of heparin.

B. Coumarin Anticoagulants - Oral anticoagulants - includes Warfarin Sodium and Phenindione. - antagonist to vitamin k - reduces synthesis of vitamin K dependent clotting factors (II, VII, IX, X). - affected by diet, bowel disease, pyrexia, age, pregnancy, liver disease. ANTIPLATELET DRUGS - Antithrombotic

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- decrease thrombin formation E.q. Aspirin, Diprydamole, Sulphin Pyrazone.

FIBRINOLYTIC DRUGS - promotes the breakdown of thrombi by activation of plasminogen to form plasmin. E.q. Streptokinase, Urokinase, Tissue Plasminogen Activator.

ANTIFIBRINOLYTIC DRUGS - these encourage the stabilization of fibrin by inhibiting plasminogen activator. E.q. Tranexamic acid - effects: Nausea, diarrhea, hypotension.

DENTAL MANAGEMENT OF PATIENTS WITH HEMOSTATIC PROBLEMS 1. Impaired Platelet Function - due to reduction in platelet count or impaired aggregation due to drug therapy. - Treatment: Low platelet count – Platelet transfusion before surgery. Thrombocytopenia due to immune destruction of platelet – Administration of corticosteroid - it is a wise precaution to suture and pack the socket to minimize the risk of post extraction hemorrhage. - drugs that impair platelet aggregation and increase bleeding time includes Aspirin, NSAID’s, Sodium Valproate, and Phenytoin.

2. Vascular Defects - associated with vitamin C deficiency and long term corticosteroid therapy. - patients have increased capillary fragility which can cause bleeding problems after surgery. - can be controlled by pressure, suturing, and packing. 3. Impaired Coagulation A. Haemophilia - sex-linked; affects only males. - patients have reduced factor VIII activity. - can be corrected by replacement therapy of freeze-dried factor VIII (cryoprecipitate). - drugs used in conjunction with factor VIII include anti-fibrinolytic agents, epsilon aminocaproic acid which should be started pre-operatively.

B. Christmas Disease - associated with a deficiency of factor IX (derived from plasma but not present in cryoprecipitate). - Replacement therapy. C. Von Willebrand’s disease - inherited disorder associated with both prolonged bleeding time and deficiency of factor VIII. - replacement therapy is necessary.

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LOCAL ANESTHETICS - reversible Blockade of Peripheral Nerve Conduction; drugs that have little or no irritating effects when injected into the tissues and that will temporarily interrupt conduction when absorbed into the nerve.

Autonomic Losses in the usual order1. Sense of Cold2. Warmth3. Pain4. Touch5. Pressure6. Vibration7. Proprioception8. Motor function

Components of Local AnestheticsA. Anesthetic DrugB. Vasoconstrictor e.g. epinephrine, levonordefrin

Role of Vasoconstrictor in Local Anesthetics Prolong Local Block Delay Systemic Absorption Limit Toxicity

C. Antioxidant e.g. Sodium Bisulfite or Sodium Pyrosulfite

D. Antiseptics methylparaben

Ideal Properties of Local Anesthetics1. Potent Local Anesthesia2. Reversible Local Anesthesia3. Absence of Local Reactions4. Absence of Systemic Reactions5. Absence of Allergic Reactions6. Rapid Onset7. Satisfactory Duration8. Adequate Tissue Penetration9. Low Cost10. Stability in Solution (long shelf life)11. Sterilization by Autoclave12. Ease of Metabolism and Excretion

Two Groups: ESTER group and AMIDE group

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CHEMISTRY OF LOCAL ANESTHETICS

Aromatic Nucleus Linkage Amino Group

ESTER O R3 R1 ------ -- C – O – R2 -- ------ N

R4 ____________________ o r ____________________________

AMIDE H O R3 R1 ------ -- N – C – R2 -- ------ N

R4

Absorption: Increase vasodilation = Increase speed of circulation Distribution: Brain, liver, kidneys, lungs, spleen. Metabolism: Ester – hydrolyzed in plasma by plasma cholinesterase. Amide – Liver Prilocaine – Lungs Excretion: Kidney

Pharmacologic Effects1. Reversible peripheral nerve conduction2. Smooth muscle effects – relaxation of smooth muscle because sensory receptors are

depressed.3. Analgesic effect4. Anticonvulsant effects.

Most Local Anesthetics are Synthetic except Cocaine1. An Aromatic, Lipophilic Group2. An Intermediate Chain (Ester or Amide Linkage)3. A Hydrophilic 2º or 3º amino group, which forms water soluble salts when

combined with acids.

Generally almost without exception, Drugs thus formed are: White and Odorless Viscid Liquids or Amorphous Solids Fat Soluble but relatively Insoluble in water All are Bases and form Water Soluble Salts with Acids

Toxicity of Local Anesthetics: Descending stimulation of the C.N.S. followed by

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DEPRESSION of certain areas of the brain

Classic Progression: 1. Restlessness, Apprehension and Tremors progressing to Excitement and Convulsions 2. Increase Blood Pressure and Pulse Rate 3. Increase Respiratory Rate 4. Respiratory and cardiovascular depression with Loss of reflexes and consciousness.

Characteristics of Lidocaine Toxicity: DEPRESSION, generally the cause of Death, may appear without initial stimulation.

GENERAL ANESTHESIA - the drug induced absence of the perception of all sensation allowing surgery or other painful procedures to be carried out. - depresses the CNS; alleviate pain and cause a loss of consciousness.

HISTORY Nitrous Oxide “laughing Gas” described by john Priest Horace Wells observed its effects as anesthetics. Ether – by T.G. Morton and C.T. Jackson Highly flammable, volatile, pungent odor. Chloroform - volatile liquid; by J.Y. Simpson

THEORIES ON MECHANISM OF ACTION OF G.A.1. Lipid or Meyer Overton Theory2. Inhibition of biochemical Action3. Molecular theories

Pharmacologic Effects1. CNS depressants2. CVS depression3. Urine output is reduced4. May produce liver damage.5. Release of ACTH, antidiuretic hormone, sympathetic neurotransmitters.

STAGES OF ANESTHESIA (Guedel’s Classification) Stage I : ANALGESIA - from administration of anesthesia – loss of consciousness Analgesia Euphoria Perceptual distortions Amnesia

Stage II : DELIRIUM - loss of consciousness – beginning of surgical anesthesia Excitement Involuntary muscular activity (Increase muscle tone) Irregular breathing

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Hypertension Tachycardia

Stage III : SURGICAL ANESTHESIA - state of analgesia associated with majority of surgical procedures - spontaneous respiration ceases

* 4 Planes based on: Respiration Size of pupils Reflex characteristics Eyeball movement

Stage IV : MEDULLARY DEPRESSION / RESPIRATORY PARALYSIS - begins with cessation of respiration – circulatory collapse - Pupils fixed and dilated - No lid or corneal reflexes

If not reverse immediately, Death occurs.

PHASES OF ANESTHESIA (Flagg)

INDUCTION - encompasses all the preparation and medication necessary for a patient up to the time the surgeon is ready to begin.

MAINTENANCE - begins with the patient at a depth of anesthesia sufficient to allow surgical manipulation and continues until completion of procedure.

RECOVERY - begins with the termination of the surgical procedure and continues through the post operative period until the patient is fully responsive to the environment.

CLASSIFICATION OF G.A. BY ROUTE OF ADMINISTRATION

Inhalation Intravenous Agents

Gases Volatile liquids

Nitrous Oxide Halogenated Hydrocarbon Neuroleptics Chloroform Fentanyl with Droperidol Ethyl Chloride (Innovar)Cyclopropane Trichloroethylene (Trilene, Trimar) Dissociative

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Ethylene Halothane (Fluothane) Ketamine (Ketalar, Ketaject) Halogenated Ether Barbiturates Methoxyflurane Methohexital (Penthrane) (Brevital) Enflurane Thiamylal Sodium (Enthrane) (Surital) Isoflurane Thiopental Sodium (Forane) (Pentothal)

Ether Narcotics Diethyl Ether Fentanyl (Sublimaze) (Ether) Morphine Vinyl Ether (Vinethene)

“BALANCED ANESTHESIA”

- PRE-ANESTHETIC MEDICATION-

- INDUCTION-

- NEUROMUSCULAR BLOCKING -AGENT

- ANESTHETICS- G O A L : ANALGESIA SLEEP MUSCLE RELAXATION ABOLITION OF REFLEXES

PREMEDICATION Features Required of PREMEDICATION Agents

1. Alleviate pre-operative anxiety.2. Provide some degree of post-operative amnesia esp. in children.3. Make the induction and maintenance anaesthesia easier.4. Reduce the amount of anaesthetic agents required by enhancing their effects5. Provide additional analgesia.6. Reduce salivary and bronchial secretions.7. Reduce activity in the parasympathetic nervous system.

PREMEDICATION AGENTS OPIOIDS - e.q. Morphine, Pethidine, Papaverum Therapeutic Effects: Analgesic, Sedative, Euphoriant, Respiratory depression, Suppression of cough reflex Unwanted Effects: Nausea, Vomiting

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ANXIOLYTICS - e.q. Benzodiazepines - used orally to provide post-operative sedation.

ANTIPSYCHOTICS (Neuroleptics) e.q. Penothiazines derivatives – promethazine and Trimeprazine. - pre-anaesthetic sedatives; anti-emetic; for patients who fear or has predisposition to post-operative vomiting; depresses respiration: cause varying amount of hypotension.

ANTICHOLINERGIC Atropine Sulphate; Hyoscine; Glycopyrrolate - reduce secretions; prevent overactivity of the parasympathetic nervous system.

Atropine Sulphate - commonly used to reduce salivary and bronchial secretions during anesthesia by antagonizing the actions of acetylcholine at muscarinic receptors.

Hyoscine - antagonizes the effect of endogenous acetylcholine at muscarinic receptors; given IM 30-60 minutes before induction anesthesia; a CNS depressant – causes drowsiness and depression of the vomiting center -anti-emetic. Athigh doses, it may act as stimulant of the CNS. Both atropine and hyoscine block the action of acetylcholine released from the vagal nerve endings which gives some protection against vagal stimulation.

Glycopyrrolate - a quarternary ammonium; produces prolonged and good control of salivary and pharyngeal secretions; less effect on the cardiovascular system; used as preoperative or intraoperative antimuscarinic to attenuate or prevent the intra-operative bradycardia sometimes associated with the use of suxamethonium or due to cardiac vagal reflexes..

NEUROMUSCULAR BLOCKING AGENTS - by specific blockage of the neuromuscular junction, they enable light levels of anesthesia to be used with adequate relaxation of the muscles of the abdomen and diaphragm; produce relaxation of the abdominal muscles, and paralysis of the respiratory muscles; relaxes the vocal cords allowing the passage of a tracheal tube.

Two Types of Neuromuscular Blocking Agents I. NON DEPOLARIZING MUSCLE RELAXANTS(competitive)

Tubocurarine - highly ionized; given IV ; produce paralysis of all voluntary muscles; action commences 3-4 mins. and lasts up to 40 mins.; used as an adjunct to G.A.; action may be reversed by administration of neostigmine ; a weak ganglion blocker – causes the release of histamine -- peripheral vasodilation - - will lower the b.p. ; may also cause flushing and bronchospasm due to the release of histamine; does not cross the blood brain barrier or the placenta.

Pancuronium - more potent than Tubocurarine but has a shorter action; acts by competitive block but does not normally block transmission in autonomic ganglia and so does not significantly alter the blood pressure. However, if rapidly injected

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IV, it may cause a rise in bp due to vagal blocking and tachycardia; does not cause histamine to be released; may also be used to produce relaxation in a number of pathological conditions such as tetanus; also used extensively in ICU. Atracurium and Vecoronium - most often used at the present time; have little effect on the cardiovascular system; may release little of histamine; more advantageous to patient’s with renal or hepatic impairment.

II. DEPOLARIZING MUSCLE RELAXANTS Suxamethonium - depolarizes the postsynaptic membreane and maintains this state so that the adjacent m. fibers are electrically inexcitable; injected IV; produces complete muscular relaxation in half a minute; has a number of muscarinic action including increase in salivary secretion, muscle injury occasionally due to direct action on the muscle or may follow K depletion from muscles.; may cause malignant hyperpyrexia – maybe treated by rapid cooling, inhalation of 100% oxygen and IV of Dantrolene 1 mg/kg of body weight.

* MUSCLE CONTRACTIONaction potential ---- travels down the motor nerve---- release of packets of acth (quanta- millions of acth molecules) ----- acth crosses the synaptic cleft and interacts with the cholinergic receptors on the end plate of a muscle fiber ---- surge of acth brings a massive increase in the permeability of the post-synaptic membrane to Na ions and to a < extent to K ions (Na ions enter and generate a local end plate potential (depolarization) until it reaches a critical threshold --- triggers off a muscle action potential propagated along the muscle fiber causing it to contract.Acth is then broken down by cholinesterase in the neuromuscular junction; the motor end plate polarizes and is then ready to be stimulated again.

INDUCTION AGENTS (IV ANESTHETIC AGENTS) - widely used to induce anaesthesia

Sodium Thiopentone - an ultra short acting barbiturate; given IV; produces loss of consciousness in 10-20 seconds. Max. depth occurs 40 secs. ; px becomes conscious 2-3 mins. after dosage; provide anes. for short operative procedures; induce unconsciousness prior to inhalation anaesthesia; rapidly enters the brain; 85% bound to plasma protein; metabolized in the liver; excreted in the kidney; depresses many of the functions of CNS; no analgesic properties; low doses may increase sensitivity to pain; an anticonvulsant; often associated with laryngospasm; bronshospasm; cough; extravascular injection may cause pain and necrosis when the concentration is > 2.5%; endothelial and deeper layer may be damaged when inadvertently injected into an artery; must not be given to patients with porphyria no effect on the uterus but can cross the placenta and depress the fetal cardiovascular system; there is transient drop in blood pressure.

Methohexitone - an ultra short acting barbiturate; Pharmacological properties – same with Thiopentone Unwanted effects - pain on injection, involuntary movements, cough, and laryngospasm; has convulsant properties

Etomidate - a carboxylated imidazole derivative; rapid recovery and lack of “hangover’

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effect may be due to short plasma half life; does not release histamine; painful, cause involuntary movements; prolonged use may cause adrenocortical suppression in ICU; has little or no effect on the cardiovascular system.

Ketamine - given IV but can be given IM; associated with profound sedation and analgesia; produces dissociation but not sedation and so airway reflexes are maintained; vivid hallucinations and nightmares; raises b.p. and pulse rate; useful in management of mass casualties.

Propofol - a new phenolic IV induction agent and maintenance anaesthesia provided the surgical procedure does not exceed 1 hour.; recovery is usu. rapid and often accompanied by euphoria; sexual fantasies can also occur; highly lipophilic; More expensive. Unwanted effects - cardiac respiratory depression; apnea and marked hypotensive effect; pain on injection.

INHALATION ANAESTHESIA - most widely used form of maintenance anaesthesia

INHALATION ANAESTHETIC AGENTS Nitrous Oxide - E.q. Entonox colorless, odorless gas; weak anaesthetic; an adjunct to other inhalation agents; may produce severe hypoxia when used alone; an excellent analgesic agent; a direct myocardial depressant; stimulates sympathetic nervous system; may cause nausea, vomiting, (megaloblastic anemia and neuropathy in animals); suppresses spermatogenesis and production of WBC and RBC in bone marrow; Uses: changing painful dressing, an aid to post-operative physiotherapy and emergency ambulances. Halothane - a halogenated hydrocarbon; colorless at room temperature; has pleasant smell;not inflammable; non explosive; causes dose-related reduction in b.p.,slowing of heart rate; severe dysrhythmia; bronchodilation ; depresses respiration; no analgesic property and does not produce a degree of relaxation; may cause hepatic necrosis. Enflurane - a halogenated ether; colorless at room temperature; non flammable with a mild sweet odor; alters electrical activity in the brain; 80% excreted unchanged in expired gases, 2.5 % metabolized in the liver and excreted in the kidney; produces a dose-related reduction in b.p.; causes respiratory depression; twitching of the limbs, jaws, face and neck but self limiting; no significant effect on the liver Isoflurane - isomer of enflurane; a halogenated methylethyl ether; physical properties similar to enflurane; reduction in b.p. but has little or no effect on cardiac output; increase in heart rate but no arrythmias; depresses respiration and stimulates airway reflexes causing increased secretion, coughing and laryngospasm. Ether - one of the earliest and safest volatile liquids irritating to the mucus membrane; inflammable and explosive; often associated with nausea and vomiting; now rarely used.

ANAESTHETIC EMERGENCIES1. Respiratory Obstruction2. Hypersensitivity reaction

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ANTISEPTICS AND DISINFECTANTS - substance that kill or prevent the growth of microorganism Antiseptics - used on living tissues. Disinfectants – applied on inanimate objects.

1. ALCOHOLS A. Ethyl Alcohol and Isopropyl AlcoholB. Chlorhexidine and IodineC. Surgical Spirits – mixture of ethyl/methyl alcohol

2. ALDEHYDES A. Formaldehyde – bactericidal activity on bacteria, fungi, and viruses; action is very slow – 0.5% will take 12 hrs.; 2-8% concentrations to disinfect inanimate objects. B. Glutaraldehydes – acts against all microorganisms; less viruses, odor; 2% concentration; for cold sterilization; for articles contaminated by hepatitis B virus that cannot be heat sterilized; 1 – 12 hour exposure. C. Chlorhexidine (Hibitane) – antiseptic and disinfectant 1. Hibiscrub ICI – pre-operative preparation of skin and hand disinfection. 2. Hibisol ICI – disinfection of sin and hands. 3. Corsodyl ICI – in dental gel; mouthwash 0.2% solution.

Hibitane Obstetric cream (ICI) – pre-operative preparation of hands and skin of midwife/doctor. Hibitane Concentrate – general purpose antiseptic

3. DYES – complex organic substances from coal tar e.q. aniline dyes, gentian violet, brilliant green, acnidine dyes, acriflavin and proflavine.

4. HALOGENS – reacts with bacterial proteins.

5. CHLORINE – has a rapid, potent and brief action; effective against most bacteria, some fungi, yeast, and viruses; in the form of hypochlorites, organic chloramines, chlorinated isocyanurates; inactivated by organic matter.

6. IODINE – acts as much the same way as chlorine but not readily inactivated by organic matter; bactericidal and fungicide; present in weak solution of 2.5% iodine in potassium iodine, water and alcohol; stains skin.

7. IODOFORM – mild antiseptic E.q. whiteheads varnish incorporated into ribbon gauze for infected sockets and dressing for surgical removal; contains iodoform with benzoin, storax, and balsam of tolu in solvent ether; Kri-paste- used as root canal filler; Kri liquid - sterilize root canals.

8. IODOPHORS – combination of iodine and surface active detergents; effective against gram + - organisms after 15 secs.; doesn’t stains skin. E.q. Povidone Iodine

9. OXIDIZING AGENTS – liberates oxygen which oxidizes proteins of bacteria and tissue

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proteins.

Hydrogen Peroxide – mild antiseptic; 30% aqueous solution to bleach discolored root filled teeth; mouthwash in acute ulcerative gingivitis.

Sodium Perborate – treatment of acute ulcerative gingivitis; liberates oxygen when in contact with organic matter.

10. PHENOLS, CREOSOLS and their derivatives

Phenol - 80% in water; irritant and caustic producing a burning pain; produces feeling of anesthesia CMCP (Camphorated para-aminophenol) – 35% in camphor; medicament in root canals. Cresol – 3x bacteridal potency of phenol; also toxic E.q. Metacrsyl acetate (Cresatin) – irrigation of root canals; not irritant to periapical tissues. Chloroxylenols – less effective than phenolic agents; activity reduced in the presence of organic matter. E.q. Dettol (5% chloroxylenol). Hexachloropane – excellent disinfectant; for gram + cocci; not very irritant to tissues but has neurotoxic effects on babies (dusting powders).

11. SURFACE ACTIVE AGENTS Classification according to ionic charge: CATIONIC - positive charge; includes quarternary ammonium compounds such as:

1. Benzalkonium chloride (Zepiran)2. Cetylpyridinium (Ceepryn)3. Cetrimide (Cetavlon)

- bactericidal against some gram + and some gram negative bacteria; little effect on tubercle bacilli, spore forming microbes and psuedomonas aeruginosa; ANIONIC - negative charge; not bactericidal, only enhances physical removal of bacteria; effective against gram + microorganism; E.q. Sodium lauryl sulfate and green soap.

DENTAL USES OF ANTISEPTICS1. Skin preparation before surgery or injection2. Pre-operative preparation of the oral mucosa3. Sometimes as an ingredient of dentrifices4. Inhibition of dental plaque5. Cleaning of operating areas6. Cold sterilization of instruments and equipment 7. Storage of sterilized surgical equipment8. Preparation of surgeon’s hand9. Irrigation of root canals in endodontics.

DEFINITION OF TERMS

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Antimicrobial Agents – substances that kill or suppress the growth or multiplication or prevent the action of microorganismsAnti-infective Agents – substances that act against or tend to destroy infection. Antibacterial Agents – substances that destroy or suppress the growth or multiplication of bacteria.Antiviral Agents – substances that destroy or suppress the growth or multiplication of viruses.Anti-fungal Agents – substances that destroy or suppress the growth or multiplication of fungi.Antibiotic Agents – chemical substances produced by microorganisms that have the capacity, in dilute solutions, to destroy or suppress the growth or multiplication of organisms or prevent their action.

Antibacterial (Antimicrobials) – are obtained from natural sources or are manufacturedAntibiotic – chemicals that are produced by one kind of microorganism that inhibit or kill another kind of organism.

* The difference between antibiotic and synthetic antibacterial agents is that antibiotics are produced by microorganisms and the antibacterial agents are made in the laboratory.

Classification of Antibacterials According to its ACTION

1. Bacteriostatic – inhibit or retard the multiplication or growth of bacteria but does not kill them. E.q. Tetracyclines, sulfonamides, chloramphenicol - bacteria can grow again when drug is withdrawn. - Host defense mechanism (e.q. phagocytosis) are required to kill the microorganism. 2. Bactericidal – drugs that kill bacteria. E.q. Penicillin, Cephalosphorins, Aminoglycosides, Vancomycin, Metronidazole, Imipenem. - best choice in treatment especially in life threatening infections, endocarditis and in patients whose leukocyte count is <500μ/L * some drugs may be bacteriostatic at low concentrations and bactericidal at high concentrations against the same or different microorganisms; In patients with impaired defense mechanism, a bactericidal is preferred over a bacteriostatic agent because the body’s ability to fight infection is compromised.

Classification According to RANGE OF ACTIVITY Spectrum – the range of activity of a drug. 1. Narrow Spectrum – acts against either gram positive or gram negative organisms. one type of organism; only selective. E.q. Penicillin and erythromycin – gram + bacteria.

2. Broad Spectrum – acts against a wide variety of organisms – effective on both gram + and gram – bacteria as well as some viruses; treats infection not identified by culture and sensitivity test. E.q. Tetracylcine and Cephalosphorins.

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INFECTION – invasion of the body by pathogenic microorganism and the reaction of the tissues to their presence and to the toxins generated by them.

Principal factors that determine a microorganism causing an infection1. Virulence of the microorganism2. Number of organisms present 3. Resistance of the host

How do Microorganism cause an infection?1. Infectivity (must enter the right portal of entry)2. It must be able to multiply on the body of the susceptible host.3. Invasiveness (effective mechanism for transmission)4. It must be able to produce toxins, enzymes and other metabolites that affect the cell

or toxigenecity.

Two Goals to be achieved to prevent infection1. Reduce the number of bacteria in the surgical wound.2. Enhance the host’s defenses so as to prevent the bacteria that entered the wound from

causing clinically evident infection. INDICATION FOR ANTIMICROBIAL AGENTS A. Prophylactic Indications - used for high risk patients whose immune system are weak. E.q. in rheumatic or congenital heart disease, Renal dialysis patients, or the presence of a heart prosthesis. Any dental procedure may precipitate a bacteremia, therefore, prophylactic antibiotics must be given to prevent bacterial endocarditis. B. Therapeutic Indication - for the treatment of infection. “Does this particular patient need the assistance of antimicrobial agents to resolve this particular infection?"

* NOT ALL INFECTIONS REQUIRE ANTIBIOTIC THERAPY, it all depends on:1. The patient. “host responses”

- Defense mechanism is considered. - The presence or absence of systemic manifestation such as fever, malaise, and lymphadenopathy are indicators of how well the patient is doing without antimicrobial therapy.

2. The Infection. - The virulence and invasiveness of the etiologic microorganism are important in determining the acuteness, severity, and spreading tendency of the infection which is obviously need to be treated with antimicrobial agents.

Five Basic Principles in the Use of Antibiotics / Antimicrobials 1. Infection must be present or imminent - consider the signs of inflammation. 2. Identify the organism - accomplished through culturing, gram stain or educated guesses. Purpose: To determine the specific type of antimicrobial sensitive to the specific type of microorganism. 3. Choose the specific type of antibiotic ---------------------------------------------------------------------------------------------------------

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Antibiotics G- & G+ G- -------------------------------------------------------------------------------------------------------- Phenoxymethyl Penicillin ++++ + Penicillin G ++++ + Ampicillin +++ Erythromycin +++ ++ Clindamycin +++ + Cephalosporins +++ + Tetracycline ++ +++ Aminohlycoside + ++++ ----------------------------------------------------------------------------------------------------------

4. Administer antibiotics properly 5. Prevent and minimize toxicity and hypersensitivity.

a. right doseb. right dose intervalc. right dose formd. right duration of therapy

Duration of dosage: - An antimicrobial agent should be continued long enough to prohibit a regrowth of the causative microorganism, but not so long to induce toxic drug symptoms or alter the normal flora to the extent that superinfection results ** It should continue 48 hours after the symptoms of infection are absent. If beta hemolytic streptococci are the causative organisms, usually penicillin should be continued for at least 10 days. For osteomyelitis, it should be continued for 14 days after fever and tenderness are absent and drainage has ceased. In patients with a depressed immune system or history of prolonged healing, coverage usually needs to be continued longer than in normal patient.

MECHANISM OF ACTION OF ANTIBACTERIALS 1. Inhibition of cell wall synthesis a. Inhibition of cross linking (transpeptidation) of peptidoglycan. e.q. Penicillins; Cephalosporins. b. Inhibition of other steps in peptidoglycan synthesis. e.q. Vancomycin, Cycloserin, Bacitracin. 2. Inhibition of protein synthesis a. Action on 50S ribosomal subunit e.g. Chloramphenicol, Erythromycin, Clindamycin. b. Action on 30S ribosomal subunit. e.q. Tetracyclines and Aminoglycosides. 3. Inhibition of nucleic acid synthesis a. Inhibition of nucleotide synthesis e.q. Sulfonamides and trimethoprim b. Inhibition of DNA synthesis e.q. Quinolones (Ofloxacin) 4. Alteration of cell membrane function

a. Antibacterial activity e.q. Polymyxinb. Antifungal activity e.q. Amphotericin B, Nystatin, ketoconazole.

5. Uncertain mechanisms E.g. Isoniazid, Metronidazole.

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Resistance – ability of a microorganism to be unaffected by an antimicrobial agent. Natural resistance – occurs when an organism has always been resistant to the antimicrobial Agent; occurs without previous exposure to the drug. Acquired resistance – occurs when the organism that was previously sensitive to an antimicrobial agent develops resistance/ caused by prior exposure to the drug. Cross Resistance - occurs with antibacterials that have similar actions. E.q. Penicillin; Cephalosporins.

Genetic recombination including conjugation, transformation , and transduction, can result in the passing on of resistance from one bacterial strain to another. The second strain becomes resistant to the same antibiotics as the first strain without having been exposed to the antibiotic.

**Action depends on depends on several variables: 1. Usual therapeutic concentration of that agent 2. Type of organism 3. The mechanism of action of that agent.

GENERAL ADVERSE REACTIONS TO ANTIBACTERIALS1. Allergy / Hypersensitivity - may be mild to severe. E.q rash, pruritus, hives-treated

with antihistamine.2. Anaphylactic Shock - shortness of breath is the first symptom; treatment is

epinephrine bronchodilators and antihistamines.3. Superinfection, Suprainfection - infection caused by proliferation of microorganisms

that are different than those causing the original infection.- a secondary infection that occurs when the normal microbial flora of the body aredisturbed during antibiotic therapy. E.q. Fungal infections.- often caused by broad spectrum antibiotics such as tetracycline

CULTURE AND SENSITIVITY TESTS - only way in which one can reasonably ensure that a particular drug will kill or inhibit the growth of an infecting microorganism. However, it will not show the potency of the drug nor differentiate between bactericidal and bacteriostatic effects, they will only show which drug adversely affect the growth of the microorganism on the culture plate.

Culture – a sample from the infected site is taken and grown on culture media. After the pathogen is grown, sensitivity test can be conducted. Sensitivity – after the organism is identified, it is again grown on culture media and the effect of different antimicrobial agents on the organism is tested. One to two days are required before the result of this test are available

Advantages of Culture and Sensitivity tests1. An early correction of therapy is possible if the drug selected is ineffective against the microorganism causing the infection2. Pathogens grown on culture before antibiotic therapy is begun can be more easily identified than after a therapeutic failure has occurred.

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Blood level – the concentration of the antibacterial agent present in the blood or serum; an important index to drug dosage, since certain concentration of the drug is required in the body fluids to inhibit or kill the microorganism.Synergism – effect when a combination of two antibiotics is more rapidly bactericidal than either drug used alone. Combinations of antibiotic that are bactericidal generally are synergistic. Combinations of those that are bacteriostatic are merely additive.Antagonism – effect when the bactericidal rate for the combination of two drugs is less than that for either drug used alone; often exhibited when a bateriostatic and a bactericidal agent are used in combination.

DENTALLY USEFUL ANTI-INFECTIVE AGENTS 1. PENICILLINS - can be divided into three groups

A. Penicillin G and VB. Penicillinase-resistant penicillins

(Methacillin, Cloxacillin, Nafcillin, Floxacillin, Dicloxacillin) C. Extended-Spectrum penicillins (Ampicillin-like agents, carbenicillin-like agents and amino-penicillin group.

Administration and Body handling - can be administered orally or parenterally. - should not be applied topically because of its allergenecity. - Penicillin V is better absorbed orally than penicillin G - degraded by the gastric fluid-it should be administered one hour before meals or 2 hours after meals. - crosses placental barrier and a small amount appears to be excreted in the milk and saliva.

Spectrum: - very potent bactericidal agent that acts by interfering with the synthesis of the bacterial cell wall. - its narrow spectrum of activity includes gram positive aerobic and facultative organism(cocci: Streptococcus,and Staphylococcus; rods: Bacillus, Corynebacterium and Clostridium; Spirochetes:Treponema pallidium; and certain gram negative aerobic cocci: Neisseria gonorrhea and N. meningitidis)

Adverse reactions : - most common cause of drug allergies. 1. Toxicity - large doses of penicillin G have been associated with renal damage manifested as fever, eosinophilia, rashes, albuminuria. - gastrointestinal irritation can manifest itself as nausea with or without vomiting. 2. Allergy and Hypersensitivity Immediate - less than 30 minutes includes anaphylaxis. Accelerated - 2 to 48 hours includes serum sickness and laryngeal edema.

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Late - 3 or more days includes rashes, oral lesions, and other symptoms.

Uses: - for dental infections

a. ANUG – penicillin Vb. Periodontal abscess - penicillin Vc. Abscess, cellulitis, pericoronitis – penicillin Vd. Osteomyelitis - penicillin Ve. Rheumatic heart disease - penicillin V.

2. ERYTHROMYCIN - administered orally; available in tablets and capsules, oral suspensions and IV and IM forms. - formulated as enteric-coated tablet, capsule or insoluble ester to reduce degradation by the stomach acid. - it should be administered 2 hours before meals or several hours after meals. Activity and Spectrum: - usually bacteriostatic but may be bactericidal at normal therapeutic doses. - used against gram positive bacteria. - also a drug of choice for whooping cough, diphteria, syphilis, and gonorrhea. - cross-resistance has been reported between erythromycin and clindamycin. - poor second choice to treat dental infections.

Adverse Effect: 1. Gastrointestinal Effects - include stomatitis, abdominal cramps, nausea, vomiting and diarrhea. 2. Cholestatic Jaundice - symptoms include nausea, vomiting and abdominal cramps followed by jaundice and elevated liver enzyme levels. 3. Allergy - very uncommon.

Drug Interaction: - patients taking Theophylline chronically for asthma or acutely for bronchitis may exhibit a drug interaction with erythromycin. - has been implicated in the failure of oral contraceptive efficacy.

Uses: - drug of first choice in patients allergic to penicillin. - indicated certain situations for the prophylaxis of rheumatic heart disease. - usual adult dose is between 250 and 500 mg qid. - for bacterial prophylaxis- 1 gm 1 hour before the dental appointment

3. TETRACYCLINE - broad spectrum antibiotics affecting a wide range of microorganisms. - most commonly given by mouth. - secreted in the saliva and milk of lactating mothers.

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- stored in the dentin and enamel of unerupted teeth. - also concentrated in the gingival crevicular fluid.

Types:1. Doxycycline - excreted in the feces 2. Tetracycline – eliminated by glomerular filtration,

- oral absorption is decreased by administration of food with high calcium content, dairy products, oral iron supplements or antacids.

3. Minocycline - metabolized in the liver and excreted in urine. - may be given to patients with renal dysfunction

Spectrum: Bacteriostatic and interfere with the synthesis of bacterial protein Broad spectrum

Adverse Reactions:1. Gastrointestinal effects

- anorexia, nausea, vomiting, diarrhea, gastroenteritis, glossitis, stomatitis, xerostomia, and superinfection (moniliasis)

2. Hepatoxicity - large dose of parenteral tetracycline3. Renal toxicity4. Hematologic effects - hemolytic anemia, leukocytosis, thrombocytopenic purpura5. Effects on teeth and bones6. Superinfection7. Photosensitivity– exaggerated sunburn8. Allergy

Uses:1. Alternative drug to treat chlamydial and rickettsial infections2. Used to treat cholera, acne, and pulmonary infections3. Doxycycline is used to treat travelers diarrhea4. Indicated for the treatment of periodontitis5. Mixture of equal parts of tetracycline syrup and lidocaine viscous for the

management of recurrent aphthous stomatitis6. ANUG may also be treated with tetracycline

4. CLINDAMYCIN - bacteriostatic antibiotic effective primarily against gram-positive organisms. - administered orally, intramuscularly, or intravenously. - food does not interfere with absorption - cross-resistance between Clindamycin and tetracycline (competition for binding site)

Adverse Reaction:1. Gastrointestinal effects (Pseudo Membranous Colitis- PMC )

-severe, persistent diarrhea and the passage of blood and mucus in the stool2. Superinfection3. Allergy

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Uses:1. Should be used only when specifically indicated 2. Mixed infections insensitive to penicillin- anaerobes

5. METRONIDAZOLE - taken orally - bactericidal and penetrates all bacterial cells.

Adverse Reactions:1. Gastrointestinal effects - nausea, anorexia, diarrhea and vomiting, epigastric

distress and abdominal cramping2. Oral effects - unpleasant metallic taste; altered taste of alcohol; glossitis,

stomatitis and a black furred tongue; dryness of the mouth3. Effects on CNS - headache, dizziness, vertigo, ataxia, confusion, depression,

weakness, insomnia, and convulsive seizures4. Renal toxicity - cystitis, polyuria, dysuria, incontinence5. Disulfiram-like reaction - alcohol should be avoided; symptoms include

nausea, abdominal cramps, flushing, vomiting or headache

Uses:1. Treatment of trichomoniasis, amebiasis2. Not the drug of choice for any dental infections (alternative drug)3. Shown to be effective for the treatment of B. fragilis infections following

mandibular fracture

6. CEPHALOSPHORINS - chemically related to penicillin - bactericidal agents - can be administered orally, intramuscularly, or intravenously.

Adverse Reactions:1. Gastrointestinal effects2. Nephrotoxicity3. Superinfection4. Local reaction5. Allergy6. Cross sensitivity with penicillin

Uses: 1. For infections that are sensitive to these agents but resistant to penicillin

7. VANCOMYCIN - administered only intravenously - bactericidal - narrow spectrum of action against many gram positive cocci.

Adverse Reactions:1. Ototoxicity

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2. Nephrotoxicity3. Anaphylaxis4. Superinfection

Uses: 1. Useful in the prophylaxis of infective endocarditis for patients with prosthetic heart valves who are allergic to penicillin. 2. Used orally to treat PMC.

8. AMINOGLYCOSIDES (Neomycin, Streptomycin, Kanamycin, Gentamycin, Tobramycin, Amikacin, Netilmicin) - bactericidal - have a broad antibacterial spectrum - poorly absorbed after oral administration & so must be administered by IM or IV injection for a systemic effect - used for the treatment of aerobic gram-negative infections

Adverse Reaction:1. Ototoxicity

- toxic to the 8th cranial nerve, which can lead to auditory and vestibular disturbances. Patients may have difficulty in maintaining equilibrium and can develop vertigo.

2. Nephrotoxicity - can cause kidney damage3. Neuromuscular blockade - act as weak neuromuscular blocking agents,

potentially producing apnea

Uses: - reserved for hospitalized patients with the serious gram-negative infections Gentamicin is used in dentistry to prophylaxis patients with prosthetic heart valves

9. CHLORAMPHENICOL - broad spectrum - bacteriostatic - active against a large number of gram-positive and gram negative organisms, rickettsiae, and some chlamydiae. Particularly active against Salmonella typhi. - has serious side effects like fatal blood dyscracias (aplastic anemia, and thrombocytopenia) - “Grey baby syndrome” occurs when infants given cannot conjugate it. - Antibiotic of first choice in the treatment of life-threatening influenza and typhoid fever.

SULFONAMIDES - cannot be classified as an antibiotic because they are not produced by living organisms. - bacteriostatic against many gram positive and gram negative bacteria.

Adverse Reaction:1. Allergic reaction (rash, urticaria, pruritus, fever, fatal exfoliative dermatitis).2. Nausea, vomiting, abdominal discomfort, headache and dizziness.

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3. Liver damage, depressed renal function, blood dyscrasias. Uses: - used when antibiotics are ineffective or cannot be used. - should not be used topically for oral lesions

ANTIFUNGAL DRUGS 1. NYSTATIN - effective against candida albicans - not absorbed from the skin or mucuos membranes. - used for local effects in the treatment of candidiasis on the skin or any part of the alimentary tract. - has a very unpleasant taste.

Uses:a. Thrushb. Denture stomatitisc. Antibiotic stomatitisd. Some forms of mucocutaneous candidiasis.

2. AMPHOTERICIN B - poorly absorbed from the GIT and probably not all from the unbroken skin. - used locally to treat conditions for which nystatin could be used. - available in intravenous injection.

3. IMIDAZOLE AGENTS (Miconazole, Ketoconazole) - used in the treatment of systemic fungal infections and candidiasis

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G E N E R A L R E F E R E N C E S

Ansel, H.C., Popovich, N.G., and Allen, L.V.: “Pharmaceutical Dosage forms and Drug Delivery Systems”, Sixth edition, William and Wilkins, USA, 1995.

Asperheim, M. K.: “Pharmacology AN INTRODUCTORY TEXT”, Seventh Edition W.B. Saunders Company, Philadelphia, Pennsylvania, USA, 1992.

Grajeda-Higley, L.: “Understanding Pharmacology: A Physiologic Approach”, Appleton and Lange, Stanford, USA 2000.

Kee, J.L. and Hayes, E.R.: “Pharmacology: A Nursing Process Approach”, 1st edition, W.B.

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Saunders Company, Philadelphia, Pennsylvania, USA.

Musser, R. D. and O’Neil, J. J.: “Pharmacology and Therapeutics”, 4th edition. The McMillan Company, London, 1969.

Mycek , M. J., Harvey, R. A., and Champe, P. C.: “Lippincott’s Illustrated Reviews: Pharmacology”, 2nd edition, Lippincott-Raven Publishers, Inc. New York 1997

Olson, J.: “Clinical Pharmacology Made Ridiculously Simple”, international editions 2000, McGraw-Hill Book Company, Singapore, 1997.

Stringer, J.L.: “Basic Concepts in Pharmacology”, A Student’s Survival Guide, 2nd edition, McGraw-Hill Companies, Inc., Singapore, 2001.

Walton, J. G., Thompson J. W., and Seymour, R. A.: “Textbook of Dental Pharmacology and Therapeutics”, Second edition, Oxford University Press, New York, 1994

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CENTRO ESCOLAR UNIVERSITYCollege of Dentistry

Course Title: PHARMACOLOGY Course Number: PHA100/PHA100L

Units: Lecture – 2 Hours / Week: Lecture – 2 hours/week Laboratory – 1 Laboratory – 3 hours/week

Pre-requisites: Anesthesiology

Course Description: The course presents the principles in the use of drugs for the diagnosis, prevention, and treatment of diseases. Each drug is considered according to its indication, mechanism of action, pharmacokinetics, contraindications and precautions, unwanted effects and drug interactions. The course deals more on the commonly prescribed drugs used and related in the practice of Dentistry.

General Objectives: 1. To explain the basic and clinical pharmacology upon which drug therapy is based with

particular emphasis on drugs used in Dentistry.2. To demonstrate the physical and biological behavior of some drugs in order to familiarize

students with the actual effects of drugs.3. To expose students to the type of questions they will encounter in the licensure

examinations.

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COURSE PLAN:

Course Content Specific Objectives

Suggested Teaching

Methodology/Strategy and

Materials

Time Allotment(no. of hours)

Evaluative Measures and Requirements

Introduction to Pharmacology

To introduce the general principles of pharmacology

Lecture Lec. = 4Lab. = 3

Recitation/QuizzesLaboratory Manual

Drug Nomenclature

To identify drugs according to their generic, chemical, and trade names

Lecture Lec. = 2Lab. = 3

Recitation/QuizzesLaboratory ManualMIMS

Drug Therapy To know and understand the different processes involved in drug therapy.

Lecture Lec. = 4 Recitation/Quizzes

Route of Drug AdministrationA. IM/SubcutaneousB. Cutaneous

To effectively apply drugs according to its route of administration

Lecture demonstration method

Lab. = 3 Lab. = 3

Practical exerciseQuizzes

Dosage Forms To familiarize students on the different dosage forms of drugs; differentiating one from the other

“Show and Tell Method”

Lab. = 6 Written ReportOral ReportLaboratory ManualPractical/Written Quiz

Drug Literature

To interpret different drug literature

Lecture Lab. = 3 Interpretation of literaturesLaboratory Manual

Systems of MeasurementConversion

To know how to convert units and doses of drugs

LectureBoard exercises

Lec. = 2Lab. = 3

Exercise/QuizzesLaboratory Manual

Computation of a child’s dose

To know how to properly compute for a child’s dose.

LectureBoard exercises

Lec. = 2Lab. = 3

Exercise/QuizzesLaboratory Manual

Prescription Writing and Prescription Orders

To equip students with the knowledge of prescription writing.To learn how to interpret prescription order.

LectureBoard exercises

Lec. = 2Lab. = 6

QuizzesLaboratory Manual

Pharmacology of Pain and Inflammation

To know the different processes involved with pain.To know the different

Lecture Lec. = 2 RecitationQuizzes

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mediators of inflammation.

Analgesics To know the mechanism of action and application of the different groups of analgesics.

LecturePrescription Writing exercises

Lec. = 4 RecitationQuizzes

Antihistamines To know the pharmacokinetics and pharmacodynamics of antihistamines

Lecture Lec. = 2 RecitationQuizzes

Hemostasis / Hemostatic agents

To know the mechanism of action of hemostatic agents and its importance in Dentistry.

LectureTest for bleeding time/clotting time of white mice

Lec. = 2Lab. = 3

RecitationQuizzesLaboratory Manual

Anesthetic agents

To describe the pharmacokinetics and pharmacodynamics of these drugs.

LectureTests the effects on white mice

Lec. = 2Lab. = 3

RecitationQuizzesLaboratory Manual

Antimicrobials To know the different types of antimicrobials and its corresponding mechanism of action.To apply through prescription writing the antimicrobials learned.

LectureInoculation of bacteriaCulture and sensitivity Test

Lec. = 4Lab. = 3

RecitationQuizzesPractical exercisesLaboratory manual

Antiseptics and Disinfectants

To know the pharmacokinetics and pharmacodynamics of these drugs.

Lecture Lec. = 2Lab. = 3

RecitationQuizzesLaboratory manual

Drugs acting on the Central Nervous System

To describe the mechanism of action of sedative-hypnotics

Lecture Lec. = 2Lab. = 3

RecitationQuizzesLaboratory manual

Therapeutic Measures of Common Dental Conditions and Emergency Drugs.

To familiarize students with common dental diseases and its therapeutic measures. To understand the proper management of some dental office emergencies.To understand the pharmacologic

Lecture Lec. = 6Lab. = 9

Research papersRecitationQuizzesLaboratory manual

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orientation of AIDS and Hepatitis.

Suggested References:

Textbook of Dental Pharmacology and Therapeutics by: John G. Walton Pharmacology by: Goodman and Gillman Pharmacology by: Katzung Clinical Pharmacology in Dental Practice by: Sam V. Holroyd

LABORATORY TOPICS MANUAL TOPICS LECTURE TOPICS

1. Introduction and definition of terms

1. Introduction to Pharmacology

1. Introduction and definition of terms

2. Demonstration of Routes of Administration

2. Drug Nomenclature 2. Drug Nomenclature

3. Skin Testing 3. Routes of DrugAdministration

3. Drug Therapy

4. Interpretation of Drug Inserts

4. Skin Testing 4. Routes of Drug Administration

5. Conversion of doses and measurements

5. Drug Dosage Forms 5. Dosage Forms

6. Prescription Writing 6. Drug Literatures 6. Drug Literatures7. Prescription Orders 7. System of measurements 7. System of Measurements PRELIM EXAM 8. Conversions 8. Prescription Writing /

Orders8. Narcotics and Non- Narcotics Analgesics

9. Prescription Writing 9. Analgesics

9. Histamine and Antihistamines

10. Prescription Orders 10. General Anesthetics

10. Hemostasis and Hemostatic Agents

11. Analgesics 11. Local Anesthetics

11. General Anesthetics 12. Antihistamines 12. Histamines and Antihistamines

12. Local Anesthetics 13. Hemostasis and Hemostatics Agents

13. Hemostasis and hemostatic Agents

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13. Antimicrobials – culture and Sensitivity

14. General Anesthetics 14. Antimicrobials

15. Local Anesthetics 15. Antiseptics / Disinfectants14. Sedative – Hypnotics 16. Antimicrobials 16. Sedative-Hypnotic Drugs15. Antiseptics and

Disinfectants17. Sedative-Hypnotic Drugs 17. Office Emergencies

16. Common Oral Diseases 18. Antiseptics / Disinfectants 18. Common Oral diseases17. Office Emergencies 19. Common Dental Diseases 19. AIDS / Hepatitis18. AIDS and Hepatitis 20. Office Emergencies

21. AIDS and Hepatitis

OUTLINE OF TOPICS IN PHARMACOLOGY

PRELIM LECTURE

1st Meeting Orientation

2nd Meeting Definition of terms Introduction History of pharmacology Branches of Pharmacology Importance of Pharmacology to dentistry Fundamental action of drugs Uses of Drugs Drug Nomenclature Drug Publications Quiz

3rd Meeting

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Stages in the development of a drug Introduction to Drug Therapy Quiz 4th meeting Process of Drug Therapy Quiz

5th meeting Continuation of Drug Therapy Quiz

LECTURE PRELIM EXAM

LABORATORY

1st Meeting Orientation

2nd Meeting Exercise 2 & 3 *Exercise 1 will be given as a quiz How to use MIMS Quiz

3rd Meeting Exercise 4 Routes of Drug administration Quiz

4th meeting Exercise 5 Quiz

LABORATORY PRELIM EXAM

General Principles / Factors / Terminologies 1. Factors affecting Patient's Reaction to Drugs

A. Routes of Drug Administration 1. Enteral

2. Parenteral B. Passage of Drug Across Body Membrane 1. Active Transfer 2. Passive Transport C. Fate of Drug 1. Absorption

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2. Distribution 3. Metabolism / Biotransformation 4. Excretion / Elimination

2. Considerations in Drug Administration A. Tolerance B. Pathologic State C. Age and Weight 3. Action vs. Effect Anaphylaxis Placebo Immunity Idiosyncrasy Tolerance Tachyphylaxis Drug Resistance Refractory Hyporeaction Hyper-reaction Hypersensitivity Supersensitivity

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3rd Meeting

General Anesthetics Local Anesthetics Locally Acting Medication: Antimicrobials, Hemostatics and Protectives

4th Meeting

Diuretics and Antihypertensive Sedative Hypnotics Psychotherapeutic

5th Meeting

Central Nervous System Stimulants Anticonvulsant Antineoplastic Adrenocorticosteroids

FINALS

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* SPECIAL TOPICS 1st Meeting

Emergency Drugs

2nd Meeting

Pharmacologic Considerations

3rd Meeting

Disease Status of Common Interest

4th Meeting

Pharmacologic Management of Certain Common Oral Disease Entities

5th Meeting

Drug Interactions

Predictable Reaction: 1. Excess pharmacological activity 2. Rebound response upon discontinuation

Excessive Pharmacological Effects:1. Respiratory depression in severe bronchitic patients given morphine or benzodiazepine hypnotics2. Hypotension resulting in stroke, myocardial infarction or renal failure in patients receiving excessive doses of antihypertensive drugs.3. Bradycardia in patients receiving excessive DIGOXIN

Withdrawal Symptoms:1. Extreme agitation, tachycardia, confusion, delirium and convulsions may occur following the discontinuation of long-term CNS depressants such as barbiturates, benzodiazepine and alcohol.2. Acute Addisonian crisis may be precipitated by the abrupt cessation of corticosteroid therapy.3. Severe hypertension and symptoms of sympathetic overactivity may arise shortly after discontinuing clonidine therapy.4. Withdrawal symptoms after narcotic analgesics.

Allergic Responses: Allergy - altered capacity of the body to react to various antigens with which it comes in contact.

* 2 Types of Hypersensitivity:

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1. Immediate - antibody is circulating or fixed to certain tissues. - Antigen reacts to antibody.2. Delayed - a reaction of T-cells that have been stimulated by antigen to react against targets such as infectious agents. - Antibody is not involved.

Genetically Determined effects - major toxicity of some drugs is restricted to individuals with particular genotype or genetic make-up.

DEFECT TOXIC DRUG SYMPTOMS

Pseudocholinesterase Deficiency Succinylcholine Paralysis Apnea Glucose-6-Phosphate Dehydrogenase deficiency Sulfonamides Quinidines Hemolysis Primaquine Acetylator-Polymorphism Procainamide Systemic Lupus Hydralazine Isoniazid Neuropathy Hepatic Porphyria Barbiturates Symptomatic prophyria

Idiosyncratic Drug Reaction: Idiosyncracy - used primarily to cover unusual, unexpected, bizarre drug effects that cannot readily explained or predicted in individual recipients.

*DRUG INDUCED MALIGNANT DISEASE IS FORTUNATELY RARE...

PHARMACOLOGY OF THE AUTONOMIC NERVOUS SYSTEM: - generally, all drugs influence blood pressure, heart rate, potassium pump

Diversity of ANS on Body functions specific to Dentistry:1. Practical application of vasoconstrictors in local anesthetic solutions.2. Agents that reduces salivary flow3. Alterations of the ANS mechanism both centrally and peripherally antihypertensive drug.4. Significant peripheral changes in ANS activity produced by antipsychotic phenothiazines and antidepressants.5. Entire concept of chemical neurotransmitters and receptors are founded on the principles of the ANS.

*2 Divisions of the ANS1. Sympathetic

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2. Parasympathetic

* Both are regarded as peripheral in modes of action and drug reactions even though these cell bodies are located within the CNS and receive considerable CNS input.

Autonomic Nervous System - concerned with the maintenance of a constant internal environment to provide for optimal cellular function and survival.

Functions: Reflex vasodilation Regulates Body temperature Blood glucose level Cardiac Rate Water Balance

SYMPATHETIC DIVISION - designed to cope with sudden emergencies. E.q. Fright and flight phenomenon

PARASYMPATHETIC DIVISION - conservation of bodily processes E.q. Reflex slowing of the heart

Action Potential - bioelectric signals / self propagated impulses along the nerves.

Neurotransmitters - chemical mediators that transmit signals across nerve to nerve, or nerve to effector tissue.

Acetylcholine - specific chemical mediator at all autonomic ganglia and parasympathetic post ganglionic synapses. - transmitter substance of the neuromuscualr junction in skeletal muscle.

Norepinephrine - principal chemical mediator of the sympathetic postganglionic neuron.

Epinephrine - major mediator released by the adrenal medulla.

Cholinergic - nerves releasing acetylcholine.

Adrenergic - nerves releasing norepinephrine.

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