Pharmacogenetics

1. PHARMACOGENETICS DR. ALMAS MUHAMMAD ARSHAD BDS (UOL), RDS, PGAGD

2. Introduction: Pharmacogenetics = Pharma and genetics Pharma is derived from the Greek word i.e. PHARMACON, related to Drugs. Genetics means related to genes / genome. Now known as “PHARMACOGENOMICS”

3. Definition: “..It is the branch of Pharmacology, that deals with the altered drug response shown due to variation in the Genetics..”

4. What are Genetic Variations? Are described as naturally occurring genetic differences among individuals of the same species. Occur during crossing over of DNA during Meiosis (type of cell division).

5. Genetic Variation (Types) Two types of variation are common in the genome: Changes in single letters called ‘Single nucleotide polymorphisms‘ ( SNPs) Changes in DNA, can be a missing whole block of DNA (a deletion), or might have one, two, three or more copies. This is known as Copy number variation .

6. Significance Of Pharmacogenetics: It is significant in the modification of drug therapy with respect to the patients Genotype to: Ensure maximum efficacy and Minimize the adverse effects of a drug. It lead to the development of Personalized medicine.

7. Personalized Medicine [PM]: Abbreviated as ‘PM’ It is the use of Pharmacogenetics to form a drug therapy according to individual’s drug response. It increases the chances of a successful outcome and reduced possible adverse effects of a drug therapy.

8. How is tailored drug therapy useful? Tailored Drug therapy limits down the complications of altered drug response. Alterations in drug response can be dangerous.

9. Did You Know? Studies show that every year about 2 million people are hospitalized for drug adverse reactions. And every year 100,000 people die because of these reactions This makes it the 6th leading cause of death worldwide Complications of Altered drug response: Unusual drug responses include accumulation of the drug in the body leading to adverse effects, that can sometimes prove fatal.

10. W e may say that ONE type of Drug cannot FIT ALL!

11. So…. While prescribing, a drug, dosage and frequency of administration, genetic differences MUST be considered by the physician.

12. What Genetic variations contribute to altered Drug response? Genetic variations are seen following protein structures due to differences in the genes. Receptors Enzymes

13. Cntd .. Receptors: Cell surface proteins where the drug will bind. Absence of receptors on the effector organ will result in no therapeutic effect but adverse effects due to the accumulation of drug.

14. Cntd .. 2. Enzymes: Are globular proteins that are responsible for metabolizing drugs. Deficiency or other defects in enzymes will result in no drug breakdown and thus accumulation of drug in the body, showing drug’s adverse effects. Example: G-6-P-D deficiency, Pseudocholinesterases deficiency.

15. Some Genetic Variations/Disorders and the altered Drug response: Less active or inactive Cytochrome P450 : The system is unable to breakdown and efficiently eliminate the drug from the body which leads to drug over-dosage and thus adverse effects in patients. E.g.: Slow Hydroxylation of Warfarin cause accumulation of drug and resulting in Warfarin side effects

16. Cntd .. 2. Cytochrome 2C19 Deficiency: It is a type of P450, that are liver enzymes. The Cytochrome 2c19 catalyzes the hydroxylation of Mephenytoin ( i.e. an anti-epileptic drug) Results in Mephenytoin adverse effects. Some Drugs whose metabolism is affected by P450 Variants: Anti- arrhythmics Beta – Adrenergic receptor blockers Neuroleptics Tricyclic Anti-depressants Decongestants

17. Cntd .. 3. Pseudocholinesterases Deficiency: An enzyme that breaks down cholines . It’s deficiency causes increased sensitivity to certain muscle relaxant drugs (Succinylcholine) used during general anesthesia. Patient will be unable to move or breathe on their own for a few hours after the drugs are administered. Incidence of this deficiency is 1/3000 patients.

18. Cntd .. 4. Glucose-6-Phosphate Dehydrogenase Deficiency: It is an enzyme that converts Glutathione to a reduced form, that keeps membrane proteins in operative condition. Deficiency leads to altered cell membrane and thus causing hemolysis on administration of some drugs like Anti-malarial, Sulphonamides, Analgesics, Sulphones etc

19. Cntd .. 5. Vitamin D Resistance: X-linked genetic variation Patient fails to metabolize Vitamin D to it’s active form and develop Vitamin D resistant rickets.

20. Cntd .. 6. Acetylation: Defect is less synthesis of N- acetyltransferase (liver) Slow Acetylation. Rest, Fast Acetylators ! Slow Acetylation may lead to higher blood levels of the drug and thus, result in toxic effects. Drugs Metabolized by Acetylation: Isoniazid Procainamide  ( antiarrhythmic ) Sulfa drugs (e.g. sulfonamide antibiotics) Dapsone  (anti-leprosy, antiparasitic )

21. Cntd .. 7 . Malignant Hyperpyrexia: Autosomal Dominant Disorder Mutation of the  Ryanodine receptor, located on sarcoplasmic reticulum mediate the release of calcium ions resulting in a drastic increase in intracellular calcium thus, muscle contraction consumes large amounts of ATP and generates the excessive heat (hyperthermia) Triggered by exposure to certain drugs used for  general anesthesia (Halothane etc)

22. Cntd .. 8. Acatalasia Single gene defect Complete lack of enzyme ‘ Catalase ’ Hydrogen peroxide ineffective to the patient 9. Acute Intermittent Porphyria Rare Autosomal dominant metabolic disorder  Deficiency of the enzyme ‘ Porphobilinogen deaminase ’ anti-psychotics aggravate the disease.

23. Cntd .. 10. Methaemoglobinaemia: Patient lacks the enzyme ' Methaemoglobin reductase ’ that normally prevent formation of Methaemoglobin. Drugs that cause Methaemoglobinaemia in this case: Sulphonamides Phenacetine Nitrates Quinones

24. References: Katzung – Basic and Clinical Pharmacology (12 th Edition) Lippincott Illustrated Review (5 th Edition) Katzung & Trevors Pharmacology Review (9 th Edition)

25. Thank You for your Attention! Almas Muhammad Arshad Roll No. 01