Introduction to pharmacology.ppt

This presentation well describes the general pharmacology in detail.

1. Introduction to Pharmacology Jony Mallik Executive, Quality Control, Popular Pharmaceuticals Limited.

2. Introduction & Definition Pharmacology Pharmacon - Drug Logos - Study It is defined as the study of the substances which interact with living system by activating or inhibiting normal body processes. (In simple terms, it is study of all the aspects of drug.)

3. INTRODUCTION TO PHARMACOLOGY Pharmacology: It is the science of drugs derived from two Greek words: Pharmakon (Greek word for drugs) and logos (the Greek word for science). It is the study of the actions of drugs on living system . It includes physical and chemical properties, biochemical and physiological effects, mechanism of action, therapeutic uses and adverse effects of drugs.

4. PHARMACOLOGY, Link to other biomedical principles

5. Subdivisions of Pharmacology: These are followings Pharmacy: It deals with study of collection, compounding, and dispensing of drugs so as to make them fit for administration to patient. Immuno pharmacology: It deals with the immunological actions of drugs in immune system and development of antibodies in response to a drug. Pharmacoeconomics: It is the branch which deals with economics of drug, which aims to quantify drug in economic terms, the cost and benefit of drugs used therapeutically. Pharmacokinetics: It deals with Absorption, Distribution, Metabolism and Excretion (ADME) of drugs.

6. Subdivisions of Pharmacology Pharmacodynamics: It deals with study of biochemical and physiological effects of drugs and their mechanism of actions. Pharmacotherapeutics: it deals with the use of drugs in prevention and treatment of diseases. Clinical Pharmacology: It deals with the study of drugs in human/animals when given in diseased condition. Pharmacognosy: It deals with the sources of drugs. Pharmacogenetics: It deals with the study of genetically determined variations in response to drugs. Pharmacometrics: It deals with the study of qualitative and quantitative evaluation of drugs activity.

7. Subdivisions of Pharmacology Experimental Pharmacology: It deals with the study of drugs action in animals under laboratory conditions. Pharmacoepidemiology: It deals with the study of both beneficial and adverse effects of drug on human/animal population. Chemotherapy: It deals with study of drugs that inhibits specific agents of diseases such as bacteria, virus and fungi Toxicology: It deals with the study of adverse effects of drugs or chemicals on living system. Materia Medica: It is a book containing information about pharmacy, pharmacognosy, posology and uses of drugs. Now a days it is replaced by modern science of pharmacology

8. INTRODUCTION TO PHARMACEUTICS Pharmaceutics: It deals with the process of turning a new chemical entity into a medication to be used safely and effectively by patients. It is also called the science of dosage form design. There are many chemicals with pharmacological properties, but need special measures to help them achieve therapeutically relevant amounts at their sites of action. Branches of pharmaceutics include: Pharmaceutical formulations Pharmaceutical manufacturing Dispensing Pharmacy Pharmaceutical Technology Physical Pharmacy Pharmaceutical Jurisprudence

9. HISTORY OF PHARMACOLOGY Knowledge of drugs and their uses in diseases are as old as history of mankind. Primitive men gather the knowledge of healing and medicines by observing the nature, noticing the animals while ill and personal experience after consuming plants and herbs as remedies. Ancient civilizations discovered that extracts from plants, animals, and minerals had medicinal effects on body tissue. These discoveries became the foundation of pharmacology. Pharmacology in the present form is relatively recent branch about hundred years old.

10. Historical developments in Pharmacology PEN PSAO (2700 BC) It was the great herbal materia medica written in china. Kahun Papyrus (2000 BC) is an oldest Egyptian document containing information about veterinary medicines and uterine diseases of women. Ebers papyrus (1550 BC) also an Egyptian document containing information about number of diseases and 829 prescription where castor oil, opium like drug are being used. Hippocrates (460-375 BC) A greek physician consider “father of Medicine” . He was the first person who recognize disease as abnormal reaction of body. He introduce use of metallic salts for the treatment of disease.

11. Historical developments in Pharmacology Theophrastus (380-287 BC) a great philosopher called father of Pharmacognosy. He classified medicinal plants on the base of medicinal characteristics. Dioscorides (AD 57) a greek, produced one of the first materia medica of approximately 500 plants and remedies. Claudius Galen (AD 129–200) first attempted to consider the theoretical background of pharmacology. Paracelsus (1493–1541) a Swiss scholar and alchemist, often considered the “ grandfather of pharmacology ”. He introduces the use of chemicals for treatment of disease. Valerius Cordus (1514-1544) He compiled the first pharmacopeia where he described techniques for the preparation of drugs.

12. MODERN PHARMACOLOGY Conversion of old medicines into the modern pharmacology start taking shape following the introduction of animal experimentation and isolation of active ingredients from plants. Francois Megendie (1783-1855) a first pharmacologist established the foundation of modern pharmacology. He developed experiment to elucidate the physiological processes and action of drugs on the body. Frederich Sertürner, German pharmacist’s assistant, isolated morphine—the first pure drug—in 1805 Claude Bernard (1813-1878) considered Father of experimental Medicine. He identifies the site of action of curare (arrow Poisoning).

13. MODERN PHARMACOLOGY Rudolph Buchheim (1820–1879) German pharmacologist a key figure in the development of pharmacology, a who at the University of Dorpat, created the first pharmacological institute. Oswald Schmiedeberg (1838–1921) “ Father of Pharmacology ” established pharmacology as an independent discipline. He start teaching Pharmacology in University of Strasbourg (France). John Jacob Abel (1857-1938) founded first department of pharmacology in USA in the University of Michigan in 1893. In 1897 he established pharmacology department at Johns Hopkins University. Abel also co-founded the Journal of Pharmacology and Experimental Therapeutics in 1909.

14. MODERN PHARMACOLOGY L. mayer Jones (1912-2002) regarded as father of modern veterinary pharmacology. He authored first book of veterinary pharmacology therapeutics in 1954. SCOPE OF PHARMACOLOGY It provides the rational basis for the therapeutic use of the drug. Before the establishment of this discipline, even though many remedies were used, but doctors were reluctant to apply scientific principles to therapeutics . In 1920s, many synthetic chemicals were first introduced and the modern pharmaceutical companies began to develop .

15. SCOPE OF PHARMACOLOGY Scientific understanding of drugs enables us to predict the pharmacological effect of a new chemical that will produce a specified therapeutic effect. The scope of pharmacology has expanded greatly over the last decade to incorporate many new approaches such as computer-assisted drug design, genetic screens, protein engineering and use of novel drug delivery vehicles including viruses and artificial cells . Our society needs pharmacologists who understand the basis of modern therapeutics for careers within academic, pharmaceutical and governmental laboratories to study and develop tomorrow’s drugs.

16. Pharmacodynamics Pharmacokinetics

17. Routes of drug administration (R.O.A.) IV:Intravenous, IM:Intramuscular, SC:Subcutaneous, SL:Sublingual, TD:Transdermal

18. Routes of drug administration (R.O.A.) Continued. . Local Routes: Very low or no systemic absorption Systemic Routes: Oral : Safer and Economical, some drugs are ineffective because of High first Pass Metabolism (eg. nitrates, lignocaine, propranolol, ), Degradation (Insulin, penicillin G) Sublingual : Avoids First Pass Metabolism , Used in Emergencies, Only lipid soluble and non irritating drugs (eg. of drugs administered by this route Nitroglycerine, isosorbidedinitrate etc.) Transdermal : Only for drugs Highly lipid soluble

19. Routes of drug administration (R.O.A.) Continued. Nasal : eg. Nafarelin (GnRH agonist), calcitonin and desmopressin Inhalational : Rate of drug delivery can be controlled like I.V. Infusion , antiasthmatic and inhalational anaesthetic agents Rectal : Avoids first pass metabolism upto 50% (Diazepam in febrile seizures) Intravenous: Bolus (Dose injected at once) or Infusion(Continuous delivery over a period of time) Intradermal: Through Bleb, Vaccines

20. PHARMACOKINETICS ADME study: A bsorption, D istribution, M etabolism, E xcretion ABSORPTION:

21. 1. Absorption contd… So, for absorption of drug from biological membrane it should be present in unionised lipid soluble form Ionisation depends on pH of surrounding medium and pKa of drug Lets make it simple, ABSORPTION WILL OCCUR WHEN MEDIUM IS SAME, Means acidic drugs will remain unionised in acidic environment and get absorbed while basic drugs will remain unionised in basic environment and get absorbed Ionisation of a drug is neither 100% nor 0% (Weak acids or bases), therefore a drug should never be 100% lipid or water soluble

22. Absorption (contd…) pH-pka relationship pka is the pH at which drug is 50% ionised and 50% unionised Acidic drug will remain unionised in acidic medium but will ionise in basic medium and basic drug will remain unionised in basic medium and ionise in acidic medium Suppose an acidic drug having pKa of 4 was placed in pH 4, it will be 50 % ionised and 50% unionised, NOW same drug is kept in medium of pH 3 (acidic), it remains lipid soluble. But, if it is kept in pH 2 what will happen, obviously it becomes more lipid soluble because more of the drug is un-ionised, But Numerically HOW MUCH??? Concepts: If the pH of the medium is less than pKa (Medium becomes acidic) For Acidic drugs, unionised form increases and ionised form decreases For Basic drugs, ionised form increases and unionised form decreases If the pH of the medium is more than pKa (Medium becomes basic), opposite happens

23. Bioavailability Fraction of administered drug that reaches into the systemic circulation in the unchanged form By IV route it is 100% Pre-systemic or first pass metabolism

24. Bioavail. (contd…) Fig. Plot between plasma conc. and time to calculate bioavailability It can be calculated by comparing AUC (Area under the curve) for I.V. route and for the desired route or can also be calculated by comparing excretion in urine AUC tells about extent of absorption Tmax tells about rate of absorption Cmax is max conc. obtained in plasma Bioequivalence = ±20% bioavailability   MEC: Min. effective conc., MTC: Max therapeutic conc.

25. 2. Distribution After drug reaches to the blood it is distributed to many tissues, which is determined by a hypothetical parameter Volume of Distribution (Vd) It is the volume that would be required to contain the administered dose if that dose was evenly distributed at the at the conc. measured in plasma Higher Vd means more amount of drug was entering in tissue Depends on lipid solubility and protein binding Lipid soluble drug crosses blood vessel easily and thus have high Vd If a drug is highly bound to plasma protein it behaves like a large molecule and unable to cross the blood vessel, thus goes less into the circulation and have low Vd Only free form (not bound to plasma protein) of drug is responsible for action as well as metabolism of a drug. Thus, Plasma protein binding makes drug long acting by reducing its metabolism

26. Distribution (contd…)  

27. 3. Metabolism (Biotransformation) Chemical alteration of the drug in the body Needed to render the nonpolar (lipid soluble) compounds into polar (lipid-insoluble) to excrete them outside the body Primary site is liver, others are kidney, intestine lungs and plasma Biotransformation of drug may lead to following three events: 1. Inactivation Most drugs render inactive or less active metabolites 2. Active metabolite from an active drug Many drugs are partially converted to one or more active metabolites;

28. Active Drug Active Metabolite Chloral hydrate Trichloroethanol Morphine Morphine-6-Glucoronide Cefotaxime Desacetyl cefotaxime Allopurinol Alloxanthine Procainamide N-acetyl procainamide Primidone Phenobarbitone Diazepam Oxazepam Digitoxin Digoxin Imipramine Desipramine Amitriptyline Nortriptyline Codeine Morphine Spironolactone Canrenone

29. Metabolism (Contd…) Biotransformation reactions are of two types: 1. Nonsynthetic/Phase I/Functionalisation reactions: Functional group is generated or exposed Metabolite may be active or inactive Major reactions involved are: Oxidation ( Major ), Reduction, Hydrolysis, Cyclisation, De-cyclisation 2. Synthetic reaction/Phase II Conjugation by endogenous substrate to form a highly polar water soluble compound which is easily excreted Major reactions involved are: Glucuronide conjugation ( Major ), Acetylation, Methylation, sulphate, glycine, or glutathione conjugation

30. Metabolism (Contd…) Metabolism may occur with the help of: Microsomal enzyme: present in smooth endoplasmic reticulum Ex; monooxygenases, cytochrome P450, and glucoronyl transferases May be induced or inhibited by other drug Non microsomal enzyme: present in cytoplasm and mitochondria Ex; flavoprotein oxidases, esterases, amidases and conjugases Not inducible by other drugs but shows genetic polymorphism

31. Metabolism (Contd…) Drug metabolising by microsomal enzyme is called as substrate and chemical increasing or decreasing that enzyme is called as inducer or inhibitor respectively

32. Cytochrome P-450 450 denotes their strong absorbance at  450  nm Superfamily of microsomes CYP3A4 is involved in metabolism of 50% drugs Root word Family Sub-family Gene number CYP3A4 Nomenclature

33. 4. Excretion Passage out of systemically absorbed drug Major route is kidney; involves glomerular filtration, tubular reabsorption and tubular secretion 1. Glomerular filtration: Depends on plasma protein binding and renal blood flow. Does not depends upon lipid solubility because all substances crosses the fenestrated glomerular membrane 2. Tubular reabsorption: Depends on lipid solubility Lipid solubility depends on ionisation, ionised drug will be excreted

34. Barbiturates, salicylate Sodiumbicarbonate Acidic drug in basic medium Morphine, amphetamine Ammonium chloride

35. Excretion (contd…) 3. Tubular secretion: Does not depend on lipid solubility or plasma protein binding. Separate pump for acidic and basic drugs are present in nephron; drug utilising same pump may show drug interaction; eg. Probenecid decreases excretion of penicillin

36. Kinetics of elimination Pharmacokinetics model may be one or two compartment One compartment Model: Drug having less or no distribution in tissues, elimination is continuous and the log plasma conc. vs time curve is linear (frst order kinetics)

37. First order kinetics (linear) Zero order kinetics (Non linear) Constant fraction of drug is eliminated per unit time Constant amount of drug is eliminated per unit time ROE proportional to Co ROE independent of Co Clearance (Cl) remains const. Cl is more at low conc. and less at high conc. Half life (T 1/2 )remains const. T 1/2 less at low conc. and more at high conc. Most drugs follow first order kinetics Very few drugs eg; Alcohol

38. Half life (t 1/2 ) Time required to reduce the plasma conc. half to its original value It is a secondary P’kinetic parameter derived from two primary P’kinetic parameter Vd and clearance (Cl) Determines dosing interval and time required to reach steady state conc. Does not affect dose of the drug t 1/2 = (0.693 * Vd)/Cl

39. Drug : A chemical substance that is used for diagnosis, prevention & treatment of disease. (French: Drogue -Dry herb) Contraceptives General Anaesthetics Vaccines WHO : “Any substance or product that is used or intended to be used to modify or explore the physiological system or pathological state for the benefit of the recipient”

40. Classification of Drugs Based on site of action Based on Chemical Structure Based on Mechanism of Action Based on Ionization of Drugs Based on Therapeutic Uses Based on Anatomical Therapeutics Classification (ATC)

41. Sources of Drugs A) Plant Sources B) Animal Sources C) Microorganism D) Chemicals E) Recombinant DNA Technology

42. A) Plant Sources- 1) Alkaloids – Atropine ( Atropa belladona ) Morphine ( Papaver somniferum ) 2) Glycosides- Digoxin ( Digitalis purpura ) 3) Oils- Essential oil (Volatile oil)-leaves & Flower eg- clove oil, pipermint, eucalyptus Fixed oil- seeds eg- ground nut, coconut, castor, olive oil Mineral oil- liquid paraffin 4) Gum - excretory products (gum acacia) 5) Resins - Tolu balsam (cough mix) 6) Tannins - catechu

43. B) Animal Sources 1 ) Hormones - Insulin ( Pork-Procine), (Beef-Bovine ) 2) Vaccines - Polio, Antirabies 3) Sera - ATS (Antitetanus Serum) 4) Vitamins - Vit B12 from Liver extract C) Microorganism- Antibiotics D) Chemicals – synthetic drugs E) Recombinant DNA Tech – Human Insulin, Calcitonin, Gonadotropins, erythropoietin etc.

44. Nomenclature of Drugs Chemical Non-Proprietary Proprietary OR OR Generic Name Brand Name OR OR Approved Name Trade Name OR OR Official Name Commercial

45. Some examples of Chemical, Generic, Brand Names Chemical Name Generic Name/ Non- Proprietary Name Brand Name/ Proprietary Name Acetyl Salicylic Acid Aspirin Disprin Acetaminophen Paracetamol Crosin, Calpol, Metacin Aminobenzyl Penicillin Ampicillin Roscillin

46. Generic/Non-Proprietary Name- Given by USAN Council (United States Adopted Name) Advantages- World-wide acceptance, name remains the same in all countries. Usually have similar suffix in a group. Economical than Branded/Proprietary Medicines . Disadvantages- Naming of Fixed Dose combinations.

47. Brand Name/Proprietary Name- Name given by Pharmaceutical company for commercial purpose. Advantages- The consistency or Pharmacokinetics or efficacy does not change with same brand. Single brand name for a Medicine with multiple ingredients. Bioavailability remains same where a patient is maintained on a particular brand. Disadvantages - Branded Medicines are costlier. Multiple brands for a same Medicine.

48. Drugs Confusing Names Drugs with some similarity in names or suffix but different in action or different in class. DRUG NAME DIFFERENCE Cotrimoxa zole AMA Clotrima zole Anti fungal Omepra zole H2 blocker Ornida zole Antiamoebic Tenida zole Antiamoebic Albenda zole Anthelmintic Anastro zole Fomepi zole Aromatase inhibitor Alcohol

49. Drug Categories Prescription Drugs OTC (Over The Counter) Non-Prescription Drugs

50. Sources of Drug Information Official Compendia Pharmacopoeia (IP, BP, USP) Formulary (NFI) Non-Official Compendia Physician’s Drug References(PDR)- USA Martindale Pharmacopoeia – Great Britain Other Sources of Drug Information Drug indices ( CIMS, IDR, MIMS, Drug Index) Drug advertisement Internet, Medical Rep.

51. Essential Drugs WHO in 1977 published a list of drug as “Model list of Essential drugs”. “List of drugs that satisfy the health care needs of majority of the population; they should therefore, be available at all times in adequate amount & in appropriate dosage form.” The current WHO list is revised in 2011 as 17 th edition for adults with 23 FDC & 3 rd edition for children. India produced its National Essential Drug List in 1996, presently it is revised in 2011 with title “ NLEM (National List of Essential Medicines)” which includes 348 medicines.

52. Types of Drug Action EFFECT (Type of responses):- 1.Stimulation 2.Inhibition/Depression 3.Replacement 4.Irritation 5.Cytotoxic

53. Mechanism of Action of Drugs Drug act either by receptor or by non receptor or by targeting specific genetic changes. Majority of drugs acts by ( HOW) Receptor mediated Non receptor mediated

54. Receptor Mediated action Drug produce their effect through interacting with some chemical compartment of living organism c/s Receptor. Receptors are macromolecules Most are proteins Present either on the cell surface , cytoplasm or in the nucleus

55. Receptor Functions : Two essential functions 1. Recognization of specific ligand molecule (Ligand binding domain) 2. Transduction of signal into response (Effector domain) Ligand binding domain Transduction of signal into response

56. Drug(D) +Receptor® Drug receptor complex Response Drug receptor interaction:- 1. Selectivity :- Degree of complimentary co relation between drug and receptor. Ex:- Adrenaline Selectivity for α, ß Receptor 2. Affinity:- Ability of drug to get bound to the receptor. 3. Intrinsic activity (IA) or Efficacy :- Ability of drug to produce a pharmacological response after making the drug receptor complex.

57. Drug classification (on the basis of affinity & efficacy)

58. Response No response

59. Partial agonist :These drug have full affinity to receptor but with low intrinsic activity (IA=0 to 1). These are only partly as effective as agonist ( Affinity is lesser when comparison to agonist) Ex: Pindolol, Pentazocine

60. Inverse agonist : These have full affinity towards the receptor but intrinsic activity is zero to -1 i.e., produces effect is just opposite to that of agonist. Ex:- ß-Carboline is inverse agonist for Benzodiazepines receptors.

61. Receptor families Four types of receptors families 1 . Ligand-gated ion channels (inotropic receptors) 2 .G-protien coupled receptor (Metabotropic receptors) 3 . Enzymatic receptors (tyrosinekinase) 4 .Receptor regulating gene expression (transcription factors/ Steroid )

62. Characteristics of receptor families Ligand gated G-protein coupled Enzymatic Nuclear Location Membrane Membrane Membrane Intracellular Effector Ion channel Ion Channel or enzyme Enzyme Gene coupling Direct G-protein Direct Via DNA Example Nicotinic Muscarinic Insulin Steroid , hormone

63. Signal transduction mechanism Ion gated receptors :- Localized on cell membrane and coupled directly to an ion channel. Receptor Agonist Hyper polarization or depolarization Receptor Blocker Permeation of ion is blocked Cellular effect No cellular effect Ion Na +2

64. Ex: Nicotinic cholinergic receptor

65. G-protein coupled receptors Membrane bound, which are coupled to effector system through GTP binding proteins called as G-proteins Bound to inner face of plasma membrane ( 2 nd messenger)

66. Varieties of G-protein G-protein Receptor for Signaling pathway/ Effector Gs ß adrenegic, H,5HT,Glucagon AC— cAMP Gi 1,2,3 α 2 adrenergic, Ach, AC— cAMP, Open K + Gq Ach Phospholipase-C, IP 3 ’ cytoplasmic Ca +2 Go Neurotransmitters in brain Not yet clear

67. G-protein effector systems 1.Adenylase cyclase : cAMP system 2.Phospholipase –C: Inositol phosphate system 3. Ion channels

68. cAMP system

69. Phospholipase-C system

70. Ion channel regulation G-protein coupled receptors can control the functioning of ion channel by don't involving any second messenger Ex:- In cardiac muscle

71. These receptor are directly linked tyrosine kinase. Receptor binding domain present in extra cellular site. Produce conformational changes in intra cellular Ex:- Insulin receptors Enzymatic receptors

72. Enzymatic receptors Extra cellular receptor binding domain Intra cellular changes

73. Receptor regulating gene expression (transcription factors) Unfolds the receptor and expose normally masked DNA binding site Increase RNA polymerase activity

74. Receptor regulation theory Receptors are in dynamic state. The affinity of the response to drugs is not fixed. It alters according to situation. Receptor down regulation : Prolonged use of agonist Receptor number and sensitivity Drug effect Ex: Chronic use of salbutamol down regulates ß 2 adrenergic receptors.

75. Receptor up regulation : Prolonged use of antagonist Receptor number and sensitivity Drug effect Ex:- propranolol is stopped after prolong use, produce withdrawal symptoms. Rise BP, induce of angina.

76. Agonist : Both the high affinity as well as intrinsic activity (IA=1) These drug trigger the maximal biological response or mimic effect of the endogenous substance . Ex:- Methacholine is a cholinomimetic drug which mimics the effect of Ach on cholinergic receptors.

77. Types of agonism Summation :- Two drugs eliciting same response, but with different mechanism and their combined effect is equal to their summation. (1+1=2) Aspirin Codiene PG Opiods receptor Analgesic+ Analgesic+ ++

78. Types of agonism Additive: combined effect of two drugs acting by same mechanism Aspirin PG PG Analgesic+ Analgesic+ + +

79. Synergism (Supra additive):- (1+1=3) The combined effect of two drug effect is higher than either individual effect . Ex:- 1.Sulfamethaxazole+ Trimethoprim 2. Levodopa + Carbidopa.

80. Types of antagonism Antagonism : Effect of two drugs is less than sum of the effects of the individual drugs. Chemical antagonism Ex: -heparin(-ve) protamine +ve, Chelating agents Physiological /Functional antagonism Pharmacokinetic antagonism Pharmacological antagonism Competitive ( Reversible) Non competitive (Irreversible )

81. Pharmacokinetic antagonism One drug affects the absorption, metabolism or excretion of other drug and reduce their effect. Ex:-Warfarin in presence of phenobarbitone, warfarin metabolism is increased, it effect is reduced.

82. Pharmacological antagonism Pharmacodynamic antagonism between two drugs acting at same receptors. Two important mechanism according to which these antagonists 1.Reversible(Competitive) 2.Irreversible(Non)

83. Reversible antagonism (Competitive antagonism ) These inhibition is commonly observed with antagonists that bind reversibly to the same receptor site as that of an agonist. These type inhibition can be overcome increasing the concentration of agonist Ex:- Atropine is a competitive antagonist of Ach.

84. Irreversible Antagonism It occurs when the antagonist dissociates very slow or not at all from the receptors result that no change when the agonist applied. Antagonist effect cannot be overcome even after increasing the concentration of agonist

85. Non receptor mediated action All drugs action are not mediated by receptors. Some of drugs may act through chemical action or physical action or other modes. Chemical action Physical action (Astringents, sucralfate) False incorporation (PABA) Being protoplasmic action (antiseptics) Formation of antibody (Vaccines) Targeting specific genetic changes.

86. Dose It is the required amount of drug in weight, volumes, moles or IU to provide a desired effect. In clinical it is called as Therapeutic dose In experimental purpose it is called as effective dose. The therapeutic dose varies from person to person

87. Single dose : 1.Piperazine (4-5g) is sufficient to eradicate round worm. 2.Single IM dose of 250mg of ceftriaxone to treat gonorrhoea. Daily dose : It is the quantity of a drug to be administered in 24hr, all at once or equally divided dose. 1.10mg of cetrizine (all at once) is sufficient to relive allergic reactions. 2.Erythromycin is 1g per day to be given in 4 equally divided dose (i.e., 250mg every 6 hr)

88. Total dose : It is the maximum quantity of the drug that is needed the complete course of the therapy. Ex:- procaine penicillin →early syphilis is 6 million unit → given as 0.6 million units per day for 10days. Loading dose :- It is the large dose of drug to be given initially to provide the effective plasma concentration rapidly. The drugs having high Vd of distribution. Chloroquine in Malaria – 600 mg Stat 300mg after 8 hours 300 mg after 2 days.

89. Maintenance dose :- Loading dose normally followed by maintenance dose. Needed to maintain the steady state plasma concentration attained after giving the loading dose.

90. Therapeutic index : Margin of safety Depend upon factor of dose producing desirable effect → dose eliciting toxic effect. TI →should be more than one

91. Toxic Therapeutic window : Optimal therapeutic range of plasma concentrations at which most o the patients experience the desired effect. Therapeutic range→ Therapeutic window Sub optimal optimal

92. Cyclosporine – 100-400ng/ml Carbamazapine- 4-10µg/ml Digoxin- 0.8-2ng/ml Lithium- 0.8-1.4 mEq/L Phenotoin – 10-20µg/ml Qunindine- 2-6µg/ml

93. Tolerance : Increased amount of drug required to produce initial pharmacological response. Usually seen with alcohol, morphine, barbiturates, CNS active drugs Reverse tolerance :- Same amount drug produces inc pharmacological response. Cocaine, amphetamine → rats- inc. motor activity

94. Types of tolerances Innate tolerance : Genetically lack of sensitivity to a drug. Ex: Rabbits tolerate to atropine large doses Chinese→ Castor oil Negros → Mydriatic action of sympathomimetics Eskimos→ high fatty diets

95. Acquired tolerances : Occurs due to repeated use of drug Pharmacokinetic tolerances Pharmacodynamic tolerance Acute tolerance Pharmacokinetic tolerances :- Repetitive administration causes decrease their absorption or inc. its own metabolism Ex: Alcohol → dec. absorption Barbiturates→ Inc. own metabolism

96. Pharmacodynamic tolerance Down regulation of receptors Impairment in signal transduction Ex: Morphine, caffeine, nicotine. Acute tolerance: Tachyphylaxis Acute development of tolerance after a rapid and repeated administration of a drug in shorter intervals Ex; Ephedrine, tyramine

97. Ex: Monday disease. Nitroglycerine – Monday , Tuesday workers get headache, after they get tolerances. After holiday (Sunday) they get again headache . Cross tolerances : Cross tolerance among drugs belonging to same category. MORPHIN→HEROIN→ NARCOTIC

98. Factors modifying the EFFECTS OF DRUGS

99. Individuals differ both in the degree and the character of the response that a drug may elicit Variation in response to the same dose of a drug between different patients and even in the same patient on different occasions.

100. One or more of the following categories of differences among individuals are responsible for the variations in drug response: Individuals differ in pharmacokinetic handling of drugs Variation in number or state of receptors, coupling proteins or other components of response Variation in neurogenic/ hormonal tone or concentrations of specific constituents

101. These factors modify drug action either: Quantitatively The plasma concentration and / or the drug action is increased or decreased Qualitatively The type of response is altered, eg: drug allergy and idiosyncrasy

102. The various factors are: Body weight/size: It influences the concentration of drug attained at the site of action The average adult dose refers to individuals of medium built

103. For exceptionally obese or lean individuals and for children dose may be calculated on body weight basis BSA=BW(Kg)0.425 x Height(cm)0.725 x 0.007184

104. Age: Infants and Children: The dose of drug for children often calculated from the adult dose

105. However, infants and children are have important physiological differences Higher proportion of water Lower plasma protein levels More available drug Immature liver/kidneys Liver often metabolizes more slowly Kidneys may excrete more slowly

106. Elders: In elderly, renal function progressively declines (intact nephron loss) and drug doses have to be reduced Chronic disease states Decreased plasma protein binding Slower metabolism Slower excretion Dietary deficiencies Use of multiple medications Lack of compliance

107. Sex: Females have smaller body size, and so require doses of drugs on the lower side of the dose range They should not be given uterine stimulants during menstruation , quinine during pregnancy and sedatives during lactation

108. Pregnancy: Profound physiological changes which may affect drug responses: GI motility reduced –delayed absorption of orally administered drugs Plasma and ECF volume expands Albumin level falls Renal blood flow increases markedly Hepatic microsomal enzyme induction

109. Food: Delays gastric emptying, delays absorption (ampicillin) Calcium in milk –interferes with absorption of tetracyclines and iron by chelation Protein malnutrition Loss of BW Reduced hepatic metabolizing capacity Hypoproteinemia

110. Species and race: Rabbits resistant to atropine Rat & mice are resistant to digitalis In humans: blacks require higher Mongols require lower concentrations of atropine and ephedrine to dilate their pupil

111. Route of drug administration: I.V route dose smaller than oral route Magnesium sulfate: Orally –purgative Parenterally –sedative Locally –reduces inflammation

112. Biorhythm: (Chronopharmacolgy) Hypnotics –taken at night Corticosteroid –taken at a single morning dose Psychological state: Efficacy of drugs can be effected by patients beliefs, attitudes and expectations Particularly applicable to centrally acting drugs In some patients inert drugs (placebo) may produce beneficial effects equivalent to the drug, and may induce sleep in insomnia

113. Presence of diseases/pathological states: Drug may aggravate underlying pathology Hepatic disease may slow drug metabolism Renal disease may slow drug elimination Acid/base abnormalities may change drug absorption or elimination Severe shock with vasoconstriction delays absorption of drugs from s.c. or i.m Drug metabolism in: Hyperthyroidism –enhanced Hypothyroidism -diminished

114. Cumulation: Any drug will cumulate in the body if rate of administration is more than the rate of elimination Eg: digitalis, heavy metals etc.

115. Genetic factors: Lack of specific enzymes Lower metabolic rate Acetylation Plasma cholinesterase (Atypical pseudo cholinesterase) G-6PD Glucuronide conjugation

116. Tolerance: It means requirement of a higher dose of the drug to produce an effect, which is ordinarily produced by normal therapeutic dose of the drug Drug tolerance may be: Natural Acquired Cross tolerance Tachyphylaxis (ephedrine, tyramine, nicotine) Drug resistance

117. Other drugs: By interactions in many ways

118. Drug classification (on the basis of affinity & efficacy) Agonist : Both the high affinity as well as intrinsic activity (IA=1) These drug trigger the maximal biological response or mimic effect of the endogenous substance . Ex:- Methacholine is a cholinomimetic drug which mimics the effect of Ach on cholinergic receptors.

119. Antagonist :- Which have only the affinity no intrinsic activity (IA=0). IA=0 so no pharmacological activity. Rather these drug bind to the receptor and produce receptor blockade. Atropine blocks the effects of Ach on the cholinergic muscarinic receptors.

120. cAMP system Some drugs, hormones or neurotransmitters produce their effect by increasing or decreasing the activity of adenylate cyclase and thus raising or lower cAMP with in the cell.

121. Stimulation Some of drug act by increasing the activity of specialized cells. Ex: Catecholamines stimulate the heart and Heart rate, Force of contraction

122. Inhibition Some drug act by decreasing the activity of specialized cells. Ex: Alcohol, Barbiturates, General anesthetic these drug depress the CNS system. Atropine inhibits Ach action.

123. Replacement When there is a deficiency of endogenous substances, they can replaced by drugs. Ex: Insulin in Diabetes mellitus Throxine in cretinism and myxedema

124. Irritation Certain drugs on topical application cause irritation of the skin and adjacent tissues. These drugs are using for counter irritant. Ex: Eucalyptus oil, methyl salicylates (Used in sprains, joint pain, myalgia.

125. Cytotoxic Treatment of infectious disease/cancer with drugs that are selectively toxic for infecting organism/cancer cells Ex: Anticancer drugs All Antibiotics

126. E Cam E* Gq PLC PIP 2 DAG S Agonist Hydrolysis Activation IP 3 PKC ATP ADP Product Ca +2 Cam Water soluble release Response Phospholipase-C system Hydrolysis PLC= Phospholipase-C PIP2 =Phosphotiydl inositol 4,5 di phosphate IP3 =Inositol tri phosphate DAG = Diacylglycerol E= Ezyme PKC = Phosphokinase -C

127. Extra cellular site of action 1.Antacids neutralizing gastric acidity. 2.Chelating agents forming complexes with heavy metals. 3.MgSo 4 acting as purgative by retaining the fluid inside the lumen of intestine.

128. Cellular Site of Action 1.Ach on Nicotinic receptors of motor end plate, leading to contraction of skeletal muscle. 2.Effect of sympathomimetics on heart muscle and blood vessels.

129. Intracellular site of action -Folic acid synthesis inhibitors. Folic acid which is intracellular component essential for synthesis of proteins. Trimethoprim and sulfa drug interfere with synthesis.

130. or FC of heart muscle Lipolysis Glycogen Glycogen breakdown synthesis to glucose G protein + - Effector AC cAMP ATP Protein kinase Active Ca +2 release Phosphorylation Gs/Gi

131. Physical action Absorption : Kaolin absorbs bacterilal toxin and thus acts as antidiarrhoeal agent. Protectives :- Various dusting powders.

132. Antagonist :- Which have only the affinity no intrinsic activity (IA=0). IA=0 so no pharmacological activity. Rather these drug bind to the receptor and produce receptor blockade. Atropine blocks the effects of Ach on the cholinergic muscarinic receptors.

133. Physical Action Osmosis :- MgSo 4 acts as a purgative by exerting osmatic effect within lumen of the intestine. Astringents :- They precipitate the surface proteins and protect the mucosa Ex: tannic acid in gum patients Demulcent :- These drugs coat the inflamed mucus membrane and provide soothing effect. Ex: Menthol

134. False incorporation Bacteria synthesis folic acid from PABA (Para Amino Benzoic Acid), for growth sand development. Sulfa drugs resemble PABA, therefore falsely enter into the synthesis process of PABA, cause nonfunctional production and no utility for bacterial growth.

135. Protoplasmic poison Germicides and antiseptics like phenol and formaldehyde act as non specifically as protoplasmic poison causing the death of bacteria

136. Through formation of antibodies Vaccines produce their effect by inducing the formation of antibodies and thus stimulate the defense mechanism of the body Ex:- Vaccines against small pox and cholera

137. Targeting specific genetic changes . Anti cancer drugs that specifically target genetic changes. Inhibitors of specific tyrosine kinase that that block the activity of oncogenic kinases.

138. Physiological antagonism Two antagonists, acting at different sites, counter balance each other by producing opp. effect on same physiological system. Histamine –Vasodilatation Nor epinephrine – Vasoconstriction

139. Chemical action 1.Ion Exchanges :-Anticoagulant effect of heparin(-ve charge) antagonized by protamine (+ve charged) protein. 2. Neutralization :- Excessive gastric acid is neutralized by antacids. 3. Chelation :-These are trap the heavy metals. Ex:-EDTA, BAL.

140. References Garg GR, Gupta S. Review of Pharmacology, sixth edition, 2012, Jaypee publishers, New Delhi Tripathi KD. Essentials of medical pharmacology, sixth edition, 2008, Jaypee publishers, New Delhi