Pharmaco-Kinetics 2 PDF

PHARMACO- KINETICS 2 By Harshika Patel KeMU 3rd year Medicine Basics of Pharmacology and Toxicology Drug metabolism/ biotransformation Enzymatically mediated alteration in drug structure. Transforms lipophilic drugs into more polar readily...

PHARMACO- KINETICS 2 By Harshika Patel KeMU 3rd year Medicine Basics of Pharmacology and Toxicology Drug metabolism/ biotransformation Enzymatically mediated alteration in drug structure. Transforms lipophilic drugs into more polar readily excretable products. (inactivation) Basically, Metabolism/biotransformation is a mechanism of drug elimination because it leads to:- Reduced lipid solubility – increase polarity. Reduced biological activity. Main site - LIVER Major site for drug metabolism, but specific drugs may undergo biotransformation in other tissues, such as the kidney, intestines, and skin(minor). Biotransformation is catalyzed by specific enzymes systems(hepatic microsomal systems) which may also catalyze metabolism of endogenous substances e.g. steroids. Note: Some agents are initially administered as inactive compounds (pro- drugs) and must be metabolized to their active forms. Metabolism may results: 1. Active and More active metabolite Chloroquine - Hydroxychloroquine Amitriptyline - Nortriptyline Diazepam - Oxazepam 2. Activation of inactive drugs Sulindac - Sulindac sulphide Enalapril - Enalaprilat 3. Inactivation of drugs Propranolol Lidocaine Phases of biotransformation Reactions Phase 1 (Non-synthetic reactions) Phase 2 (synthetic reactions) Phase 1 (Non-synthetic reactions) Involve enzyme – catalyzed biotransformation of the drug without any conjugations. Includes, oxidations, reductions and hydrolysis reactions They usually introduce a functional group e.g. – OH; -COOH; -SH; -HN2 which serves as the active center for conjugation in phase II reactions. Examples of enzymes catalyzing these reactions include: - Cytochrome P-450 mono-oxygenase system (mixed function oxidase). - Aldehyde alcohol dehydrogenase - Aldehyde dehydrogenase - Deaminase - Esterase - Amidases - Epoxide hydratases Phase II (synthetic) reactions Are conjugation reactions which involve the enzyme – catalyzed combination of a drug (or metabolite) with an endogenous substance e.g. glucuronide, sulfate, amino acids, glutathione, methyl groups, acetyl groups etc. Enzymes used in phase II reaction include: - Glucoronyl transferase – glucuronide conjugation. -Sulfotransferase – sulfate conjugation. -Transacylase – amino acid conjugation -Acetylases, Ethylases,, -Methylases Cytochrome P-450 mono - oxygenase/ mixed function oxidase Primarily located in liver Play vital role in metabolism of drugs Large variety of P-450 exists Each catalysis metabolism of a unique spectrum of drugs with some overlaps in the substrate specificities Six isozymes are responsible for the vast majority of  P450-catalyzed reactions: CYP3A4, CYP2D6, CYP2C9/10, CYP2C19, CYP2E1, and CYP1A2. Most involved in phase I reactions: Catalyses such reactions as Aromatic & aliphatic hydroxylation, dealkylations at Nitrogen, sulphur, & oxygen atoms; Heteroatom oxidations at Nitrogen, sulphur atoms and reductions at Nitrogen atoms. factors that influence metabolism include : Physiological factors: like starvation, obstructive jaundice , Liver diseases; cardiovascular problem  These depresses microsomal enzyme systems. Age: People in extremes of age have decreased metabolism e.g. young – immaturity enzyme system while the elderly have degenerative enzyme function. Genetically determined differences exist: e.g. isoniazid, procainamide, hydralazine metabolized by acetyltransferase system.  They portray the tendency for fast and slow acetylation which may lead to toxicity from metabolite and parent drug respectively. Prior administration of the particular drug or other drug e.g. repeated administration of a drug may cause induction or inhibition of microsomal enzymes.  Inducers The cytochrome P450 enzymes are an important target for pharmacokinetic drug interactions. Certain drugs, most notably phenobarbital, rifampin, and carbamazepine, are capable of increasing the synthesis of one or more CYP isozymes. This results in increased biotransformation of drugs. 1. Decreased plasma drug concentrations. 2. Decreased drug activity if metabolite is inactive. 3. Increased drug activity if metabolite is active. 4 Decreased therapeutic drug effects Possible uses of enzyme induction 1. Congenital non-haemolytic jaundice  occurred, due to deficient glucoronidation of bilirubin phenobarbitone hastens clearance of jaundice. 2. Cushing’s syndrome: phenytoin may reduce the manifestations by enhancing degradation of adrenal steroids which are produced in excess. 3. Chronic poisonings: by faster metabolism of the accumulated poisonous substance. 4. Liver disease.  Inhibitors Inhibition of CYP isozyme activity is also an important source of drug interactions that leads to serious adverse effects. The most common form of inhibition is through competition for the same isozyme. For example, omeprazole is a potent inhibitor of three of the CYP isozymes responsible for warfarin metabolism.  If the two drugs are taken together, plasma concentrations of warfarin increase, which leads to greater inhibition of coagulation and risk of hemorrhage and other serious bleeding reactions. CYP inhibitors are erythromycin, cimetidine, ketoconazole, and ritonavir, because they each inhibit several CYP isozymes. ONSET OF EFFECT INHIBITOR S INDUCER S Enzyme inhibition occurs by direct effect on Induction involves microsomal enzymes the enzyme, it has a fast time course (within in liver and other organs and increases hours)  compared to inducer. the rate of metabolism by 2–4 fold. Induction takes 4–14 days to reach its peak and is maintained till the inducing agent is being given. Thereafter the enzymes return to their original value over 1–3 weeks.  Drug excretion Removal of a drug from the body occurs via a number of routes. The major routes of excretion include renal excretion, hepatobiliary excretion & pulmonary excretion. The minor routes of excretion are saliva, sweat, tears, breast milk , vaginal fluid & hair. The rate of excretion influences the duration of action of drugs. If the drug is excreted slowly, the concentration of drug in the body is maintained and the effects of the drug will continue for longer period. Routes of drug excretion a. Renal excretion For water soluble and non volatile drugs. The three principal processes that determine the urinary excretion of a drug. – Glomerular filtration – Active tubular secretion – Passive tubular reabsorption The function of glomerular filtration and active tubular secretion is to remove drug out of the body, while tubular reabsorption retain the drug. Various factors influence the renal clearance of drugs Age: normal g.f.r. reduce in old age (~120 ml/min is normal)  In geriatrics overall kidney functions are suppressed and affect the excretion of drug. Small population (at the time of birth) has less developed tubular secretion process and may varies the duration of many drug action like, penicillin, aspirin, cephalosporin. Urine pH may affect the clearance  Weak bases ionize more and are less reabsorbed in urine*.  Weak acids ionize more and are less reabsorbed in alkaline urine. b. Hepatobiliary Excretion The conjugated drugs are excreted by hepatocytes in the liver. After excretion of drugs through bile to the intestine; certain amount of drug is reabsorbed in to the portal vein leading to an entrohepatic cycling which can prolong the action of drug. E.g. Chloramphenicol, estrogen c. Gastro intestinal excretion When a drug is administered orally, part of the drug is not absorbed and excreted in the faces. The drug which do not undergo enterohepatic cycling after excretion in to the bile are subsequently passed with stool. E.g. Aluminum hydroxide changes the stool color in to white, Ferrous sulphate darkens it and Rifampicin gives orange red colour to the stool. d. Pulmonary excretion Many inhalation anesthetics and alcohol are excreted through the lungs. e. Sweat E.g. Rifampicine, metalloids like arsenic are excreted in to the sweat. f. Mammary excretion Many drugs are excreted in to breast milk. Lactating mothers should be cautious about the intake of these drugs because they may enter in to baby through milk and produce harmful effects in the baby. E.g. Ampicillin, Aspirin, Chlorodizepoxide, Streptomycin.  Kinetics of Elimination  Quantitative aspects of renal drug elimination  Elimination occurs in two orders:  First-order kinetics: majority of drugs eliminated thr’ this kinetics  The rate of elimination is directly proportional to the drug concentration (CL remains constant) “However, if the dose is high enough, elimination pathways of all drugs will get saturated”.  Zero-order kinetics: some drug’s elimination kinetics change from 1st to zero/ 2nd order kinetics  The rate of elimination remains constant irrespective of drug concentration,  CL decreases with increase in concentration; or a constant amount of the drug is eliminated in unit time.  Cont’d… Elimination/excretion rate: Extraction ratio = decline of drug concentration in the plasma from the arterial (c1) to the venous(c2) side of the kidney (= c2/c1) Clearance = extcretion rate(mg/min)/ Cp (mg/ml) Total body clearance : is the sum of the clearances from the various drug-metabolizing and drug- eliminating organs. Not possible so   is used to Kinetics of following dosage forms home exercise? Kinetics of continuous administration A. Kinetics of IV infusion B. Kinetics of fixed-dose/fixed-time- interval regimens 1. Single IV injection 2. Multiple IV injections 3. Orally administered drugs Half life (hours): “This is the period of time required for the concentration or amount of drug in the body to be reduced by one-half”. usually consider the half life of a drug in relation to the amount of the drug in plasma. A drug's plasma half-life depends on how quickly the drug is eliminated from the plasma. Adjustment in dosage is required…! When and T1/2 inc’ by: T1/2 dec’ by: why? 1) diminished renal plasma 1)increased hepatic flow or hepatic blood flow, Eg. in cardiogenic shock, blood flow, heart failure, or 2)Dec’ protein hemorrhage; 2) Dec’ extraction ratio, Eg. binding, in renal disease 3)Inc’ metabolism. 3) Dec’ metabolism, Eg. when another drug inhibits its biotransformation or cirrhosis  Therapeutic drug monitoring Plasma concentration of drug during the therapy It is important in the following conditions: 1. Drugs with low safety margin, e.g. —digoxin, lithium, cyclosporine 2. If individual variations are large, e.g.— antidepressants, lithium. 3. Potentially toxic drugs used in the presence of renal failure, e.g. —aminoglycoside antibiotics, vancomycin. 4. In case of poisoning. 5. In case of failure of response without any apparent reason, e.g. —antimicrobials Pharmacodynamics Pharmacodynamics include: Mechanism of actions of the drug. How does a drug act in the body? Effects of the drug: both beneficial & harmful effects. What does a drug do in the body *Remember this, Drugs modify physiological activity but do not confer any new function on a tissue or organ in the body. Meanwhile, drug molecules are few compared to tissue molecules  drugs are not distributed erratically, otherwise  the response would be negligible.  Hence drugs have to bind to particular constituents of cell/tissue to exert their effect. Drug specificity is important However, no drug is completely specific in its actions. In many cases, at higher dose of a drug  it affects different targets other than the main one and this can lead to side-effects E.g. TCA block reuptake at amine pump but also block acetylcholine receptors. Most drugs produce effects by binding to protein molecules Others may bind to macromolecules like DNA and RNA among other sites. The common protein molecules on which drugs bind to include Enzymes Carrier molecules Ion channels Receptors A. Enzyme For examples: Angiotensin converting enzyme is inhibited by enalapril (an antihypertensive). This leads to less formation of angiotensin II, causing vasodilatation and less sodium and water retention. b. Ion-channel Protein molecules designed to form water-filled pores that span the membrane and can switch between open and closed states. 1. Ligand-gated ion channels/ ionotropic receptors incorporate a receptor and open only when an the receptor is occupied by an agonist. 2. voltage – gated ion channels e.g. Na+, K+ & Ca++ channels – open when there is polarization of the cell. Drugs affect ion channels function by interacting either with the receptor site of ligand – gated channels or with other parts of the channel molecule. Interaction can be: Direct – Drug bind to the channel & alter its function or Indirect which involves G-protein and other intermediaries like allosteric sites. C. Carrier molecules Carrier proteins are for transport of ions and small organic molecules across cell membranes –insufficiency of lipid soluble to penetrate lipid membrane on their own. Examples of c. molecule mediated processes:- Renal tubule transport of ions & many organic molecules. Uptake of transmitter precursors e.g. choline or neurotransmitter e.g. noradrenalin, 5-HT3, glutamate & peptides by nerve terminals. Some C. proteins are inhibited by some drugs: Weak acid carrier – probenecid Noradrenalin uptake by reserpine Proton pump – omeprazole (gastric mucosa) Na+/ K+ pump – cardiac glycosides  d. Receptors Mechanisms of drug action In Two types: gener A. Receptor mediated mechanism al Receptors- targets of drug action. “It is a protein molecule that receives chemical signals from outside a cell”. May present either on the cell surface or inside the cell. D + R → DR → Biological effect Where; D=Drug, R=Receptor, DR=Drug Receptor Complex B. Non-receptor mechanisms Simple physical or chemical reaction. E.g. Antacids: neutralization reaction. Types of receptors Cytosolic enz activity GDP cAMP Intracellular receptor  Induced fit model The binding of substrate is accompanied by quiet larger alteration in the structure of the active site of the receptor. Different theories involved Lock and key theories Rate theory (association and dissociation rate from its target) Occupation theory (magnitude of drug response depends on proportion of receptors occupies by the drugs) Resting state model: Resting Activated Eg, high and moderate affinity towards receptors-drugs response rate might be full agonist and partial agonist  Implications of drug-receptor interaction Drugs can potentially alter rate of any function in the body. Drugs cannot impart entirely new functions to cells. Drugs do not create effects, only modify ongoing ones. Drugs can allow for effects outside of normal physiological range. Three aspects of drug receptor function 1. Receptors determine the quantitative relation between drug concentration and response. This is based on receptor’s affinity to bind and it’s abundance in target cells. 2. Receptors (as complex molecules) function as regulatory proteins and components of chemical signaling mechanisms that provide targets for important drugs. 3. Receptors determine the therapeutic and toxic effects of drugs in patients. Dose response relationship Dose: amount of a drug required to produce desired response in an individual. Dosage: the amount, frequency and duration of therapy. Potency: measure of how much a drug is required to elicit a given response. The lower the dose, the more potent is the drug. Efficacy: the intrinsic ability of the drug to produce an effect at the receptor. Maximal efficacy: largest effect that a drug can produce.  Dose response relationship... Drug response depends on: Affinity of drug for receptor. Intrinsic activity (degree to which a drug is able to induce intrinsic effects). We want both efficacy and affinity which cause 100% good response Agonism and Antagonism Agonists facilitate receptor response. Antagonists inhibit receptor response.  Types of drug-receptor interactions Agonist drugs: bind to and activate the receptor which directly or indirectly brings about the effect. Some agonists inhibit their binding molecules to terminate the action of endogenous agonists. E.g. slowing the destruction of endogenous acetylcholine by using acetyl cholinesterase inhibitors. Antagonist drugs: bind to a receptor to prevent binding of other molecules, but lack intrinsic activity. Atropine decreased the effects of acetylcholin. …cont Partial agonist drugs: acts as agonist or antagonist depending on the circumstance, have affinity but have lowered maximal efficacy. E.g. Pindolol can act as an antagonist if a “full agonist” like Isoproterenol is present. Inverse agonist: Is a ligand which produces an effect opposite to that of the agonist by occupying the same receptor. E.g. metoprolol in some tissues.  Graded dose–response relations As the concentration of a drug increases, its pharmacologic effect also gradually increases until all the receptors are occupied (the maximum effect). It is used to determine affinity, potency, efficacy and characteristics of antagonists.  Potency Is relative strength of response for a given dose. Effective concentration (EC50) is the concentration of an agonist needed to elicit half of the maximum biological response of the agonist. The potency of an agonist is inversely related to its EC50 value. D-R curve shifts left with greater potency.  Efficacy Maximum possible effect relative to other agents. Indicated by peak of D-R curve. Full agonist = 100% Partial agonist = 50% Antagonist = 0% Inverse agonist = -100%  Quantal(cumulative) dose response r/ship: Is between the dose of the drug and the proportion of a population that responds to it. For any individual, the effect either occurs or it does not (‘all’ or ‘none’). Are useful for determining doses to which most of the population responds; ED50%, TD50%, LD50%, TI(r/ship b/n dose & toxicity) & inter subject variability in drug responses. They do not predict idiosyncratic reactions and hypersensitivity. Home work: refer book Understand the dose – response relationship by using different methods, like 1. Graded dose response relationship 2. Quantal (cumulative) dose- response relationship  Therapeutic index Median Lethal Dose (LD50): dose which would be expected to kill one half of a study population. Median Effective Dose (ED50): dose which produces a desired response in 50% of the test population. Therapeutic Index: gives a rough idea about the potential effectiveness and safety of the drug in humans. Therapeutic Index (TI) = LD50/ED50 The smaller the TI, the less safer the drug is. Margin of safety=LD1/ED99. Therapeutic Index… Risk- benefit ratio Very frequently used  a judgement on the estimated harm (adverse effects, cost, inconvenience) vs expected advantages (relief of symptoms, cure, reduction of complications/mortality, improvement in quality of life). The ratio can hardly ever be accurately measured for each instance of drug use, because ‘risk’ is the probability of harm; and harm has to be qualified by its nature, quantum, time-course (transient to life- long) as well as the value that the patient attaches to it The physician has to rely on data from use of drugs in large populations (pharmacoepidemiology) and his own experience of the drug and the patient. Factors modifying the dosage & action of drugs DO HOME  Age EXECERCISE:  Gender ELABORATE EACH  Race/species FACTORS AND TRY  Body weight/size TO DISCUSS  Genetics APPROPRIATELY  Route of administration  Food and time of administration  Physiological state  Pathological/Disease states  Other drugs  Cumulation  Tolerance (natural and acquired)  Emotional conditions/psychological factors Dosage calculation For exceptionally obese or lean individuals Individual dose = BW (kg)/70 × average adult dose Individual dose = BSA(m^2)/ 1.7× average adult dose  Drug- Drug interactions Consequences of Drug- Drug Interactions 1. Intensification of effects: increased therapeutic or adverse effects. Additive Drug Effects (Summation): 1 + 1 = 2. Most frequently seen when two drugs possess similar intrinsic activity. E.g. sedative-hypnotic type drugs (i.e., barbiturates, alcohol, benzodiazepines (diazepam, etc.) administered in combination will produce additive effects resulting in over-sedation. Synergism - the effect of two drugs in combination is greater than the sum of the drugs administered alone (1 + 1 > 2). E.g. Aminoglycosides with penicillins. Potentiation – one substance alone does not have effect but when added to another chemical, it becomes effective. (1 + 0 > 1). 2. Reduction of effects – inhibit drug effects; Either beneficial or detrimental. Antagonism: it occurs when the effect of one drug is diminished by another drug. (1+1