Pharmacokinetics - Lecture notes 1 PDF

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PHARMACOKINETICS Pharmacokinetics is the quantitative study of drug absorption, distribution, metabolism and excretion and its mathematical relationship. Pharmacokinetic knowledge allows adjustment of dosage schedules according to body size and composition, circulatory state, hepatic and renal function. The three most important pharmacokinetic parameters are: 1. Bioavailability 2. Volume of distribution 3. Clearance.

Absorption of Drugs Absorption is the passage of the drug through body barriers or cell membranes to reach its site of action. Diffusion is the most important means by which drugs enter the body and are distributed within it. It is dependent on the drug being lipid soluble. Unionized drugs are lipid soluble and diffusible. Ionization is pH-dependent. Most drugs are weak organic acids or bases and, in solution, they are ionized to different degrees depending on the pH of the solution and the pKa of the drug. pKa (Ionization Constant): It is the pH at which the drug molecules are half ionized and half non-ionized. Clinical Significance of pKa The pH of the body affects the diffusion of drugs across cell membranes. 1. G.I.T: Aspirin (weak acid) is mostly unionized in the acid pH of the stomach, therefore well absorbed from the gastric mucosa while weak bases such as Theophylline are absorbed from the intestine (alkaline pH). 2. Kidney: In drug poisoning, renal elimination of drugs can be enhanced by changing urinary pH. This increases drug ionization and inhibits tubular reabsorption. Examples: Alkalinization of urine in poisoning by acidic drugs, e.g. Salicylate Acidification of urine in poisoning by basic drugs, e.g. Amphetamine.

Bioavailability It is the percentage of drug released from a formulation that reaches the systemic circulation and becomes available for biological effect. It is calculated by comparison of the area under the serum concentration-time curve (AUC) after I.V.I with that observed when the same dose is given by another route.

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Plasma

Serum Concentration-Time Curve

Time

Factors Affecting Bioavailability: I. Factors affecting G.I.T absorption. II. First pass metabolism. I. Factors Affecting Drug Absorption from G.I.T 1). Drug: Molecular weight, Lipophilicity, pKa, stability in gut contents 2). Formulation: Disintegration time, rate of dissolution, excipients 3).Patients: pH of gut, rate of gastric emptying, transit time, surface area available for absorption, presence of G.I.T disease and other drugs can modify G.I absorption of drugs. Clinically important examples of drugs having variable bioavailability include: Digoxin, Phenytion, Prednisolone, Warfarin. II. First-Pass Metabolism (Pre-systemic Elimination) It is the metabolism of some drugs in a single passage through the liver, gut wall or the lungs before reaching the systemic circulation to the liver. Some drugs are extensively metabolized in their first pass, e.g. organic nitrates (nitroglycerine) and B-blockers (Propranolol) - Intestinal first-pass effect due to intestinal mucosal metabolism (Isoprenaline and Tyramine). - Pulmonary drug metabolism after aerosol inhalation e.g. Isoprenaline and Nicotine. The first-pass effect can be avoided by: Sublingual, Parenteral, and to some extent by rectal administration.

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Distribution of Drugs After a drug is absorbed, it will distribute between blood and tissue The drug passes through body compartments (Plasma, intestinal and intracellular fluids) which are divided by capillary wall and cell membrane. Volume of distribution (Vd): - It is defined as the apparent volume that would accommodate all drugs in the body if its concentration throughout the body was the same as that in the plasma. Vd = Amount of drug in the body / Plasma concentration. -

Small Vd is favored by: low lipid solubility, high plasma protein binding, low level of tissue binding (The reverse is true).

Importance of Vd: 1- It is an estimate of the extent of extravascular tissue uptake of drugs: Small Vd (e.g. Frusemide) indicates that tissue uptake is limited. Large Vd (e.g. Digoxin) indicates extensive tissue distribution. 2- In cases of toxicity: Dialysis is not useful for drugs with high Vd because of extensive tissue distribution. Dialysis is useful for drugs with low Vd where most of the drug is in the circulation. 3- Vd is important to calculate the size of a loading dose and to estimate the fluctuations in plasma levels during repetitive dosing (Vd = Dose / plasma concentration). Factors affecting distribution of drugs: 1- Physical-chemical properties of the drug, e.g. Lipophilicity 2- Size of the tissue and its amount of blood flow. 3- Binding to plasma proteins. 4- Binding to cell and tissue constituents.

Drug binding to plasma proteins -

Proteins responsible for binding include Albumin and alpha-1-acid glycoprotein. The bound protein is inactive, non-diffusible, cannot be metabolized or excreted. The free drug is active, diffusible and can be metabolized and excreted. The two functions exist in equilibrium, when the free part is metabolized and/or excreted; another part is released from the plasma proteins. Results of binding to plasma protein: - Drugs with higher affinities to plasma proteins can displace drugs with lower ones.

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It provides a reservoir as the bound part is in equilibrium with the free part. It prolongs the half life of the drug because the bound part is not metabolized or excreted. Binding of drugs to plasma proteins determines its Vd and tissue penetration. Binding of a drug may facilitate drug absorption by reducing its free concentration in the plasma. The concentration of the active or free part of highly protein bound drugs may be low to be effective against dangerous infections.

Drug binding to cell and tissue constituents 1. 2. 3.

It is due to an affinity to some cellular constituents, Examples; Chloroquine is concentrated in the liver. Tetracyclines deposit in the bone and teeth as they chelate calcium. Iodides are concentrated in the thyroid and salivary glands.

BIOTRANSFORMATION -

These are the changes that occur to drugs after absorption until excretion. Drug metabolism occurs mainly in the liver, though also in other organs, e.g. intestinal lumen or wall, lung, plasma, skin and kidney.

Consequences of drug metabolism; 1- Abolishes the activity of most drugs 2- Promotes or increases the activity, e.g. Prednisone to Prednisolone. 3- Changes active to another active substance, e.g. Codeine to Morphine. Types of Biotransformation reactions: 1- Non-synthetic (Phase I): It converts the parent drug to a more polar metabolite which is excreted or becomes liable to subsequent conjugation or phase II reactions. Phase I reactions include: Oxidation, Reduction, and Hydrolysis. 2- Synthetic (Phase II): The body adds one of its components to the drug ‘conjugation’ to form highly polar rapidly eliminated conjugates. Products are always inactive. Types of metabolizing enzyme systems: Microsomal enzyme systems. Non-microsomal enzyme systems. Factors affecting biotransformation: 1- Species variations 2- Age: Extremes of age are more susceptible to drug effects. 3- Sex: Estrogen inhibits while testosterone stimulates microsomal enzymes. 4- Pathological factors: In liver disease, drug metabolism is depressed. The metabolism of some drugs is reduced in cases of heart failure and shock that reduce the hepatic blood flow.

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5- Environmental factors, e.g. tobacco smoking and pesticides. 6- Drugs can stimulate (enzyme induction) or inhibit (enzyme inhibition) microsomal enzymes. Enzyme Induction (Drugs that stimulate drug metabolism) Certain drugs stimulate microsomal enzymes increasing their own metabolism and metabolism of other drugs. Examples: Phenytoin, Carbamazepine, Phenobarbitone, Rifampicin, Nicotine. Enzyme induction is reversible, it occurs over a few days and it passes off over two to three weeks after withdrawal of the inducer. Importance of Enzyme Induction; 1- It is the cause of some drug interactions. 2- Tolerance is sometimes explained by a drug inducing its own metabolism e.g. ethyl alcohol, continued oral steroid therapy. 3- In therapy: In hyperbilirubinemia, phenobarbitone induces biliribin conjugation. 4- It is a mechanism to adapt to environmental pollutants (enzyme induction increases metabolism of pollutants reducing their toxic effects). Enzyme Inhibition It is a cause of serious drug interactions. It occurs faster than enzyme induction. Examples: Chloramphenical, Erythromycin, Ciprofloxacin, Ketoconazole, MAOI’s, Cimetidine.

DRUG CLEARANCE It is the measure of the body’s ability to eliminate drugs. It is the volume of a fluid from which all the drug is removed per unit time. Clearance (Cl) = Rate of elimination / Drug concentration Elimination of drugs from the body may involve processes occurring in the kidney, liver, lung and other organs. The two major processes are: 1- Hepatic metabolism - biliary excretion. 2- Renal filtration - Secretion. Total body clearance is the sum of all individual organ clearance which consists of: Renal Clearance and non-renal clearance. Factors affecting Drug Clearance; 1- Blood flow to the clearing organ. 2- Binding of the drug to plasma proteins. 3- Activity of processes responsible for drug removal as hepatic enzymes, glomerular filtration rate and secretory processes.

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Hepatic Clearance. Hepatic clearance = hepatic blood flow X extraction ratio. Extraction Ratio (E):- It is the proportion of drug removed by a single transit of blood through an organ. E = (arterial drug conc.) – (venous drug conc.) / (arterial drug conc.) Elimination half-life (t1/2):- It is the time required to reduce the plasma concentration of the drug to half the initial concentration. Elimination half-life = 0.693 Vd / Cl Volume of elimination t1/2 ; 1- It indicates the time required to attain steady state concentration (Css). Css is the concentration of the drug when the rate of absorption equals the rate of elimination. For most drugs, Css is reached after 4-5 half-lives following repeated administration every half-life. 2- It determines the dosage interval. For most drugs, inter dose fluctuations in the blood level are acceptable when the dosage interval equals t1/2. 3- It is an index of drug clearance (t1/2 = 0.693 Vd / Cl). Types of Elimination Kinetics I. First Order Kinetics: For most drugs, clearance is directly proportional to the concentration of the drug in the plasma. This means that a constant ratio of the drug is eliminated per unit time. This is because the capacity of metabolizing enzymes and carrier systems responsible for drug elimination is unlimited. Characteristics of First Order Kinetics: 1. Constant half-life. 2. Bioavailability, Steady state concentration and the amount of drug excreted unchanged in urine; all are proportional to the dose. 3. The time required to reach Css is 5 times the t1/2. 4. Drug metabolites do not vary with the dose. II. Zero Order Kinetics: Drug elimination occurs at a constant rate and independent of the concentration of the drug in the plasma. This means that a constant amount of drug being eliminated per unit time, e.g. ethanol clearance. This is because the capacity of the metabolizing enzymes and carrier systems responsible for drug elimination is very limited. Characteristics of Zero Order Kinetics: 1. Half-life increases with dose. 2. The time required to reach Css is unpredictable 3. Bioavailability, Css and renal clearance are not proportional to the dose

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4. Drug metabolites may vary with the dose (increasing the dose of the drug results in depletion of metabolizing enzyme with diversion of the drug to other metabolic routes giving different metabolites). III. Saturable Kinetics: The elimination of some drugs as Phenytoin, Salicylate, and Theophylline does not follow 1st Order kinetics throughout the dose range. They follow 1st Order kinetics in low concentrations and Zero Order kinetics at higher concentrations when the elimination processes become saturated. Modest changes in dose or bioavailability of these drugs may produce unexpected toxicity. Drug interactions are also common.

DOSAGE REGIMENS Maintenance Dose (m.d) It is the dose needed to keep the plasma drug concentration constant at a steady state i.e. to compensate for drug loss between doses. Drugs are administered in a series of repetitive doses or continuous infusion to maintain the target plasma concentration at steady state. The rate of drug administration is adjusted such that the rate of input equals the rate of loss according to the equation; m.d = Css X Cl Loading Dose (L.d) L.d = Css X Vd It is the dose given at the onset of therapy to achieve rapid increase in plasma drug concentration to reach Css. It is used with drugs that have a long t1/2 (Amiodarone, Digoxin) or when there is urgent demand....