Determinants of Response to Drugs

By: Dr. Arlene Maceren Diaz M.D ,FPSECP

Pharmacology Dept.

S.W.U MHAM College of Medicine

A. Biologic VariationA. 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 VariationDrug 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 Allergy2nd exposure

Drug Antigen O

O Y Ag + Ab reaction

Release of substances of anaphylaxis

Degranulation of mast cell

Acts as

antigen

Drug

B. Disease process or pathological condition that influence response

A. liver disease

B. renal disease

C. Presence of other Drugs1.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

Aspirin = Non-steroidal Anti-inflammatory Analgesic

= 325 mg

Combine Aspirin +

Codiene =

Paralgin or codalgine

Lesser GIT irritation

Lesser resp. depression

Stronger analgesic with anti-inflammatory effect

C.I.b. Synergism – If the response is greater than that of the full dose of either drug

Synergism = 1 + 1 = 3

Sulfamethoxazole + Trimethoprim

= Cotrimoxazole

Narrow Spectrum antibiotic

Extended spectrum

antibiotic

Broad spectrum

C.1.c- Potentiation = if a second drug which has no effect , increases the effect of the first drug. 1+ 0 = 2

Clavulanic Acid Amoxycillin + = C0-Amoxyclav

(augmentin)

Beta Lactamase inhibitor,BUT HAS NO Antibacterial activity

AntibacterialActivity but easily destroyed by Beta-Lactamase producing bacteria

Antibacterial, but resistant to the destruction of Beta -Lactamase

II. Antagonism 1 + 1 = 0

- Diminishing response by opposing actions of 2 drugs

AGONISTANTAGONIST

Physiological Effect

AGONIST AGONIST

No Effect

Kinds of antagonism

1. Chemical – one drug is rendered inert or inactive by precipitation, conjugation, oxidation

2. Physiological antagonism – 2 drugs have opposing action on the same physiologic sites

3. 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

Opiate receptor

Heroin Agonist

Addiction Resp. depression

Naloxone Antagonist

Example:D. Antagonism = 1 + 1 = 0

Competitive Antagonism

HeroinAgonist

Reversal of effects esp. resp. depression

Naloxone displaces Heroin from receptor

OUT

Antagonist

IV. Pharmacokinetic antagonism – drugs may affect efficacy of other drugs by:

a. Altered absorption from GITb. Reduce binding to plasma proteinc. Altered renal excretiond. Inhibition of metabolic degradatione. Induction of metabolic degradation

Altered dose – response due to special features of drug metabolism.

a. Tolerance b. Tachyphylaxisc. Cumulative effect

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

Causes :

1. 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:

1. 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