General Pharmacology- Introduction and Basic Concepts-1.pptx

POC 3

1. General Pharmacology: Part 1 Introduction and Some Basic Concepts

2. Pharmacology Pharmacology: Science of drugs Pharmacon: Drug Logos: Discourse in Interaction of exogenously administered substances with living systems Drug: A single active chemical entity in a medicine used for diagnosis, prevention, treatment or cure of disease WHO definition: Any substance/product used/intended to be used to modify/explore physiological systems or pathological states for the benefit of the recipient.

3. Historical Aspects For 1000s of years, most drugs were crude natural products Unknown composition Limited efficacy Overt effects were known rather imprecisely How were they exerted? Not known Animal experiments started in 18 th century Pioneered by Francois Magendie and Claude Bernard Also adapted them to study the effect of certain drugs

4. Historical Aspects Rudolf Buchheim ushered pharmacology as experimental science Founded the first institute in 1847 in Germany Later 19the century: Oswald Schmiedeberg put forth some fundamental concepts in pharmacology with his disciples Including pharmacokinetics and pharmacodynamics “Father of pharmacology”

5. Nature of Drugs All are chemical entities Simple/complex structure Majority o drugs are organic compounds Some are inorganic Organic drugs may be weakly acidic/basic or non-electrolytes Most drugs are normally solid Some are liquid (Propofol, Glyceryl trinitrate) A few are gases (Nitrous oxide)

6. Nature of Drugs Molecular weight of most drugs is 100-1000 Daltons (D) Molecules smaller than 100 D cannot bind to only one or few targets Molecules larger than 1000 D don’t readily pass the membranes Few exceptions Some drugs are as small as lithium ion (7 D) Some like heparin (10-20 kD), proteins, antibodies (>30 kD) Bulky molecules have to be administered parenterally

7. Sources of Drugs Plants Oldest source of drugs Clues about medicinal plants obtained from traditional systems of medicine Several categories of active ingredients Alkaloids Glycosides Oils

8. Sources of Drugs Animals Animal parts have been used as cures since early times Study of activity of organ extracts led to introduction of animal products into medicine E.g. Adrenaline, Insulin, liver extract (vitamin B 12 ) Antisera and a few vaccines are also produced from animals

9. Sources of Drugs Microbes Source of most antibiotics E.g. Penicillin, Gentamicin, Tetracycline Some enzymes also have microbial source Streptokinase from Streptococci Minerals A few minerals like iron salts, calcium salts are used as medical substances

10. Sources of Drugs Synthetic chemistry Made its debut in 19 th century Now the largest source of drugs Advantage of purity and uniformity of product Can be manufactured in any quantity as needed Congeners of naturally obtained substances: Selective E.g. β 2 -agonists

11. Sources of Drugs Synthetic chemistry Entirely synthetic families of drugs have been synthesized E.g. Benzodiazepines, Thiazides, Fluoroquinolones Many drugs are synthesized to target specific biomolecules ACE inhibitors, glycoprotein IIb/IIIa receptor antagonists etc. Biotechnology Proteins and peptides are now produced by recombinant DNA technology Monoclonal antibodies, erythropoietin and other growth factors are of biochemical origin

12. Essential Drugs (Medicines) WHO: Those that satisfy the priority healthcare needs of population Selected with due regard to Public health relevance Evidence of efficacy and safety Comparative cost-effectiveness

13. Essential Drugs (Medicines) Intended to be available within the context of functioning health system At all times In adequate amounts In appropriate dosage forms With assured quality and adequate information At a price affordable to individual and the community

14. Essential Drugs (Medicines) Only a handful of medicines can meet needs of majority of populations Many well-tested and cheaper drugs are as efficacious and safe as their more expensive counterparts Governments should focus on these drugs Call them “essential medicines”

15. Essential Drugs (Medicines) WHO’s criteria to guide the selection of essential drugs

16. Essential Drugs (Medicines) WHO made first Model List of Essential Drugs in 1977 To guide the member countries Could be adopted after suitable modifications as per local needs Revised from time to time Current list is 22 nd , published in 2021 India produced its National Essential Drug List in 1996 Revised in 2011 Now known as National List of Essential Medicines (NLEM- 2015 version)

17. Essential Drugs (Medicines) India’s current NLEM includes 376 medicines 20 of them are fixed-dose combinations Marked into 3 categories for being available at different levels of care Primary, secondary and tertiary Adoption of essential medicines list for procurement and supply of drugs Improved availability Cost-saving More rational drug use

18. Routes of Drug Administration Most drugs can be administered by various routes Choice of appropriate route: Drug as well as patient-related factors

19. Local Routes of Drug Administration Can only be used for Localized lesions at approachable sites Drugs whose systemic absorption from these sites is minimal High concentration of drug at desired site Without involving the entire body Minimal systemic side-effects/toxicity

20. Local Routes of Drug Administration Topical External application to surface for localized action Often more convenient and reassuring to patient Drug can be delivered to lesions on skin, mucosa, eyes, ear canal etc. Other forms of topical administration Non-absorbable drugs given orally for action on GI mucosa Sucralfate, Vancomycin Inhalation for action on bronchi (e.g. Salbutamol) Irrigation solution/jelly applied on urethra (e.g. Lidocaine)

21. Local Routes of Drug Administration Deeper tissues Certain deep areas can be approached by syringe and needle Systemic absorption should be slow E.g. intra-articular (Hydrocortisone), intrathecal (Lidocaine) Arterial supply Close intra-arterial injection for contrast media in angiography Infusion of anticancer drugs in femoral/brachial artery Localize the effect for limb malignancies

22. Systemic Routes of Drug Administration Oral Oldest and most common routes Safer, more convenient, non-invasive, often painless Medicament need not be sterile, so cheaper Solid as well as liquid dosage forms can be given

23. Systemic Routes of Drug Administration Oral (continued) Slower action; not suitable for emergencies Unpalatable drugs are difficult to administer May be filled in capsules to combat this May cause nausea and vomiting Not useful for uncooperative/unconscious/vomiting patient Absorption may be variable and erratic Certain drugs are destroyed by digestive juices or in liver

24. Systemic Routes of Drug Administration Sublingual or buccal Tablet/pallet is kept under tongue or crushed in mouth Only lipid-soluble and non-irritable drugs can be administered Relatively rapid absorption: Action within minutes Can be spit out after desired effect is achieved Drugs with high first pass metabolism can be administered this way Liver is bypassed; drug right into systemic circulation

25. Systemic Routes of Drug Administration Rectal Some irritant and unpleasant drugs can be put into rectum for systemic effect Also useful when patient is continuously vomiting or unconscious Rather inconvenient and embarrassing Slower, irregular, and often unpredictable absorption Rectal inflammation can result from irritant drugs Diazepam, Indomethacin, Paracetamol etc are sometime given

26. Systemic Routes of Drug Administration Cutaneous Highly lipid-soluble drugs on skin For slow, prolonged absorption Liver is also bypassed Drug can be made into ointment; applied Absorption can be enhanced by Rubbing Using oily base

27. Systemic Routes of Drug Administration Cutaneous (transdermal therapeutic systems: TSS) Devices in the form of adhesive patches Deliver the drug at a constant rate into circulation Via stratum corneum Drug is held in a reservoir between Occlusive backing film and Rate-controlling micropore membrane Under surface is smeared with an adhesive impregnated with priming dose Adhesive layer protected by another file to be peeled of before use

28. Systemic Routes of Drug Administration Cutaneous (TTS) Drug is delivered at a constant and predictable rate Designed to last for 1-3 days Though more expensive: Provide smooth plasma concentration without fluctuations Minimize inter-individual variation Little first-pass metabolism Minimize side effects More convenient; preferred by patients to tablets of same drug

29. Systemic Routes of Drug Administration Inhalation Volatile liquids and gases are given for systemic action E.g. general anaesthetics Absorbed from vast surface of alveoli Action is rapid On discontinuation, drug is diffused back Rapidly eliminated through expiration Irritant vapors (e.g. ether) cause inflammation and increase secretion

30. Systemic Routes of Drug Administration Nasal Nasal mucus membrane can absorb many drugs Digestive juices and liver bypassed Only a few drugs have been given this way Being tried for some peptide drugs like insulin

31. Systemic Routes of Drug Administration Parenteral Conventionally refers to injection; takes drug directly to tissue/blood Without having to pass GI mucosa Limitations or oral administration are circumvented Disadvantages Preparation needs to be sterile, so costlier Invasive and painful Assistance is mostly needed Chances of local tissue injury Generally riskier than oral

32. Important Parenteral Routes Subcutaneous (SC) Drug deposited into loose subcutaneous tissue Richly supplied by nerves Less vascular Only small volumes can be injected Deep penetration not needed; self-injection possible Pellet implantation : Solid pellet introduced with trochar and cannula Sustained release over weeks to months E.g. Testosterone

33. Important Parenteral Routes Subcutaneous (SC) Dermojet : High-velocity jet projected from microfine orifice Using a gun-like implant Solution passes through superficial layer into SC tissue Essentially painless Sialistic and biodegradable implants : Crystalline drug packed in tubes/capsules Implanted under skin Slow, uniform leaching of drug over months Tried for hormones and contraceptives

34. Important Parenteral Routes Intramuscular (IM) Injected in one of the large skeletal muscles Deltoid, triceps, gluteus maximus etc Muscle is less richly supplied with nerves; more vascular Mild irritants can be injected Faster absorption from aqueous solution Depot preparations can be injected Less painful Self-injection often impracticable: Deep penetration is needed

35. Important Parenteral Routes Intravenous (IV) Injected as bolus or infused slowly in a superficial vein Reaches directly into circulation Effects produced immediately Valuable in emergency Highly irritant drugs can be injected Intima of veins is insensitive Drug gets diluted with blood

36. Important Parenteral Routes Intravenous (IV) Hazards: Thrombophlebitis of injected vein Necrosis of adjoining tissue if extravasation occurs Minimized by diluting or injecting into a running IV line Inject only aqueous solution No depot preparations for this route Another risk: Chances of air embolism

37. Important Parenteral Routes Intravenous (IV) Small doses needed (100% bioavailability) Large volumes can be infused Riskiest route Vital organs exposed to large concentrations of drug Intradermal Injected into skin raising a bleb Or else, scarring/multiple puncture of epidermis through drop of drug Employed for specific purposes (e.g. BCG vaccine, sensitivity testing)

38. Routes of Drug Administration: In a Nutshell

39. Receptors Specific regulatory macromolecules controlling the effectors Enzymes, channels, structural proteins etc Most of the drugs act through receptors Receptor is defined as a macromolecule or binding site located on the surface or inside of the effector cells that serves to recognize the signal molecule/drug and initiate the response to it, but itself has no other function

40. Terms Used for Drug-Receptor Interaction Agonist : Activates the receptor to produce an effect similar to that of the physiological molecule Antagonist : Prevents the action of agonist on receptor or subsequent response; but doesn’t have an action of its own Inverse agonist : Activates the receptor to produce an effect in opposite direction to that of agonist Partial agonist : Activates the receptor to produce submaximal effect, but antagonizes the action of a full agonist Ligand : A molecule attaches to a particular receptor

41. Competitive Antagonism Antagonist is chemically similar to agonist Binds to the same site to the exclusion of agonist Has affinity but no intrinsic activity Log DRC of agonist is shifted to right Binding is reversible; depends on relative conc of agonist & antagonist Higher conc of agonist progressively overcomes the block Partial agonist antagonizes the full agonist Produces submaximal response of its own

42. Non-Competitive Antagonism Antagonist is chemically unrelated to agonist Binds to a different “allosteric” site Alters the receptor so that It is unable to bind to agonist, or Is unable to transduce the response Also called “allosteric antagonism” No competition due to binding at different sites High conc of agonist can’t overcome the block completely

43. Spare Receptors Not all the receptors in tissue are needed to achieve maximal response Spare receptors exist when maximal response is achieved prior to saturation of all receptors Also called “reserve receptors” Spare receptors: Receptors that exist in excess of those needed for full effect Agonist response is elicited at conc that doesn’t produce full receptor occupancy Cardiac muscles: <10% receptors need to be occupied for full effect of catecholamines

44. Drug Tolerance and Dependence Drugs capable of altering mood and feelings Liable to repetitive use to derive: Euphoria Recreation Withdrawal from reality etc Some subjects take drugs repeatedly for personal gratification Progress in indulgence Give higher priority to taking drug than basic needs

45. Drug Tolerance and Dependence Many such drugs induce adaptive physiological changes Result into escalation of dose needed for same effect “Tolerance” develops Disturbed physiological equilibrium in absence of drug Drug dependence : Altered physiological state due to repeated administration Necessitates continuous presence of drug for equilibrium Discontinuation results in “withdrawal symptoms” Drugs producing dependence: Opioids, barbiturates, alcohol, benzodiazepines

46. Drug Addiction Person feels emotionally distressed if drug is not taken Believes that optimal state of well-being is only achieved with drug Often starts as a liking to effects of the drugs Progresses to compulsive drug use in some individuals Lose control and cannot stop taking the drug Despite knowing that it is harmful Earlier called “psychological dependence” Called “drug addiction” to avoid confusion

47. Drug Addiction Procuring and taking the drug takes priority over other activities Most addicts tend to relapse even after withdrawal Dependence is not an essential feature of addiction Although a strong impetus Amphetamines, cocaine, cannabis: Addiction, but little/no dependence Nalorphine: Dependence without imparting addiction Little drug-seeking behavior

48. Tachyphylaxis Rapid development of tolerance Marked reduction in response Following drug doses repeated in quick succession Usually seen with indirectly acting drugs E.g. Ephedrine, Tyramine Release catecholamine Catecholamine synthesis can’t match the release Stores get depleted

49. Tachyphylaxis Other mechanisms Slow dissociation of drug from receptor Desensitization/internalization or down-regulation of receptors Drug resistance Tolerance of microbes to inhibitory action of antimicrobials E.g. Resistance of Staphylococci to Penicillin

50. Idiosyncrasy Genetically determined abnormal reactivity to a chemical Drug interacts with a unique feature in an individual Not found in majority of individuals Produces uncharacteristic reaction As such, restricted to a particular genotype Also, certain bizarre effects due to peculiarities of an individuals Barbiturates: Excitement and mental confusion Quinine/Quinidine: Cramps, diarrhoea, purpura, asthma, angioedema of face, and hypotension Chloramphenicol: Non-dose-related serious aplastic anemia

51. Drug Allergy (Hypersensitivity) Immunologically mediated reaction Produces stereotype response unrelated to pharmacodynamic profile May appear even with much smaller doses Different time course of onset and duration Target organs primarily affected Skin Airways Blood vessels Blood cells GI tract

52. Drug Allergy (Hypersensitivity) Occur only in small proportion of population Can’t be produced in others at any dose Prior sensitization is needed Latent period of 1-2 weeks after 1 st exposure Sensitizing exposure may go unnoticed/may be environmental Drug (or metabolite): Antigen (AG) Or “hapten” (incomplete antigen) Induces production of antibody (AB)/sensitized lymphocytes

53. Drug Allergy (Hypersensitivity) Chemically related drugs often show cross-sensitivity Different types of reactions in different individuals Widely different drugs can produce similar reactions Course of drug allergy is variable Previously sensitive person my tolerate Previously non-allergic person may show reaction Skin tests or intranasal test may forewarn in type-I hypersensitivity Not in other types Not always reliable: False positives and false negatives aren’t rare

54. Types and Mechanisms of Allergic Reactions Type-I (Anaphylactic Reaction) IgE antibodies produced, get fixed to mast cells & basophils AG-AB reaction on mast cell surface Release mediators like histamine, 5-HT, leukotrienes etc Urticaria, itching, angioedema, bronchospasm, rhinitis, anaphylactic shock Anaphylaxis: Paresthesia, flushing, lip swelling, itching, wheezing, palpitations Followed by syncope Occurs quickly; called “immediate hypersensitivity” Antihistaminic drugs are beneficial

55. Types and Mechanisms of Allergic Reactions Type-II (Cytolytic Reaction) AG: Drug + component of specific tissue cell IgG, IgM antibodies bind to target cells AG-AB reaction on surface of cells on re-exposure Complement activation, cytolysis Thrombocytopenia Agranulocytosis Aplastic anemia Haemolysis Organ damage Systemic lupus erythematosus (SLE)

56. Types and Mechanisms of Allergic Reactions Type-III (Retarded, Arthus Reaction) Mediated by circulating antibodies Predominantly IgG AG-AB complexes bind complements Precipitate on vascular endothelium and basement membrane in tissues Release chemotactic mediators and lytic enzymes Rashes, serum sickness, polyarteritis nodosa, SJ syndrome Develops 3-4 days after exposure Usually subsides in 1-2 weeks

57. Types and Mechanisms of Allergic Reactions Type-IV (Delayed Hypersensitivity Reaction) Mediated through production of sensitized T-lymphocytes Carrying receptors for AG Produce lymphokines on contact with AG Generate inflammatory response Contact dermatitis Certain types of rashes Fever Photosensitization Takes 2-3 days to develop

58. Treatment of Drug Allergy Stop the offending drug immediately Most mild reactions subside by themselves Antihistamines beneficial in some type-I reactions Itching, urticaria, swelling of lips, rhinitis etc Also useful in some skin rashes Bronchospasm: Adrenaline followed by short course of glucocorticoid Type-II, III and IV reactions: Only glucocorticoids are effective

59. Treatment of Anaphylactic Shock Guidance by Resuscitation Council of UK Put patient in reclining position; oxygen at high flow rate CPR if necessary Inject adrenaline 0.5 mg IM; 1 in 1000 solution 0.5 ml for adult, 0.3 ml for 6-12 yr old; 0.15 ml for up to 6 yr old Repeat every 5-10 min if needed Only life-saving measure Don’t inject Adrenaline IV unless shock is immediately life threatening Dilute to 1 in 10,000-1 in 100,000 Infuse slowly with constant monitoring

60. Treatment of Anaphylactic Shock Guidance by Resuscitation Council of UK Administer H1-antihistamine IM/slow IV Pheniramine 20-40 mg/Chlorpheniramine 10-20 mg May have adjuvant value Add IV glucocorticoid in severe/recurrent cases Hydrocortisone sodium succinate 200 mg Acts slowly Specially valuable for prolonged reactions and in asthmatics May be followed by oral Prednisolone for 3 days