General pharmacology By Mohamad-Hesham Daba,MD,PhD Associate professor of Clinical pharmacology
PHARMACOGENETICS• Pharmacogenetics refers to the study of inherited differences (variation) in drug metabolism and response.• Pharmacogenomics refers to the general study of all of the many different genes that determine drug behavior.• N.B.The distinction between the two terms is considered arbitrary, however, and now the two terms are used interchangeably.
A. Heritable conditions causing increased or toxic drug response1. Hereditary methemoglobinemia2. Glucose -6- phosphate dehydrogenase deficiency3. Malignant hyperthermia4. Pseudo cholinesterase deficiency5. Acetylator phenotypes
Hereditary methemoglobinemia• It is due to deficiency of methemoglobin reductase enzyme responsible for reduction of oxidized Hb (methemoglobin) to reduced Hb.• When the affected individual takes oxidizing drug (e.g. nitrates), much of his Hb is converted to methemoglobin and accumulates in his blood → cyanosis. •
Glucose -6- phosphate dehydrogenase deficiency• G-6-PD is an important source of reduced NADPH which maintains glutathione in the RBCs in its reduced form. Reduced glutathione keeps Hb in the reduced (ferrous) form.• Individuals with deficiency in G-6- PD enzyme may suffer acute hemolysis if they are exposed to oxidizing drugs e.g. nitrates, antimalarial drugs, and others.
Malignant hyperthermia• It is rare genetic disorder of skeletal ms characterized by sudden release of stored Ca2+ from the sarcoplasmic reticulum• when the patient is exposed to certain types of general anesthetics leading to generalized ms rigidity, high fever, and lactic acidosis• (could be treated by dantroline)
Pseudocholinestrase deficiency• Succinylcholine is a neuromuscular blocker metabolized by pseudo- cholinestrase enzyme.• Some individuals have deficient PsChE, when they take succinylcholine, severe ms paralysis and death from paralysis of respiratory ms may occur due to lack of succinylcholine metabolism (succinylcholine apnea).Treated by plasma transfusion*
Acetylator phenotypes• Two types of abnormal acetylators could be detected; Rapid acetylators and slow acetylators:• Isoniazide (first line antituberculus drug) causes two distinct forms of toxicity :- peripheral neuropathy whose incidence is greater in slow acetylators due to interference with pyridoxine metabolism- acute hepatocellular necrosis occurs more commonly in rapid acetylators and is related to formation of a hepatotoxic metabolite.
B. Heritable conditions causing:decreased drug response• Resistance to cumarin anticoagulant• Resistance to Vit. D• Resistance to mydriatics:
Resistance to cumarin anticoagulant• Those patients have a variant of the enzyme that converts Vit.K to its reduced (active) form. Cumarins normally inhibits this step.• Presence of this variant of the enzyme antagonizes the effect of cumarines and these patients needs 20 times the usual dose to get the response.
Resistance to Vit. D• True end organ resistance due to mutation of vit D receptors.• Individuals who exhibit this condition develop rickets that responds only to huge doses of Vit. D.
Resistance to mydriatics:.Dark eyes are less responsive to mydriatics
Pharmacogenetics• The risk of neurotoxicity from isoniazid ( used for tuberculosis) is higher in Egyptians than in Eskimo populations. Questions:• Give an explanation?• What is proper treatment for neurotoxicity?• When hepatotoxicity occur?
Pharmacodynamics• A 70-year –old man has been taking beta-blockers for many years for his angina (stable). He develops severe intermittent claudication and his legs were cold, and his doctor stops the B.B suddenly. His angina worsens within days, and he is admitted to hospital with myocardial infarction.• Give an explanation?
Pharmacodynamics• A 30-year-old man has been abusing heroin for many years. Gradually, the dose needed to achieve the desired effect has increased. He was found dead in the street.• Give an explanation?
Match the following• A-Median lethal dose (LD50)• b-Therapeutic index (T.I)• c- Full agonist• d- Partial agonist• 1- LD50 / ED50 ratio(…..)• 2-maximum response obtained from tissue(…..)• 3-can not produce maximal response(…..)• 4-can produce maximal response(…..)• 5-Dose kills 50% of experimental animals (…..)