Factors affecting drug response I

Lecture I

Professor Ahmed Shaaban

Professor of Pharmacology &

Senior Consultant of Endocrinology

Drug response

Patient, dose & / or therapy duration - dependent pharmacological actions (beneficial) &

adverse effects (harmful).

Affected by pharmacokinetics.

Dose and route – dependent indications.

Treatment objectives

1. Treatment (ttt) of patient (pt.) rather than disease.

Patient – centered approach rather than guidelines.

2. Adding life to years rather than years to life.

Decrease morbidity & mortality.

3. Choice of specific drug, dose and therapy duration.

Causes of individual variationsDose producing same response varies up to > 5 fold.1. Drug targets:

Number of receptors, receptor signaling, ion channels, target enzymes, subcellular structures as microtubules,

transporters, ...Genetically controlled. Changeable.

2. Neurogenic & hormonal tone:e.g. sympathetic or parasympathetic predominance and

insulin resistance respectively. Anticholinergic drugs are more potent in children

(high vagal tone).3. Pharmacokinetics as metabolic enzymes, plasma protein binding, hepatic or renal clearance → variable plasma and target site drug concentration.

Plasma concentration – time curveMEC = minimal effective plasma concentration of drug.

MTC = maximal therapeutic plasma concentration of drug.

C max = maximal plasma C by a certain dose & route of drug.

t max = time required by a certain dose & route to elicit maximal response.

Halving of dose, absorption or plasma C does not mean halving of pharmac. response.

Therapeutic Drug Monitoring in certain drugs & pts.

Variations in drug response

1. Hyporeactivity

Less than expected response. Inadequate ttt. Higher dose is required.

2. Hyperreactivity

More than expected response. Higher cure rate. Smaller doses are required.

Adverse effects are more common & severe.

3. Paradoxical actions

Effects produced are opposite to that in most population. e.g.

a. In children commonly CNS stimulants are depressants & vice versa.

b. Antihistaminics in most pts. treat allergic diseases and

cause sedation. Opposite effects are produced in many pts.

c. Caffeine is CNS depressant in some people.

d. Paradoxical drug interactions: actions produced by combination of 2 drugs

are opposite to actions of each drug monotherapy. e.g.

i. β blockers or clonidine monotherapy decreases BP.

Combination therapy increases BP.

ii. Clonazepam or sodium valproate monotherapy is antiepileptic.

Combination therapy causes status epilepticus.

Drug receptor interaction

Whole drug molecule binds with receptor causing affinity.

Receptor signaling:

Ligand (reactive chemical group in drug molecule) binds

to specific reactive part of receptor, initiating coupling

and efficacy.

Agonist has free ligand e.g. dihydoxy benzene in epinephrine.

So, affinity and efficacy.

Antagonist has no or inactive ligand e.g. β blockers.

So, affinity but no efficacy.

4.Tolerance

↓ drug response on chronic use, so ↑ the dose to get the same response.

Causes (mechanism or types): a is metabolic, others are functional.

a) Enzyme induction.

b) Down (↓ number or internalization) & up regulation of receptors by

chronic use of agonists and antagonists respectively.

c) Receptor desensitization: ↓receptor- G pr. coupling.

d) Changes in effector enzymes.

So, in most drugs: small initial dose. Exceptions include drugs highly

bound to plasma proteins as….., antibiotics,….

Cross tolerance: between related drugs. e.g. benzodiazepines (…), morphine

related drugs,..

Selective tolerance: e.g. tolerance develops to most actions

of morphine (& related drugs) except miosis & constipation.

Diagnosis of addicts.

5. Tachyphylaxis

Acute tolerance, no response occurs on repeated drug use over a

short period of time, even if we increase the dose. Causes:

a) Exhaustion of endogenous stores e.g. ephedrine depletes

catecholamine stores.

b) Receptor desensitization e.g. succinyl choline.

6. Refractoriness

A period of time required before response by next dose.

7. Hypersensitivity: immunological, allergic.

8. Pharmacogenomics: genetic.

9. Idiosyncrasy: atypical unusual response in few patients.

Genetic or allergic.

Quantitative: 1 – 6. Dose, therapy duration & pt. dependent.

Qualitative : 7 – 9. Pt. – dependent.

Criteria of lipophilic drugs

1) Regular rapid oral absorption.

2) Large Vd.

3) Pass BBB & placental barrier.

4) Metabolism in liver (and are affected by liver disease).

5) Hepatic 1st pass metabolism.

6) Short t1/2 (usually).

7) Enzyme induction or inhibition interactions.

8) Excretion changed by kidney (not affected by renal function).

e.g. many examples in CNS, ANS & chemotherapy.

Criteria of lipophobic drugs: opposite.