PCT312 Pharmacology I Week 3 PDF

PCT312 PHARMACOLOGY I GENERAL PHARMACOLOGY PHARMACOKINETICS CONT. PHARMACODYNAMICS Week 3 By Assoc. Prof. Mennatallah Ismail 1  PCT 312 Pharmacology I “General Pharmacology- By the end of this lecture,...

PCT312 PHARMACOLOGY I GENERAL PHARMACOLOGY PHARMACOKINETICS CONT. PHARMACODYNAMICS Week 3 By Assoc. Prof. Mennatallah Ismail 1  PCT 312 Pharmacology I “General Pharmacology- By the end of this lecture, students will be able to:  Define clearance, and elimination  Describe the concept of plasma steady state. Importance of t1/2 1- Determine doing frequency 2- To estimate time to reach steady state 3- Estimate time required for drug removal after stopping it Steady State  When the drug is first administered, the rate of administration is much greater than the rate of elimination, because the plasma concentration is so low.  As the drug continues to be administered, the rate of drug elimination gradually increases, whereas the rate of administration remains constant.  Eventually, as the plasma concentration rises sufficiently, the rate of drug elimination equals the rate of drug administration. At this point, the steady-state equilibrium is achieved. The time to reach the steady state is a function of the elimination half-life of the drug. Any first- order process requires about 4-5 half-lives to be completed. 2 Css: The steady-state drug concentration depends on the drug dose administered per unit of time and on the half-life of the drug. Using smaller doses at shorter intervals reduces the amplitude of fluctuations in drug concentration. Factors affecting the steady state Dose or Rate of administration Rate of elimination e.g: Change in liver function or kidney function Drug Excretion Excretion is the removal of drug from body fluids and occurs primarily in the urine. Other routes include in bile, sweat, saliva, tears, feces, breast milk, and exhaled air. 1. Glomerular filtration:  Free Drug The glomerular filtration rate (GFR) is normally about 90-120 mL/min but may diminish significantly in renal disease. Lipid solubility and pH do not influence the passage of drugs into the glomerular filtrate. However, variations in GFR and protein binding of drugs do affect this process. 2. Proximal tubular secretion: Secretion primarily occurs in the proximal tubules by two energy-requiring active transport systems: one for anions and one for cations. Each of these transport systems shows low specificity and can transport many compounds. Thus, competition between drugs for these carriers can occur within each transport system. For example, the secretion of penicillins and other weak acids is inhibited by probenecid, an agent used to treat gout. 3 3. Distal tubular reabsorption: As a drug moves toward the distal convoluted tubule, its concentration increases and exceeds that of the perivascular space. The drug, if uncharged, may diffuse out of the nephric lumen, back into the systemic circulation.  Ion trapping/ forced diuresis Manipulating the urine pH to increase the fraction of ionized drug in the lumen may be done to minimize the amount of back diffusion and increase the clearance of an undesirable drug. As a general rule, weak acids can be eliminated by alkalinization of the urine, whereas elimination of weak bases may be increased by acidification of the urine. This process is called “ion trapping.” For example, a patient presenting with phenobarbital or aspirin (weak acid) overdose can be given bicarbonate, which alkalinizes the urine and keeps the drug ionized, thereby decreasing its reabsorption. Total body clearance It is defined as the volume of body fluid (blood/ plasma) from which a drug is removed per unit of time. Drug clearance may also occur via the intestines, bile, lungs, and breast milk, among others. 4 Biliary excretion E.g. Digoxin Biliary excretion favors compounds with high molecular weight. Conjugation, particularly with glucuronate, increases biliary excretion. After the bile empties into the intestines, a fraction of the drug may be reabsorbed into the circulation and eventually return to the liver. This phenomenon is called enterohepatic cycling. Excreted conjugated drugs can be hydrolyzed back to the parent drug by intestinal bacteria, and this facilitates the drug’s reabsorption. Biliary excretion eliminates substances from the body only when some of the excreted drug is not reabsorbed from the intestine. Renal Clearance Drug clearance = creatinine clearance 100 ml/min??? Drug clearance > creatinine clearance ??? Drug clearance < creatinine clearance ??? Drugs that are eliminated primarily by glomerular filtration, with little tubular secretion or reabsorption, will have a renal clearance approximately equal to the creatinine clearance, which is normally about 100 mL/min in an adult. A renal drug clearance higher than the creatinine clearance indicates that the drug is a substance that undergoes tubular secretion. A renal drug clearance lower than the creatinine clearance suggests that the drug is highly bound to plasma proteins or that it undergoes passive reabsorption from the renal tubules. 5 Total CL is a composite estimate reflecting all mechanisms of drug elimination and is calculated as follows: 𝑉𝑑 Cl = 0.693 × 𝑡1/2 Dosage Calculations Loading Dose Sometimes rapid obtainment of desired plasma levels is needed (for example, in serious infections or arrhythmias). Therefore, a “loading or priming dose” of drug is administered, followed by a maintenance dose to maintain the steady state A loading dose is most useful for drugs that have a relatively long half-life.  Divided loading dose 𝑉𝑑 𝑃𝑙𝑎𝑠𝑚𝑎 𝐶𝑜𝑛𝑐  Loading Dose= ×𝐷𝑒𝑠𝑖𝑟𝑒𝑑 𝐹 Maintenance Dose It is given to establish or maintain the desired steady-state plasma drug concentration. The amount of drug to be given is based on the principle that, at the steady state, the rate of drug administration equals the rate of drug elimination. Maintenance Dose = Rate of drug elimination × Dosage interval= 𝑨𝒗𝒆𝒓𝒂𝒈𝒆 𝑪𝒔𝒔×𝑪𝒍 × Dosage interval 𝑭 Dose Adjustment Assume a heart failure patient is not well controlled due to inadequate plasma levels of digoxin. The difference between the two values is the additional dosage needed= Vd (C2 − C1) 6  PHARMACODYNAMICS Intended learning outcomes (ILOs) Discuss drug-receptor interaction. List targets by which drugs can interact to exert an effect. Define Potency, Efficacy, Therapeutic Index. Definition: Is the study of the biological & therapeutic effects of drugs i.e. what a drug does to the body. Main targets of drug action  Receptors  Ion channel  Enzymes  Carrier molecules Drug Receptors: They are a sensing elements and specialized target macromolecule, present on the cell surface or intracellularly, that bind a drug & mediate its pharmacologic actions. Receptors recognize a specific chemical signal and initiate a series of events that leads to the final response such as muscle contraction, muscle relaxation, altered gland secretion The magnitude of the response is proportional to the number of drug- receptor complex. Drug+R → Drug R complex → Biological Effect 7  Drugs acting on receptors Agonist: Drugs which stimulate a receptor to elicit a response. It initiates changes in cell function, producing various effects. Its potency depends on: Affinity: tendency to bind to receptor Efficacy: ability to initiate changes which lead to effects on binding to receptors - Full agonist: agonists with high efficacy that produces maximal effects - Partial agonist: agonists with intermediate efficacy that produces submaximal effects - Inverse agonists, which are also called negative antagonists. Signal transduction proceeds at a basal rate and that an inverse agonist decreases the rate of signal transduction. The β-carboline drugs act to decrease chloride conductance by the GABAA receptor–chloride ion channel, and this can cause anxiety and seizures. Antagonist: Drugs which block a receptor to prevent the action of an agonist. It binds to the receptor without initiating changes; thus its efficacy is zero which means no intrinsic activity These receptors may be divided into four families: 1) ligand-gated ion channels 2) G protein–coupled receptors 3) enzyme-linked receptors 4) Intracellular receptors 8