Pharmacokinetics Lecture 1 PDF

General pharmacology  Pharmacology : The science of drugs. Drugs: Substances used to prevent, diagnose, and treat diseases. Pharmacokinetics: : Describe what is the body does to the drug: absorption, distribution, metabolism and excretion of drugs. Pharmacodynamics: The mechanism...

General pharmacology  Pharmacology : The science of drugs. Drugs: Substances used to prevent, diagnose, and treat diseases. Pharmacokinetics: : Describe what is the body does to the drug: absorption, distribution, metabolism and excretion of drugs. Pharmacodynamics: The mechanism of action and pharmacological action of drugs  PHARMACOKINETICS 1) Absorption: Passage of drug from site of administration to systemic circulation. 2) Distribution: It involves the distribution of the substance throughout the body compartments. 3) Metabolism: It is the break-down of the substance into its metabolites. For lipid soluble (Unionized) 4) Excretion: It refers to the elimination of the un- metabolized drug and its metabolites from the body. Only Water-soluble drug or metabolite  1) Absorption Mechanisms of drug absorption (how drugs cross biological membranes): 1- Passive diffusion: The most common and most important mechanism. it includes: Movement of water-soluble drugs across the aqueous pores (A). Movement of lipid soluble drugs across the cell membrane (B). 2- Carrier mediated transport (C): a) Facilitated diffusion: no energy is required, and the drugs pass according to the concentration gradient by carrier or transporter. b) Active transport: Energy (ATP) is required because the drug movement may be against the concentration gradient by drug carrier or transporter. 3- Endocytosis and exocytosis (D): Drug of high molecular weight binds to the cell membrane then enveloped to allow the drug to move inside/ outside the cell.  Factors affecting absorption: I) Factors related II) Factors related to the patient to the drug I) Factors related to the patient: 1- Route of administration: I.V. and inhalation > I.M. > S.C. > Oral > Topical. 2- Absorbing surface: Vascularity (Skeletal muscle > S.C. tissue). Surface area (Intestine > Stomach). Pathological conditions: Diarrhea decrease oral absorption. 3- Systemic circulation: Shock decrease absorption; oral and subcutaneous routes are not suitable. 4- Specific factors: Intrinsic factor is essential for vitamin B12 absorption. 5- Coadministration of other drugs & food: S.C. adrenaline induces V.C. so decreases absorption of local anesthetics → longer duration of action of local anesthetics. Ca+2 (e.g. in milk) decreases oral absorption of tetracyclines.  Factors affecting absorption: II) Factors related to the Drug: 1- Water and lipid solubility: ↑ lipid solubility → ↑ absorption. 2- Valency: Ferrous iron (Fe+2) is absorbed better than ferric iron (Fe+3). 3- Nature: Inorganic compounds more absorbed than organic compounds. 4- Pharmaceutical preparation: Dosage form: Solution > Suspension > tablet. Excipients containing Ca+2 decreases oral absorption of tetracyclines. 5- Ionization of the drug: Ionization decreases lipid solubility and absorption of drugs. unionized drugs are more absorbed  The effect of pH on drug ionization Most of drugs are weak acid or weak bases. Weak acids are unionized and more absorbed in acidic media (low pH) while weak bases are unionized and more absorbed in alkaline media (high pH). The pH at which the concentrations of the ionized and unionized forms of the drug are equal is termed pKa (Acid dissociation constant). Each drug has its own pKa; A smaller pKa value indicates a stronger acid; a larger pKa value indicates a weaker acid.  A substance will become more lipid soluble in a solution with a pH similar to its own pH. 1. A weak acid is more lipid-soluble in an acidic solution 2. A weak base is more lipid-soluble in an alkaline solution. 3. A weak acid is more WATER-soluble in an alkaline solution 4. A weak base is more WATER-soluble in an acidic solution.  Bioavailability Bioavailability: It is the percentage of drug that reaches the systemic circulation and becomes available for biological effect. Factors affecting bioavailability: 1- The extent of drug absorption. 2- Route of administration: 100% with intravenous. 3- 1st pass effect (1st pass metabolism): It is the metabolism of some drugs in a single passage through gut wall, liver or lungs before reaching systemic circulation. Hepatic 1st pass effect: Nitroglycerin and propranolol Intestinal 1st pass effect: Estrogens.  2) DRUG DISTRIBUTION After absorption the drug is distributed to one or more of the three body compartments: 1) Vascular compartment 2) Vascular and Interstitial compartments 3) Vascular, interstitial and intracellular compartments  2) DRUG DISTRIBUTION Factors affecting distribution of drugs: 1- Blood flow: drug delivered to particular organ is proportional to its blood flow. 2- Lipophilicity: diffusion across cell membranes depends on the drug lipophilicity. 3- Plasma protein binding: Drug in blood exists in two forms: Bound form: inactive, non diffusible and cannot be metabolized or excreted. Free Form: active, diffusible and can be metabolized or excreted. The two forms exist in equilibrium, when fraction of the free form is metabolized or excreted similar fraction is released from plasma protein binding sites. 4- Binding to tissue: Iodides are concentrated in thyroid and salivary glands. Blood-brain barrier (BBB) - Due absence of pore in capillary endothelium with thick basement membrane and surrounding by glial tissues only lipid-soluble drugs can pass. - Inflammation increases permeability of BBB. Placental barrier: Drugs that pass placental barrier may cause: - During pregnancy: Teratogenicity. - During labor: Neonatal asphyxia.  3) Metabolism (Biotransformation) The importance of biotransformation: 1) is the conversion of unionized drugs to ionized, water soluble metabolite which is easily excreted. 2) The liver is the main organ of metabolism but can occur in other organs like lung, kidney and intestine.  Consequences of drug metabolism: 1. Convert active drug to inactive metabolite (most drugs). 2. Convert inactive prodrug into active drug. 3. Convert active drug to active metabolite. 4. Convert drugs to toxic metabolites eg. Paracetamol → hepatotoxic epoxides.  Factors affecting biotransformation: 1. Physiological changes (age, Sex). 2. Pathological factors (liver cell failure). 3. Enzyme induction & enzyme inhibition. Consequences of enzyme induction: 1. Failure of drug action. 2. Drug interactions Consequences of enzyme inhibition on metabolized drugs: 1. Exaggerated pharmacological actions and adverse effects. 2. Increased duration of action and half life of some drugs. 3. Drug interactions.  3) EXCRETION OF DRUGS Kidney is the most important organ for excretion. Excretion occurs through: 1) Glomerular filtration 2) Proximal convoluted tubules (PCT) 3) Distal convoluted tubules Other sites of excretion: Bile and Lungs. ELIMINATION HALF LIFE (t1/2) It is the time required to reduce the plasma concentration of the drug to half the initial concentration (the time required for drug concentration to be changed by 50%). Importance of elimination T1/2: 1- It determines the dosage interval (T). If "t1/2"is very short (minutes), the drug should begiven by IV infusion. 3- If "t1/2"is long, the drug should be administered in loading dose to achieve target concentration (Tc) followed by maintenance dose to keep Tc.