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Transcript
Pharmacology Lecture 5 Pharmacogenetics 1) Define pharmacogenetics. Pharmacogenetics is the study of how individual genetic differences influence the variability in responses to drugs. 2) Understand the major mechanisms through which genetic variation can alter responses to drugs. The most common type of variation change is a change in a single nucleotide pair termed a single nucleotide polymorphism or SNP. If SNPs occur in the coding region of a gene they can have qualitative effects on gene function. Quantitative effects may be due to SNPs on the promoter region or the mRNA tail thus altering stability. Insertions and deletions are less common than SNPs but they also contribute to genetic variation. Gene products that affect drug response include: enzymes (metabolism), receptors, and transporters. 3) Describe an inherited trait that influences drug metabolism in a clinically significant fashion. a) Atypical plasma cholinesterase – results from an SNP that reduces its affinity for choline esters resulting in prolonged response to succinylcholine (1:3000pop). b) N-Acetyltransferase (NAT) Polymorphism – NAT 1 and 2 act on many drugs transferring an acetyl group from acetyl Co-A to amines producing an amide thus enhancing elimination. Polymorphism of NAT2 results in people with slow and people with rapid acetylation of certain drugs (e.g. isoniazid, hydralazine, and dapsone). Slow acetylators of isoniazid may develop a peripheral neuropathy due its blocking of pyridoxal phosphokinase (required for myelin sheaths) unless given supplemental pyridoxine (Vitamin B6). The anticonvulsant phenytoin can be toxic when given with isoniazid in a slow acetylator. c) Glucose-6-phosphate Dehydrogenase (G6PD) Deficiency – an X-linked disorder that reduces the ability of RBCs to respond to oxidative stress. The antimalarial drug primaquine causes hemolytic anemia in susceptible individuals. In fact, more than 50 drugs may cause hemolysis in people with G6PD deficiency. d) Cytochrome P450 polymorphisms – CYP2D6 has polymorphisms resulting in poor metabolizers (5-10% white pop.) and extensive metabolizers. Poor metabolizers may experience toxicity to certain drugs such as beta-blockers and tricyclic antidepressants. They may also poorly metabolize codeine to morphine. CYP2C19 polymorphisms result in higher cure rates for H pylori in poor metabolizers of proton pump inhibitors (omeprazole and lansoprazole). e) Thiopurine methyltransferase (TPMT) deficiency – administration of azathiorine and mercaptopurine for autoimmune, dermatologic, and hematologic disorders results in fatal myelosuppression in people with TPMT deficiency (1:300). f) MDR1 polymorphisms – gene produces a transporter (P-glycoprotein) that may affect the efficacy and toxicity of lipophilic drugs transported by P-glycoprotein (antibiotics, vinblastine, and cyclosporin A). g) Β2-Adrenergic receptor polymorphisms – results in variable responses to inhaled β2 agonist (bronchodilator) albuterol. Polymorphism Phase 1 enzyme CYP2C19 (PM) CYP2D6 (PM) Phase 2 enzymes Atypical Cholinesterase NAT2 (slow acetylator) TPMT Receptors Β2AR Other Drug targets P-glycoprotein Drug Clinical Outcome Omeprazole Codeine Increased ulcer cure rate Failure to form morphine from codeine – Inadequate pain control Succinylcholine Isoniazid Azathioprine Mercaptopurine Prolonged neuromuscular blockade-apnea Peripheral neuropathy Myelosuppression Albuterol Altered Responsiveness of airways to the β2 agonist – clinical significance still under study. Polymorphisms identified but functional significance is yet to be determined