Patient Factors Affecting Response to Drugs

Patient Factors

1. Age, Sex, Weight, Pathological status
2. Pharmacogenetic factors
3. Tolerance and Tachyphylaxis
4. Rebound effect and Withdrawal effect

1 - Age, Sex, Weight, Pathological status

• Patient response is different between different age groups, male and female and between different weights
• Pathological status:
• Liver or kidney disease significantly alter response to drugs due to altered metabolism
• Patient with Heart failure more sensitive to digoxin than patient with normal heart
• Patient with hyperthyroidism require higher doses of drugs because of fast metabolism

2 - Pharmacogenetic factors

Pharmacogenetics is the study of role of genome in drug response, sometimes there is difference in drug response between people due to genetic abnormality that has relation with the drug response.

Examples of genetic conditions causing EXAGGERATED drug response:

1. Pseudocholinesterase deficiency: PsChE metabolizes acetylcholine and some drugs like succinylcholine. Some individuals with deficient PsChE, when they take succinylcholine (used as muscle relaxant in surgery) and because there is deficiency in the PsChE, that lead to succinylcholine accumulation and severe muscle paralysis occurs due to lack of succinylcholine metabolism, and may lead to death from respiratory paralysis (succinylcholine apnea).
2. Glucose-6-phosphate dehydrogenase (G6PD) deficiency: G6PD is the most common human enzyme defect. G6PD enzyme catalyzes the reduction of NADP+ into NADPH which maintains glutathione in the RBCs. Reduced glutathione keeps Hb in the reduced (ferrous) form and prevent formation of methemoglobin and prevent cell membrane injury (hemolysis) caused by oxidative stress. Individuals with deficiency of G6PD may suffer acute hemolysis if they are exposed to oxidizing drugs e.g. nitrates, antimalarial drugs, sulfonamides, aspirin and others.
3. Thiopurine methyltransferase (TPMT) deficiency: TPMT is an enzyme that methylates thiopurine anticancer drugs (e.g. 6-mercaptopurine and 6-thioguanine) into less toxic compounds. And genetic deficiency in TPMT leads to conversion of thiopurine into more toxic compounds in different pathways than the TPMT one, leading to severe myelotoxicity and bone marrow suppression; TPMT deficiency prevalence is 1:300 and screening before giving anticancer drugs is important.
4. Acetylator phenotype: many drugs are metabolized in liver by acetylation process like isoniazid which used to treat TB, rate of acetylation is different between people, there is rapid acetylators and slow acetylators and the difference in genetics. If isoniazid given to slow acetylators, this would lead to accumulation and toxicity (antagonizing vit B6 leading to neuropathy) and that’s why isoniazid is given with vit B6, just in case the patient is slow acetylator to prevent side effects. In patients with fast acetylation, the liver will metabolize isoniazid faster and isoniazid metabolites are toxic to liver leading to liver injury and solution is decreasing dose if you suspect patient is fast acetylator. Fast acetylators complain of liver symptoms, slow acetylators complain of neuropathy symptoms so pay attention for that. Hydralazine is also metabolized by acetylation and if given to slow acetylators, this will lead to SLE like symptoms in the patient.

Examples of genetic conditions causing Decreased drug response:

1. Resistance to coumarin anticoagulants (warfarin and its group), so liver synthesize clotting factors 1972 by help of enzyme vit K epoxide reductase, warfarin inhibit that enzyme to give anticoagulant effect, some people have abnormal variant of the enzyme leading to warfarin not working on it, and some people have another enzyme similar to vit k epoxide reductase so liver inhibit that enzyme but liver has another enzyme that do the function
2. Vitamin D resistant Rickets: x linked disease that doesn’t respond to vit D.
3. The darker eye color the more resistant to mydriatic topical drugs, and the lighter its color, the more sensitive and it is also related to genetics

3 - Tolerance and Tachyphylaxis

Tolerance means progressive decrease in drug response with successive administration, the same response could be obtained by higher doses. It occurs over long period.

Tachyphylaxis is an acute type of tolerance that occurs very rapidly.

Body tries to do the opposite of drug action.

Mechanisms of tolerance:

1. Pharmacodynamic tolerance due to:
   • Receptor desensitization: prolonged exposure to the drug leads to slow conformational changes in the receptors by which the receptor shape becomes no longer suitable for the drug.
   • Receptor down-regulation: prolonged exposure to the drug leads to decrease number of the functional receptors.
   • Exhaustion of mediators: e.g. depletion of catecholamines by amphetamine. (amphetamine secretes norepinephrine from nerve endings leading to decrease the norepinephrine)
2. Pharmacokinetic tolerance due to increase metabolic degradation of a drug by induction of hepatic enzymes e.g. with chronic administration of ethanol.
3. Behavioral tolerance: because of drug independent learning of the brain how to actively overcome a certain drug-induced effect through practice e.g. with psychoactive drugs.

Overcoming tolerance by drug free intervals and using a drug with a different mechanism or different target receptor.

4 - Rebound effect and Withdrawal effect

Rebound effect: is recurring of symptoms in exaggerated form when a drug is suddenly stopped after a long period of administration.

Mechanism: prolonged administration of the antagonist leads to up-regulation (increase number) of receptors or increase sensitivity of receptors. When the antagonist is suddenly stopped, severe reaction occurs e.g. severe tachycardia and arrhythmia occurs after sudden stopping of beta-blockers.

Withdrawal effect: is recurring of symptoms in exaggerated form plus addition of new symptoms when a drug is suddenly stopped. E.g. withdrawal effects that occur after sudden stopping of opioids in opioid addicts, They get suicidal thoughts in addition to their depression which was already existing before the drug use.

The body does the opposite of the drug action.

Examples:

Course Menu

This lecture is part of the Clinical Pharmacology Basic Principles Free Course; this course also include these lectures:

• Routes of drug administration
• Pharmacokinetics 101: Drug absorption
• Pharmacokinetics 101: Drug distribution
• Pharmacokinetics 101: Drug elimination
• Drug targets: Receptors, ion channels, enzymes and carrier molecules
• Pharmacodynamics 101: Agonist dose response curves
• Pharmacodynamics 101: Types of antagonists
• Drug factors affecting patient response
• Patient factors affecting response to drugs