Biological Determinants Of Drug Responses

Determinants of Response to Drugs

By:

Dr. Arlene Maceren Diaz M.D ,FPSECP Pharmacology Dept. S.W.U MHAM College of Medicine

A. Biologic Variation A. Hypersusceptibility or Drug intolerance Exaggerated response to an ordinary dose of a drug (supersensitivity) B. Idiosyncrasy – extreme susceptibility of an individual to an expected pharmacologic action of the drug C. Drug Allergy – is a response that results from a previous exposure to a drug; it is mediated by an immunologic mechanism

Biologic Variation Drug Allergy – is a response that results from a previous exposure to a drug; it is mediated by an immunologic mechanism 1. Immediate or anaphylactic drug allergy -Anaphylaxis, urticaria, angio-neurotic edema, drug fever, asthma 2. Delayed drug allergy reaction – serum sickness, contact dermatitis

Drug Allergy First Exposure

Drug

Stimulate PRODUCTION OF IgE

Y

IgE settles at mast cell surface

Drug Allergy 2nd exposure

Drug Antigen O

O Y Ag + Ab reaction

Degranulation of mast cell

Release of substances of anaphylaxis

Drug Acts as antigen

B. Disease process or pathological condition that influence response A. liver disease

B. renal disease

C. Presence of other Drugs 1.Summation C.I.a. – Additive effect-when two(2) drugs are given and half of each dose used simultanously elicits the same effect as the full dose of either drug use alone.

Example: A. Additive Effect = ½ + ½ = 1 Codiene =

Narcotic Analesic

=

60 mgs

Non-steroidal Anti-inflammatory Aspirin = Analgesic Combine Aspirin + Codiene = Lesser GIT irritation

Lesser resp. depression

= 325 mg

Paralgin or codalgine Stronger analgesic with antiinflammatory effect

C.I.b. Synergism – If the response is greater than that of the full dose of either drug Synergism = 1 + 1 = 3 Sulfamethoxazole +

Narrow Spectrum antibiotic

Trimethoprim

Extended spectrum antibiotic

= Cotrimoxazole

Broad spectrum

C.1.c- Potentiation = if a second drug which has no effect , increases the effect of the first drug. 1+ 0 = 2 Amoxycillin + AntibacterialActivity but easily destroyed by Beta-Lactamase producing bacteria

Clavulanic Acid

Beta Lactamase inhibitor,BUT HAS NO Antibacterial activity

= C0-Amoxyclav (augmentin) Antibacterial, but resistant to the destruction of Beta -Lactamase

II. Antagonism 1 + 1 = 0 - Diminishing response by opposing actions of 2 drugs ST I N GO

A

AGONIST

Physiological Effect

AG

ANTAGONIST

No Effect

ON

IS

T

Kinds of antagonism 4. Chemical – one drug is rendered inert or inactive by precipitation, conjugation, oxidation 6. Physiological antagonism – 2 drugs have opposing action on the same physiologic sites 8. Competitive antagonism – when 2 drugs will compete on a certain receptor cell and the antagonist displaces the other drug from the receptor site.

Example: D. Antagonism = 1 + 1 = 0 Competitive Antagonism 1

2

Heroin Agonist Opiate receptor

Addiction Resp. depression

Naloxone Antagonist

Example: D. Antagonism = 1 + 1 = 0 Competitive Antagonism OUT

Heroin Agonist

Reversal of effects esp. resp. depression

Antagonist Naloxone displaces Heroin from receptor

IV. Pharmacokinetic antagonism – drugs may affect efficacy of other drugs by: a. b. c. d. e.

Altered absorption from GIT Reduce binding to plasma protein Altered renal excretion Inhibition of metabolic degradation Induction of metabolic degradation

Altered dose – response metabolism.

due

to

special

features

a. Tolerance b. Tachyphylaxis c. Cumulative effect

of

drug

TOLERANCE- when there is a diminishing response to an ordinary dose of a drug that is administer over a period of time Causes

:

3. Drug inactivation by the liver microsomal enzyme- this called pharmacokinetic tolerance or drug disposition tolerance. 2. When there are less receptor sites available receptor downregulation.

Cross –tolerance=when an individual develops tolerance to a group of drugs which are pharmacogically related. Example: If a patient develop tolerance to diazepam (valium); which belongs to a class called benzodiazepines he may also develop to another benzodiazepine drug.

Tachyphylaxis = a rapidly developing tolerance,or a phenomenom of acute acquired tolerance.

• Cumulative effect – the effects of previously administered doses is superimposed to the effects of succeeding doses. causes: 3. Absorption of the drug is more rapid than excretion 2. Drug metabolism is slow in cases of liver disease 3. There is normal absorption but slow excretion of the drug such as in renal failure