FACTORS MODIFYING DRUG ACTION

DR NARENDRA KUMARDR NARENDRA KUMAR

FACTORS MODIFYING DRUG ACTION

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

I. Physiological Factors

• Age• Sex• Pregnancy• Body weight• Lactation• Food

Physiological Factors

1. AGENewborn– ↓ 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 neonates due 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

Old Age– ↓ Liver function diazepam, theophylline.

– ↓ Kidney function Gentamycin ,Digoxin ,Pencillins are contraindicated in old

people.

– ↓ 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.

II. Pathological FactorsDiseases cause individual variation in drug

response – ↓ 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 ↓excretion of digoxin-lithium-gentamycin-

penicillin.

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

III. Genetic Factors GENETIC POLYMORPHISM The existence in a population of two or more

phenotype with respect to the effect of a drug.

e.g. Acetylation enzymes deficiency

• Acetyl transferase (non-microsomal).

(SHIP) Sulphonamides, Hydralazine, Isoniazid,

Procainamide etc. metabolized by acetylation.

• Slow acetylator phenotype → peripheral neuropathy in INH .

• Rapid acetylator phenotype can decrease effect of drug.

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.

• ↑ Ca release, muscle spasm, ↑ Temp.

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.

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 reactionsA, B, C, D and E

1) Type A reactions–Excessive therapeutic effect –Side effects

I) Type A reactions– Common – 75 % of all adverse reaction– Related to pharmacological actions– Dose-dependent– Predictable – Can be avoided by adjusting the dosage regimen– Most of them are reversible upon stopping druge.g. Hypotension (antihypertensives) Hypoglycemia (insulin)

Type A reactions

1.Excessive therapeutic effect Unwanted effects related to the main pharmacological actions of the drug that occur when the drug produce greater therapeutic effect than is necessary.

• Warfarin → Anticoagulant → Bleeding• Insulin → Normoglycemia → Hypoglycemia

2. SIDE EFFECTS

Unwanted effects unrelated to the main pharmacological actions of the drug but due to other normal actions of the drug.

e.g. Morphine cause constipation during its use as analgesic.

II) Type B reactions–Are bizarre reactions –Not related to the normal pharmacological

actions of the drug.–Unpredictable–Not dose-related.–Occur only in minority of patients.

Types–Allergic reactions (Hypersensitivity )–Genetic disorders (Idiosyncrasy)

Type B 1) Hypersensitivity ( allergic reactions)

Abnormal response to the drug due to antigen-antibody reactions e.g. Penicillin

• Allergic response to a drug

• Rashes, hypotension and bronchospasm (anaphylactic reaction)

Types of allergic reactions• Type –I/ immediate type/acute hypersensitivity/anaphylatic –

Ig E mediated

• Type -II reaction/cytotoxic reaction – damage of cells e.g. haemolytic anemia due to methyldopa or penicillin.

• Type- III/immune complex mediated- antigen antibody react to make immune complex which is engulfed by leukocytes and initiate inflammatory process- e.g. serum sickness, nephropathy and vasculitis.

• Type IV/delayed hypersensitivity/cell mediated- occurs 2-3 days after exposure to antigen- T lymphocytes are involved- e.g. contact dermatitis, urticarial rash and fever.

Type B 2) Idiosyncrasy is abnormal response to the drug due to

genetic disorders.

•Succinylcholine apnea•Malignant hyperthermia•Porphyria

SECONDARY EFFECTS

• Unwanted effects that occur secondary to the wanted actions of the drug.

• Overgrowth of microorganisms following use of broad spectrum antibiotics

e.g. Pseudomembranous colitis

Type C reactions ( Continuous reaction)

– Due to long term use e.g. NSAIDs analgesic nephropathy

Type D reactions (Delayed adverse reactions)

Teratogenesis Is congenital malformations occurring in the

fetus due to exposure to drugs during pregnancy

e.g. Thalidomide → Phocomelia

Carcinogenesis Ability of some substances to induce cancer. e.g. Stilbesterol → adenocarcinoma of vagina in

female off springs.

Mechanisms1. DNA alterationGriesofulvin & alkylating cytotoxics

2. Immunosuppressionimmunosuppressant increase incidence of cancere.g. organ transplantation & rheumatoid arthritis

3. Hormonallong term use of estrogen replacement in PMW induce endometrial cancer

Type E reactions (Ending of drug)

• Sudden discontinuation ( abrupt withdrawal).

• Rebound adrenal insufficiency e.g. Corticosteroids• Antihypertensive • Antiepileptics

Treatment of drug allergy

• The offending drug must be immediately stopped.

• Most mild reactions (like skin rashes) subside by themselves and do not require specific treatment.

• Antihistamines (H1) are beneficial in some type I reactions (urticaria, rhinitis, swelling of lips, etc.) and some skin rashes.

Treatment of drug allergy• In case of anaphylactic shock or angioedema of larynx the

resuscitation council of UK has recommended the following measures:

• Put the patient in reclining position, administer oxygen at high flow rate and perform cardiopulmonary resuscitation if required.

• Inject adrenaline 0.5 mg (0.5 ml of 1 in 1000 solution) i.m.

• Repeat every 5-10 min in case patient does not improve or improvement is transient. This is the only life saving measure.

Treatment of drug allergy

• Adrenaline should not be injected i. v. (can itself be fatal) unless shock is immediately life threatening.

• If adrenaline is to be injected i.v., it should be diluted to 1:10,000 or 1:100,000 and infused slowly with constant monitoring.

• Administer a H1 antihistaminic (chlorpheniramine 10-20 mg) i.m./slow i.v. lt may have adjuvant value.

Treatment of drug allergy

• Intravenous glucocorticoid (hydrocortisone sod. succinate 100-200 mg) should be added in severe/recurrent cases.

• Intravenous glucocorticoid acts slowly, but is specially valuable for prolonged reactions and in asthmatics.

• Glucocorticoids are the only drug effective in type II, type III and type IV reactions.

Photosensitivity• It is a cutaneous reaction resulting from drug induced

sensitization of the skin to UV radiation.

• Phototoxic Drug or its metabolite accumulates in the skin, absorbs light and undergoes a photochemical reaction resulting in local tissue damage (sunburn-like), i.e. erythema, edema, blistering followed by hyperpigmentation and desquamation.

• The shorter wave lengths (290-320 nm, UV-B) are responsible.

• Drugs involved in acute phototoxic reactions are tetracyclines (especially demeclocycline) and tar products.

Photosensitivity

• Photoallergic Drug or its metabolite induces a cell mediated immune response which on exposure to light of longer wave lengths (320- 400 nm, UV -A) produces a papular or eczematous contact dermatitis like picture.

• Drugs involved are sulfonamides, sul- fonylureas,

griseofulvin, chloroquine, chlorpromazine.

Drug dependence

• Psychological dependence

• Physical dependence

• Drug abuse

Drug interactions

• It is the modification of the effect of one drug

(the object drug ) by the prior or concomitant

administration of another (precipitant drug).

Outcomes of drug interactions

1) Loss of therapeutic effect2) Toxicity3) Unexpected increase in pharmacological activity4) Beneficial effects e.g. additive & potentiation

(intended) or antagonism (unintended).5) Chemical or physical interaction e.g. IV incompatibility in fluid or syringes mixture

Mechanisms of drug interactions

Pharmacokinetics Pharmacodynamics

Involve the effect of a drug on another from the

point of view that includes absorption ,distribution ,

metabolism and excretion.

Are related to the pharmacological activity of the interacting drugs

e.g. synergism, antagonism, altered

cellular transport, effect on the receptor site.

Pharmacodynamic interactions

1. Excessive sedation, respiratory depression, motor incoordination due to concurrent administration of a benzodiazepine, a sedating antihistaminic (promethazine), a neuroleptic (chlorpromazine), an opioid (morphine) or drinking alcoholic beverage while taking any of the above drugs.

2. Fall in BP and fainting due to concurrent administration of α1 adrenergic blockers, vasodilators, ACE inhibitors, high ceiling diuretics and cardiac depressants.

Pharmacodynamic interactions

• Pronounced and asymptomatic hypoglycaemia can occur when propranolol is administered to diabetics receiving insulin/ sulfonylureas, due to blockade of β adrenoceptors which contribute to recovery from hypoglycaemia as well as some hypoglycaemic symptoms.

• Increased risk of bleeding due to concurrent use of antiplatelet drugs (aspirin, clopidogrel) with anticoagulants (warfarin).

Pharmacodynamic interactions

5. Severe hyperkalaemia by concurrent use of ACE inhibitors and K+ sparing diuretics.

6. Additive ototoxicity due to use of an aminoglycoside antibiotic in a patient receiving furosemide.

7. Antagonism of bactericidal action of β lactam antibiotic by combining it with a bacteriostatic drug like tetracycline, erythromycin or clindamycin.

Drug interactions before administration

• Certain drugs react with each other and get inactivated if their solutions are mixed before administration.

• In practical situations, these in vitro interactions occur when injectable drugs are mixed in the same syringe or infusion bottle. Some examples are:

1. Penicillin G or ampicillin mixed with gentamicin or another aminoglycoside antibiotic.

2. Thiopentone sodium when mixed with succinylcholine or morphine.

3. Heparin when mixed with penicillin/ gentamicin/hydrocortisone.

4. Noradrenaline when added to sodium bicarbonate solution.

• In general, it is advisable to avoid mixing of any two or more parenteral drugs before injecting.

Fixed dose ratio combination preparations

Advantages1. Convenience and better patient compliance

2. Certain drug combinations are synergistic, e.g. sulfamethoxazole + trimethoprim levodopa + carbidopa/benserazide combination oral contraceptives.

3. The therapeutic effect of two components being same may add up while the side effects being different may not, e.g. amlodipine + atenolol as antihypertensive.

4. The side effect of one component may be counteracted by the other, e.g. a thiazide + a potassium sparing diuretic.

5. Combined formulation ensures that a single drug will not be administered. This is important in the treatment of tuberculosis and HIV-AIDS.

DISADVANTAGES OF FIXED DOSE RATIO COMBINATIONS1. The patient may not actually need all the drugs present in a combination: he is

subjected to additional side effects and expenses.

2. The dose of most drugs needs to be adjusted and individualised. When a combined formulation is used, this cannot be done without altering the dose of the other component(s).

3. The time course of action of the components may be different: administering them at the same intervals may be inappropriate.

4. Altered renal or hepatic function of the patient may differently affect the pharmacokinetics of the components.

5. Adverse effect, when it occurs, cannot be easily ascribed to the particular drug causing it.

6. Contraindication to one component (allergy, other conditions) contraindicates the whole preparation.

7. Confusion of therapeutic aims and false sense of superiority of two drugs over one is fostered, specially in case of antimicrobials whose combinations should be avoided.

8. Corticosteroids should never be combined with any other drug meant for internal use.

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