PK metabolism and elimination pharmacology.pptx

PK metabolism and elimination pharmacology

1. PHARMACOKINETICS Metabolism Elimination By Mumbi Ng’ang’a

2. Drug metabolism/ biotransformation Enzymatically mediated alteration in drug structure. Transforms lipophilic drugs into more polar readily excretable products. Basicaly , Metabolism or biotransformation is a mechanism of drug elimination because it leads to:- Reduced lipid solubility – increase polarity. Reduced biological activity. Liver – major site for drug metabolism, but specific drugs may undergo biotransformation in other tissues, such as the kidney and the intestines. 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.

3. Examples Active More active metabolite Chloroquine - Hydroxychloroquine Amitriptyline - Nortriptyline Diazepam - Oxazepam Inactive (Pro-drug) Active metabolites Sulindac - Sulindac sulphide Enalapril - Enalaprilat

4. Phases of biotransformation Reactions Phase 1 (Non-synthetic reactions ) Phase 2 (synthetic reactions )

5. 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

6. 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

7. 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 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.

8. 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.

9. 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

10. 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.

11. 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.

12. Quantitative aspects of renal drug elimination Extraction ratio = decline of drug concentration in the plasma from the arterial (c1) to the venous(c2) side of the kidney (= c2/c1) Total body clearance : is the sum of the clearances from the various drug-metabolizing and drug-eliminating organs . Clearance(L/H/70Kg): the rate of drug elimination divided by the plasma concentration of the drug.

13. 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.

14. Adjustment in dosage is required…! T1/2 inc’ by: diminished renal plasma flow or hepatic blood flow, Eg. in cardiogenic shock, heart failure, or hemorrhage; Dec’ extraction ratio, Eg. in renal disease Dec’ metabolism, Eg. when another drug inhibits its biotransformation or cirrhosis When and why? T1/2 dec’ by: increased hepatic blood flow, Dec’ protein binding, Inc’ metabolism.

15. 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.

16. 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.

17. 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.

18. 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.

19. 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.

20. Pharmacodynamics

21. 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 organism 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.

22. Drug specificity is important  However, no drug is completely specific in its actions. In many cases, at higher dose of a drug  affect 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

23. A. Enzyme For examples: Angiotensin converting enzyme is inhibited by enalapril (an antihypertensive). This leads to less formation of angiotesin II, causing vasodilatation and less sodium and water retention.

24. b. Ion-channel Protein molecules designed to form water-filled pores that span the membrane and can switch between open and closed states. Ligand-gated ion channels / ionotropic receptors incorporate a receptor and open only when an the receptor is occupied by an agonist. 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.

25. 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

26. d. Receptors Mechanisms of drug action Two types: A. Receptor mediated mechanism 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. In general

27. Types of receptors GDP cAMP Cytosolic enz activity

28. Intracellular receptor

29. Induced fit model The binding of substrate is accompanied by quiet larger alteration in the structure of the active site of the receptor.

30. 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.

31. 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.

32. 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.

33. 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).

34. Agonism and Antagonism Agonists facilitate receptor response. Antagonists inhibit receptor response.

35. 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 acetylcholine.

36. … 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.

37. Full agonist - A drug with high positive efficacy & produce the system maximal response. Partial agonist - maximal response to the ligand is below the system maximal response. Antagonists- no efficacy or such a low level of efficacy with no visible response. Inverse agonist- A ligand with negative efficacy can reduce the basal response .

38. 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.

39. 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.

40. 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%

41. 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.

42. 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.

43. Therapeutic Index…

44. 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.

45. Factors modifying the dosage & action of drugs Age Sex/ gender * Body weight Species and race Genetics ( pharmacogenetics = improving precision in drug therapy, pharmacogenomics= to guide the choice of drug and dose on an individual basis ) Drug tolerance Drug intolerance Disease states

46. 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 BSA (m2) = BW (kg)^0.425 × Height (cm)^0.725 × 0.007184 Child dose = AGE/20× adult dose ... (Dilling’s formula)

47. Drug- Drug interactions Consequences of Drug- Drug Interactions 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).

48. 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<1 ). Types of antagonism; Chemical antagonism Pharmacokinetics antagonism Antagonism by receptor block Non-competitive antagonism i.e. block receptor – effector- linkage Physiological antagonism

49. Antagonism Occurs when two or more drugs oppose the action of one another. Types Chemical antagonism :e.g. use of chelating agents e.g. dimercaprol that bind to heavy metals & reduce their toxicity. Antacids + tetracycline form a complex which is excreted in feces. Pharmacokinetics antagonism: Situation where the concentration of the active drug at the site of action is reduced. Antagonism by receptor block Receptor – block antagonism involves two mechanisms:- i . Reversible competitive antagonism ……? ii. Irreversible, non-equilibrium competitive antagonism. ........?

50. d. Non-competitive antagonism i.e. block receptor – effector- linkage Situation where the agonist blocks at some point the chain of events that lead to the production of a response by the agonist e.g. Veraparmil & nifedipine  block the influx of Ca++ ions through the cell membrane  thus block the contraction of the smooth muscle produced by some drugs cholinesterase inhibitors like neostigmine e. Physiological/ functional antagonism: Interaction of two drugs whose opposing actions in the body tend to cancel each other. Also called functional antagonism e.g. B-adrenoceptor blocker overdose cause bradycardia.  relieved by atropine which inc. heart rate by blocking parasympathetic system. Bronchoconstriction by histamine during anaphylactic shock can be counteracted by adrenaline which relaxes bronchial smooth muscles (B2 adrenoceptor effect). Histamine acts on parietal cells to increase Hcl production while omeprazole blocks this effect by inhibiting proton pump

51. Clinically important Drug interactions may occur under the following circumstances : With drugs that have steep dose- response curve and small therapeutic index i.e. small quantitative changes at target site lead to substantial changes in effect e.g. Digoxin, theophylline and Lithium. Enzyme inducers/ inhibitors Drugs that exhibit saturable metabolism (zero-order kinetics) e.g. Phenytoin, theophylline. In polypharmacy In extremes of age Patients with kidney or liver dysfunctions

52. Basic mechanisms of Drug- Drug interactions Direct chemical or physical interaction - can occur with drugs mixed together. Pharmacokinetic interaction – can alter all four processes. Absorption – increase or decrease (e.g., PH, laxative, changes in blood flow). Distribution – competition for protein binding or changes in extra cellular PH. Metabolism - induction of drug metabolizing enzymes, inhibition of metabolizing, and competition of metabolism. Excretion - altered renal excretion (e.g. filtration, reabsorption, and secretion). Pharmacodynamic interaction Interactions at same receptor almost always inhibitory. Interactions resulting from actions at separate sites (if drugs influence same physiologic process)

53. Drug- Food interactions Impact of Food on Drug Absorption Decreasing rate and/or extent of absorption Some foods can increase extent of drug absorption. Impact of Food on Drug metabolism The grapefruit juice effect (can inhibit metabolism of certain drugs  increased drug levels). Impact of Food on Drug Toxicity MAOIs with tyramine Caffeine with theophylline Impact of Food on Drug Action Vitamin K with warfarin

54. Adverse drug reactions (ADRs) Any undesired response to a drug. Can range in intensity from annoying to life threatening. Types of adverse drug reactions: Type A (augmented): side effect, secondary effects or toxic effcet Type B (bizzare): allergic rxn, idiosyncratic reactions due to aantibody Type c: chronic use, analgesic  nephropathy Type D: delayed use: teratogenic effects Type E: end of use: angina after atenolol, withrawal sysmptoms after opiods drugs

55. Contd’… Side Effects: unavoidable secondary drug effect produced at therapeutic drugs doses. E.g. 1. Drowsiness that often accompanies the use of antihistamines 2. Gastric bleeding that can be produced by low therapeutic doses of aspirin. Toxicities: an adverse drug reaction caused by excessive levels of drug. E.g. Coma caused by overdose with morphine. Allergic reactions: (type I to I) Prior sensitization of the immune system. Re- exposure to that drug can bring on an allergic response.

56. ADRs... Idiosyncratic effects: an unusual drug response resulting from a genetic predisposition. Physical dependence : a state in which the body has adapted to prolonged drug exposure in such a way that if drug use is discontinued abstinence syndrome will result. Develop during long-term use of certain drugs (e.g. Opoids , barbiturates etc) Carcinogenic effects : ability of certain mediations /chemicals to cause cancer. Although a number of carcinogenic compounds have been identified, very few of these are employed therapeutically. .

57. Iatrogenic Responses : Responses produced unintentionally during the treatment of client e.g. dermatological responses, hepatic toxicity; Cushing syndrome – steroids, teratogenic effects (malformations & developmental effects) Teratogenic Effects : drug- induced birth defect