2003 cvs shifa permeation through biological membranes
Cardiovascular System-Theme 1 Dr. Fahad Azam Pharmacology and Therapeutics
THEME 1: BREATHLESSNESS AND SWELLING (CCF)• CASE 1• A 64 years old male with heart failure was put on digoxin therapy in tablet form, formulated by XYZ pharmaceutical. Initially he was given 0.5mg 8 hourly for three days followed by 0.125mg/day. Simultaneously he was suffering from severe cough, fever and malaise, the physician after thorough investigations diagnosed him as a case of lower respiratory tract infection and prescribed 100mgday doxycycline initially for one week which was further extended to 10 days. The patient suffered from diarrhea, doxycycline was discontinued, a course of metronidazole was given and patient got cured.•• After few days patient presented with complaints of nausea, vomiting, fatigue, palpitations. The dose of digoxin was increased to 0.25 mg/day and he felt better.•• After few years he was diagnosed for chronic renal failure, blood urea and creatinine were raised. He developed heart sinking and palpitation. On examination, the patient had an irregular pulse. ECG showed pulses bigeminy. Serum digoxin was 2.8 ng/ml. Digoxin therapy was stopped for three days. KCI was administered for few days. The plasma level was now repeated and was 1ng/ml. The dose of digoxin was adjusted to 0.125 mg /day. The patient became stable in a week.
LEARNING OBJECTIVES1. Describe general principles of pharmacology, sources of drugs, routes of drug administration, Essential Drugs concept.2. Describe drug transport across biological membranes.3. Relate concepts of half life of drug, plasma protein binding drug and volume of distribution of drugs to its bioavailability.4. Describe loading dose, steady state concentration, target concentration and maintenance concentration and bioequivalence of drugs.5. Describe drug excretion, clearance, zero and first order kinetic of drugs.6. Relate drug metabolism, factors affecting drug metabolism and its clinical significance.7. Relate drug receptor concepts, antagonism, synergism, drug-receptor interaction and signaling mechanism of drugs.8. Define relation between drug concentration and response and define drug response curves (graded and quantal).9. Describe dose response curves, pharmacokinetic and pharmacodynamic drug interactions, drug toxicity, therapeutic index and therapeutic window.
Modes of Transport Across Biological MembranesMechanism Direction Energy Required Carrier SaturablePassive diffusion Down gradient No No NoFacilitated Down gradient No Yes YesdiffusionActive transport Against gradient Yes Yes Yes (concentration/electrical)
Drug permeation is dependent on:• Fick’s law of Diffusion: – Solubility – Concentration gradient – Surface area – Vascularity – Thickness
• Drugs are either weak bases or weak acids (depending on their pKa) and can exist in either ionized or non ionized form (depending on their pKa and pH of the environment)• Ionized = water soluble• Non ionized = lipid soluble
• pKa is the intrinsic value of a drug, it does not change• pKa is the pH at which the drug or molecule is 50% ionized and 50 % non ionized
Clinical Application of Henderson-Hasselbalch Equation• Ionization increases renal clearance of Drugs• Only free, unbound drug is filtered• Both ionized and nonionized forms of drug are filtered• Non ionized forms are reabsobred whereas ionized forms are non absorbed as they have a charge and cannot pass through lipid membranes (lipid insoluble)• Ionized forms of drugs are “trapped” in the filtrate
Clinical Application of Henderson-Hasselbalch Equation• Both ionized and nonionized forms of drug are filtered• Non ionized forms are reabsobred whereas ionized forms are non absorbed as they have a charge and cannot pass through lipid membranes (lipid insoluble)• Ionized forms of drugs are “trapped” in the filtrate• Acidification of urine increases ionization of weak bases increases renal elimination• Alkalinization of urine increases ionization of weak acids increases renal elimination