GENERAL PHARMACOLOGY PPT. DT 2nd year.pptx

Pharmacology

1. GENERAL PHARMACOLOGY KING EDWARD MEDICAL UNIVERSITY LAHORE B.Sc.(Hons.) DENTAL TECHNOLOGY BATCH 2021-24 SUBMITED TO: DR. SHARMEEN

2. Learning objectives: Definitions of terms used in pharmacology Sources of drugs Routes of drug administration Drug absorption Membrane transporters Distribution of drugs Biotransformation of drugs Drug excretion, elimination and clearance Dose-effect relationship Processes of pharmacokinetics Mechanisms of drug action Adverse drug reactions Drug-drug interactions

3. WHAT IS PHARMACOLOGY? Pharma = Drugs Logos = Knowledge “It is the science of drugs that deals with their actions on living system.” It includes physical and chemical properties, biochemical and physiological effects, mechanism of action, therapeutic uses and adverse effects of drugs.

4. WHAT IS DRUG? “Any chemical that affects the processes of a living organism.” or “Any substance that is used to prevent, diagnose, treat, or relieve symptoms of a disease or abnormal condition.”

5. DEFINITION OF TERMS USED IN PHARMACOLOGY

6. PHARMACOLOGY Detailed study of drugs. PHARMACOKINETICS Study of what the body does to the administered drug. It includes: Absorption Distribution Metabolism Excretion PHARMACODYNAMICS Study of what the administered drug does to the body. It includes: Mechanism of action of drugs Pharmacological effects of the drug Clinical uses of the drugs Adverse effects of the drugs

7. PHARMACY Study of identification, selection preparation, compounding and dispensing of medicines. THERAPUTICS Art and science of treatment of disease. Or Study concerned with cure of disease or relief of symptoms. TOXICOLOGY Study of undesirable effects of chemicals on living system from individual cells to complex ecosystems and their treatment.

8. CHEMOTHERAPY Study of effects of drugs on microorganisms and parasites, living and multiplying in the living body without damage to the host cells. It includes: Anti-microbial drugs Anti-mycobacterial drugs Anti-viral drugs Anti-fungal drugs Anti- protozoal drugs PHARMACOGNOSY Study of identification of drugs from natural sources. POSOLOGY Study of doses (a specified amount of drug used at a time) of drugs.

9. SOURCES OF DRUGS

10. SOURCES DRUGS PLANTS Alkaloids Glycosides Morphine, Atropine, Quinine, Reserpine, Ephedrine Digoxin, Digitoxin ANIMALS Insulin, Heparin MINERALS Magnesium sulphate, Ferrous sulphate MICROORGANISMS Antibiotics: Penicillin, Streptomycin, Grisiofulvin SYNTHETIC Aspirin, Paracetamol, Sulphonamide SEMI-SYNTHETIC Hydromorphone, Hydrocodone, Amoxicillin, Doxycycline BIO-SYNTHETIC Human insulin, Human growth hormone, Hepatitis B vaccine

11. ROUTES OF DRUG ADMINISTRATION

12. 1- ENTERAL ROUTE

13. 2- PARENTRAL ROUTE I- INJECTIONS

14. II- INHALATIONS

15. IV- TOPICAL

16. 1- DRUG ABSORPTION

17. “The transfer of a drug from its site of administration to the blood stream is called drug absorption .”

18. FACTORS AFFECTING DRUG ABSORPTION Physical nature of the drugs Lipid solubility Drug concentration S urface area Blood supply Presence of other substances in the GIT Diseases of GIT First pass effect

19. MEMBRANE TRANSPOERTERS

20. 2- Drug Distribution

21. “Drug distribution is the process by which a drug reversibly leaves the bloodstream and enters the interstitium and then the cells of the tissues.”

22. FACTORS AFFECTING DRUG DISTRIBUTION The delivery of a drug depends on: Bl ood flow Lipid solubility Capillary permeability Volume of distribution Degree of binding of the drug to plasma and tissue proteins R edistribution of drug

23. 1- BLOOD FLOW The rate of blood flow to tissue capillaries vary widely due to the unequal distribution of cardiac output to various organs. High blood flow and high lipid solubility permits drugs like thiopental and propofol to rapidly move into CNS. A subsequent slower distribution to skeletal muscles and adipose tissue lowers the plasma concentration sufficiently so that the higher CNS concentrations fall and consciousness is regained. Brain, liver and kidneys have higher flow rates whereas adipose tissue, skin and viscera have lower flow rates.

24. 2- CAPILLARY PERMIABILITY It depends on capillary structure and chemical nature of the drug. In liver and spleen there are large discontinuous capillaries through which plasma proteins can pass whereas in brain the capillary structure is continuous and there are no slit junctions. Ionized or polar drugs generally fail to enter the CNS because they are unable to pass through the endothelial cells of the CNS.

25. 3- BINDING OF DRUGS TO PLASMA PROTEINS AND TISSUE PROTEINS Binding to plasma proteins: Reversible binding to plasma proteins sequesters drugs and slows their transfer out of vascular compartment. Plasma albumin is the major drug protein and act as drug reservoir Binding to tissue proteins: Numerous drugs accumulate In tissues as a result of binding to lipids proteins or nucleic acids. E.g. Acrolein (cyclophosphamide metabolite) is toxic to the kidney because of its accumulation in renal cells. Hydrophobicity: The chemical nature of a drug strongly influences its ability to cross cell membranes. Hydrophobic drugs can pass through membranes in contrast to hydrophilic drugs which must pass through the slit junctions.

26. 4-VOLUME OF DISTRIBUTION “The apparent volume of body fluids into which a drug is able to distribute according to it’s concentration in blood or plasma is called volume of distribution.” It is calculated by dividing the dose that gets into systemic circulation by the plasma concentration at zero time. V d = amount of drug In the body plasma concentration of drug

27. Distribution into water compartments

28. PLASMA COMPARTMENT Drugs with very large molecular weight bind extensively to plasma proteins which cannot pass through the endothelial slit junctions. Makes almost 6% of body weight. In a 70 kgs male about 4L of body fluid. Heparin shows this type of distribution.

29. EXTRACELLULAR FLUID Drugs with low molecular weight can reside in plasma and also move to interstitial fluid. Together both these compartments make extracellular fluid. This is about 20% of the body weight . 14 L in a 70 kg man. Aminoglycosides show this type of distribution.

30. TOTAL BODY WATER Drugs with low molecular weight and hydrophobic move across cell membranes. It makes almost 60% of the body weight . About 42L in a 70 kg man. Ethanol shows this distribution.

31. 3- BIOTRONSFORMATION OF DRUGS

32. “Chemical alteration of a drug by the body.” Biotransformation or metabolism of a drug usually produces following two important changes in it: S olubility :Drug becomes water soluble B iological activity :Drug usually becomes biological inactive SIGNIFICANCE: Lipid soluble drugs ------------- Water soluble drugs/Hydrophilic drugs Active drug ---------------------- Inactive drug Inactive drug -------------------- Active drug SITES: liver , kidneys , lungs , Skin , blood

33. TYPES OF METABOLISM Drugs are metabolized or alter due to changes in pH It can be due to: Microsomal reactions in smooth ER e.g. Cytochrome P450 Non-Microsomal reactions in mitochondria or cytoplasm e.g. Oxidases, Esterases , Amidases

34. PHASES OF METABOLIC REACTIONS PHASE – I REACTIONS PHASE – II REACTIONS “Reactions that convert the parent drug to a more polar product by unmasking or inserting a polar functional group such as –OH, -SH, -NH2” “Reactions that increase water solubility by the conjugation of drug molecule functional group with a polar substrate such as glucoronate, acetate, or sulfate, forming covalent bond.” It includes oxidation, reduction, deamination and hydrolysis. It includes glucuronidation, acetylation, sulfation, etc. Phase –I enzymes are found in SER of liver. Phase –II enzymes are found in cytosol. Enzymes are CYP3A4 , CYP2D6 Enzymes are monoamine oxidase, xanthine oxidase, alkyl dehydrogenase.

35. FACTORS AFFECTING METABOLISM Genetic factors A ge Sex Food Environment Diseases of liver I ndividual factors Effects of other drugs E nzyme induction Enzyme inhibition

36. DOSE- RESPONSE RELATIONSHIP

37. As drug binds to a receptor, it alters the physical, biochemical or molecular activities of cell through signal transduction and generate a response. “ T he process which describes the relation between dose of a drug with the degree of it’s response is called dose response relationship.” Magnitude of drug response depends on: Receptor sensitivity Drug concentration at receptor site

38. 1- Graded Dose – Response Relationship “It shows the response of one or more drugs in a single individual.” The horizonal axis of the curve shows log of dose. The vertical axis of the curve shows the response. It can be described under following headings: Potency : “The amount of drug neend to produce a biological effect.” Efficacy : “The ability of a drug to produce a maximum biological effect.” Slope: “It determines the change in the degree of response to a change in the dose of the drug.” A steep and prolonged curve shows that a small change in the dose of drug will produce a large response. A short and low sloping curve shows that a change in the dose produces a small change in its response.

39. 2- Quantal Dose – Response Relationship “It shows the response of a drug in a large number of experimental animals or human beings.” I t is required int two situations: For diseases or events which occurs in attacks For great individual variations in the degree of response to a drug

40. Dose-response relationship Intrinsic activities of drug Competitive Full agonists Partial agonists Non-competitive Allosteric Inverse agonists Physiological/ functional Agonist Antagonist

41. 4- Elimination of drug

42. “Elimination is irreversible removal of drug from the body. It involves biotransformation (metabolism) and excretion (intact removal of drug from body).” Metabolism results in products with increased polarity which allows the drug to be eliminated. Once a drug enters the body, elimination begins. Major routes of elimination are hepatic metabolism , biliary elimination and urinary excretion. These elimination processes decrease plasma concentration exponentially. “A constant fraction of drug is eliminated per unit of time.”

43. Clearance of drug

44. “Volume of blood from which the drug is cleared per unit of time.” CL= 0.693 × V d / t 1/2 Where; CL = Clearance life 0.693 = Natural log constant V d = Volume of distribution t 1/2 = Elimination half life

45. DRUG CLEARANCE BY KIDNEY Drugs must be sufficiently polar to be eliminated from body. Kidney cannot efficiently excrete lipophilic drugs that readily cross cell membrane and are reabsorbed in distal convoluted tubules. Therefore lipid soluble agents are first metabolized into hydrophilic (more polar) substances in the liver via phase I and phase II reactions. Drug passes through various process in kidney before elimination.

46. 1- GLOMERULAR FILTERATION Drugs enter the kidney through renal arteries which divide to form glomerular capillary plexus. Free drug floats through capillary slits into bowman space as part of glomerular filtrate. Glomerular filtration rate is 120 mL/min/1.73m 2

47. 2- PROXIMAL TUBULAR SECRETION Secretion primarily occurs in the proximal tubules by two active transport systems: One for anions One for cations

48. 3- DISTAL TUBULAR REABSORPTION As drug moves toward DCT its concentration increases and exceeds that of perivascular space . The drug may diffuse out of nephrotic lumen back into the systemic circulation . 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 increases the clearance of an undesirable drug .

49. ION TRAPPING Weak acids can be eliminated by alkalization of the urine, elimination of weak bases may be increased by acidification of urine. This process is called ion trapping. For example, a patient presenting with phenobarbital (weak acid) overdose can be given bicarbonate which alkalinizes the urine and keeps drug ionized thereby decreasing its reabsorption.

50. Excretion by other routes

51. Drug excretion may also occur via intestine , bile , lungs and breast milk . Drugs that are secreted into the intestine or into bile are excreted into feces . Lungs are involved in elimination of anesthetic gases. Excretion of most drugs into sweat , saliva , tears , hair and skin occurs only to a small extent.

52. TOTAL BODY CLEARANCE “The total body clearance is the sum of all clearances from drug metabolizing and drug-eliminating organs.” CL total = CL hepatic + CL renal + CL pulmonary + CL other When a patient has an abnormality that alters half life of a drug adjustment in dosage is required.

53. The half life of a drug may be increased by decreased hepatic blood flow, renal disease and decreased metabolism .This may require decrease in dosage or less frequent dosing intervals. The half life may be decreased by Inc. hepatic blood flow or increased metabolism. This may require Inc. in dosage or more frequent dosing intervals.

54. PROCESSES OF PHARMACOKINETICS

55. Four processes of pharmacokinetics Absorption Distribution Metabolism Elimination

56. Absorption – transfer of a drug from site of administration to the bloodstream. Distribution – process by which a drug leaves the bloodstream and enters the extracellular fluid and tissues. Metabolism- detoxification or breakdown of drug into metabolites that no longer exert any effect. Elimination- metabolic waste products are removed from body . e.g by kidneys, lungs , bile , skin.

57. MECHANISMS OF DRUG ACTION

58. Pharmacodynamics – “action of drug on body” Drugs can interact with following target sites In a cell Receptors Ion channels Enzymes Carrier molecules

59. TYPES OF MECHANISM Based on target sites actions of drugs can be classified as following: Receptor mediated mechanism Non receptor mediated mechanism

60. RECEPTOR MEDIATED MECHANISM Receptor – “membrane bound or intracellular macromolecular protein which is capable of binding the specific functional groups of drug or endogenous substance” Types of receptors and signal transduction mechanism Ionotropic receptors ( ligand gated ion channels) Metabotropic receptors ( G-protein coupled receptors) Enzyme linked receptors Intracellular receptors

61. 1- IONOTROPIC MECHANISM Also known as “ ligand gated ion channels” These are cell surface receptors Agonist binding open the channel and causes depolarization/hyperpolarization/ change in ionic composition Na, K , Ca, Cl… Examples Nicotinic cholinergic, GABA, etc.

62. 2- METABOTROPIC RECEPTORS These are large family of cell membrane receptors linked to the effector through GTP activated proteins. Agonist binding site is located on extracellular face While another recognition site is formed by Cytosolic segments binds the G protein. Examples Muscarinic, Dopamine D2 beta adrenergic.. etc .

63. 3- ENZYME LINKED RECEPTORS These receptors cause conformational changes on activation resulting in increased intracellular enzyme activity. These also cause a signal cascade effect. They posses tyrosine kinase activity. Examples Insulin , growth hormone, etc.

64. 4- INTRACELLULAR RECEPTORS These are intracellular soluble protein which respond to lipid soluble chemical messenger that penetrate the cell. Capable to binding specific genes and facilitates their expression so that specific mRNA can be synthesized. Examples All steroid hormones, thyroxine, vitamin D, etc.

65. NON-RECEPTOR MEDIATED MECHANISMS By chemical action . Neutralization . Chelating . Ion exchange By physical action . Osmosis . Absorption

66. DRUG INTERACTIONS

67. ADVERSE DRUG EFFECTS

68. ADVERSE DRUG REACTION