Lecture 3-Pharmacokinetics-The Kinetics of Drugs in the Human Body PDF

 MED102 General Chemistry Pharmacokinetics - The kinetics of Drugs in the Human Body Dr Stella Loizou Learning Objectives (LOBs) Define half-life of a drug Describe the action of drugs in human body using examples Pharmacokinetics A...

 MED102 General Chemistry Pharmacokinetics - The kinetics of Drugs in the Human Body Dr Stella Loizou Learning Objectives (LOBs) Define half-life of a drug Describe the action of drugs in human body using examples Pharmacokinetics A branch of pharmacology dedicated to determining the fate of substances administered to a living organism Attempts to: from the moment that it is analyze chemical metabolism administered up to the point at which discover the fate of a chemical it is completely eliminated from the body Pharmacokinetics vs Pharmacodynamics Pharmacokinetics (PK) is the study of how an organism affects a drug Pharmacodynamics (PD) is the study of how the drug affects the organism → Both together influence dosing, benefit and adverse effects of a drug Pharmacokinetics vs Pharmacodynamics Clinical pharmacokinetics Is the application of pharmacokinetic principles to the safe and effective therapeutic management of drugs in a patient A drug’s effect is often related to its concentration at the site of action → useful to monitor this C Half-life of a drug The duration of action of a drug is known as its half life (t½) The period of time required for the concentration of drug in the body to be reduced by one-half (by 50%) Half-life of a drug Half-life of a drug Example 40 mg of a drug is administered IV to a patient and after 2hrs the concentration becomes 20mg → reduced by 50% of its original value What is the half life of the drug? The half life of the drug is 2 hours  Half-life of a drug - Plasma half time It is the time in which the concentration of the drug in plasma falls by 50%  Half-life of a drug - Plasma half time Dosage Age of the Route of schedule Dosage of the patient administration drug Excretion Distribution The faster the The more widely a excretion, the Plasma half-life drug is distributed the shorter the half life depends on longer the half life Plasma protein binding Drug biotransformation of the drug If a patient suffers from liver The more the plasma disease and there is decreased protein binding the longer Tissue binding Genetic factors drug biotransformation then is the half life of a drug and The more the tissue Determines the half life of drugs increases vice versa binding of a drug, whether a person the longer the half is fast or slow life of that drug acetylator Main routes of drug administration Half-life of a drug Examples of half lives of drugs Long half life Short half life Digoxin 1-5 days Dopamine 2 min Digitoxin 7 days Aspirin ~15 min Warfarin 25-60 hours Insulin 10 min Lidocaine 2 hours Diazepam 40-50 hour Paracetamol 1-4 hours Morphine 2.5hours Importance of half life of a drug 1. Gives a gross idea about the PK and PD of a drug 2. Predict the duration of its action 3. Formulate a dosage schedule (amount of drug and frequency of interval) long half life : should be given once/twice daily to prevent accumulation short half life : should be given repeatedly 4. Handle a case of overdose of a drug 5. Determine the time to achieve steady state plasma concentration 6. Give general knowledge: Whether the drug is metabolized or eliminated unchanged Whether the drug itself is active or converted into active metabolite or both Whether the drug has irreversible action or not Presence of disease in the organ of metabolism or excretion Advantages and Disadvantages of long half life Therapeutic disadvantages Therapeutic advantages Cannot be given in emergency by oral route Long duration of action More cumulative effect Less dose frequency More drug interaction Better patient compliance Chance of toxicity is more as it is less Can be used in prophylaxis rapidly metabolised or eliminated Does not develop tolerance Advantages and Disadvantages of short half life Therapeutic disadvantages Therapeutic advantages Short duration of action so cannot be used Can be given in emergency to prevent as prophylactic measure acute attack e.g GTN in acute MI More dose frequency Rapidly excreted → less chance of toxicity Development of tolerance is more if No cumulative effect frequently used No drug interaction Example 1: Paracetamol Paracetamol (also known as acetaminophen or APAP) Over the counter medication (trade names: Panadol, Tylenol) Indications: Pain (mild to moderate), Fever Route of administration: oral, rectal, IV Half-life: ~4 hours Daily dosage: max 4g (for healthy adults) Overdose can cause liver damage Paracetamol Overdose Paracetamol is the most common medicine taken in overdose Overdose may occur accidentally or in the context of self-harm Significant overdose can result in liver failure if not promptly treated with the antidote Liver failure can be fatal Paracetamol Overdose Symptoms of paracetamol overdose: There may be no symptoms on the first day Nausea and vomiting After 24 hours: Pain under the ribs on the right side (where the liver is) Jaundice (yellowing of the whites of the eyes and the skin) Acute liver failure → death Paracetamol Overdose Treatment Main goal of treatment: prevent or minimise liver injury Decision depends on the clinical scenario → time of presentation after the overdose Compare with a standard graph and: If the paracetamol levels are above a certain line → patient needs treatment If the paracetamol levels are below a certain line → may not require treatment Treatment is with intravenous N-acetylcysteine (NAC) → antidote Paracetamol Curve Example 2: Aspirin Aspirin (also known as acetylsalicylic acid-ASA) Over the counter medication Belongs to the class of NSAIDs (Non-Steroidal Anti-Inflammatory Drugs) Indications: Pain (mild to moderate), Fever, Inflammation, Lowers the risk of heart attack or stroke Plasma half-life: ~15min (dosage dependent) Aspirin Daily dosage Aspirin shouldn’t be taken with empty stomach Doses range from 50 mg to 6000 mg daily, depending on the use! Usual doses for mild to moderate pain are 350-650 mg/4 hours or 500 mg/6hours (doses of 300-650 mg have a half-life of ~3 hours) Aspirin Mode of Action NSAIDs block the enzyme that makes prostaglandins [cyclooxygenase (COX)] →Lowering concentrations of prostaglandins →Reduction of inflammation, pain and fever →Inhibition of prostaglandins also reduces the function of platelets and the ability of blood to clot Aspirin Side effects Gastrointestinal: can cause stomach irritation, stomach ulcers, stomach bleeding Summary Pharmacokinetics vs Pharmacodynamics Half-life of a drug Importance of half-life Paracetamol - Paracetamol Overdose - Paracetamol Curve Aspirin Question 1 Based on the paracetamol curve shown below, what is the half life of paracetamol? Question 2 Drug A has a half-life of 2 hours. If the initial plasma level of the drug, given as a single dose, is 1200mg/L, what will its plasma level be after 8 hours? Question 3 Half-life of aspirin does not depend on the dosage of the drug. True False