Factors modifying drug action

Dr. Datten Bangun , MSc.SpFK

Dept.Farmakologi & Therapeutik Fak.Kedokteran U S U

M E D A N

Therapeutic Objective of using drugs

To provide: = maximum benefit = with minimum harm

Factors that determine Intensity of Response• Administration- dosage size and route• Pharmacokinetic processes• Pharmacodynamics• Individual Variations

General ConceptsDrug Dose

Administration

Drug Effect or Response

Pharmaceutical

Pharmacokinetics

Pharmacodynamics

Pharmacotherapeutics

Disintegrationof Drug

Absorption/distribution

metabolism/excretionDrug/Receptor

Interaction

Factors modifying drug action

A multitude of host and environmental factors influence drug response. These factors influence drugresponses either: I. Quantitatively:- plasma concentration/ the action of the drug is either increased or decreasedII. Qualitatively : - the type of the responses is altered e.g. drug allergy or idiosincrasy

Factors modifying drug action

I. Physiological Factors.II. Pathological Factors (Diseases).III. Genetic Factors.IV. Environmental Factors.V. Interaction with other drugs.

Route of drug administrationTime of administration Environmental factor

I. Physiological Factors•Age•Sex•Pregnancy•Body weight•Lactation•Food

* Route of drug administration* Time of administration* Environmental factor

I. Physiological Factors1. AGENewborn:Decreased– gastric acid secretion.– liver microsomal enzymes (glucuronyl

transferase). – Plasma protein binding.– GFR & tubular secretion.–Immaturity of BBB in neonates.

-GIT absorption of ampicillin and amoxicillin is greater in neonatesdue to decreased gastric acidity.

Chloramphenicol ---Grey baby syndromeInadequate glucouronidation of chloramphenicol with drug accumulation).

Sulfonamides ------Hyperbilirubinemia & Kernicterus

CHILDREN•Tetracyclines =Permanent teeth staining•Corticosteroids =Growth & development retardation•Antihistaminics =Hyperactivity.

Considerations for Pediatric Patients

• Wide variation between age and degree of organ-system development

• Reevaluate all doses at regular intervals.• Be sure the dosage is appropriate for the

child’s age.• Always double-check all computations.

Considerations for Elderly Patients

Physiologic Function Changes– Optic– Auditory– Gastrointestinal– Pulmonary– Cardiovascular– Urinary– Hormonal– Composition of the body

Considerations for Elderly Patients• Altered Drug Responses• Adverse Drug Reactions (ADRs)• Polypharmacy• Noncompliance

Old Age– Liver function. = diazepam, theophylline.– Kidney function. =Digoxin, lithium.– Plasma protein binding– sensitivity to CNS depressants. =diazepam, morphine

2. SEX.•Testosterone increases the rate of biotransformation of drugs.•Decreased metabolism of some drugs in female (Diazepam).•Females are more susceptible to autonomic drugs ( estrogen inhibits choline estrase).

3. Pregnancy• Cardiac output • GFR and renal elimination of drugs.• Vd • Metabolic rate of some drugs.•Lipophilic drugs cross placental barrier & slowly excreted.

Developmental factors; during pregnancy, drugs taken during pregnancy pose a risk throughout the pregnancy, but pose the highest risk during the first trimester, due to the formation of vital organs and functions of the fetus during this time.

Environment; = for example receiving medication in an environment that lack of oxygen effects drug reaction, also pt who receives pain medication or sedative in a busy, noisy environment may not benefit as fully as if the environment were quiet and peaceful.

1. Administration- dosage size and route 1. Administration- dosage size and route - Because of errors in administration routes and - Because of errors in administration routes and

dosage and at wrong time there are many discrepancies in dosage and at wrong time there are many discrepancies in what patient gets and could cause more harm than goodwhat patient gets and could cause more harm than good

- Errors could be made by - Errors could be made by pharmacists, physicians, orpharmacists, physicians, or nursesnurses

- Should give patients complete instruction about their - Should give patients complete instruction about their medication and how to take itmedication and how to take it

1. Oral Medication

2. Sublingual Medication

3. Buccal Medication “pertaining to the cheek’’

4. Parenteral Medication

Time of administration; = the presence of food in the stomach delays the absorption of oral administration of medication, = some medications should be given with the food to prevent gastric irritation.

Diet; = nutrients can affect the action of a medication, for example, vitamin K found in green leafy vegetables can counteract the effect of an anticoagulant such as warfarin.

4. Plasma Protein Binding–Malnutrition.----- plasma protein decrease-- free drug concentration increases---- intoxication---- Mentawai victims

–Drug Interaction: 1. drug-drug interaction: = synergism = potentiation = summation/addism = antagonism 2. food- drug interaction

• Illness and disease; The presence of a disease affect the action of

drugs.

For example, aspirin can reduce the body temperature of a feverish client but has no effect on the body temperature of a client without fever. The liver is the primary organ for drug breakdown and the pathologic conditions that involve the liver may slow down metabolism

II. Pathological Factors

II. Pathological Factors

Diseases cause individual variation in drug response(A) Liver Disease–Prolong duration of action = (t1/2). Plasma protein binding for warfarin, tolbutamide-adverse effects.– Hepatic blood flow clearance of morphine-propanolol.

–Impaired liver microsomal enzymes Diazepam-rifampicin-theophylline

(B) Renal Disease– GFR.– tubular function.– Plasma albumin digoxin-lithium-gentamycin-penicillin.

(C) Malnutrition– plasma protein binding of drugs.– amount of microsomal enzymes. –------ Increases portion of free, unbound drug–warfarin

III.Genetic Factors

Pharmacogeneticsis the study of the relationship b/w genetic factors and drug response.

Idiosyncrasy;abnormal drug reaction due to genetic disorder .–Acetylation.–Oxidation.–Succinylcholine apnea.–Glucose 6-phosphate dehydrogenase deficiency.

III. Genetic Factors

GENETIC POLYMORPHISMThe existence in a population of two or more phenotype with respect to the effect of a drug.

Acetylation enzymes deficiency•acetyl transferase (non-microsomal).•Isoniazid, sulphonamides, etc.

•Slowacetylator phenotype ---peripheral neuropathy .•Rapidacetylator phenotype ---hepatitis.

Pseudocholinesterase deficiency.•Succinyl choline ( Sk.muscle relaxant ) ----------Succinylcholine apnea due to paralysis of respiratory muscles.

Malignant hyperthermia•By succinyl choline due to inherited inability to chelate calcium by sarcoplasmic reticulum. • Carelease, muscle spasm, Temp.

Oxidation PolymorphismDebrisoquine.–Extensive metabolizers (EM) –need larger dose.–poor metabolizers (PM) –need smaller dose.

Porphyria

Deficiency of Glucose–6 phosphate dehydrogenase (G-6-PD).G-6-PD Deficiency in RBCs --------hemolytic anemia upon exposure to some oxidizing drugs.–Antimalarial drug, primaquine.–Long acting sulphonamides.–Fava beans ( favism).

IV. Environmental Factors: Microsomal Enzyme Inducers–Tobacco Smoke –Smokers metabolize drugs more rapidly than non smoker.

Adverse drug effects:

Undesirable or harmful effects which can occur at therapeutic doses and need a reduction of dose or drug withdrawal .•Nausea and vomiting •Deafness with gentamycin•Death with penicillin

Types of adverse drug reactions: =A, B, C, D and E etc -------- prior lectures

Drug dependence

State in which use of drugs for personal satisfaction is accorded a higher priorit than other basic needs,often when the risks to health are known

Drugs capable of altering mood & feelings are liable to repetitive use to derive euphoria, withdrawal from reality, social adjustment, etc

Drug dependence

Psychological dependence

Physical dependence

Drug tolerance Requirement of higher dose of a drug to produce a given response It’s an adaptive biological phenomenon

Drug tolerance may be: Natural or Acquired Natural – the individual is inherently less sensitive to the drug. E.g. black races are tolerant to mydriatics

Acquired – developed by repeated use of a drug in an individual who was initially responsive

Cross tolerance It is the development of tolerance to pharmacologically related drugs E.g. alcoholics are relatively tolerant to barbiturates & general anaesthetics

Tachyphylaxis – rapid development of tolerance ( as in doses repeated at quick successions)

Drug resistance:

Refers to tolerance of microorganisms to inhibitory action of antimicrobials e.g. P.falciparum shows resistance to Chloroquin at certain geographical areas

Drug resistance:

Refers to tolerance of microorganisms to inhibitory action of antimicrobials e.g. P.falciparum shows resistance to Chloroquin at certain geographical areas

Key Points• The most important properties of an ideal drug

are: effectiveness, safety, and selectivity.• If the drug is not effective, it should not be used.• There is no such drug as safe drug: all drugs can

cause harm.• There is no such thing as selective drug: all drugs

can cause side effects.• The objective of drug therapy is to provide

maximum benefit within minimum harm.• Because all patients are unique, drug therapy

must be tailored to each individual.