General Pharmacology: Kinetics and Dynamics PDF

General Pharmacology: kinetics and dynamics Dr. Amal Youssef Ass. Prof. of pharmacology Faculty of Medicine, Cairo University 1 Introduction-Sources of drugs: Plant sources: atropine from leaves of belladonna Animal sources: a...

General Pharmacology: kinetics and dynamics Dr. Amal Youssef Ass. Prof. of pharmacology Faculty of Medicine, Cairo University 1 Introduction-Sources of drugs: Plant sources: atropine from leaves of belladonna Animal sources: animal insulin from pancreas of pigs Mineral sources: magnesium sulphate, iodine, radioactive isotopes as 131I Micro-organisms: penicillin from the fungus penicillium Synthetic drugs: produced in the laboratory like aspirin and sulphonamides Biotechnology: human insulin produced by genetic engineering Rational drug design 2  DRUG-BODY INTERACTIONS The interactions between a drug and the body can be divided into two classes. The actions of the drug on the body are termed MCQ pharmacodynamic processes The actions of the body on the drug are called pharmacokinetic Pharmacokinetic processes: MCQ Absorption, Distribution, and Elimination of drugs. 3 Possible mechanisms of action of drugs 1. Physical such as adsorbants and demulcents 2. Chemical such as chemical antacids 3. Interference with cell division such as cancer chemotherapy 4. Interference with a metabolic pathway such as some antibiotics 5. Inhibition of enzymes such as some analgesics- NSAIDs 6. Action on ionic channels in cell membranes such as hypnotics 7. Action on specific receptors- most drugs 4  Pharmacodynamics- Introduction Pharmacodynamics describes pharmacological actions of drugs & their mechanisms of action and the influence of drug concentrations on the magnitude of the response. Most drugs exert their effects, both beneficial and harmful, by interacting MCQ 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. 5  Major receptor families A receptor as any biologic molecule to which a drug binds and produces a measurable response. Drug The most common form of receptors are proteins that transduce extracellular signals into intracellular responses. R These receptors may be divided into four families: Biological response MCQ 1) ligand-gated ion channels, 2) G protein– coupled receptors, 3) Enzyme-linked receptors, and 4) Intracellular receptors 6 Whalen, K., Finkel, R., & Panavelil, T. A. (2018) Lippincott's Illustrated Reviews: Pharmacology (7th edition.). Philadelphia: Wolters Kluwer 7 Transmembrane ligand- Na+Na+ + Na gated ion channels ACh ACh The extracellular portion of ligand-gated ion channels usually contains the ligand- binding site. For example, stimulation of the nicotinic receptor by acetylcholine results in sodium influx and potassium outflux, generating an action potential in a neuron or contraction in skeletal muscle. 8  Transmembrane G protein–coupled receptors The extracellular domain of this receptor contains the ligand-binding area, and the intracellular domain interacts with a G protein or effector molecule. There are many kinds of G proteins (for example, Gs, Gi, and Gq Binding of an agonist to the receptor  interaction with cellular effectors, usually an enzyme, a protein, or an ion channel, that are responsible for further actions within the cell. 9  Enzyme-linked receptors When activated, these receptors undergo changes resulting in increased cytosolic enzyme activity, depending on their structure and function. The most common enzyme-linked receptors (insulin) possess tyrosine kinase activity as part of their structure. For example, when the peptide hormone insulin binds to two of its receptor subunits, tyrosine kinase activity  autophosphorylation of the receptor itself phosphorylation of other peptides or proteins  activation of important cellular signals. Intracellular effects 10 Intracellular receptors The receptor is entirely intracellular The ligand must diffuse into the cell to interact with the receptor (must have sufficient lipid solubility). The activation or inactivation of these factors causes the transcription of DNA into RNA and translation of RNA into proteins. The time course of activation and response of these receptors is on the order of hours to days. For example, steroid hormones Intracellular effects 11  Receptor interacts specifically with a ligand (drug, transmitter, or hormone) to produce a biological response. Emax Affinity: the ability of drug to fit onto the receptor to form drug-receptor (D-R) complex. Efficacy: is the magnitude of response a drug causes when it interacts with a receptor. Response Maximal efficacy of a drug (Emax) assumes that all receptors are occupied by the drug, and no increase in response is observed if a higher concentration of drug is obtained. Potency: refers to the doses or concentration of drug log dose required to produce certain effect. The concentration ED50 of drug producing 50% of the maximum effect (EC50) is usually used to determine potency. 12  Relative potency and maximal efficacy of two drugs. Drug A is more potent, and Drug B has a greater maximal efficacy. EC50 EC50 EC50 = drug dose causing 50% of maximal response. 13  MCQ Drugs are classified, according to the nature of their interaction with receptors, into: Agonists: drugs that have affinity, efficacy and rapid dissociation. Antagonists: drugs that block receptors. They have affinity, no efficacy and slow dissociation. Partial agonists: drugs that initially stimulate Antagonist then block receptors. So, they have affinity, weak efficacy and slow dissociation No response D 14  Types of ligands Type / Agonist Antagonist Partial agonist Character Affinity Yes Yes Yes Intrinsic activity Yes No Yes Efficacy 1 0r 100% for a Zero More than zero full agonist and less than one Notes 15 Types of antagonism E-max E-max E-max 1. Competitive antagonists: Antagonists bind Reversibly with the receptors. Antagonists can be Displaced by excess agonists. EC50 ↓Potency. Competitive Non competitive 2. Non-competitive antagonists: Antagonist is NOT displaced by agonist ↓ Potency. Decrease maximum response (E-max) = ↓ Efficacy. Types of Non-Competitive Block: REVERSIBLE: The block ends by the Metabolism of the blocker. IRREVERSIBLE: The block ends by Resynthesis of new receptors. Usually of Long duration of action. 16 Types of antagonism 3. Functional “physiologic” antagonism: An antagonist may act at a completely separate receptor, initiating effects that are functionally opposite those of the agonist. MCQ A classic example is the physiologic antagonism by epinephrine to histamine- induced bronchoconstriction. Histamine binds to H1 histamine receptors on bronchial smooth muscle, causing bronchoconstriction of the bronchial tree. Epinephrine is an agonist at β2-adrenoceptors on bronchial smooth muscle, which causes the muscles to relax. β2 H1 Epinephrine Histamine 17 Dosage of drugs Therapeutic dose: Average dose required to produce therapeutic effect, in adult male. Loading dose: Initial large dose to build up therapeutic blood level (LD= Vd X Css). Maintenance dose: Daily doses required to maintain therapeutic level (MD= Cl X Css X Tm) 18  Kinetic processes Absorption: Absorption is the transfer of a drug from its site of administration to systemic blood stream. Distribution: the drug may then reversibly leave the bloodstream and distribute into the interstitial and intracellular fluids. Metabolism: the drug may be bio-transformed by metabolism by the liver or other tissues. Elimination: the drug and its metabolites are eliminated from the body in urine, bile, or feces. 19 Factors affecting drug absorption: B) Factors Related to the Patient: 1- Route of Administration: I.V. and inhalation > I.M. > A) Factors Related to the Drug: S.C. > Oral > Skin. 2- Absorbing Surface: Water and lipid solubility: a. Vascularity: Alveoli > Skeletal muscle > Subcutaneous. Drugs MUST be Water soluble as well b. Surface area: Alveoli > Intestine > Stomach as Lipid soluble. c. State of absorbing surface: Gastritis & malabsorption Ionization: syndrome →↓ absorption Non-ionized → More lipid soluble → d. Motility of the gut and rate of dissolution: Better absorption Prokinetic drugs increase the gut motility increase Valency: absorption of rapidly disintegrated drugs (paracetamol) Ferrous iron (Fe2+) > Ferric Iron and decrease absorption of slowly disintegrated drugs. (Fe3+). e. pH: Weak acids (aspirin) are better absorbed in acidic media, so better absorbed in stomach Weak bases (ephedrine) are better absorbed in alkaline media of intestine 3-Systemic circulation: Shock & Heart failure → ↓ Absorption 20  First pass effect: Gastric acidity Digestive enzymes Metabolism of drug in gut wall or liver before reaching systemic circulation. A] Gut first pass effect: 1- Gastric acidity: destroys benzyl penicillin. 2- Digestive enzymes: destroy insulin & pituitary hormones B] Hepatic first pass effect: e.g. Nitroglycerine & Lidocaine. propranolol. MCQ To avoid: ↑ the oral dose. Or change route of administration 21 Bioavailability MCQ MCQ Bioavailability is the percentage of a drug that reaches the systemic circulation unchanged. After IV administration, 100% of the drug rapidly enters the circulation. MCQ Routes of administration other than intravenous may result in partial absorption and lower bioavailability. Lippincott's Illustrated Reviews: Pharmacology: Whalen, K., Finkel, R., & Panavelil, T. A. (2015) Lippincott's Illustrated Reviews: Pharmacology (6th edition.). Philadelphia: Wolters Kluwer. 22 II) Distribution: After absorption from whatever route of administration a drug will be distributed among body compartments. Intracellular = 28 liters Cell membrane The total Interstitial Fluid= 10 liters body fluid Endothelium of = 42 liters capillary wall Extra-cellular Intravascular (Plasma) = 4 liters = 14 liters The body compartments 23  One compartment model (intravascular) MCQ So, drugs with High MW or Highly bound to plasma proteins are trapped in the intravascular compartment pp and are thus distributed in a Heparin volume of 4 L 2. Highly bound to plasma 1. High molecular weight proteins e.g. Heparin e.g. warfarin 24 Two compartment model (extracellular distribution) Drugs having low MW but are Intracellular compartment not highly lipid soluble (hydrophilic), are distributed + + Interstitial compartment + to the extracellular fluid i.e to MCQ Extra-cellular + + a volume of 14 L + Intravascular (Plasma) compartment Quaternary ammonium Mannitol compounds 25  Multicompartmental model (extracellular and intracellular distribution) Intracellular Drugs having low MW & Lipid compartment soluble are distributed to Total body fluid + Interstitial compartment i.e. to a volume of 42 L Total body fluid Intravascular (Plasma) compartment Alcohol Phenytoin 26  Selective distribution: MCQ Some drugs have special affinity for certain tissue: (Vd > 42 L) Distribution:  It is dependent on: MCQ  Ionization  Lipid solubility Iodide in thyroid gland  Molecular size calcium in bones  Binding to plasma proteins  Rate of blood flow  Special barriers. Tetracycline in bone and teeth 27  Volume of distribution The apparent volume of distribution, Vd, is defined as the fluid volume that is required to contain the entire drug in the body at the same concentration measured in the plasma. It is calculated by dividing the dose that ultimately gets into the systemic circulation by the plasma concentration at time zero (C0). Significance: MCQ 1. Determine the loading dose and the total amount of drug in the body: ** total amount (mg) = Vd x C (mg/ml). ** Loading dose = Vd x Desired concentration (Css) 2. Drugs with large Vd are not removed by hemodialysis 28  Drug elimination Once a drug enters the body, the process of elimination begins. The three major routes of elimination are hepatic metabolism, biliary elimination, and urinary elimination. 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 MCQ more polar (hydrophilic) substances in the liver via two general sets of reactions, called phase I and phase II 29 Phases of drug metabolism Phase I: Phase I reactions convert lipophilic drugs into more polar molecules by: MCQ Reduction, Oxidation, or Hydrolysis. Phase I metabolism may increase, decrease, or have no effect on pharmacologic activity. Are most frequently catalyzed by the cytochrome P450 system (also called microsomal mixed- function oxidases). Lippincott's Illustrated Reviews: Pharmacology: Whalen, K., Finkel, R., & Panavelil, T. A. (2015) Lippincott's Illustrated Reviews: Pharmacology (6th edition.). Philadelphia: Wolters Kluwer. 30 2. Phase II: This phase consists of conjugation reactions. Examples: conjugation reaction with Glucuronic acid, MCQ Sulfuric acid, Acetic acid, or An amino acid, It results in polar, usually more water-soluble compounds Glucuronidation is the most common and the most important conjugation reaction. 31  Factors affecting hepatic microsomal enzyme activity 1. Drugs Hepatic microsomal enzyme inhibitors 2. Age: lower activity in extremes of age; Hepatic microsomal enzyme Inhibit activity of Grey Baby Syndrome in neonates with inducers HMEs chloramphenicol Stimulate activity of HMEs Specific: Ex: Cimetidine, 3. Sex: androgen stimulates and estrogen Phenobarbitone, phenytoin, ciprofloxacin, and progesterone inhibit rifampicin, griseofulvin, Chloramphenicol, carbamazepine, cortisol, ketoconazole 4. Pathological condition: liver disease  testosterone, Estrogen, increased susceptibility to drug toxicity coffee, tea, tobacco smoking erythromycin Increase metabolism of other Grape fruit, 5. Starvation: decreased enzyme activity; omeprazole drugs: depleted glycine  reduced glycine oral contraceptives, Sodium valproate conjugation oral anticoagulants, Non-specific: Hepatotoxins: oral hypoglycemic  6. Genetic factors: polymorphism  CCl4, CO, O3 decreased duration of Drugs that variation of susceptibility to drug action toxicity; succinylcholine apnea in cases decrease hepatic They increase their own blood flow as beta of pseudo-choline esterase deficiency metabolism  Tolerance blockers32  Excretion Drugs must be sufficiently polar to be eliminated from the body The most important route is through the kidneys. Sites of excretion A. Renal B. Lungs C. Alimentary tract 1. Non-volatile drugs and metabolites are  Saliva excreted in the urine  Stomach 2. Patients with renal dysfunction may be unable  Bile to excrete drugs and are at risk for drug  Large intestine accumulation and adverse effects. D. Skin glands  Sweat  Milk 33  Renal Excretion Renal excretion is the result of glomerular filtration and active tubular secretion and re-absorption 1. Glomerular filtration is for water soluble, un-bound drugs (not bound to albumin) with MW < 500 daltons e.g. mannitol. Variations in GFR and protein binding of drugs affect this process. 2. Active tubular secretion (saturable, site for competition and drug interactions); two energy-requiring active transport systems: Weak acidic drugs Weak basic drugs 34  Renal Excretion 3. Distal tubular reabsorption; Changes in urinary pH affects the excretion of weak acids and weak bases: Alkalinization of urine (by sodium or potassium acetate, bicarbonate, or MCQ citrate)  increased renal excretion of weak acid drugs [ION TRAPPING] Acidification of urine (by ammonium chloride or ascorbic acid)  increased MCQ renal excretion of weak basic drugs e.g. ephedrine and amphetamine [ION TRAPPING] 35  Enteral Route Route Advantages Disadvantages Dosage form Oral Easy, safe, Not suitable for Liquid convenient 1. Emergency situations 2. Uncooperative patients: comatose, psychotics& Tablets Capsule children. 3- vomiting or severe diarrhea. 4- highly irritant drugs 5. Poorly absorbable drugs 6- Drugs with extensive first pass metabolism. Effervescent granules Liquid Sublingual -Rapid onset -No first pass Pellet metabolism Or -Proper control Buccal spray of dose Rectal Rapid onset 1- Inconvenient to most patients. -No first pass 2- Psychological trauma. metabolism 3- Unsuitable in cases of diarrhea. - Alternative if 4- irritant rugs(and on repeated administration) → oral route not proctitis suitable Enema Suppository 36  Parenteral Route Route Advantages Disadvantages Dosage form Injection -Rapid onset -Transmission of infection -High bioavailability -Local irritation, pain - Suitable for emergency, coma -Toxic and allergic reactions Inhalation -Rapid onset -Irritation of bronchi -Avoid first pass effect -Irregular dosage -Large surface area for systemic absorption Transdermal -Drugs applied topically for systemic -Irritation effect - provide steady, prolonged delivery via medicated patch Topical Applied for Local effects Ointment Cream Eye, Ear or Nasal drops 37 General Rules Parenteral dosage forms: 1- Solution 2- Suspension 3- Emulsion 4- Powder 5- Subcutaneous implants 38  General Rules Dosage forms are enclosed in: 1- Ampules 2- Vials. 3- Bottles. 4- Plastic bags. 39 Subcutaneous Implantation Drugs for subcutaneous implantation Should be in solid pellet form. 40 Intramuscular injection Dorsogluteal 41 Intravenous injection 1- Site of absorption: Blood 2- Onset of action: Seconds 3- Duration of action: Short 4- Drug plasma level: High peak 42  Intravenous injection 5- Vehicle: Solution (Also emulsions can be given intravenously, e.g. propofol emulsion). (Note: if suspension: drug precipitates occluding the vein and causing phlebitis. If oily: occludes the vein and causes embolism). Very irritant drugs can be given if: 1- Using large veins. 2- Diluting the drug and administering it by infusion. 43 Intravenous injection Types of intravenous administration: 1- I.V bolus (shot or push): - Using a syringe, few milliliters are injected rapidly. - A cannula could be used if repeated administration is required. 2- Slow intravenous injection: - as IV shot but given over few minutes (e.g. IV calcium). 3- Intravenous infusion: - Using an intravenous catheter (tube) and a cannula, large volume of I.V. fluids can be administered. 44 Intravenous injection 45 Cannula 46 Drug Interactions [DI] Drug Interactions are altered pharmacological responses due to multiple drugs acting concurrently. These can be desired (beneficial) or undesired (harmful). Beneficial DI: Are obtained by combining drugs with different mechanisms or drugs that correct adverse effects of each other e.g. in treatment of cancer, TB. Harmful DI: Can be in the form of a predictable effect of one or both drugs (or an unpredictable toxicity. Most clinically important DI involve more than a single mechanism due to drugs with narrow safety margin e.g. digitalis. 47 I.Pharmacokinetic drug interactions(Affect ADME) 1-Drug interactions affecting GIT Absorption: Drugs affecting gut motility: Motility changes (increase by metoclopramide & decrease by atropine) affect absorption of other drugs. Drugs affecting gut pH: Gastric acidity increases absorption of acidic drugs as aspirin & Intestinal alkalinity increases absorption of basic drugs as ephedrine, quinine. Drug binding, adsorption or chelation: Tetracyclines chelate metals as Ca, Mg, Al & Fe, decrease their absorption 2-Drug Interactions affecting Distributions: Drugs with high affinity binding to plasma proteins as aspirin, sulfa can displace other drugs bound to plasma proteins as warfarin leading to increase free concentration and toxicity. 3-Drug interactions affecting Metabolism (Biotransformation): Enzyme Induction: HME Inducers increase metabolism & increase activity of the inducer & co-administered drugs e.g. phenobarbitone, phenytoin & tobacco smoking. Enzyme Inhibition: HME Inhibitors decrease metabolism &decrease activity of their own & co-administered drugs e.g. chloramphenicol & estrogen 4- Drug interactions affecting Renal Excretion: Competition for active renal tubular secretion: Probenecid blocks excretion of weak acids; penicillins. Changes in urinary pH: - Acidification of urine by ammonium chloride increases excretion of basic drugs as ephedrine. - Alkalinization of urine by sodium bicarbonate increases excretion of acidic drugs as aspirin 48  II) Pharmacodynamic drug interactions Drug interactions occur at sites of action, receptor sites or secondary physiological mechanisms; leading to changes in drug responses. 1-Drug interactions at specific receptor sites: (Pharmacological Antagonism = 2 drugs acting on 1 receptor) -Types of Pharmacological Antagonism: A. Competitive Antagonism: (antagonist displaced by the excess agonist) e.g. Acetylcholine & Atropine (M) B. Non-competitive antagonism: (antagonist not displaced by the excess agonist) - Reversible: Block end by metabolism of antagonist e.g. succinylcholine (N) - Irreversible: Bind covalently, block end by resynthesis of new receptors e.g. phenoxybenzamine 2. Drug interactions on the same physiologic system: - Caffeine antagonizes CNS depressant effect of barbiturates. 2. Drug interactions involving Combined Toxicity: - Combined use of 2 or more drugs with toxic effects on the same organ can greatly increase the organ damage. e.g. use of 2 nephrotoxic drugs (e.g. aminoglycosides & cephaloridine). 49 III) Pharmaceutical drug interactions These are drug interaction occurring outside the body before drug administration (in vitro), as a result of physical or chemical reaction between the drugs. e.g Mixing drugs with IV infusion fluids 50  Intracellula G protein ligand- Enzyme- r receptors coupled gated ion linked receptors channels receptors Binding of agonist to extracellular ligand must be lipid soluble to portion opens the channel allowing diffuse into the cell to interact with ions to cross the membrane the receptor Binding of an agonist to the receptor The agonist binds receptor  interaction with cellular tyrosine kinase activity effectors, usually an enzyme, a autophosphorylation of the receptor protein, or an ion channel, that are itself phosphorylation of other responsible for further actions peptides or proteins within the cell 51  Efficacy Bioavailability Affinity Potency Potency Amount of drug required to produce a response and EC50 is usually used to determine it. Bioavailability Is the percentage of a drug that reaches the systemic circulation unchanged No increase in response is observed if a higher concentration of drug is Efficacy obtained. The ability of drug to fit onto the receptor to form drug-receptor (D-R) Affinity complex 52  Take-home massage - Pharmacodynamics involves the study of …... - What does “pharmacokinetics” include? - Types receptor families - Definition of affinity, potency, efficacy. Agonist & Antagonists - Types of antagonism - Define drug bioavailability and how it is calculated - Interpretation of volume of distribution, factors affecting, how to be calculated, clinical significance - Purpose and phases of metabolism of drugs- and how hepatic metabolism prepares drugs for renal elimination - Advantages & disadvantages of different route of administration 53