PHARMACOLOGY - science of drugs

- interactions between living systems & molecules introduced from outside the system

GOAL

- to understand the mechanisms by which drugs interact with biologic systems in the diagnosis & treatment of disease

Drug

- a natural product, chemical substance, or pharmaceutical preparation to be used in the diagnosis or treatment of a disease

- varies in terms of : molecular size shape chemical nature

Drug Names :

A. Chemical name - chemical structure of the drug

B. Nonproprietary name - generic name

C. Proprietary name trade name or brand name

Pharmaceutical preparations

- tablets & capsules- drug solutions and particle suspensions- skin patches- aerosols, nasal sprays- ointments and creams- suppositories

Branches of Pharmacology1. Pharmacy - involved in the compounding, preparation, collection, standardization and dispensing of the drug.

2. Pharmacognosy recognize the drugs (description, sources, chemical composition, nature of doing, etc) - study of the physical and chemical properties of the drugs with the description and identification of their sources and nature.)

3. Biochemorphology (structure activity relationship or SAR) how the chemical structure of the drug is related to physiological, biological and biochemical effects.

endogenous catecholamines- synthesized in the body (epinephrine, norepinephrine, dopamine, tyrosine)synthetic (exogenous) catecholamines- from outside given to the body (isoproterenol)ephedrine- mixed-acting symphatomimetic agent; CNS stimulation; not a catecholamine but its effects on bronchi and other smooth muscles are quantitatively similar to those of epinephrineamphetamine- acts indirectly by releasing norepinephrine; also a CNS stimulant; depresses the appetite by affecting the feeding center in the lateral hypothalamusNorepinephrine affects 1, 2 and 1Epinephrine affects 1, 2, 1 and 2

4. Toxicology study of the harmful effects of drugs and other chemicals on human, animals and plants

5. Posology deals with the dosage of the drug required to produce a therapeutic response

6. Molecular Pharmacology studies the mechanism of action of a drug at enzymatic level (gene therapy; genetic engineering)

7. Developmental Pharmacology deals w/ drug given to mother as it affects the fetus during natal, prenatal, perinatal & neonatal periods.

8. Pharmacogenetics studies the influence of heredity on the pharmacokinetic and pharmacodynamic response of the drug.

9. Pharmacogenomics describes the use of genetic information to guide the choice of drug therapy on an individual basis discovers which specific gene variations are associated with a good or poor therapeutic response to a particular drug

10. Pharmacoepidemiology studies the response in population at a given time and space of the pharmacologic events, whether they are adverse or beneficial with the use of measures of epidemiology

11. Pharmacoeconomics studies the cost effectiveness of drug treatment

12. Ethnopharmacology deals with the interethnic differences in response to or metabolism of chemical substances, and the presence and absence of enzymes in different regions of the Phil. or of different races.

13. Clinical Pharmacology deals w/ rational development of drugs, their safe & effective use, and other proper evaluation of drugs in humans for the prevention, diagnosis, treatment, alleviation or cure of a disease. refers to the rational use of drugs (ESSC crirteria)

Efficacy considers pharmacodynamics, pharmacokinetics, of the different drug groups; ability of drug to accomplish what it is intended to do.Safety side effects, toxicity, frequency and severitySuitability convenience, compliance, practicality, contraindications and possible interactions.Cost

14. Pharmacokinetics movement of the drug in the body and how the body acts on the drug fate of drug in the body involves four processes Absorption Distribution Metabolism (biotransformation) Excretion

15. Pharmacodynamics biochemical and physiological effects of drugs and their mechanism of action (includes enzymatic or molecular level and also toxicological or adverse effects.)

PharmacologySystems pharmacologyChemotherapyMolecularpharmacologyBiochemicalpharmacologyPharmacokinetics/Drug metabolismNeuro-pharmacologyGastrointestinalpharmacologyCardiovascularpharmacologyImmuno-pharmacologyRespiratorypharmacologyPSYCHOLOGYPsycho-pharmacologyCLINICALMEDICINETHERAPEUTICSClinicalpharmacologyPHARMACYPharmaceuticalSciencesVETERINARYMEDICINEVeterinarypharmacologyBIOTECHNOLOGYBiopharmaceuticalsPATHOLOGYToxicologyCHEMISTRYMedicalchemistryGENETICSPharmacogeneticsGENOMICSPharmacogenomicsCLINICALEPIDEMOLOGYPharmacoepidemiologyHEALTHECONOMICSPharmacoeconomics

Phases of a Clinical Drug InvestigationPhasePurposeIEstablish safetyIIEstablish efficacy and doseIIIVerify efficacy and detect ADRsIVObtain additional data following approval

Phases of Drug Manufacture

I. ANIMAL TESTING (Pre-clinical testing)- tested in at least 2 rodent & 1 non rodent species- 1 to 3 yrs. (ave. 18 months)- here you determine for the:~ Acute toxicity - observation of animal 7-14 days using a simple dosage of the drug being tested.~ Subacute toxicity - 2 weeks to 3 months.~ Chronic toxicity - 6 months to 2 years.

II. FDA - 30 days safety review

CLINICAL TESTING

Includes humans (healthy adult males)2-10 yrs (average 5-6 yrs)the lowest effective dose given to man because humans can react differently to the drugpediatric patients not included in the testing because some drugs can have adverse effects on the development of the patient. Short termLong term (chronic toxicity, reproduction, teratogenicity)

Phase I involves normal healthy adult male to measure the initial drug safety, biological effects, metabolism, kinetics done by the clinical pharmacologist

Phase II involves selected patients, needing the treatment to measure therapeutic efficacy, dosage range, metabolism, kinetics done by clinical pharmacologist

Phase III involves large sample of selected patients to measure the safety and efficacy done by clinical investigators

IV. New Drug Application (NDA) - Review (BFAD)- Marketing approval

V. Post Marketing Surveillance (PMS)- to look for chronic effectsPhase IV drug is available commercially involves patient given the drug treatment to look for adverse reactions, patterns of drug utilization, additional indications discovered. Done by all physicians.

Phases of Product Development- It takes 12 years on average for an experimental drug to travel from lab to medicine chest. Only five in 5,000 compounds that enter preclinical testing make it to human testing. One of these five tested in people is approved.

Clinical TrialsPreclinical TestingFile IND at FDAPhase IPhase IIPhase IIIFile NDA at FDAFDAPhase IVYears3.51232.512 TotalAdditional Post marketing testing required by FDATest PopulationLaboratory and animal studies20 to 80 healthy volunteers100 to 300 patient volunteers1000 to 3000 patient volunteersReview process / ApprovalPurposeAssess safety and biological activityDetermine safety and dosageEvaluate effectiveness, look for side effectsVerify effectiveness, monitor adverse reactions from long-term useSuccess Rate5,000 compounds evaluated5 enter trials1 approved

Placebo I shall please Used to achieve blindness and subjective bias Response may involve objective, physiologic and biochemical changes as well as change in subjects complaints associated with the disease. Two types: 1. do not contain pharmacologically active ingredients (used for negative control)2. contain some compound with pharmacological activity different from the test drug (used for positive control)

FUNDAMENTAL TYPES OF DRUG ACTION

STIMULATION enhances the specialized tissues

DEPRESSION diminished functional activity of specialized tissues

IRRITATION either stimulate or depress non-specialized tissues

OTHER DRUG ACTIONS

REPLACEMENT THERAPY- replaces what is sufficient and deficient

ANTI-INFECTIVE- entails the use of anti-microbial agents

LOCAL- Topically applied, and action is just on the area itself

SYSTEMIC- produces a systemic effect even if you just apply it on your on your skin; sprayed or injected

ACTIONS IN RELATION TO SPECIFIC EFFECTS

Cathartic- increases bowel movement

Laxative- for constipated patients

Hypnotic- induces sleep

Diuretic- increases urination

Antacid- has buffering actions; neutralizes HCl

Vasodilator- relaxed vascular smooth muscles (Ca 2+ blocker)

VARIABLES INVOLVED IN DRUG ACTIVITY

Dose of drug administeredPharmaceutical phase(bioavailability)(disintegration and dissolution)Pharmacokinetic Phase Pharmacodynamic phase(drug-cell, drug-receptor, drug-drug interactions;individual sensitivity; pathological conditions)Effects (toxic, therapeutic, subtherapeutic)

PHARMACEUTICAL PHASE involves disintegration of dosage form (generally water soluble) & dissolution of active ingredients (lipid soluble)

Bioavailability fraction of unchanged drug reaching the systemic circulation following administration by any route

PHARMACODYNAMIC PHASEDrug-drug interaction simultaneous intake of two different drugs, one drug may displace another for its binding site. another may reduce the metabolism of the other Individual sensitivity interpatient variability (for hyperactive and hypoactive people.Pathological conditions renal, cardiac, hepatic dysfunctions, malnutrition

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Drug formulation - depends on the ff. factors :

A. The barriers that the drug is capable of passingB. The setting in which the drug will be usedC. The urgency of the medical situationD. Stability of the drugE. First Pass EffectRoutes of Drug Administration

A. Enteral - sublingual, oral, rectalB. Parenteral - IV, IM, SubQ, IntrathecalC. TransdermalD. Inhalational E. Topical

Factors governing choice of routePhysical and chemical properties of the drug (solid/liquid/gas; solubility, stability, pH, irritancy)Site of desired action localized and approachable or generalized and not approachable.Rate and extent absorption of the drug from different routes.Effect of the digestive juices and first pass metabolism on the drug.Rapidity with which the response is desired (routine treatment or emergency)Accuracy of dosage required (i.v. and inhalational can provide fine tuning)Condition of the patient (unconscious, vomiting)

Limitations of Oral Route of Administration Action is slower and thus not suitable for emergencies. Unpalatable drugs (paraldehyde) are difficult to administer; drug may be filled in capsules to circumvent this. May cause nausea and vomiting (emetine). Cannot be used for uncooperative/unconscious/vomiting patient Certain drugs are not absorbed (streptomycin) Others are destroyed by digestive juices (penicillin G, insulin) or in liver (nitroglycerine, testosterone, lignocaine).

Pharmacokinetic ParametersAbsorptionDistributionMetabolismEliminationPharmacokinetic VariablesHalf-life Clearance Bioavailability

PHARMACOKINETICS

Factors affecting Pharmacokinetics : rates of drug absorptiondistributionmetabolismelimination

Drug Absorption - passage of a drug from its site of administration into the circulation - route of administration

4 Major Mechanisms of Drug Transport across Membranes

A. aqueous diffusionB. lipid diffusionC. facilitated diffusion / special carriersD. pinocytosis / receptor-mediated endocytosis

Effect of pH on absorption of weak acids and basesweak acids and bases - exist in both ionized and nonionizedforms in the body - only the uncharged species ( the protonated form for the weakacid; the unprotonated form for aweak base ) can diffuse across lipid membranes pH partition pH partition weak acids tend to accumulate in compartments of relatively high pH, weak bases do the reverse

Some important consequences of the pH partition mech.:

1. urinary acidification accelerates excretion of weak bases & retards that of weak acids, while urinary alkalinization has the opposite effect

2. increasing plasma pH causes weakly acidic drugs to be extracted from the CNS into the plasma

Factors affecting GI Absorption :

1. GI motility 3. particle size & formulation

2. splanchnic blood flow 4.physicochemical factors

Drug Distribution:Major Compartments : plasma 5% of B.W. interstitial fluid 16% intracellular fluid 35% transcellular fluid 2% fat 20%Volume of Distribution the volume of plasma that would contain the total body content of the drug at a concentration equal to that in the plasma

Dose ( Q )Ex. : 500 mgVd = ____________ _________ = 100 L Cp 5 mg / L

Vd provides an indication of the physiologic distribution of the drugsmall Vd drugs distribution is restricted to the plasma & ECFlarge Vd concentrated intracellularly

Factors Affecting Distribution :Organ blood flowPlasma protein bindingMolecular sizeLipid solubilityDrug Biotransformation to inactivate drugs & other foreign compounds drug metabolites more water soluble than the parent molecule prodrugs inactive compounds that are biotransformed to active metabolites first-pass effect drugs are converted to inactive metabolites during their first pass through the liver and have low bioavailability after oral administration

Phases of drug biotransformation :Phase I ( nonsynthetic ) drugs are oxidized or reduced to a more polar form1. oxidative reactions - microsomal cytochrome P450 monooxygenase - cytoplasmic enzymes 2. hydrolytic reactions - cholinesterases hydrolyze ester & amide drugs3. reductive reactions - hepatic nitroreductasePhase II ( synthetic ) - drugs are conjugated with acetate, glucuronate, sulfate or glycine - most conjugated drug metabolites are inactive

Kinetics of Metabolism

1st order kinetics - rate of drug elimination is proportional to the plasma druga. Elimination Half-life - time required to eliminate half of the amount of a drug in the body or to reduce the plasma drug concentration by 50%b. Drug Clearance - volume of body fluid from which a substance is removed per unit of time - liters per hour elimination rate ( mg/hr ) - CL = ________________________ drug concentration ( mg/L )

2. Zero-order kinetics ( nonlinear or dose-dependent kinetics )- drugs that saturate routes of elimination disappear from plasma in a non-concentration dependent manner- a constant amount of drug is lost per unit time- half-life is not constant but depends on the concentration- metabolism in the liver involving specific enzymes is one of the most important factors

total clearance renal clearance + metabolic clearance + all other clearancerenal clearance renal excretion rate divided by the time plasma drug concentration

Drug ExcretionAmount of drug excreted = sum of the amounts filtered & secreted minus the amount reabsorbedrenal drug excretion - glomerular filtration - passive tubular reabsorption - active tubular secretionbiliary excretion & enterohepatic cycling

Pharmacokinetic Variables : volume of distribution3. half-life clearance4. biolavailability

Single-Dose Kinetics

Plasma drug concentration curve after a single dose of drug administered, plasma concentration increases as the drug is absorbed, reaches a peak as absorption is completed & then declines as the drug is eliminated

2. Bioavailability fraction of the administered dose of the drug that reaches the systemic circulation in an active form

Continuous & Multiple-Dose Kinetics

Drug accumulation & the steady-state principle When a drug that exhibits first-order pharmacokinetics is administered continuously or intermittently, the drug will accumulate until it reaches a plateau or a steady-state plasma drug concentration.a. time required to reach the steady-state condition b. steady-state drug concentration

Dosage calculationsa. loading dose Vd + desired plasma during concentration b. maintenance dose drug clearance X average steady-state plasma drug concentration

Mechanics of Drug ActionNature of Drug Receptors receptors specific cell molecules to which most drugs interact to produce their effectEffects of Coupling : 1. opening or closing of an ion channel 2. activation of biochemical messengers ( 2nd messengers ) 3. physical inhibition of a normal cellular function 4. turning on of a cellular functionType of Receptors : hormones & neurotransmitters enzymes ion channels & transporters membrane lipids or nucleic acids

B. Drug Receptor Interactions : 1. Receptor Binding & Affinity - form H+, ionic or hydrophobic bonds with a receptor site - form covalent bonds with a receptor Affinity - tendency of a drug to combine with its receptor - strength of binding Dissociation Constant ( KD ) - measure of a drugs affinity for a given receptor - concentration of a drug required in solution to achieve 50% occupancy of its receptors ( molar concentration ) - the lower the KD, the greater is the drugs affinity for the receptor 2. Signal Transduction receptor binding initiates a cascade of biochemical events leading to a physiologic effect ( G protein )

3. Intrinsic Activity - ability of a drug to initiate a cellular effect ( alteration of cell physiology )

Agonists drugs that have both receptor affinity & intrinsic activity

Antagonists lack intrinsic activity

Type of Agonists : full - maximal response - increases rate of signal transduction partial - submaximal response inverse - decreases rate of signal transduction

Types of Antagonists : competitive noncompetitive irreversible ( nonequilibrium competitive ) physiological chemicalC. Functions of Receptors : 1. to propagate regulatory signals from outside to within the effector cell when the molecular species carrying the signal cannot itself penetrate the cell membrane 2. to amplify the signal 3. to integrate various extracellular & intracellular regulatory signals 4. to adopt to short term & long term changes in the regulatory milieu & maintainhomeostasis Dose - Response Relationship - the relationship between the concentration of a drug at the receptor site & the magnitude of the response- response elicited with each dose of a drug is described in terms of a percentage of the maximal response

Efficacy - maximal response produced by a drug

Potency - expressed in terms of the median effective dose ( ED50 ), the dose that produces 50% of the maximal response - determined by the affinity of a drug for its receptor

2 components of dose response relationships

dose-plasma concentration relationshipplasma concentration-response relationship

EC50 ( Effective Concentration 50% ) -drug concentration which induces a specified clinical effect in 50% of the subjects to which the drug is administered

LD50 ( Median Lethal Dose ) -concentration of a drug whiich induces death in 50% of the subjects to which the drug is administered

TI ( Therapeutic Index )- ratio of LD50 TO ED50- measures safety of a drug

Margin of Safety- margin between therapeutic & lethal doses of a drug

Drug Interactions :

Mechanisms : altered absorption altered metabolism plasma protein competition altered excretion

1. Addition response elicited by the combined drugs is EQUAL TO the combined responses of the Individual drugs

2. Synergism response elicited by combined drugs is GREATER THAN the combined responses of the individual drugs3. Potentiation a drug which has no effect enhances the effect of a second drug4. Antagonism drug inhibits the effect of another drug

PATIENT PROFILE

Factors to Consider :

agepregnancy statussmoking & drinking habitsliver or kidney diseasepharmacogeneticsdrug interactionspsychosocial factors