Pharmacodynamics 20/03/1440 Saja Hamed, Ph.D

The study of what drugs do to the body and how they do it Efficacy: the study of the biochemical and physiologic effect of drugs and the molecular mechanisms by which those effects are produced The study of what drugs do to the body and how they do it Efficacy: The maximal response produced by a drug Depend on the no. of drug receptor complexes formed and the efficiency they produce a cellular action. A compound may bind to a receptor and have a zero efficacy. Not elicit a response, and may act as antagonist 20/03/1440 Saja Hamed, Ph.D

A measure of how much drug is required to elicit a given response Potency: A measure of how much drug is required to elicit a given response The lower the dose required for a given response the more potent the drug 20/03/1440 Saja Hamed, Ph.D

20/03/1440 Saja Hamed, Ph.D

20/03/1440 Saja Hamed, Ph.D

If a patient has a headache we would not select a powerful analgesic (e.g. morphine) for relief, rather we would select an analgesic with lower maximal efficacy such as aspirin 20/03/1440 Saja Hamed, Ph.D

D + R -> D-R complex -> Response Receptor: specialized target macromolecules, on the cell surface or intracellular that binds a drug and mediates its pharmacologic action D + R -> D-R complex -> Response When a drug binds to a receptor -> mimic or block the actions of endogenous regulatory molecules 20/03/1440 Saja Hamed, Ph.D

20/03/1440 Saja Hamed, Ph.D

Four primary receptor families: 1. Cell membrane embedded enzymes: the ligand binding domain is located on the cell surface, and the enzyme’s catalytic site is inside. e.g. insulin 2. Ligand gated ion channels: regulate flow of ions into and out of cell. Ligand binding domain is on the cell surface. E.g. Acetylcholine 3. G protein coupled receptor systems: have the receptor, G protein, and an effector. e.g. NE 4. Transcription factors: found within the cell situated on DNA in the cell nucleus and regulate protein synthesis. Stimulate transcription of mRNA which act as template for prtn synthesis. Activated by lipid soluble ligands. E.g. thyroid and steroid hormones (Testosterone, cortisol) 20/03/1440 Saja Hamed, Ph.D

20/03/1440 Saja Hamed, Ph.D

Agonists: molecules that activate receptors Antagonists: molecules that prevent receptor activation Competitive: bind reversibly to receptors (They compete with agonists for receptor binding. The receptor will be occupied with agent present at high conc.) Noncompetitive: bind irreversibly to receptors Partial agonists: produce maximal effect that is lower than that of a full agonist. In addition, they can act as antagonist. Antihistamine suppress allergy symptoms by binding to receptor of histamine thus preventing activation of these receptors by histamine 20/03/1440 Saja Hamed, Ph.D

determined using laboratory animal measure of drug safety Warfarin Therapeutic index: the ratio of the dose that produces toxicity to the dose that produces a clinically desired or effective response LD50:ED50 ratio determined using laboratory animal measure of drug safety Warfarin Penicillin 20/03/1440 Saja Hamed, Ph.D

20/03/1440 Saja Hamed, Ph.D

The overlap in curves mean that high doses to produce therapeutic effects in some people may be large enough to cause death 20/03/1440 Saja Hamed, Ph.D

20/03/1440 Saja Hamed, Ph.D

Variables that may affect drug action and effect AgeMetabolism and excretion are slower in elderly.. cumulative effect Weight The bigger the person the greater the dose. Many drugs calculated on the basis of weight Sex Ratio of fat per body mass differ and hormones level. Pregnant or lactating women most drugs are CI 20/03/1440 Saja Hamed, Ph.D

Variables that may affect drug action and effect Psychological state: The more positive the patient feel about the medications the more positive the physical response is this is referred to as placebo effect Placebo: Inactive substance that resembles the medications, e.g. sugar tab. or saline soln. 20/03/1440 Saja Hamed, Ph.D

Drug Food Interaction 20/03/1440 Saja Hamed, Ph.D

Impact of food on drug absorption: Decreased absorption: calcium containing food and tetracycline antibiotics digoxin and higher fiber foods like wheat bran, rolled oats and sunflower seeds. Digoxin has low therapeutic index so result in therapeutic failure Increased absorption: high calorie meal increase the absorption of saquinavir Drug for HIV infection. If taken without food  absorption may be insufficient for antiviral activity 20/03/1440 Saja Hamed, Ph.D

Impact of food on drug toxicity: drug food interactions sometimes increase toxicity theophylline plus caffeine can result in excessive CNS excitation potassium-sparing diuretics (spironolactone) plus salt substitutes can result in dangerously high potassium levels aluminum containing antacids (Maalox) plus citrus beverages can results in excessive absorption of aluminum 20/03/1440 Saja Hamed, Ph.D

Impact of food on drug action: food rich in vitamin K (broccoli, cabbage) can reduce the effect of warfarin  Warfarin act by inhibiting vitamin k dependent clotting factors. when vitamin k is abundant warfarin is less able to inhibit the clotting factor 20/03/1440 Saja Hamed, Ph.D

Timing of drug administration with respect to meals: many drugs cause stomach upset when taken without food. If food does not reduce their absorption then administer with meal if food reduce their absorption? Select alternative drug that does not upset the stomach “Administer a drug with food”: to administer it with or shortly after meal “administer a drug on an empty stomach”: either 1 hour before a meal or 2 hours after Ask if drug should be taken with meal or not and if there are any food or beverages to avoid 20/03/1440 Saja Hamed, Ph.D

Drug-herb interactions: St. John’s wort induce drug-metabolizing enzymes  reduce blood levels of many drugs 20/03/1440 Saja Hamed, Ph.D

Medication Errors 20/03/1440 Saja Hamed, Ph.D

miscommunication involving oral and written orders: poor hand writing human factors, communication mistakes, and name confusion account for 90% of all errors human factors: administering IV instead of IM, miscalculation of dosage miscommunication involving oral and written orders: poor hand writing - 2 mg warfarin was misread as 5mg death from hemorrhage 10 mg of methotrexate once a week was misread as 10mg once a day  death  (An immunosuppressant) - Cisapride one-fourth of a 10mg tablet 4 times a day was misread as one 10mg tablet 4 times a day death (child) www.nccmerp.org (National Coordinating Council for Medication Error Reporting and Prevention) 20/03/1440 Saja Hamed, Ph.D