Pharmacodynamics

Pharmacodynamics Saja Hamed, Ph.D

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 Saja Hamed, Ph.D

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 Saja Hamed, Ph.D

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 Saja Hamed, Ph.D

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 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) 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 Saja Hamed, Ph.D

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 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 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 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. Saja Hamed, Ph.D

Drug Food Interaction 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 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 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 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 Saja Hamed, Ph.D

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

Medication Errors Saja Hamed, Ph.D

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) Saja Hamed, Ph.D

Pharmacodynamics