Pharmacology I Lecture Notes PDF Fall 2024 GALALA University

Pharmacology I Prof. Mohamed Hamzawy  Bioavailability Bioavailability is a fraction of administered dose of a drug that reaches the systemic circulation in the unchanged form.  Bioavailability Bioavailability of IV route : 100 % as it directly en...

Pharmacology I Prof. Mohamed Hamzawy  Bioavailability Bioavailability is a fraction of administered dose of a drug that reaches the systemic circulation in the unchanged form.  Bioavailability Bioavailability of IV route : 100 % as it directly enters the circulation. The term bioavailability is generally used for drugs given through oral route if 100 mg of a drug is administered orally and 70 mg is absorbed unchanged, the bioavailability is 0.7 or 70%.  Bioavailability Bioequivalent: Two formulation of the same drug having equal bioavailability. Bioinequivalent: if formulation differ in there bioavailability.  Bioavailability Therapeutic equivalence: Two drug formulations are therapeutically equivalent if they are pharmaceutically equivalent (that is, they have the same dosage form, contain the same active ingredient, and use the same route of administration) with similar clinical and safety profiles.  Bioavailability N.B. Therapeutic equivalence: Clinical effectiveness often depends on both the maximum serum drug concentration and the time required (after administration) to reach peak concentration. Therefore, two drugs that are bioequivalent may not be therapeutically equivalent  Bioavailability Determination of bioavailability: by comparing plasma levels of a drug after a particular route of administration with levels achieved by IV administration. By plotting plasma concentrations versus time, AUC can be measured. AUC reflects the extent of absorption of the drug. Bioavailability of oral drug is the ratio of AUC following oral administration to the AUC following IV administration.  Factors influence bioavailability 1. First-pass hepatic metabolism 2. Solubility of the drug 3. Chemical instability 4. Nature of the drug formulation  Factors influence bioavailability 1. First-pass metabolism First-pass metabolism by the intestine or liver limits the efficacy of many oral medications. More than 90% of nitroglycerin is cleared during first-pass metabolism. So, it is primarily administered via the sublingual. Drugs with high first-pass metabolism are given in doses sufficient to ensure enough active drug reaches the site of action.  Factors influence bioavailability 2. Solubility of the drug Very hydrophilic drugs are poorly absorbed due to inability to cross lipid-rich cell membranes. Paradoxically, drugs that are extremely lipophilic are also poorly absorbed, because they are totally insoluble in aqueous body fluids and, therefore, cannot gain access to the surface of cells. For a drug to be absorbed, it must be largely lipophilic, yet have some solubility in aqueous solutions. This is one reason why many drugs are weak acids or weak bases  Factors influence bioavailability 3. Chemical instability Some drugs, such as penicillin G, are unstable in the pH of the gastric contents. Others, such as insulin, are destroyed in the GI tract by degradative enzymes.  Factors influence bioavailability 4. Nature of the drug formulation Drug absorption may be altered by factors unrelated to the chemistry of the drug. e.g. particle size, salt form, crystal polymorphism, enteric coatings, and the presence of excipients can influence the ease of dissolution and, therefore, alter the rate of absorption.  Distribution Is the process by which a drug reversibly leaves the bloodstream and enters the interstitium (extracellular fluid) and the tissues. Factors influence distribution 1. Blood flow 2. Capillary permeability 3. Binding of drugs to plasma proteins and tissues 4. Lipophilicity 5. Volume of distribution  Metabolism (Biotransformation) It means chemical alteration of the drug in the body. Primary sites of drug metabolism is liver , others are –kidney, intestine lungs and plasma. Biotransformation of drug may lead may lead to the following: a. Inactivation b. Active metabolite from an active drug c. Activation of inactive drug (prodrug).  Metabolism (Biotransformation) Chemical alteration of the drug AIMING to convert: Drugs (Active, Non-ionized & Lipid soluble) → Metabolite (Inactive, Ionized & water soluble) → Easily excreted in urine & bile.  Metabolism (Biotransformation) Reactions of drug metabolism The kidney cannot efficiently eliminate lipophilic drugs that readily cross cell membranes and are reabsorbed in the distal convoluted tubules. Therefore, lipid-soluble agents are first metabolized into more polar (hydrophilic) substances in the liver via two general sets of reactions, called phase I and phase II A) Phase-I (Non-Synthetic) 1- Oxidation: - Phenacetin (Active) → Paracetamol (Active) 2- Reduction: - Chloral hydrate (Active) → Tri-chloro-ethanol (More active) 3- Hydrolysis: - Di-acetyl-morphine (Heroin) → Acetic acid + Morphine (Active) a. Phase I reactions utilizing the P450 system The phase I reactions most frequently involved in drug metabolism are catalyzed by the cytochrome P450 system (also called microsomal mixed-function oxidases). The P450 system is important for the metabolism of many endogenous compounds (such as steroids, lipids) and for the biotransformation of exogenous substances (xenobiotics). Cytochrome P450, designated as CYP, is heme-containing isozymes that are located in most cells, but primarily in the liver and GI tract. A) Hepatic Microsomal Enzyme Inducers (Activators): Examples: Phenobarbitone, Phenytoin, Carbamazepine, Rifampicin, Testosterone, Cortisol & Tobacco smoking. They  Metabolism of other drugs e.g. Oral anti-coagulants, Oral hypoglycemics & Oral contraceptives →  Their duration of action. They  Their own metabolism (Auto-induction) → Tolerance. B) Hepatic Microsomal Enzyme Inhibitors: Estrogen, Cimetidine, Chloramphenicol, Erythromycin & Ciprofloxacin are examples of drugs inhibit Hepatic Microsomal Enzyme Inhibitors.  B) Phase-II (Synthetic, Conjugation): Many phase I metabolites are still too lipophilic to be excreted. A subsequent conjugation reaction results in polar, usually more water-soluble compounds that are often therapeutically inactive. Usually leads to inactivation A notable exception e.g. Morphine → Morphine-6-Glucoronoid (More active) - Types: 1- Glucuronic acid → Aspirin, Paracetamol & Chloramphenicol. 2- Acetic acid (Acetylation) → Isoniazide, Sulfonamides & Hydralazine. 3- Methylation → Noradrenaline (→ Active Adrenaline) & Histamine. 4- Glycine → Aspirin Clearance Drugs must be sufficiently polar to be eliminated from the body. Removal of drugs from the body occurs via a number of routes, the most important being elimination through the kidney into the urine. Patients with renal dysfunction may be unable to excrete drugs and are at risk for drug accumulation and adverse effects. A. Renal elimination of a drug Elimination of drugs via the kidneys into urine involves the processes of: Glomerular filtration, Active tubular secretion, Passive tubular reabsorption. B. Clearance by other routes Drug clearance may also occur via the intestines, bile, lungs, and breast milk, among others. Drugs that are not absorbed after oral administration or drugs that are secreted directly into the intestines or into bile are eliminated in the feces. The lungs are primarily involved in the elimination of anesthetic gases (for example, isoflurane). B. Clearance by other routes Elimination of drugs in breast milk may expose the breast- feeding infant to medications and/or metabolites being taken by the mother and is a potential source of undesirable side effects to the infant. Excretion of most drugs into sweat, saliva, tears, hair, and skin occurs only to a small extent. Drug clearance depends on: Total body clearance. Drug half-life. They are important measures of drug clearance that are used to optimize drug therapy and minimize toxicity. The total body (systemic) clearance, CL total, is the sum of all clearances from the drug-metabolizing and drug-eliminating organs. Dosage regimen, design and optimization Designing and optimization of dosage regimen depends on: Patient factors. Drug factors, including how rapidly therapeutic levels of a drug must be achieved. The regimen is then further refined, or optimized, to maximize benefit and minimize adverse effects. Drug–Receptor Interactions and Pharmacodynamics Pharmacodynamics aims to study the actions of a drug on the body and the influence of drug concentrations on the degree of the response. Most drugs exert their effects, both beneficial and harmful, by interacting with receptors (that is, specialized target macromolecules) present on the cell surface or within the cell. The drug–receptor complex initiates series of modifications in biochemical and/or molecular activity of a cell by a process called signal transduction  Pharmacodynamics Most drugs exert their effects by interacting with receptors (that is, specialized target macromolecules) present on the cell surface or within the cell. The drug–receptor complex initiates alterations in biochemical and/or molecular activity of a cell by a process called signal transduction.  Signal Transduction Drugs act as signals, and their receptors act as signal detectors. Receptors transduce their recognition of a bound agonist by initiating a series of reactions that ultimately result in a specific intracellular response. Agonist refers to a naturally occurring small molecule or a drug that binds to a site on a receptor protein and activates it. Second messenger or effector molecules are part of the cascade of events that translates agonist binding into a cellular response.  Signal Transduction A. The drug–receptor complex Cells have many different types of receptors, each of which is specific for a particular agonist and produces a unique response. Cardiac cell membranes, for example, contain β receptors that bind and respond to epinephrine or norepinephrine, as well as muscarinic receptors specific for acetylcholine. These different receptor populations dynamically interact to control the heart’s vital functions.  Signal Transduction The magnitude of the response is proportional to the number of drug-receptor complexes. This concept is closely related to the formation of complexes between enzyme and substrate or antigen and antibody. These interactions have many common features, perhaps the most noteworthy being specificity of the receptor for a given agonist. Most receptors are named for the type of agonist that interacts best with it. For example, the receptor for histamine is called a histamine receptor.  Signal Transduction Although the effect of the drugs centers on the interaction of drugs with specific receptors, it is important to know that not all drugs exert their effects by interacting with a receptor. Antacids, for instance, chemically neutralize excess gastric acid, thereby reducing the symptoms of “heartburn.”.  Signal Transduction B. Receptor states Receptors exist in two states, inactive (R) and active (R*), that are in reversible equilibrium with one another, usually favoring the inactive state. Binding of agonists causes the equilibrium to shift from R to R* to produce a biologic effect. Antagonists occupy the receptor but do not increase the fraction of R* and may stabilize the receptor in the inactive state.  Signal Transduction B. Receptor states Some drugs (partial agonists) cause similar shifts in equilibrium from R to R*, but the fraction of R* is less than that caused by an agonist (but still more than that caused by an antagonist). The magnitude of biological effect is directly related to the fraction of R*. Agonists, antagonists, and partial agonists are examples of ligands, or molecules that bind to the activation site on the receptor.