Grg Pharma Pharmacology PDF

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3 36 S - 93 98 23 SP I 66 - 6 213 - 229 235 23-  Introduction and Routes of Drug Administration Pharmacology is the science dealing with drugs. Two branches: 1. PharmacoKinetics → Effect of Body on Drug 2. PharmacoDynamics → Effect of Drug on Body Drug: Drug is a substance which is intended to be used to modify or explore the physiological function or pathological state for the benefits of recipient. Risk benefit ratio: If it is favorable, then drug is used e.g. Streptokinase is used in MI but not for peripheral vascular disease Essential drugs These are the drugs that cater to priority health care needs of a population. These drugs should be –– Always available –– In adequate quantity –– With assured quality Mostly available as single compound. Orphan drugs- –– These are drugs for which the expenditure done for the development of the drug is unlikely to be recovered from sale of the drug. –– Include drugs which are used for rare diseases. –– Also include drugs for relatively common diseases in third world; countries with less paying capacity 2 General Pharmacology Route Angle of needle with horizontal Advantage Intravenous 25° Used in emergencies Intramuscular 90° - Subcutaneous 45° Self-administration possible Intradermal Almost 0° For BCG and Allergy testing –– Intravenous route can be of two types: Bolus Infusion –– Because the drug is directly entering the systemic circulation, any volume of fluid can be given by itravenous route. –– Titration is possible by intravenous route –– Disadvantages of intravenous route are: Sterile precautions should be followed Require an expert person for administration It is costly –– By Intramuscular route, maximum 5-10 ml volume can be given  Pharmacokinetics: Absorption Pharmacokinetics → aka ADME Study –– Absorption –– Distribution –– Metabolism –– Excretion Absorption → It is the movement of drug from site of administration to blood. → Lipid Solubility is the most important factor in absorption. When The Medium Is Same, Then The Drug Will Cross DRUG MEDIUM FORM SOLUBILITY CROSS Acidic Acidic Non ionized Lipid Soluble  Basic Basic Non ionized Lipid soluble  Acidic Basic lonized Water Soluble  Basic Acidic lonized Water Soluble  2 General Pharmacology Extra Edge How much a drug will cross in different media? e.g. Nature - Acidic Pka = 6.0 pH Lipid soluble Water soluble 3.0 99.9% 0.1% 4.0 99% 1% 5.0 90% 10% 6.0 50% 50% 7.0 10% 90% 8.0 1% 99% 9.0 0.1% 99.9% Henderson Hasselbach Equation pH = pKa + [X ] — [HX] –– Acidic Drug [Aspirin], mainly absorbed from stomach –– Basic Drug [Morphine] mainly absorbed from intestine But practically all drugs (even acidic drugs like aspirin) are absorbed more from intestine as compared to stomach because: Large surface area of intestine Longer time drug stays in intestine Bioavailability → It is the fraction of given dose which that reaches the systemic circulation in unchanged form → Bioavailability → Determines the Dose  3 Pharmacokinetics Absorption High bioavailability → Low Dose Low bioavailability → High dose Factors affecting: 1. Absorption ↑ Absorption → ↑ Bioavailability ↓ Absorption → ↓ Bioavailability 2. Route of Administration Route % Bio-availability Fractional Bio-availability Oral 5-100 0.05 < F < 1 I.M. 75-100 0.75 < F < 1 S.C. 75-100 0.75 < F < 1 IV 100 1 3. First Pass metabolism/Pre systemic metabolism ↑ First Pass metabolism → ↓ Bioavailability ↓ First Pass metabolism → ↑ Bioavailability NTG [Nitroglycerine] –– Has High First pass metabolism –– Sub Lingual Route is Preferred Advantages of sublingual route –– Fast acting → Can be used in emergencies –– No First pass metabolism –– Self administration is possible –– After desirable action, we can spit/ingest the extra dose How to calculate bioavailability? To know the bioavailability of Drug A by oral route ↓ Give drug A 100 mg by IV route Now same dose (100 mg) given orally and plot ↓ the same graph Then plot a graph 4 General Pharmacology AUCo Bioavailability = AUCiv Bioequivalence (Biologically Equivalent) –– 2 brands of same drug are compared If two brands of same drug have almost similar bioavailability (20%), these are called bioequivalent Most of the drugs are bioequivalent except phenytoin Plasma Concentration Vs Time Graph Cmax: Maximum concentration obtained by a particular dose Should lie between MTC and MEC Tmax: Time in which plasma concentration becomes maximum Tells Rate of absorption AUC: Total area covered by graph Tells Extent of absorption  Pharmacokinetics: Distribution Distribution is a measure of amount of drug in tissues after absorption in the systemic circulation Factors affecting: 1. Lipid Solubility → Most important Factor Lipid soluble Drugs → Higher Distribution Water Soluble Drugs → Lower Distribution 2. Plasma Protein Binding (PPB) ↑ PPB → Low Distribution → Acidic drugs bind to → Albumin → Basic drugs bind to → a1 Acid Glycoprotein → Different drugs have different percentage of binding Acidic drugs Basic drugs Examples Aspirin Atropine Barbiturates Morphine Methotrexate Amphetamine Bind to Albumin α-1 acid Glycoprotein Mnemonic Salt with cations like Na & K e.g., Phenytoin + + Drugs ending with ‘INE’ sodium Salts with anions like Ipratropium bromide Extra Edge Importance of PPB a. Distribution: → if PPB is high, its volume of distribution (Vd) → ↓↓ b. Duration: → If drug has ↑ PPB Duration of action of drug ↑, because plasma protein to which it is bound serves as storage site. c. Displacement interactions: → PPB sites on albumin & α1 - Acid glycoprotein arenon -specific → One drug may displace another drug leading to increase in free concentration of latter. This may result in toxicity. → For example, Warfarin is displaced by sulfonamides leading to bleeding. d. Dialysis: → If a drug has ↑ PPB; dialysis of that drug cannot be done → Because proteins are not filtered during dialysis; thus the drug with ↑ PPB is retained along with plasma proteins e. Filtration: → If, drug has ↑ PPB, its filtration would be lesser. 2 General Pharmacology 3. Barriers –– Brain is bound by Blood Brain Barrier. –– In circumventricular Organs, this barrier is absent. –– CTZ [chemoreceptor Trigger Zone] is important circumventricular organ. –– Vomiting not caused by → Anti-emetics and Anti-psychotics Volume of Distribution (Vd) Amount given → Vd= Co → Volume of Distribution Vd ∝ Amount of Drug in Tissues EXTRA EDGE More Vd → More distribution Chloroquine Drug with maximum Vd [> 1300 L] Mostly distributed in Liver but site of preferred action is RBC Loading Dose [LD] Initial high dose given to start the action LD = Vd x Target Plasma Concentration Maintenance Dose Repeated doses given to maintain the plasma concentration. MD = CL x Target PC  Pharmacokinetics: Metabolism Elimination → Termination of action of Drug → ELIMINATION → Includes Metabolism and Excretion Prodrugs: Metabolism (Biotransformation) All - ACE inhibitors (PRIL) except captopril and isinopril Fate of Metabolism Prefer - PPI’s (Prazole), Prednisone 1. Active → Inactive Doing - Dipivefrine 2. Active → Active M - Methyldopa, Minoxidil, 6-MP DIAZEPAM → OXAZEPAM D - levo-Dopa 3. Inactive → Active In - Irinotecan [PRODRUG] Clinical - Clopidogrel, Carbimazole LEVODOPA → DOPAMINE Subjects - Sulfasalazine, Sulindac Aim of Metabolism → To Make a Drug Water Soluble (Polar) PHASE I REACTIONS PHASE II REACTIONS → Mostly catabolic Reactions → Mostly anabolic reactions → Includes → Includes –– Oxidation (MC Phase I reaction) –– Glucuronide [MC Phase II Reaction] conjugation –– Reduction –– Glutathione conjugation –– Hydrolysis –– Acetylation –– Cyclization –– Methylation –– Deamination –– Sulfate conjugation Purpose of Phase I → Expose the Functional Group on the drug Purpose of Phase II → Makes the drug water soluble 2 General Pharmacology Enzymes → Divided into Microsomal and Non-microsomal Microsomal Non-microsomal –– Present in smooth endoplasmic reticulum –– Present outside SER –– Can be induced or inhibited –– Cannot be induced or inhibited –– Most Phase I reactions and glucuronidation –– Most Phase II reactions → Enzyme inhibitors (e.g., erythromycin) decrease the metabolism of drugs metabolized by microsomal enzymes (e.g., theophylline). This increases their plasma concentration and thus can lead to toxicity. → Enzyme inducers (like rifampicin) increase the metabolism of drugs metabolized by microsomal enzymes (e.g., warfarin). This reduces plasma concentration and thus action of these drugs. We should increase the dose of warfarin when rifampicin is given concurrently. Enzyme Inducers Enzyme inhibitors G Griseofulvin Vit Valproate P Phenytoin K Ketoconazole R Rifampicin Can’t Cimetidine S Smoking Cause Ciprofloxacin Cell Carbamazepine Enzyme Erythromycin Phone Phenobarbitone Inhibition Isoniazid → Most of antiepileptics are Enzyme Inducers except Valproate → Most of antibiotics are Enzyme Inhibitors except Rifampicin and Griseofulvin Cytochrome p450 Enzymes These are one type of microsomal enzymes. P → Stands for pigment 450 → This pigment absorbs maximum light at wavelength 450 nm Nomenclature: e.g.: CYP-3A4 3→ Family A → Subfamily 4 → Isoform Most of the drugs are metabolized by CYP3A4 followed by CYP2D6  3 Pharmacokinetics Metabolism Drugs metabolized by 3 A4 (CT SCAN) C Cyclosporine T Tacrolimus S Statins Cisapride C CAT Drugs Astemizole -These are withdrawn from market becasuse these cause QT prolongation in ECG A Amiodarone Terfenadine N Navirs (HIV protease inhibitors) Drugs metabolized by 2C9 Clotting (Warfarin) [C means clotting] Phenytoin [Mirror image of 9 looks like P of Phenytoin] Drugs metabolised by 2C19 Clopidogrel Ticlopidine Clopidogrel – CYP2C19 PPI Active Therefore, PPIs are avoided with clopidogrel  Pharmacokinetics: Excretion → Most of the drugs are excreted through kidney → Some of the drugs are excreted through sweat (e.g., Lithium) Glomerular Filtration → Lipid soluble as well as water soluble drugs can befiltered → Filtration is inversely proportional to Plasma Protein binding Tubular Reabsorption → 99% of GFR is reabsorbed –– Lipid soluble drugs reabsorbed –– Water soluble drugs excreted Weak Acidic drug poisoning Weak basic drug poisoning (Aspirin, Barbiturates, Methotrexate) (Amphetamine) ↓ ↓ Urine is made alkaline by giving NaHCO3 Urine is made acidic by giving NH4Cl ↓ ↓ Acidic drugs gets ionized (water soluble/polar) Basic drugs gets ionized ↓ ↓ No tubular reabsorption No tubular reabsorption ↓ ↓ Drug is excreted out Drug is excreted out 2 General Pharmacology Tubular Secretion → Due to pumps/transporters in proximal tubules → The drug is secreted from blood into urine through these transporters a) Organic anion transporter b) Organic cation transporter → These transporters are Saturable (One drug can be transported at one time) Clinical Importance –– Penicillin is short acting (Due to rapid tubular secretion) –– Penicillin + Probenecid → Long acting –– Probenecid has higher affinity for transporters and Prevents Penicillin secretion –– It makes penicillins long acting. Extra Edge If CL > GF Tubular secretion must be present CL < GF Tubular reabsorption must be present  Kinetics of Elimination Rate of Elimination [R] → Incomplete parameter Amount of drug eliminated R→ Time Clearance [CL] → Complete parameter Rate of Elimination CL = Plasma concentration Extraction Ratio (ER) Artery It is amount of drug extracted by an organ. 100 It is calculated as Vein CA = Conc. of drug in arteries entering the organ 80 CV = Conc. Of drug in veins leaving the organ. Clearance by an organ = Extraction Ratio X Blood Flow –– Hepatic Clearance = Hepatic Extraction Ratio x Blood Flow to liver –– Renal Clearance = Renal Extraction ratio x blood flow to Kidney –– Total body clearance = Sum of all the clearances of individual organs. If a drug has high hepatic extraction ratio, on oral administration, liver can extract large amount of drug before it reaches the systemic circulation, leading to poor bioavailability which is known as First Pass Metabolism. The drugs with High First pass metabolism / High hepatic extraction ratio L - Lignocaine P - Propranolol G - GTN (Glyceryl trinitrate/Nitroglycerine) Half Life [t1/2] It is the time in which plasma concentration of a drug becomes half. Half-life is constant in first order kinetics. 2 General Pharmacology → t1/2 for most drugs is constant Question: t1/2= 6hrs, after 1 day 100 ↓ t1/2 → How much drug remains in body → 6.25% 50 → How much drug eliminated from body →100 - remaining → 93.75% ↓ t1/2 Importance of t ½: 25 –– Dose cannot be calculated –– Dosing Interval/ Frequency can be known ↓t1/2 12.5 Formula of Half-life: ↓t1/2 1 0.693 t = 6.25 2 K (where, K is elimination rate constant) As K = CL Vd 1 Vd So, t = 0.693 X 2 CL Steady State → Is a state at which the rate of administration of a drug is equal to rate of elimination. Points to remember about steady state 1. Time to reach steady state depends on half-life. It takes approximately 4-5 half lives. 2. Steady state plasma concentration achieved depends on dose rate. –– If we give more dose, more concentration will be achieved. –– If we give less dose, less concentration will be achieved. 3. Variation between peak and trough concentration at steady state depends on frequency of administration. If we give more frequently variation will be less and vice versa. Therapeutic Drug Monitoring [TDM] → Adjustment of dose of a drug according to its plasma concentration is called TDM → Criteria for doingTDM 1. Response should not be measurable. So, TDM is never done for antidiabetic and anticoagulant drugs. 2. Drug should have Low Therapeutic Index. So, TDM is not done for penicillins which have very high TI. 3. Inconsistent Pharmacokinetics of Drugs TDM done For A → Aminoglycosides Drug → Digoxin Possessing → Phenytoin [most antiepileptic drugs] Low → Lithium Therapeutic → Tricyclic Anti-Depressants [TCA] Index → Immunosuppressant Drugs – Cyclosporine – Tacrolimus  3 Kinetics of Elimination Order of Kinetics Rate of elimination (Plasma concentration)order – In First order Kinetics - Rate of elimination a plasma concentration – Zero order Kinetics - Rate of elimination is constant – Second order Kinetics - Rate of elimination a (plasma concentration)2 – Third order Kinetics - Rate of elimination a (plasma concentration)3 First order kinetics Zero order kinetics → Fraction is constant → Amount is constant R a PC R = Constant CL = Constant CL a 1/PC t½ = Constant t½ a PC Majority of drugs follow First Order Kinetics Drugs Following Zero Order Kinetics are Zero → Zero order Kinetics W → Warfarin A → Alcohol/Aspirin T → Theophylline T → Tolbutamide Power → Phenytoin Reason → Order of Kinetics depends on Enzyme Saturation –– If enzymes are abundant → Follow 1st order Kinetics –– If enzymes are limiting factor → Follow Zero Order Kinetics. Zero order Kinetics is also known as Pseudo-Zero order kinetics/Non-Linear Kinetics.  Pharmacodynamics: Introduction and Enzyme Inhibitors Pharmacodynamics deals with effect of a drug on the body. Enzyme inhibition Competitive - Drug competes with substrate by binding to active site of enzyme. Noncompetitive - Drug binds to allosteric site of enzyme. Property Competitive Inhibition Non-Competitive Inhibition Structure Same as substrate Different Binding site Active Allosteric site Reversibility Surmountable Unsurmountable Km Increases Do not change Vmax Do not change Decreases Lineweaver Burke Plot: –– Also known as double reciprocal plot –– Graph between 1/S (on X-axis) and 1/V (on (N) Is Normal graph Y-axis) –– X-axis tells Km and Y-axis tells Vmax (1) Is competitive –– If lines intersect at X-axis, it is non-competitive inhibitor inhibition (2) Is non-competitive –– If lines intersect at Y-axis, it is competitive inhibitor inhibition  Pharmacodynamics: Receptors –– Affinity → Ability of a drug to bind to a receptor –– Intrinsic Activity → Ability of a drug to produce action after binding to receptor Thus, a drug cannot produce action if it does not bind to a receptor Classification of Drugs Based on Intrinsic Activity Agonist Maximum intrinsic activity [+1] Partial Agonist Submaximum intrinsic activity [0 to +1] Inverse Agonist Opposite action to agonist [-ve] Antagonist No action of itself but interfere with action of other drugs Classification of Receptors Based on Signal Transduction Mechanism Receptors Examples 1. Ionotropic GABAA, NMDA, NN, NM, 5HT3 2. Enzymatic Cytokines, Prolactin, Insulin, GH 3. Intracellular A. Cytoplasmic Vit D, Glucocorticoids, Mineralocorticoids B.Nuclear Vit A, Thyroid hormones, Sex hormones 4. GPCR Most others 2 General Pharmacology 1. lonotropic Receptors → The receptors present on ion channels are known as ionotropic receptors. → Fastest acting receptors → Examples – GABAA receptor – NMDA receptors – NN receptors – NM receptors – 5HT3 receptors 2. Enzymatic Receptors → These are present on cell membrane with intracellular and extracellular ends. → Drug binds outside and enzyme is activated inside and action is produced → Aka Tyrosine Kinase Receptors [Mostly associated enzyme is Tyrosine Kinase] → Examples of Enzymatic receptors 1. Cytokines: TNF-α IFN IL 2. Hormones: P – Prolactin I – Insulin G – Growth Hormone 3. G-Protein Coupled Receptors [GPCR] → Also k/a heptahelical/ Serpentine/ Metabotropic Receptors → Near these Receptors, a protein is present called G-protein Drug binds the Receptor from outside ↓ Receptor is activated ↓ Receptor activates the G-protein ↓ G-protein breaks into two components ↓ Active components works by one out of the 3 mechanisms – By changing the level of CAMP – Can act through Ca2+ – Can open the ion channels  3 Pharmacodynamics Receptors –– G Protein has 3 subunits: α, β and γ –– GDP binds to α-subunit. Its function is to stabilize G-protein. –– On activation via receptors, G-proteins gets phosphorylated (GDP is converted to GTP) and breaks into two parts α-component is active β, γ is mostly inactive –– α component also has GTPase activity, it Converts GTP to GDP G protein stabilization occurs Recycling of G protein Types of G proteins Type Mechanism Second/Third messenger GS Stimulate adenylate cyclase ↑ cAMP Gi Inhibit adenylate cyclase ↓ cAMP Gq Convert PIP2 to IP3 and DAG IP3 DAG Calcium 4. Intracellular Receptors A. Cytoplasmic Receptors B. Nuclear Receptors → Only Lipid soluble drugs acts through these receptors Drug Drug ↓ ↓ Binds to cytoplasmic receptors Binds to nuclear receptor ↓ Drug-receptor complex enters the nucleus ↓ In the nucleus it binds to DNA ↓ Affects replication, transcription &translation → Thus, whether a drug binds the cytoplasmic receptors or the nuclear receptors, it will finally work through DNA (nuclear mechanism) → These are slowest acting receptors. 4 General Pharmacology Nuclear Receptor Superfamily [Intra-cellular Receptors] Cytoplasmic receptors Nuclear receptors C – Corticosteroids S – Sex hormones – Glucocorticoids – Estrogen – Mineralocorticoids – Progesterone D – Vitamin D – Testosterone A – Vitamin A T – Thyroid hormones – T3 –T4 Q: Which of the following works through nuclear Q: Which of the following works through nuclear receptors? mechanism? a Retinol a Retinol b Prednisolone b Prednisolone c Aldosterone c Aldosterone d All of these d All of these Ans: a Retinol Ans: d All of these Extra Edge Different type of Receptors 1. Pre-synaptic receptors Present on pre-synatic neurons Can be autoreceptors (Present on its own neurons) or heteroreceptors (present on some other neurons) 2. Post - synaptic receptors Present on post-synaptic neurons or end organs 3. Spare receptors Maximum response can be achieved even when only a fraction of total number of receptors are bound to ligands. These extra unbound receptors act as spare receptors. 4. Orphan receptors These are receptors for which there is no known endogenous ligand e.g. BZD receptors 5. Silent receptors Here, the drug binds but do not produce any biological response e.g. plasma proteins  Dose Response Curve [DRC] Dose Response Curve Log Dose Response Curve (Log DRC) → It is hyperbola in shape → S-shaped curve [Sigmoid Curve) → It is not used clinically → Clinically more useful than DRC → 3 important parameters obtained from log DRC: 1. Potency 2. Efficacy 3. Slope Potency → To produce a similar response if a drug is required in lesser dose, it is more potent → On log DRC, left-sided curve is more potent drug whereas right-sided curve is less potent Efficacy → Relates to maximum effect of a drug regardless of dose → Higher the curve, more is efficacy → Clinically Efficacy is more important than potency C → Most efficacious (Highest curve) D → Least efficacious (Lowest curve) D → Most potent (Most left) B → Least potent (Most right) → From log DRC, we can tell efficacy of a drug but not its effectiveness. 2 General Pharmacology Slope → Slope is related to safety → Drug with flat curve is safer → Drug with steep curve is less safe Clinically Benzodiazepines are preferred over barbiturates for insomnia because Benzodiazepines are safer than barbiturates. Extra Edge Selectivity: If one drug has two actions and log DRC is plotted for these actions, then the drug is said to be –– Selective for left-sided action if graph is far apart on X-axis –– Non-selective if graphs are near on X-axis In given figure, Drug A is selective bronchodilator whereas drug B is non-selective Quantal DRC –– For All or None phenomenon, where grade of response cannot be plotted. –– Percentage of subjects responding are kept on Y-axis  3 Dose Response Curve [DRC] i) If 50% respond to a particular dose, Then it is called ED50 (Median Effective dose) ii) If 50% of animals die after receiving a particular dose it is median lethal dose (LD50). LD50 Therapeutic index = ED50 –– Therapeutic index is margin of the safety of a drug If ↑ Therapeutic index-drug is safe If ↓ Therapeutic index-drug is unsafe.  Clinical Trials and Pharmacovigilance Pre - clinical studies → Done in animals under CPCSEA guidelines Clinical Trials → Testing of drugs in humans Licensing authority → Authority to give approval for a new drug in USA = US – FDA → Authority to give approval for a new drug in India = CDSCO (Central Drug Standards Control Organization), headed by DCGI (Drug Controller General of India) Phase l → Done in Healthy People → Efficacy Testing cannot be done → MTD [Maximum tolerable dose] can be found → Phase I can also be done in Patients for Toxic drugs → Aim of Phase I trials: MTD > Dosing > PK > Safety Phase II → Done in patients [50-500 numbers] → Indicator of Efficacy [1st time efficacy is done] → Maximum risk of failure is in phase II Phase III → Done in patients [upto 5000] → Multicentric trials done [Covers different genetic makeup] → Efficacy Confirmation can be Known Phase IV → Post marketing study done [Max no. of patients tested] → Rare Side Effects can be studied → Chronic Side Effect can be studied All phases of studies are conducted under GCP guidelines. 2 General Pharmacology FDA Applications INDA → Investigational New Drug Applications → Applied before starting clinical trails NDA → New Drug Application → Applied before marketing the drug (after phase III) Extra Edge → Phase Zero –– Micro-dosing study –– It is conducted on humans –– Maximum amount of drug given is 100 mcg or (1/100)th of Human Equivalent Dose, whichever is lower –– Radiolabeled substances are added with this sub therapeutic dose to know the Pharmacokinetics of the drug. –– Efficacy or safety cannot be found in phase zero. –– It is not mandatory Control & Blinding → Drug group - Newly developed drug will be given → Control group –– Placebo (Dummy medication) given –– For Life-threatening diseases – Standard drug given –– Placebo effect is mostly due to release of endorphins Blinding: To keep drug or control group or both, unaware of the treatment –– Single blind study Only the subject (Patient) is unaware of the treatment Done in Phase II –– Double blind study Both the investigator & the subject are unaware of the treatment Eliminate Investigator bias (considered as the best study) Done in Phase III –– Phase 1 are OPEN LABEL studies in which blinding is not done.  3 Clinical Trials and Pharmacovigilance Extra Edge The Drugs and Cosmetics Act –– An act to regulate the import, manufacture, distribution and sales of drugs. → Spurious drug: Imitation of or substitute of another drug in a manner likely to deceive the name of another drug. The less known pharmaceutical company try to take advantage of reputation of a well-known company. → Misbranded drug: If a drug is not labelled in prescribed manner or its label contains any statement which makes any false claims for the drug. → Adulterated drug: If it contains filthy, patrid or decomposed substances. Pharmacovigilance It is the study of detection, assessment, understanding and prevention of adverse effects of drugs. –– Adverse event (AE) - Includes anything adverse happening to the person while on drug therapy –– Adverse drug reaction (ADR) - Out of adverse events, adverse reactions caused by drugs are included. Detection –– Detect all the adverse events happened Assessment –– Assess adverse reactions caused by drugs out of all adverse events. –– All ADR are AE but all AE are not ADRs –– De-challenge and Re-challenge method can be used. –– Causality assessment can be done by Naranjo scale –– Severity of ADR is also assessed Understanding –– Postulate a mechanism for the cause of adverse reaction by the given drug Prevention –– Proper advice to avoid the adverse event from happening National pharmacovigilance program of India (NPVPI) ADR monitoring centers (AMC) –– Uses a software known as vigiflow –– It collects all the adverse drug reactions reported and send them to National Coordinating Center National Coordinating Center (NCC) –– It is Indian pharmacopoeia commission (IPC) –– Located in Ghaziabad (UP) –– From here the data is sent to Uppsala monitoring center Uppsala Monitoring Center (UMC) –– Located in Uppsala, Sweden –– Collects data from all over the world & analyses it and report it to FDA Food and Drug Administration (FDA) –– May issue black box warning or even withdrawal of drug from market if severe adverse effects are detected. 4 General Pharmacology Adverse Drug Reactions Type A Augmented Predictable and Dose related May be Toxic Effects or Side Effect Type B Bizarre Unpredictable Like Allergy Type C Chronic Steroid induced osteoporosis Type D Delayed Teratogenicity Type E End of Dose Withdrawal effects Type F Failure of Therapy FDA consider it as ADR but WHO does not  Factors Affecting Drug Action 1. General Factors: –– Body size: Dose of drug is best calculated according to body surface area. –– Age: Children require different doses than elderly. –– Sex: Drugs causing hirsutism like minoxidil are avoided in females. –– Race: Quiniodochlor (antimalarial) caused SMON in Japanese only. –– Route of Administration: IV route is preferred in emergencies. –– Disease states: Dose needs to be adjusted in renal or hepatic disease for several drugs. 2. Pharmacogenetics A. Glucose-6 Phosphate Dehydrogenase Deficiency → G-6 PD protects RBC from free radical injury → Many drugs produce free radicals and can cause hemolysis in patients with genetic deficiency of G-6-PD. –– Primaquine –– Sulfonamides Cause hemolysis in patient with G-6-PD deficiency –– Nitrofurantoin –– Furazolidone B. Acetylation → Drugs metabolized by acetylation produce different effect in different patients. S → Sulfonamide [including Dapsone] H → Hydralazine I → INH P → Procainamide → SHIP Drugs can cause SLE also C. Succinylcholine Induced Apnea –– SCh [Succinyl Choline] is the shortest acting muscle relaxant. –– It is metabolized by pseudocholinesterase. –– In patients with atypical pseudocholinesterase, it can cause prolonged apnea. 3. Pregnancy and Lactation: –– Drugs causing malformation in the baby if used during pregnancy are called teratogenic drugs. 2 General Pharmacology Condition Drugs safe in Pregnancy Drugs to be avoided in Pregnancy Anti-hypertensives Labetalol, Methyldopa ACE Inhibitors and ARBs Anti-diabetics Insulin All other Anti-coagulants Heparin Warfarin Bipolar disorder Anti-psychotics Valproate, Lithium Anti-thyroid Propylthiouracil Carbimazole (1st trimester) Anti-microbials Penicillins, Tetracyclines Cephalosporins Quinolones Macrolides Anti-emetic Doxylamine Most others Extra Edge Teratogenic Effect of Drugs Drug Teratogenic Effect Warfarin Nasal hypoplasia Calcific stippling of epiphyses Eye defects Hearing loss Valproate Neural tube defects Thalidomide Phocomelia Tetracyclines Teeth and bone problems Fluoroquinolones Cartilage and tendon damage Phenytoin Fetal hydantoin syndrome –– Microcephaly –– Cleft lip, cleft palate –– Hypoplastic phalanges Lithium Ebstein’s anomaly Alcohol IUGR Microcephaly Dysmorphic facies Carbimazole Aplasia cutis Choanal atresia Diethylstilbesterol Clear cell adenocarcinoma of vagina in female offspring Drug used in Lactation: –– Most of the drugs can be safely used in lactation as the secretion is negligible in breast milk. –– Feeding to the baby should be done just before taking the next dose to ensure minimum plasma concentration of drug in mother 4. Enteric Coating of Drugs: –– This is a coating that dissolves in alkaline medium only. –– It can be used for Protecting the acid labile drugs from gastric acid, e.g., proton pump inhibitors. It can protect gastric mucosa from irritant drugs. It increases the absorption of drugs that are preferentially absorbed distal to stomach.  Combined Effects of Drugs Combined Effect of Drugs 1. Addition/summation 2 + 2 = 4 2. Synergism 2 + 2 = 10 3. Potentiation 2 + 0 = 5 4. Antagonism 2 + 2 < 4 Addition/Summation Potentiation –– Individual effects of 2 drugs, simply added –– Levodopa + Carbidopa [inactive] = Efficacy of levodopa increases Synergism Cotrimaxozole = Sulfamethoxazole + Trimethoprim Antagonism [Bactericidal] [Bacteriostatic] [Bacteriostatic] –– Combined effect of two drugs will be lesser Types of drug antagonism Physical - Physical presence of drug stops the action of other [charcoal] Chemical - Chemical reaction stops the action [Antacids] Physiological Antagonists Pharmacological Antagonists –– Act on different receptors and produce opposite –– Acts on same receptors to produce opposite effect effects –– Adrenaline Atenolol –– Histamine Adrenaline ↓⊕ ↓⊖ ↓ ↓ b1R b1R H1 R Beta 2R Tachycardia Bradycardia ↓ ↓ Atenolol is pharmacological antagonist of adrenaline Bronchoconstriction Bronchodilation Histamine is physiological antagonist of adrenaline Fixed Dose Combinations (FDC): –– When two or more drugs are combined together in a particular ratio – Advantages: – Disadvantages: Compliance improves May be used irrationally. One drug may reduce the adverse If adverse effect occurs, it cannot be ascribed to one drug. effects of the other drug Drugs with different pharmacokinetics cannot be combined. Efficacy may increase Dose of one drug cannot be altered independently as per Cost may decrease requirement.  General Pharmacology Practicals 1. Drug Label Name –– Generic name (Aspirin) - Must be present on drug label –– Brand name (Ecosprin) –– Chemical name (Acetylsalicylic acid). Abbreviations –– IP Indian pharmacopoeia –– BP British pharmacopoeia –– USP United states pharmacopoeia –– BNF British National formulary Schedule H: –– Drugs that require prescription from a registered medical practitioner are called Schedule H drugs. –– Red line seen on the drug label which indicates that it should be given on prescription only. –– OTC (over the counter) drugs do not require prescription. Expiry date –– Expiry date indicates that the drug can be used until last day of the month –– Expiry date does not mean that the drug will become ineffective or toxic. It is the time till which the drug is expected to behave similar to, as written in pharmacopoeia. –– Shelf life- the time between manufacturing date and expiry date. Storage temperature - Keep frozen Freezer At -20-degree C - Keep cold Refrigerator At 2 to 8-degree C - Keep cool Room temperature At 8 to 15-degree C in US (8 to 25- degree C in India) 2. Promotional Drug Literature (Drug Advertisements) 1. Name –– Brand name –– Generic name (must be written compulsory) –– Chemical name The ratio of brand name to generic name should be within a ratio of 3:1 and should not exceed it 2. Details –– Indications of drug 2 General Pharmacology –– Route of administration –– Frequency of dosing –– Duration of treatment 3. Cost of therapy 4. Adverse effects of the drug –– Serious effects –– Common effects Both should be mentioned in the drug advertisement leaflet 5. References –– If some claims are made, these should be supported by appropriate reference 6. Address of manufacturing company 7. Expiry date is not required in the advertisement leaflet 3. Prescription writing Prescription is the written order by the doctor to the pharmacist to dispense some medication. Note: –– Without date and signature (initials), the prescription is invalid. –– Drug name should never be written in short form (e.g., write paracetamol, not PCM) –– Abbreviations like OD, BD, HS should not be used –– In dose of drug Leading zeros should always be mentioned (e.g., 0.5 mg is correct but.5 mg is wrong) Trial zeros should never be mentioned (e.g., 5 mg is correct but 5.0 mg is wrong) Microgram should be written as mcg not μg.  Basics and Cholinergic Drugs Origin: Neurotransmitters: Location Neurotransmitter Preganglionic parasympathetic ACh Preganglionic sympathetic ACh Postganglionic parasympathetic ACh Postganglionic sympathetic at all places NA Post ganglionic sympathetic at sweat glands ACh Actions: Location Parasympathetic Sympathetic Heart - - +++ Bronchus Bronchoconstriction Bronchodilation GIT Diarrhea Constipation Bladder Contraction Relax Glands ↑ secretions ↓ secretions Pupil Miosis Mydriasis Sexual system Erection Ejaculation 2 Autonomic Nervous System Parasympathetic system Origin Cranial nerves → 3, 7, 9, 10 Sacral nerves → 2, 3, 4 Acetyl Choline [ACh] → Rate limiting step is : Uptake of choline ↓ Parasympathetic activity 1. HEMICHOLINIUM 2. VESAMICOL 3. BOTULINUM TOXIN ACh Esterase Inhibitor → ↑ Parasympathetic activity 4. Physostigmine Cholinergic Receptors Nicotinic Receptors Muscarinic Receptors NN→ Ganglia M1 → Stomach: ↑HCl NM→ NMJ (require optimal stimulation) M2 → Heart: ↓ HR, ↓ conduction M3 → Bronchus GIT Bladder Glands Pupil Note: In CNS, all cholinergic receptors are present Cholinergic Drugs: Drugs stimulating the parasympathetic system can be: 1. Directly Acting: These have direct agonistic action on any of the nicotinic or muscarinic receptors. 2. Indirectly Acting: These act by inhibiting AChE enzyme and thus increase ACh. Directly acting cholinergic drugs: DRUG ACTS ON ACTION INDICATION Pilocarpine Pupil [M3] Miosis Angle closure glaucoma Bethanechol Bladder [M3] ↑Urine outflow Atonic bladder Methacholine Myocardium [M2] Cardiac Suppression Tachycardia Arrythmias Carbachol Common action on both Nicotinic as well as Muscarinic receptors  3 Basics and Cholinergic Drugs Drug with maximum nicotinic action → Carbachol Indirectly acting cholinergic drugs: –– These drugs act by inhibiting AChE. –– These may be reversible or irreversible AChE inhibitors. –– Reversible AChE inhibitors are used clinically whereas irreversible AChE inhibitors are toxic. Reversible AChE Inhibitors: Lipid soluble drugs Water soluble drugs Physostigmine Neostigmine Natural product → Synthetic product Tertiary Amine → Quaternary Amine 3 Atoms are attached to nitrogen 4 Atoms are attached to nitrogen Non-Polar & Non-ionized Polar &Ionized Lipid soluble, so cross the BBB Water soluble, so cannot cross the BBB GIT →  → Orally given GIT → X → Injectable BBB →  → Central effects present BBB → X → No central effects Pupil →  → used in glaucoma Pupil → X → No effect on pupil Lipid Soluble Drugs 1. Angle Closure Glaucoma: Physostigmineeye drops are used 2. Atropine Poisoning → Atropine is a non-specific muscarinic receptor blocker [M1, M2, M3]. It can cross BBB. → DOC for atropine poisoning → Physostigmine 3. Senile Dementia / Alzheimer’s Dementia → Due to degeneration of cholingeric neurons in Basal Nucleus of Meynert Treatment Physostigmine → Not used (Peripheral action leads to side effects) Tacrine → Has only central action → Was the DOC → Disadvantages 4 Autonomic Nervous System – Very short acting – Hepatotoxic D → Donepezil Long Acting R → Rivastigmine Non hepatotoxic Gobind → Galantamine DOC for Alzheimer’s disease Water Soluble Drugs 1. Neostigmine 2. Pyridostigmine 3. Edrophonium Indications: These can be used for Nicotinic Uses Muscarinic Uses – Atropine is added – Atropine not added – Uses are – Uses are Myasthenia gravis Post op paralytic ileus Cobra bite Post op urine retention Reversal of muscle relaxant Myasthenia Gravis –– It occurs due to formation of antibodies against NM receptors. This leads to blockade of these receptors and thus muscle weakness. –– Cholinergic crisis is opposite condition in which there is overstimulation of NM receptors, but it also presents with muscle weakness. Edrophonium Test (Tensilon Test) → Used to differentiate between Myasthenia and Cholinergic crisis. → IV Edrophonium given. → Very short acting [ 100 bpm 2. AChE Reactivators (Oximes) Pralidoxime [PAM] Di AcetylMonoxime [DAM] → Not DOC → Only effective in OP Poisoning → PAM acts only peripherally, DAM has both central as well as peripheral actions.  Anticholinergic Drugs Organ Receptor blocked Drugs Uses Adverse Effects Stomach M1 Pirenzepine Peptic ulcer Telenzepine Heart M2 Atropine (DOC) Bradycardia Tachycardia AV block Bronchus M3 Ipratropium Bronchial Paradoxical bronchoconstriction due to asthma –– Impurities like benzalkonium and EDTA COPD –– Hypertonic saline in nebulizer –– Presynaptic M receptor blockade leading to excessive release of ACh Bladder M3 S- Solefenacin Overactive Urinary retention O- Oxybutynin bladder Hence, C/l in BHP F- Flavoxate T - Tolterodine T - Trospium BladDAR - Darifenacin GLANDS M3 Atropine Pre Dryness [C/I Children] Glycopyrrolate anesthetic ↓ Sweating ↓ Medication Fever ↓ Hyperthermia EYE M3 Atropine Fundoscopy C/l in ACG Homatropine Refraction Blurred vision d/t cyclopegia Cyclopentolate testing Tropicamide Iridocyclitis Longest acting: Atropine DOC in children Shortest acting: – Atropine Tropicamide eye ointment 2 Autonomic Nervous System Organ Receptor blocked Drugs Uses Adverse Effects CNS → Hyoscine Motion [SCOPOLAMINE] sickness Prophylaxis →Benzhexol Drug induced [Triphexyphenidy] Parkinsonism →Benztropine (DOC) →Biperiden Poisoning DOC → Organophosphates & Carbamate Atropine → Atropine/ Belladona /Datura Physostigmine → Early Mushroom Poisoning Atropine Mushroom Poisoning Early Mushroom Poisoning Late Mushroom poisoning → Caused by - Inocybe/ Clitocybe → Caused by Amanita group of species → Shows symptoms similar to Organophosphate → It is also Known as Hallucinogenic mushroom poisoning poisoning → Shows symptoms similar to Atropine poisoning ↓ ↓ DOC- Atropine Atropine is C/l → Management is purely Symptomatic Atropine Poisoning: –– Patient has a history of taking some wild fruit (Dhatura/Belladona) and presents with D – Dry mouth, Delirium H – Hyperthermia A – Agitation T – Tachycardia U – Urinary R – Retention A – Accommodation lost (Blurred vision, Photophobia) – DOC for treatment of atropine poisoning is physostigmine.  Adrenergic Drugs ↓ NA in synapse ↓ Sympathetic activity 1. Metyrosine 2. Reserpine 3. Guanethidine Reuptake Inhibitor ↑ Sympathetic activity 4. Cocaine Adrenergic Receptors a1 a2 Location Action Presynaptic receptor → Acts like brake to sympathetic system Blood vessels Vasoconstriction Post Synaptic receptor Eye Mydriasis → Work like a1 receptors Prostatic urethra ↓ Outflow b1 b2 b3 Location Action Location Action Location Action Heart ↑ HR, BP Lungs Bronchodilation Fat Lipolysis JG cells Renin secretion GIT Constipation Bladder Relax Bladder ↓ Out flow Glands ↓ Secretions Uterus Tocolytic Blood vessels Vasodilation Skeletal muscle Tremors spindle Liver ↑ Blood sugar 2 Autonomic Nervous System Effect on blood vessels A1 -> C α1 – Cause vasoconstriction B2 -> D β2 – Cause vasodilation → Effect depends on predominance of type of receptor: –– Heart & Muscles → b2 > a1 → Vasodilation –– Skin, Internal organs → a1 > b2 → Vasoconstriction. Effect on metabolism → Sympathetic system protects from hypoglycemia by two mechanisms: – By causing warning symptoms – By reversal through metabolism In hypoglycemia Warning Symptoms → Due to sympathetic system stimulation b1 b2 M3 ↓ ↓ ↓ Tachycardia Tremors Sweating Palpitations → Should take Sugar → If sugar is not taken, even then, b2 stimulated in the Liver and Muscle and cause – ⊕ Gluconeogenesis – ⊕ Glycogenolysis – ⊖ Glycogenesis ↓ ↑ Sugar ↓ Reversal of hypoglycemia → Beta Blockers cause (in diabetic patients) 1. Masking of warning symptoms 2. Prevent reversal of hypoglycemia So, b blockers are contraindicated in diabetic patients. → Sweating is only reliable symptom of hypoglycemia in diabetics on b blocker medication. Sympathomimetic drugs: These can be divided into: → Indirectly Acting Drugs → Directly Acting Drugs Indirectly Acting Drugs A. Reuptake Inhibitors  3 Adrenergic Drugs → COCAINE – It is a local anaesthetic All LA cause vasodilation except cocaine Cocaine cause vasoconstriction and hypertension – It is an addictive drug Shows tactile hallucinations (cocaine bugs) Cause palatine perforation Overdose characterized by ○ Agitation ○ Ulcers or scratch marks on skin ○ Sympathetic symptoms (Tachycardia, Mydriasis, Hypertension, MI) B. Drugs acting by Displacement → Tyramine –– Acts by displacement of nor-adrenaline (indirect effect only). –– Major Source of tyramine is Cheese. → Ephedrine Mixed effect → Pseudo ephedrine (both direct and indirect effects) → Amphetamine → All these drugs show tachyphylaxis (Rapid development of tolerance) → Use of ephedrine and pseudo ephedrine. – Nasal decongestant → Amphetamines can cross blood brain barrier and, Reduces sleep Used for Narcolepsy (DOC is modafinil) Increases attention span Used for ADHD (DOC is methylphenidate). Directly Acting Drugs 1. Catecholamines – Not effective orally Endogenous Catecholamines Exogenous Catecholamines Adrenaline Dobutamine NA Dopexamine Dopamine Isoprenaline Fenoldopam 4 Autonomic Nervous System Dopamine Acts on Receptors Dose Organ Action D1 < 2 mg/kg/min Blood vessels Vasodilation (Max in Renal BV) b1 2-10 mg/Kg/min Heart Stimulation a1 > 10 mg/Kg/min Blood vessels Vasoconstriction Uses 1. CHF 2. Shock + Oliguria [DOC] Drug with ‘dopa’ in their name acts on D1, others do not Dobutamine Dopexamine Fenoldopam → Does not act on D1 receptors → It stimulates D1, β1 and β2 receptors → Stimulates only D1 Receptors → Mainly acts on β1 receptors → It also inhibits reuptake of NA → Used in Hypertensive emergencies → Used For CHF → It is used for CHF Effect of Catecholamines on BP and heart rate SBP DBP Heart Rate β1 α1+ β2 Direct effect (β1) Indirect effect (Opposite to DBP) Final effect Adrenaline ↑ — ↑ — ↑ Nor-Adrenaline ↑ ↑↑ ↑ ↓↓ ↓ Isoprenaline ↑ ↓ ↑ ↑↑ ↑↑↑ Effect of IV administration of NA on heart rate Condition Heart Rate Normal Heart ↓ Heart transplant ↑ Atropinized heart ↑ Uses of Catecholamines Isoprenaline → b1 → CHF → b2 → Asthma (Salbutamol is preferred now) NA → a1 → Shock → b1 → CHF  5 Adrenergic Drugs Adrenaline 1. Anaphylactic Shock –– DOC is Adrenaline –– Route of choice is I.M. or S.C. –– Concentration is 1:1000 (0.5 ml) –– If first dose fails, repeat within 10 mins. –– If second dose fails, give 1:10,000 Adrenaline by IV route 2. Cardiac Arrest –– CPR is done first –– Adrenaline is useful –– Concentration is 1:10,000 –– Preferred routes are IV > Intraoseous > ET 3. With Local Anaesthetics –– Adrenaline is added with LA to decrease systemic toxicity and increase duration of action. –– Concentration used is 1:1,00,000 – 1:2,00,000. Vasomotor Reversal of Dale Adrenaline acts on a1, a2, b1 and b2 receptors Strong Sensitive a1 b2 ↓ ↓ Vasoconstriction Vasodilation Biphasic Response When Adrenaline given iv at high doses. –– First BP increases [Due to (a1 > b2) Stimulation] –– Then BP will decrease [Due to b2 Stimulation] When Adrenaline given IV at high dose with a blocker Exaggerated Fall of BP occurs, this is called Vasomotor Reversal of Dale 6 Autonomic Nervous System Clinical Importance –– Alpha blocker alone should not be given in patient with adrenaline producing pheochromocytoma. It may result in severe hypotension and death due to vasomotor reversal. Status of Drugs in Pheochromocytoma Tumor producing a # alone b # alone a+b# Adrenaline C/I C/I  Nor adrenaline  C/I  2. Non-Catecholamines Stimulates Drugs Action a1 Phenylephrine eye drops Mydriasis without cycloplegia Methoxamine → Vasoconstriction Mephentermine → Used in shock Midodrine Xylometazoline nasal drops → Nasal decongestants (can cause rhinitis medicamentosa) Oymetazoline nasal drops Naphozoline nasal drops a2 Clonidine → Brake for sympathetic system Methyldopa → Used for hypertension b2 Salbutamol → Bronchodilation Terbutaline → Used for asthma by inhalational route Salmeterol Formoterol Ritodrine → Tocolytic Isoxsuprine → Used for preterm labour b3 Mirabegron Overactive bladder Vibegron  Anti-Adrenergic Drugs 1. ALPHA BLOCKERS These can be non-selective (α1 + α2) blockers or selective α1 blockers Non-selective α blocker α1 Blocker 1. Used in severe hypertension 1. Used in mild to moderate hypertension 2. Can cause severe tachycardia 2. Cannot cause severe tachycardia Non-Selective α blockers Irreversible Reversible Phenoxybenzamine Phentolamine, Tolazoline Used for Pheochromocytoma Used for – Cheese Reaction – Clonidine withdrawal Selective α1 Blockers –– Prazosin –– Terazosin –– Doxazosin –– Alfuzosin Uses –– BPH (Due to a1A blockade) –– Can be used in other conditions (Due to a1B/1D blocking property) like Hypertension Peripheral vascular disease (PVD) like Raynaud’s disease Scorpion sting (D.O.C is Prazosin) Adverse Effect First Dose (Postural) Hypotension → a1 # always started at bed-time. 2 Autonomic Nervous System Types of α1 receptors α1A α1B/1D Acts on Acts on Prostatic Urethra Blood vessels TAMSULOSIN SILODOSIN → No postural hypotension → DOC for normotensives with BHP Benign Prostatic Hyperplasia: (BHP) α1A blockers –– Tamsulosin - Stops the dynamic component and do not affect the size of prostate i.e they are only for the symptoms of BHP but do not stop the growth of prostate. 5-α reductase inhibitors: –– Finasteride - Stops the conversion of Testosterone to DHT which control/stops the growth of Prostate in BHP (Static Component). 2. BETA (β) BLOCKERS –– b1 + b2 # [Non selective] or 1st Generation –– Selective b1 # or 2nd Generation b # –– Selective b2 # → Butoxamine [No Clinical Significance] β1 + β 2 # β1 # Cardiac and non-cardiac uses Only cardiac uses Contraindicated in Asthma, DM and PVD Relatively safe 1. b1# or Cardio-Selective or 2nd Generation b # New → Nebivolol Beta → Betaxolol Blockers → Bisoprolol Act → Acebutolol Exclusively → Esmolol At → Atenolol Myo → Metoprolol Cardium → Celiprolol → These are relatively safe in Asthma, PVD & DM  3 Anti-Adrenergic Drugs 2. Intrinsic Sympathomimetic Activity [ISA] or Partial Agonists → Less chances of causing severe bradycardia [Safer drug] → But less efficacious Contain → Celiprolol Partial → Pindolol Agonist → Alprenolol Activity → Acebutolol 3. Membrane Stablizing / Na+ Channel # / Local Anesthetic Property → Indicated in Arrhythmias → Not used in Glaucoma Possess → Propranolol [Maximum] Membrane stabilizing or → Metoprolol Local → Labetalol Anaesthetic → Acebutolol Property → Pindolol 4. Water Solubility: → Water soluble beta blockers cannot cross blood brain barrier. → No CNS side effects like delirium, nightmares → But these beta blockers are contraindicated in Renal failure. Water soluble beta blockers: A - Atenolol N - Nadolol (Longest acting beta blocker) S - Sotalol Note: Esmolol is a lipid soluble beta blocker. It is Extremely short acting Beta blocker ( < 5 mins) because it is metabolized by Pseudocholinesterase. Extra Edge 5. 3rd Generation Beta-Blockers – Any b # which possess additional vasodilatory property Additional Property Drugs Special points a blockade Labetalol Carvedilol possess additional Antioxidant properties Carvedilol NO release Nebivolol Ca channel blockade Carvedilol K Channel Opening Tilisolol b2 Agonism Celiprolol 4 Autonomic Nervous System Uses of Blockers β1 # Uses β2 # Uses 1. Hypertension Play: Performance anxiety 2. Classical Angina [C/I in Variant angina] The – Thyrotoxicosis 3. MI G – Glaucoma 4. Chronic CHF [C/I in acute CHF] A – Akathisia 5. Arrhythmia M – Migraine prophylaxis E – Essential tremors Adverse Effects and Contra-indications β1 # β2 # 1. ↓ Rate → Bradycardia 1. Asthma (C/I in Sick sinus syndrome) 2. Peripheral vascular Disease 2. ↓ Conduction → AV Block 3. Diabetes mellitus 3. ↓ Contractility → Acute CHF 4. Variant angina.  Glaucoma → Glaucoma is characterized by ↑ IOP: It may be due to –– ↑ Aqueous humor production –– ↓ Aqueous humor drainage DRUG OF CHOICE –– POAG – Latanoprost –– Angle closure glaucoma – Acetazolamide –– Acute congestive glaucoma – Mannitol Adverse Effects → MiotiCS –– Cataract –– Stenosis of NLD → PGF2a Analogues (Latanoprost) –– Pigmentation of Iris (Heterochromia Iridis) –– Growth of eyelashes (Hypertrichosis) –– Fluid in macula (Macular edema) → ApracLonIDine –– Lid retraction → Brimonidine –– Causes Brain suppression in Infants (Leads to Apnea) –– C/l in children < 2yrs → Epinephrine (Adrenaline) –– It is metabolized to form Adrenochrome - Causes black pigmentation of Conjunctiva → Netarsudil (Rho-kinase inhibitor) –– Conjunctival hyperemia –– Cornea verticillata.  ANS Practicals –– Scientific name: Oryctalagus cuniculus –– Average weight of rabbit - 1.5-2.5 kg Rabbit Eye Experiment Reason Group Drug Active Mydriasis Contraction of dilator pupillae Sympathomimetic (α1 agonist) Adrenaline Active Miosis Contraction of sphincter pupillae Cholinergic (M3 agonist) Pilocarpine Passive Mydriasis Relaxation of sphincter pupillae M3 blocker Atropine Passive Miosis Relaxation of dilator pupillae α1 blocker Phentolamine Drug group Example Pupil Light reflex Corneal reflex Parasympathomimetics Pilocarpine Miosis Present Present Parasympatholytics Atropine Mydriasis Absent Present Sympathomimetics Adrenaline Mydriasis Present Present Local Anaesthetics Lignocaine No change Present Present 2 Autonomic Nervous System Rabbit Ileum Experiment We need to identify the nature of unknown drug by its action on rabbit ileum Stimulant Depressant –– Direct: CaCl2 or BaCl2 –– Direct: Papaverine –– Via receptors: ACh –– Via receptors: Adrenaline → Unknown Drug is parasympathomimetic like ACh. It stimulates the ileum and its effects is abolished by atropine. → Unknown Drug is directly acting stimulant like (CaCl2 or BaCl2 ) as its stimulant effect is not terminated by atropine → Unknown Drug is sympathomimetic (like adrenaline) as it relaxes ileum and its depressant effect is abolished by beta blockers. → Unknown drug is directly acting relaxant (like papaverine) as its depressant effect is not abolished by beta blockers  3 ANS Practicals Extra Edge Dog Blood Pressure Experiment A: Adrenaline B: Nor-adrenaline C: Isoprenaline Biphasic Response → Effect of high dose of adrenaline → Dog is given Phentolamine → α-blocker → BP ↓ → Then, Epinephrine (high dose) is given → BP ↓→ No Biphasic Response produced → Called Vasomotor Reversal of Dale → Dog is given Atropine first → HR ↑ → After this, a high dose of ACh given → BP & HR ↑ → Nicotinic action appear → Stimulate sympathetic ganglia → Ephedrine given → BP ↑ → Same dose is repeated → Less ↑in BP → Called Tachyphylaxis  Histamine and Serotonin Autacoids –– Have autocrine effects [Local effects] –– Based on chemical Structure Peptide Autacoids Amine Autacoids Lipid Autacoids → Angiotensin → Histamine → Prostaglandins → Bradykinin → 5-HT → Leukotrienes → Thromboxane HISTAMINE Receptors Location Action Blockers H1 CNS Bronchus Allergy First and second Generation Drugs Stimulates RAS Promote wakefulness H2 Stomach Secrete Acid Ranitidine Cimetidine H3 Pre Synaptic BRAKE H3 Inverse Agonist Tiprolisant [Pitolisant] Used for Narcolepsy H4 WBC Chemotaxis 2 Autacoids H1 Blockers 1st Generation 2nd Generation Cross BBB, cause sedation Do not cross BBB, no sedation Have Anti-cholinergic action No Anti-cholinergic action → Anticholinergic S/E occur Useful for Allergy and Useful only for allergy Possess : Parkinsonism (Drug - Induced) Anti : Acute muscular dystonia Cholinerygic : Common cold Property : Prophylaxis of Motion sickness Promethazine [Max. Ach # action] Terfenadine Not used (QT prolongation) Diphenhydramine Astemizole Dimenhydrinate Fexofenadine →Terfenadine metabolite Pheniramine Loratidine Chlorpheniramine Des-Loratidine Cyclizine Cetirizine, Levocetirizine Cinnarizine Azelastine, Olopatadine → Topical EXTRA EDGE 3rd Generation antihistamines –– Metabolite or isomer of 2nd Generation –– Drugs include: Fexofenadine Desloratidine Levo-cetrizine Withdrawn Drugs Cisapride ‘CAT drugs’ (Cat is cute ‘QT prolongation) Astemizole Withdrawn because of QT prolongation Terfenadine –– These drugs were metabolized by CYP 3A4 –– Enzyme inhibitors Ciprofloxacin Ketoconazole Erythromycin –– If any of these drugs are combined with CAT drugs (Cisapride, Astemizole or Terfenadine): Result in QT prolongation.  3 Histamine and Serotonin 5-HT (SEROTONIN) Serotonin Receptors Location Action Drugs Example Uses 5HT1A Presynaptic Brake Agonist Buspirone Anxiety 5HT1B/ID BV of Brain Vasoconstriction Agonist Ergotamine Acute Severe Migraine Sumatriptan (DOC are triptans) Naratriptan Eletriptan Rizatriptan 5HT2A/2C Brain Blockers Clozapine Atypical Antipsychotics Olanzapine 5HT2c Lorcaserin Obesity Agonist 5HT3 CTZ Emesis Blockers Ondansetron DOC for vomiting due to Granisetron Chemotherapy Tropisetron Radiotherapy Dolasetron Post-operative Palonosetron 5HT4 GIT Prokinetic Agonist Cisapride GERD Mosapride Prucalopride  Migraine Migraine: → It is unilateral and pulsatile headache. → Major reason: Inflammation and dilation of blood vessels in the brain. →Latest theory: Due to release of Calcitonin Gene Related Peptide (CGRP) later causes neuronal inflammation and vasodilation. Treatment of acute attack: → Drug of choice for mild to moderate headache – NSAIDs (Paracetamol, diclofenac) → Drug of choice for Acute severe attack – Triptans → Other drug for Acute severe migraine – Ergotamine – Because of side effects (increased vomiting and gangrene); Triptans are preferred over ergotamine. – Both triptans and ergotamine should never be given together. – Both can cause vasoconstriction resulting in coronary artery spasm, so avoided in patients with coronary artery disease. Mechanism of action: Triptans like (Sumatriptan, Naratriptan, Rizatriptan, Eletriptan, Frovatriptan) and Ergotamine act by stimulating 5HT 1B/1D receptor that –– Acts on Blood vessels (Cause vasoconstriction) –– Inhibit CGRP release Prophylaxis of migraine: A B C Of Migraine Antidepressants Beta Blockers Calcium Channel Blockers Methysergide Imipramine Propranolol (DOC) Flunarizine Ergot derivative Antiepileptics CGRP Antagonists Risk of pulmonary fibrosis Valproate Erenumab Topiramate Fremanezuma Galcanezumab Eptinezumab 2 Autacoids New Drugs for Migraine: 1. Lasmiditan (DITANS) –– Stimulates 5HT1F receptor and decreases CGRP release. –– This prevents the vasodilation and neuronal inflammation. –– Effective orally. –– It is recently approved for acute attacks of migraine. –– Advantage over triptans is that it does not induce peripheral vasoconstriction. 2. Monoclonal Antibodies Against CGRP –– Approved for prophylaxis of migraine. –– Given by injectable route. Erenumab Fremanezumab Galcanezumab Eptinezumab 3. CGRP Antagonist: (GEPANTS) –– Used for acute attack –– Effective orally –– Drugs are Olcegapant Rimegepant Ubrogepant  PGs and NSAIDs Lipid Autacoids –– LTB4 → Chemotaxis –– LTC4, LTD4, LTE4 → Bronchoconstrictor → Bronchial Asthma PROSTAGLANDINS Phospholipids PLP A2 1. General Effects –– Fever Arachidonic acid –– Pain COX LOX –– Inflammation 2. Platelets –– TXA2 → Aggregation Prostaglandins Leukotrines –– PGl2 → Inhibition of aggregation PG G2 / H2 LTA4 3. Heart –– Ductus Arteriosus is kept open by PGE1 –– PDA [Patent ductus Arteriosus] is treated TX-A2 PGI2 PGD2 /E2 / F2 by NSAIDs like Platelets Endothelium Other cells LTB4 LTC4 Aspirin LTD4 Indomethacin Ibuprofen (DOC) LTE4 –– In Transposition of Great Vessels, Alprostadil [PGE1 analogue] is indicated to keep the DA patent. 4. Blood Vessels → PGE2 and PGI2 cause vasodilation → lloprost [PGl2] → Used for pulmonary HTN → Alprostadil (PGE1) → Used for erectile dysfunction 5. Uterus → PGE2 Contracts upper segment of uterus → PGE2α –– PGE2 → Relaxes Lower segment of uterus –– Misoprostol [PGE1 analogue] 2 Autacoids Uses –– Abortion (Misoprostol is used) –– Cervical ripening in Labour (Intravaginal misoprostol is used) –– Carboprost (PGE2α ) used for PPH [DOC - Oxytocin] 6. Stomach PGE2 –– Inhibit Proton pump –– ↑ Mucous and bicarbonate Protects from PUD –– Vasodilation –– COX inhibitors (NSAIDS) cause PUD –– For NSAID Induced Peptic Ulcer Disease Most specific drug is Misoprostol DOC is proton pump inhibitors 7. Eye PGF2α → ↑ Uveo scleral outflow → Latanoprost→ DOC for Primary Open Angle Glaucoma → Adverse Effects of Latanoprost: P Pigmentation of Iris (Heterochromia iridis] G Growth of eyelashes [Hypertrichosis] F2α Fluid in macula [Macular edema] NON-STEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDS) COX 1 COX-2 Constitutive Enzyme Inducible enzyme Present normally at most places Present normally in –– Kidney –– Endothelium –– CNS NSAIDS act by inhibiting COX. These may be: Non-Selective COX Inhibitors Selective COX-2 Inhibitors ↑ Risk of PUD Less risk of PUD Non-Selective COX Inhibitors Drugs –– Aspirin –– Paracetamol [Acetaminophen] –– Ibuprofen –– Diclofenac –– Indomethacin –– Mefenamic acid –– Piroxicam –– Nimesulide –– Ketorolac  3 PGs and NSAIDs Uses –– Fever –– Pain –– Inflammation Adverse Effects –– Peptic ulcer Disease Paracetamol/ Acetaminophen –– Only NSAID with no anti-inflammatory activity –– Less risk of PUD –– COX 3 Inhibition Theory → PCM inhibits COX - 3 in CNS –– Analgesic of choice in renal disease –– Approved in children for fever and pain Paracetamol Toxicity → Occurs due to 1. Overdosage 2. Liver disease 3. Chronic Alcoholism –– Antidote of paracetamol overdose- N-Acetyl Cysteine (DOC) Aspirin –– Only irreversible COX Inhibitor –– Antiplatelet Drug –– C/I in child with viral infection [Risk of Reye’s syndrome] –– Can cause Hyperuricemia at therapeutic doses - avoid in gout Aspirin poisoning (Salicylism) Respiratory center stimulation ↓ Hyperventilation ↓ ↓ CO2 ↓ Respiratory Alkalosis → Reversible ↓ Metabolic Acidosis → Irreversible 4 Autacoids Treatment DOC is sodium bicarbonate (NaHC03) –– Reverses metabolic acidosis –– Helps in aspirin excretion Special points about other NSAIDs Ibuprofen Anti-Inflammatory of choice in children Indomethacin Cause sedation and headache Ketorolac Can be given IV Piroxicam Very long acting Nimesulide Withdrawn for use in children due to hepatotoxicity Diclofenac Preferential COX-2 selective Selective COX 2 Inhibitors Drugs –– Celecoxib –– Rofecoxib –– Valdecoxib –– Parecoxib –– Lumiracoxib These have lesser risk of causing PUD These increase the risk of MI and stroke - Etoricoxib Longest acting - Rofecoxib and Valdecoxib Withdrawn because of MI and stroke - Parecoxib is given by Parenteral route - Lumiracoxib is withdrawn Due to Liver toxicity  Gout and Rheumatoid Arthritis GOUT It is characterized by increase in serum uric acid. Acute Gout 1. NSAIDS [DOC] 2. Steroids 3. Colchicine Mechanism of Colchicine –– Inhibit granulocyte migration –– Inhibit the release of glycoprotein from neutrophils Extra Edge Uses of Colchicine U - Uric acid (Gout) C – Cirrhosis M – Acute Mediterranean Fever (DOC) S – Sarcoidosis Chronic Gout Three types of drugs can be used in chronic gout. – Drugs decreasing production of uric acid – Drugs increasing excretion of uric acid (Uricosuric agents) – Drugs increasing metabolism of uric acid Proteins / Purines