Pharmacology I - General Pharmacology & Pharmacokinetics PDF

PHARMACOLOGY I GENERAL PHARMACOLOGY PHARMACOKINETICS Week 2 By Assoc. Prof. Mennatallah Ismail 1  PCT 312 PHARMACOLOGY I “General Pharmacology” Intended learning outcomes (ILOs)  Explain drug abso...

PHARMACOLOGY I GENERAL PHARMACOLOGY PHARMACOKINETICS Week 2 By Assoc. Prof. Mennatallah Ismail 1  PCT 312 PHARMACOLOGY I “General Pharmacology” Intended learning outcomes (ILOs)  Explain drug absorption, distribution, metabolism & excretion concepts.  Define volume of distribution, clearance, elimination, half-life, first-order, zero order.  Describe the concept of plasma steady state. PHARMACOKINETICS Definition: It describes the principles of absorption, distribution, biotransformation (metabolism) and excretion of drugs. 1- Absorption Absorption is the transfer of a drug from its site of administration to the bloodstream that distributes it throughout the body. Processes of Absorption A,B: Passive Diffusion: Fick’s law; Lipid diffusion; Aqueous diffusion C: Carriers ; facilitated diffusion (cephalexin; with conc. gradient) and Active transport (5-fluorouracil; ATP and against conc. gradient) D: Endocytosis and Exocytosis (too large; vitamin B12) 2 Fick’s Law of Diffusion C1 is the higher concentration C2 is the lower concentration Permeability coefficient is a measure of the mobility of the drug molecules in the medium of the diffusion path. The rate of absorption depends on the: 1. Route of administration 2. Chemical characteristics and the solubility of the drug in the tissue in which it is placed 3. Environment where the drug is absorbed: pH Blood flow to the absorption site Total surface area available for absorption Contact time at the absorption surface Routes of administration other than IV may result in partial absorption and lower bioavailability. BIOAVAILABILITY Definition: is the fraction (F) of the administered dose of a drug that reaches the systemic circulation in an active form. Factors Affecting Bioavailability: 1. First-pass hepatic metabolism 2. Solubility of the drug: For a drug to be readily absorbed, it must be largely hydrophobic, yet have some solubility in aqueous solutions. 3  3. Chemical instability or enzymatic destruction of some drugs in GIT, such as penicillin G and insulin 4. Formulation of the drug (Pharmaceutical Form): Particle size, salt form, crystal polymorphism, enteric coatings and the presence of excipients (such as fillers, binders and dispersing agents) can influence the ease of dissolution and, therefore, alter the rate of absorption. This is critical with some drugs eg. anticoagulants, antidiabetics, adrenal steroids & some antibiotics 2. Distribution & Binding of Drugs  Once a drug has entered the circulation, it is usually distributed to different physical compartments in the body.  Most drugs distribute widely, some are dissolved in plasma water, some are bound to plasma proteins & some are bound to tissue proteins.  Distribution of drugs influences its action eg. crosses the BBB to enter the brain or not.  The strength of this binding would affect the time of its stay in the body & there for duration of action. Volume of Distribution (Vd): Definition: Is the volume in which the amount of drug would need to be uniformly distributed to produce the observed blood concentration. Vd = Total amount of the drug in the body Plasma drug concentration 4  Binding of drugs to plasma proteins: 1. After being absorbed, drugs will be bound to plasma proteins. Binding is reversible and constitutes a reservoir for drugs in plasma. 2. A part of the drug will be free which is the active part. 3. Disease may modify protein bindings of drugs eg renal, liver diseases & hypoalbuminemia. 4. Drugs can displace each other from plasma proteins eg sodium valproate when given to patients taking phenytoin.  Passage of drugs across barriers: 1. The Blood Brain Barrier( BBB ): This barrier provide a unique example of unequal distribution of drugs even if given intravenously from the blood to the brain & CSF. Lipid insoluble drugs do not cross it readily eg.atenolol compared to propranolol( lipid soluble). Lipid soluble substances enter the brain tissue with ease eg IV Diazepam( lipid soluble) & its immediate effect in status epilepticus. 2. Placental Barrier: The fetal &maternal blood streams are separated by a lipoid barrier that readily allows the passage of lipid soluble substances but excludes water soluble compounds. 3. Drug Elimination Drug elimination occurs via 1. Drug Metabolism Before being excreted in the urine, most drugs undergo metabolic alteration, which occurs predominantly in the liver. Metabolic alteration of drug molecules involves two kinds of biochemical reactions which often occur sequentially ( PHASE I & PHASE II reactions) These Phase reactions MOSTLY takes place in the LIVER 5   Phase I Reactions: There is change in the drug molecule by oxidation, reduction or hydrolysis Cytochrome P450 Metabolites (sometimes more Toxic) Eg Propranolol, phenytoin ( Oxidation) Eg.Clonazepam, chloramphenicol (Reduction) Eg.Procaine, aspirin (Hydrolysis)  Phase II Reactions: Involves Conjugation to form glucoronates, sulphates acetylated compd. Highly polar compds to be rapidly eliminated. Eg.Morphine,paracetamol, salicylates ( glucoronic acid ) Eg.Oral contraceptives steroids ( sulphuric acid) Eg.Isoniazid, Dapsone ( acetic acid ) Factors Responsible for Variation in Drug Metabolism  Genetic Factors  Age: eg. Grey baby syndrome in neonate using chloramphenicol.  Fever Thyroid Hormones:  Liver Disease  Induction or Inhibition: of drug metabolism 6  Induction of Drug Metabolism  Enzyme inducers: e.g. Phenobarbital, Phenylbutazone,. Rifampicin, Carbamazepine  Are drugs that stimulate the metabolism of other drugs that are acted upon by P450, and so will decrease their concentration in the blood  Enzyme Inhibitors: e.g. Chloramphenicol, Cimetidine, MAO Inhibitors, ketoconazole, Erythromycin  Those drugs inhibit the metabolism of certain drugs metabolized in the liver by P450, leading to an increase in their blood Level. 7 Pharmacokinetics is important to determine:  The order of reaction (zero or first order).  Plasma half-life concentration (T½).  Correlation between T½ & order of kinetics Order of Kinetics:  First Order Process: o The rate of this process is proportional to the concentration of the drug i.e follow the law of mass action. o Clinically used dosage of most drugs is subject to 1st order kinetic. (increase in dosage increase in action).  Zero Order Processes: o The rate of the process reaches a maximum at which it stays constant in spite of an increase in the dose of the drug. o The processes have limited capacity due to saturation. ( limited amount of enzymes ) o E.g. Phenytoin Zero Order Kinetics First Order Kinetics e.g. Phenytoin e.g. most of the drugs 8 Plasma Half Life Of Drugs ( T½): Is defined as the time taken for plasma concentration of the drug to decrease to half.(50%)  Correlation Between t½ & Order of Kinetics: o In 1st order kinetics, t½ is a constant character. o In zero order kinetics no single value for its t½ can be quoted. The (t1/2) is used to predict: a. The decrease line in plasma concentration of a drug after dose stopping. b. The increase in plasma concentration of a drug after starting dose administration Steady State: When a drug is given, its plasma concentration will rise, until a steady state is reached. At the steady state the rate of administration of a drug is exactly equal to the rate of its elimination. Importance of knowing steady state: Once steady state is reached, using a certain dose, the required effect of the drug is attained and this will produce a constant drug action and therefore there will be no toxicity or decreased therapeutic effect. The steady state level will change as a result of changing: 1. Dose or rate of administration 2. Rate of elimination e.g. with change in liver function (metabolism) or kidney function (renal impairment). 9