Updated 2022 General Pharmacology NUB PDF

General pharmacology For 1st year medical students Medical pharmacology Department NUB Intended learning outcomes (ILOS)By the end of this chapter the student will be able to Define Drug absorption Discuss the diffe...

General pharmacology For 1st year medical students Medical pharmacology Department NUB Intended learning outcomes (ILOS)By the end of this chapter the student will be able to Define Drug absorption Discuss the different factors influencing the absorption of drugs across biological membranes Describe the principle of first-pass effect Define Oral bioavailability and discuss factors affecting it Discuss different compartmental model of drug distribution The effect of plasma protein and tissue binding on volume of distribution outline mechanism of drug metabolism (phases and hepatic microsomal enzymes HME) interpret the effect of induction and inhibition of HME Discuss fundamental principles of drug clearance Discuss clinical importance of plasma half life compare differences between 1st order kinetics and 2nd order kinetics compare between different types of agonists compare difference between agonist and antagonists regarding affinity and efficacy discuss difference between reversible and irreversible antagonist discuss different signaling mechanisms of drug receptors interactions Pharmacology is the science dealing with drugs. Drugs: are chemical substances that stimulate or inhibit an existing cell function. They are used for treatment, prevention and diagnosis of diseases or modify a physiological process. * pharmacology deals with 1- Pharmacokinetics: It describes what the body does to the drug, which includes Absorption, Distribution, Metabolism & Excretion [ADME]. 2- Pharmacodynamics: It describes what the drug does to the body, which include the study of the pharmacological actions of drugs and their possible mechanisms of action. 3- Pharmacotherapeutics: Study the selection & use of drugs for diagnosis, prevention & treatment of disease. N.B.: The main goal of a physician is to give to the patient proper adjusted drug doses to obtain therapeutic levels that produce the desired response with the minimal adverse effects. Passage of drugs across cell membranes (MCQ) The cell membrane is a lipid bilayer interrupted by protein macromolecules in the form of ion channels, carriers and receptors, and contains water filled channels. Passage of drugs across cell membranes occurs mainly by: 1. Simple diffusion. 2.Carrier mediated. 1) Simple diffusion: The chief process involved in absorption & distribution of drugs. Simple diffusion depends on: 1) Concentration gradient: drugs pass from one side of the cell membrane to the other along concentration gradient  2) Molecular size: the smaller, the better the absorption. 3) Lipid solubility and lipid/water partition coefficient, the more, the better the absorption. N.B.: Lipid/water partition coefficient is the ratio of drug concentration in lipid medium and drug concentration in water medium when it is put in lipid water system. 4) Degree of ionization: - The more the ionization, the less the lipid solubility. - Degree of ionization depends on: * pKa of the drug * pH of the medium. 5) No energy & no carriers are needed. pKa (ionization constant of a drug). It is the pH media at which 50% of the drug is ionized and 50% nonionized e.g. pK a of aspirin 3.5. pH of the medium. ( MCQ) 1. Most drugs are either weak acids or weak bases. 2. Weak acids are better absorbed in acidic media where it is less ionized and so more lipid soluble. 3. Weak bases are better absorbed in alkaline media where it is less ionized so more lipid soluble. The degree of ionization is determined by: Henderson Hasselbalch equation (reading only) Weak acids: pKa = pH + log unionized ionized Weak bases: pKa = pH + log ionized unionized N.B- Acidic drugs as aspirin will be unionized in acidic medium of stomach → better absorbed in stomach. When filtered in glomeruli, can be reabsorbed again from renal tubules if urine is acidic, while alkaline urine enhances their excretion. - Weak base drugs as amphetamine will be better absorbed from intestine and acidic urine will enhance their excretion. 2) Carrier mediated: of 2 types: a) Facilitated diffusion: Drugs are transferred across cell membranes: o Along their concentration gradient. o Carrier for substances which are too large or lipid insoluble to diffuse passively o No energy is required. e.g. glucose uptake by cells. b) Active transport: Drugs are transferred across cell membranes: o Against their concentration gradient o Energy  o Carrier e.g. secretion of penicillin by renal tubules. Pharmacokinetics [ADME] I) Absorption Absorption is the transfer of a drug from its site of administration to the systemic circulation. Lipid soluble translated Factors affecting drug absorption: very important into A) Factors Related to the Drug: High lipid /water partition coefficient 1- Water and lipid solubility: unionized a- Drugs MUST be Water soluble as well as Lipid soluble. b- Drugs must be completely dissolved in water to be absorbed. c- More lipid solubility → high Lipid/Water partition coefficient → better absorption. 2- Ionization: a- Non-ionized → More lipid soluble → Better absorption b- Depends on pKa of the drug & pH of the medium. c- Quaternary ammonium compounds “Neostigmine” → Ionized → Poor absorption d- Tertiary amines “Physostigmine” → Non-ionized → Better absorption. 3- Valency: Ferrous iron (Fe2+) > Ferric Iron (Fe3+). 4- Nature: Inorganic (small molecules) > Organic (Big molecules). 5- Pharmaceutical Preparation: a- Dosage form: Solution > Suspension > Tablet. b- Shape & size of particles and rates of disintegration & dissolution of tables: Rapid with paracetamol & propranolol BUT slow with digoxin. c- Excipient (Filler): CaCO3 & Ca Phosphate → Absorption of Tetracyclines. B) Factors Related to the Patient: 1-Route of Administration: I.V. and inhalation > I.M. > S.C. > Oral > Skin. 2-Absorbing Surface: a- Vascularity: Alveoli > Skeletal muscle > Subcutaneous. b- Surface area: Alveoli > Intestine > Stomach (Intestine 1000 X Stomach). c- State of health: Diarrhea & mal-absorption → Oral absorption. 3-Systemic circulation: Shock & Heart failure → Absorption. 4-Specific factors: Intrinsic factor for Vit B-12. 5-Presence of other drugs: a- Adrenaline S.C. → V.C. → Absorption of Local anesthetics → Longer duration of action of local anesthetics. b- Milk (Calcium) → Oral absorption of Tetracyclines (Antibiotic). Factors affecting oral absorption: A) Factors related to the drug: See before B) Factors related to the patient: 1- Surface area of absorbing surface: The intestine has surface area 1000 times that of stomach (due to microvilli) and rich blood flow. Thus, absorption from intestine > stomach. 2- State of absorbing surface: Gastritis, malabsorption syndrome  oral absorption 3- Motility of the gut and rate of dissolution: Prokinetic drugs increase the gut motility e.g. Metoclopramide  gut motility →  gastric emptying → absorption of rapidly disintegrated drugs (paracetamol) and  absorption of slowly disintegrated drugs (digoxin). Atropine inhibits the gut motility →  gastric emptying. → Absorption of rapidly disintegrated drugs and  absorption of slowly disintegrated ones. 4- pH within the gut: Weak acids (aspirin) are better absorbed in an acidic media. So better absorbed in stomach. Weak bases (amphetamine, ephedrine) are better absorbed in an alkaline media of intestine. 5- Specific factors: Intrinsic factor from stomach is essential for Vit B12 absorption. 6- Gut contents: presence of food & other drugs: Presence of food: Bad → Food dilutes Drugs & may compete with them for absorption e.g. aminoacids compete for the same carrier of L-DOPA. Good → with IRRITANT drugs e.g. aspirin & iron. P Glycoprotien  Tetracycline  Calcium and iron absorption by chelation. Cholestyramine & charcoal  absorption of many drugs by adsorption. Grape fruit juice  absorption of drugs by inhibiting P. glycoprotein (which cause reversed transport of drug from gut wall to lumen). Tea → iron absorption by its content of tannic acid. 7- First pass effect: very important Means metabolism of drug in gut wall or liver before reaching systemic circulation. Gut first pass effect: 1. Gastric acidity: destroys benzyl penicillin. 2. Digestive enzymes: destroy insulin 3. Mucosal enzymes: destroy chlorpromazine Hepatic first pass effect: 1. Drugs extensively metabolized: e.g. Nitroglycerine. To avoid: change the route of administration: Nitroglycerine SL. 2. Drugs metabolized to a large extent: e.g. propranolol. To avoid: the oral dose. Bioavailability Bioavailability is the fraction of unchanged drugs reaching systemic circulation after any route of administration. Bioavailability is 100 % after IV administration and Variable after oral administration. AUC X100 Oral bioavailability = oral AUC IV Factors affecting oral bioavailability: very important 1. Amount of drug absorbed : Factors affecting GIT absorption. 2. First pass metabolism.  II) Distribution After absorption from whatever route of administration a drug will distribute according to the compartmental models. Patterns of distribution very important (MCQ) 1- One compartment model (intravascular): Drugs having too large MW to move out through endothelial slit junctions of the capillaries, are trapped intravascular and are distributed in a volume of plasma of 4 L which is equal to 6% of a 70-kg body weight individual. E.g. High MW Heparin or drugs highly bound to plasma proteins as warfarin. 2-Two compartments model (extracellular): These compartments are intravascular and interstitial fluid. Drugs having low MW, but not lipid soluble, are distributed to a volume of 14 L= 20% of body weight e.g. Quaternary ammonium compounds “Neostigmine”. 3-Multicompartment model (Extra and intracellular): Drugs are distributed to total body fluids (42 L / 70 Kg). They are of low MW and are hydrophobic (highly Lipid soluble). 4. Other sites: Some drugs have special affinity for certain tissue: 1. Iodine in thyroid. 2. Thiopentone in fat. 3. Tetracycline and calcium in bone and teeth. Factors affecting distribution of drugs: 1- Physicochemical properties of the drugs: Molecular weight (MW) – degree of ionization – lipid solubility. 2- Binding to plasma proteins: o Upon entering the blood, drugs may be bound to plasma proteins (chiefly albumin). Salicylates are strongly bound to plasma proteins. o So, drugs are carried in blood in 2 forms: a) Free form: Pharmacologically active – diffusible – metabolized – excreted. b) Bound form: inactive, non-diffusible, not metabolized and not excreted (act as reservoir). o The amount of drug bound to plasma protein will change according to: - Affinity for binding sites: Competition between drugs for binding sites as a drug may displace another one from its binding site (cause drug interactions) e.g. Salicylates can displace warfarin → hemorrhage. MCQ  - Hypoalbuminemia: e.g. in starvation, malnutrition → free drug → therapeutic dose changes to toxic dose e.g. Phenytoin. o The more the binding the more the duration e.g. Sulphonamides. 3- Passage across barriers: a- Passage to central nervous system across blood brain barrier (BBB) Low molecular weight, on-ionized, lipid soluble drugs can pass BBB e.g. Physostigmine can stimulate CNS, neostigmine cannot. Inflammation (Meningitis) increases permeability of B.B.B. Penicillins can pass inflamed meninges but NOT normal ones. b- Passage to fetus across placental barrier: The placental barrier acts like a cell membrane. So non-ionizable, lipid soluble drugs pass from mother to fetus more easily Drugs that pass placental barrier may cause: ▪ During pregnancy → Teratogenicity e.g. Tetracyclines ▪ During Labor → Neonatal asphyxia e.g. Morphine. c- Passage of drugs through breast milk: Most drugs administered to lactating women are detectable in milk. pH of milk is more acidic (7.0) than that of plasma (7.4), so basic drugs ionize and accumulate in milk (ion trapping). MCQ Milk contains more fat than plasma which favors retention of lipid soluble drugs. Apparent volume of distribution (Vd): If we assume that the body consists of one big fluid compartment and that the total amount of drug (A) would be uniformly distributed in that compartment such that it would have the same concentration as in plasma (C). Thus the apparent volume of distribution (Vd) = A mg. C (mg/ml) Where: A =total amount of drug in mg C = initial concentration of the drug in plasma in mg/ml. Significance: assay and MCQ 1- Rough estimation of drug distribution: Drugs with low Vd are retained in vascular compartment due to high molecular weight or high binding to plasma proteins. Drugs with high Vd occupy multicompartment or concentrated in tissues (e.g. digoxin in heart). It is called apparent volume of distribution because Vd of some drugs as digoxin (500L/70kg) can extremely exceed any physical volume in the body. 2- Determine the loading dose and the total amount of drug in the body: ** A (mg) = Vd x C (mg/ml). Small Vd equal high ** Loading dose = Vd x Desired concentration (Css) plasma protein binding Very high Vd ˃42L equal 3- In cases of drug toxicity MCQ high tissue binding Dialysis can be done only with small Vd which means most of drug is present in the circulation e.g. Aspirin. III) Metabolism (Biotransformation) The aim of drug metabolism is to change lipid soluble drugs to water soluble metabolites to be easily excreted. Site of Metabolism (Organs): a- Liver (Hepatic) is the main site for biotransformation b- Lung → Nicotine, Prostaglandins & Angiotensin (ACE). c- Kidney → Vitamin D Renal or biliary  d- G.I.T. & Gut flora → Tyramine & Histamine e- Skin → Vitamin D f- Plasma (Cholinesterase) → Succinylcholine * Types of Metabolic reactions: A) Phase-I (Non-Synthetic)→ Oxidation, Reduction & Hydrolysis 1-Oxidation: - Alcohol → Acetaldehyde → Acetic acid → CO2 + H2O + Energy 2- Reduction: - Chloral hydrate (Active) → Tri-chloro-ethanol (More active) 3- Hydrolysis: - Acetylcholine (Active) → Acetic acid + Choline (Inactive) N.B) Results of Phase-I Metabolism: 1- Inactivation (the commonest fate): Active Drug →Inactive Metabolite - Adrenaline & Noradrenaline → Vanil Mandilic Acid (VMA) 2- Activation: Inactive Drug (Prodrug) →Active metabolite - Cortisone (Inactive) → Hydrocortisone = cortisol (Active) 3- Maintain Activation: Active Drug →Active Metabolite - Diazepam (Active) → Nor-diazepam (Active) 4- Toxification: Drug→Toxic metabolite - Methyl alcohol → Formaldehyde → Blindness B) Phase-II (Synthetic, Conjugation): - Usually leads to inactivation - May lead to activation e.g. Morphine → Morphine-6-Glucoronoid (More active) 1- Glucuronic acid→ Paracetamol. 2- Acetic acid (Acetylation) → Isoniazid.  3- Methylation→ Noradrenaline (→ Active Adrenaline). 4- Glycine→ Aspirin N.B) Most drugs undergo phase I then Phase II metabolism. Some drugs have reverse order e.g. Isoniazid → Acetylation (Phase II) then → Hydrolysis (Phase I). Enzymes responsible for drug metabolism Microsomal enzymes Non-Microsomal enzymes 1- Site Hepatic Smooth endoplasmic Cytoplasm, Mitochondria, etc. 2- Organs reticulum All organs 3- Phase-I Mainly Oxidation / Reduction Oxidation/Reduction & (Cytochrome P-450) Hydrolysis 4- Phase-II Glucuronidation ONLY 5- Induction Inducible All Except Glucuronic acid 6- Substrates Usually lipophilic NOT inducible Lipophilic & hydrophilic Factors affecting metabolizing enzyme activity: 1) Drugs: act on hepatic microsomal enzyme affecting drug metabolism. A-Hepatic microsomal enzyme inducers (Activators): Are drugs which stimulate the activity of hepatic microsomal enzymes. - Examples: Phenytoin, Carbamazepine, Rifampicin and androgen Very important mention - Effect: They  Metabolism of other drugs e.g. Oral anti-coagulants, Oral hypoglycemics & Oral contraceptives→ their duration of action. N.B: They also their own metabolism (Auto-induction) → Tolerance. B-Hepatic microsomal enzyme inhibitors: Are drugs which inhibit activity of hepatic microsomal enzymes. Specific: Cimetidine ,quinolones ,clarythromycin ,Grapefruit juice, Sodium valproate, Erythromycin, Omeprazole &estrogen Very important mention - Effect: They  metabolism of other drugs (e.g. Theophylline → its plasma level →Toxicity) & also  their own metabolism. Non-specific (General): a- Hepato-toxic drugs. b- Drugs  Hepatic blood flow: Propranolol & Cimetidine. 2) Age: Lowering of drug metabolism occurs in extremities of age. So, drug doses should be reduced. e.g. Premature neonate can NOT conjugate chloramphenicol → Fatal Grey Baby Syndrome 3) Sex: Androgen stimulates drug metabolism while estrogen inhibits drug metabolism. 4) Pathological conditions: In liver diseases, drug metabolism is reduced leading to increased susceptibility to drug toxicity e.g. Effect of diazepam is prolonged and it may cause coma when given in therapeutic dose. 5) Starvation: Enzyme activity is decreased with inhibition of conjugation process e.g. depletion of glycine with inhibition of glycine conjugation. 6) Genetic factors: Genetic determined polymorphism is responsible for variation in drug toxicities. e.g. Acetylation polymorphism: slow acetylation leads to Systemic lupus erythematosus (SLE) and hepatotoxicity pseudocholinesterase deficiency: Succinylcholine is metabolized by of this enzyme→ succinylcholine apnea. CYP2C19: decreased activity leads to decreased the anti-platelets effect of clopidogrel  IV) Excretion Clearance: Clearance of drugs is the process through which drug or its metabolites can be eliminated from the body the most important being through the kidney into the urine. Other routes include: GIT, skin glands, lung. A) Renal: 1- Non-volatile drugs and metabolites are excreted in the urine. 2- Renal excretion is the result of glomerular filtration and active tubular secretion & reabsorption. 3- Passive Glomerular filtration for water soluble non-bound drugs with M.W. < 500 e.g. Mannitol. 4- Active Tubular Excretion (Saturable & Site for competition & Drug Interaction): Weak acid drugs e.g. Penicillin Weak base drugs e.g. Digoxin 5- Changes in urinary pH→ Affect excretion of weak Acid & Base drugs: a) Alkalinization of urine (Na or K Acetate, Bicarbonate or Citrate) → Renal excretion of weak Acid drugs e.g. Aspirin = Ion Trapping. b) Acidification of Urine (NH4Cl or Ascorbic acid “Vit C”) → Renal excretion of weak Base drugs e.g. Ephedrine = Ion Trapping N.B: The clearance of some drugs depends mainly on renal excretion (Little or no metabolism) e.g. Atenolol, → Caution in Renal patients. B) Lung→ Gases (CO2) & Volatile Liquids (Halothane). C) Alimentary Tract: 1- Saliva (pH = 8): Iodide. 2- Stomach→ Morphine. ( Do stomach wash) 3- Bile→ Intestine → Either: a- Excreted in large intestine b- Reabsorbed → Entero-Hepatic Circulation e.g., Rifampicin. c- Some anti-microbials are excreted in bile in an active form e.g. Ampicillin → Useful in treatment of Cholecystitis & Typhoid carrier. 4- Large Intestine: Either via the bile or unabsorbed oral drugs. D) Skin Glands: 1- Sweat→ Vit B-1, Hg, As & Rifampicin → Red discoloration of sweat. 2- Milk a- Most of drugs administered to lactating women are detectable in breast milk. b- pH of milk (7) is more acidic than plasma (7.4) → Ion trapping for basic drugs. c- Milk is rich in fat → Retention of lipid soluble drugs. d-May affect suckling baby e.g. purgatives  Fundamental Principles of Pharmacokinetics To treat a certain disease, we need to maintain a steady state concentration (Css) or constant drug level. To maintain a steady state concentration (Css) the dose regimen must be designed to replace the medication at approximately the rate with which it is eliminated (rate of drug administration = rate of drug elimination). The most accurate way to do this is with a constant intravenous infusion, but an attempt to maintain an approximate steady state can be reached with repeated doses. Elimination processes may be first or zero order kinetics. A) First-Order (Linear) Kinetics B) Zero-Order (Saturation) Kinetics: 1- Kinetics of drug (ADME) are 1- Limited capacity of drug’s kinetics due to PROPORTIONAL to its concentration. SATURATION of involved enzyme &/or carrier = Rate of kinetics is Fixed and NOT proportional to drug concentration. 2- Fixed FRACTION (%) of the drug is 2- Fixed AMOUNT of the drug is eliminated eliminated per unit time. per unit time 3- LINEAR drug disappearance curve 3- NON-LINEAR drug disappearance curve. 4- CONSTANT t1/2. 4- t1/2 increases with drug conc. 5- AUC is PROPORTIONAL to drug 5- AUC is NOT proportional to drug concentration. concentration 6- Repeated intake of the drug at regular 6- If rate of intake of drug > Rate of its intervals→ Css within 4 – 5 t1/2. elimination → Cumulation → Css → Toxicity. 7- Examples: 7- Examples: L.D. of most of drugs such as - Most drugs obey first order kinetics. Aspirin, Phenytoin - S.D. of most of drugs such as Aspirin, Phenytoin. Clearance: - It is expressed as the volume of body fluid from which drug is removed in unit time Clearance Cl = Kel x Vd - Kel is the rate constant of elimination per hour and has a formula of. - Vd = A (mg) / C (mg / ml) where A = Amount in mg, C = Initial concentration of drug in plasma mg / ml. - t1/2 = Plasma half-life of the drug. Plasma Half Life (t ½): 1- Time needed by the body to decrease a certain plasma concentration of a drug to its half. 2- It is affected by clearance and volume of distribution (Vd). Clinical significance very important assay For some drugs, their Biological t1/2> Plasma t1/2 e.g. Reserpine → Irreversible  of vesicular enzymes (Hit & Run) → Its effect does not depend on its presence in plasma. Its effect ends by resynthesis of new vesicles. Repeated administration of a drug (of first order kinetic) at regular intervals will reach a plateau plasma concentration (Steady State Concentration “Css”) within 4-5 t1/2.  Most of the drug (> 95%) disappears from the body within 4-5 t1/2 after stopping its intake: 1st t1/2 2nd t1/2 3rd t1/2 4th t1/2 5th t1/2 100 % 50 % 25 % 12.5 % 6.25 % 3.125 % ( 50%) ( 75%) ( 87.5%) ( 93.75%) ( 96.875%) t ½ is useful to determine the frequency & route of drug administration. Loading dose: 1- The initial dose of the drug which can raise its plasma level to the target concentration. 2- Used to reach Css very rapidly as in emergency e.g. digoxin in acute heart failure. 3- Loading dose = Vd x desired concentration (Css). 4- Unexpected toxicity can occur so, given once and slowly Maintenance dose: 1- The dose needed to replace the drugs eliminated since the preceding dose, so maintain steady state (Css). 2- The maintenance dose= Cl x Css x Tm Cl = Clearance Css =steady state concentration Tm = dose interval 3- The smaller the dose interval, the smaller the maintenance dose. 4- If the drug is taken by infusion, dose interval (Tm) = ONE unit of time = 1. Infusion rate (mg/min) = clearance (ml/min) x Css (mg/ml)  Pharmacodynamics (What the DRUG does to the BODY) Possible Mechanisms of Action of Drugs: Drugs may act through one or more of the following mechanisms: 1. Physical: Adsorption e.g. kaolin in diarrhea. Osmotic e.g. MgSO4 as saline purgative and mannitol as osmotic diuretic. 2. Chemical: Neutralization: i- NaHCO3 (Antacid) + HCl (Gastric acid) in treatment of hyperacidity. ii- Protamine sulfate (Basic) + Heparin (Acid) → Chemical antagonism. Chelation: Organic compound + Heavy metal → Non-toxic easy excreted complex. e.g. Desferrioxamine for ferric iron (Fe+3). 3. Interfere with cell division: e.g. anti-cancer drugs 4. Interfere with metabolic pathway: e.g. sulfonamides compete with PABA in bacteria leading to inhibition of synthesis of folic acid. 5. Inhibition of enzymes: Physostigmine ( Cholinesterase), Aminophylline ( Phosphodiesterase, PDE) & Aspirin ( Cyclooxygenase, COX). 6. Action on ionic channels in the cell membrane e.g. local anesthetic as procaine → block Na+ channel → membrane stabilization. 7. Action on specific receptors: Most common mechanism of drug action. Definition of receptor: Receptor is a chemo-sensitive and chemo-selective protein macromolecule that interacts specifically with a ligand (drug, transmitter or hormone) to produce a biological response. The receptor may be membrane or cytoplasmic or nuclear. (Ka) Drug + Receptor Drug/Receptor Complex Response (Kd) N.B) Ka = Association constant with the receptor, Kd = Dissociation constant from the receptor. * Affinity: the ability of drug to fit onto the receptor to form drug-receptor (D-R) complex. * Efficacy : ability of drug-receptor (D-R) complex to evoke a response *Potency : the dose of the drug required to produce a specific effect Relation between Drug concentration and Response: This relation, represented by the Dose-Response curves, is usually hyperbolic but becomes sigmoid when log dose is blotted against the response. Response Response Dose Dose Dose- Response Curve Log dose-Response Curve Dose – Response Curve of Drugs: 1- Relation between Log– Dose Dose Response Curve of Drugs: and Response (Effect) of a drug 1- Relation between Log Dose and Response (Effect) Emax A B 2- 2- Useful(responses): Useful to know Effects to know Effects (responses): Minimal effectMinimal (Emin),effect (Emin), C Response (Effect) Maximal Effect (Emax) & Submaximal effects Maximal Effect (Ee.g. max)50% & Submaximal effect (E50) effects (E50 = 50% effect) E50 3- Useful to know Doses that produce Minimal effect (EDmin), 3- Useful to know Doses that produce Maximal effect (EDMinimal effect (ED max) & Submaximal min), effect e.g. 50% effect (ED50) Emin Maximal effect4-(ED max)to&compare Useful Submaximal drugs: effect (ED50 = 50% effect) ED50 a- Efficacy → Compare Emax (B>A>C) Log Dose (conc.) 4- Useful to compare drugs: a- Efficacy→ Compare Emax (B>A>C) b- Potency→ Compare the doses that produce the same Submaximal effect (A>B>C). 5- Useful to determine the type of a blocker whether: a- Competitive → Parallel shift to right ( Potency) with same Emax (Same efficacy). b- Non-competitive → Non-parallel shift to right ( Potency) with decreased Emax ( Efficacy). Types of Ligands: Drugs are classified, according to the nature of their interaction with receptors, into: Agonists: drugs that have affinity, efficacy and rapid dissociation rate. Partial agonists: drugs that initially stimulate then block receptors. So, they have affinity, weak efficacy and moderate dissociation. Inverse agonists: drugs that have affinity but produce pharmacological response opposite Partial agonist to that of agonist Antagonists: drugs that block receptors. They have affinity, no efficacy and slow dissociation rate.  TYPES OFANTAGONISTS: Competitive Non competitive antagonist antagonist A) Competitive antagonists: 1- Antagonists bind REVERSIBLY with the receptors. 2- Antagonists can be DISPLACED by excess agonists → Surmountable. 3- PARALLEL shift of the curve to the RIGHT→ Potency. 4- NO effect on the maximum response (E-max) = Same Efficacy 5- Examples: Propranolol, atropine & naloxone. B) Non-competitive: 1- Antagonist is NOT displaced by agonist → Non-surmountable. 2- Non-Parallel shift of cure to the Right = Potency. 3- Decrease maximum response (E-max) = Efficacy. Types of Non-Competitive Block: REVERSIBLE: i- The antagonist binds REVERSIBLY to the receptor. ii- The block ends by the Metabolism of the blocker. iii- Usually of Short duration of action. iv- Examples: Nicotine LD & Succinylcholine.  IRREVERSIBLE: i- The antagonist binds COVALENTLY to the receptor. ii- The block ends by Resynthesis of new receptors. iii- Usually of Long duration of action. iv- Examples : Phenoxybenzamine & organophosphorus compounds. N.B) Chronic Use of Drugs Affects the No. & Sensitivity of Receptors: MCQ 1- Long use of Agonists→ No. & Sensitivity of Receptors → Down Regulation. 2- Long use of Antagonists or drugs that  transmission → No. & Sensitivity of Receptors → Up Regulation. Types of receptors and signal transduction mechanism The receptor has two main functions ligand binding and generating effector response by interacting with closely associated cellular proteins called signaling systems. There are 4 types of receptors: Types of Receptors Transmembrane signaling mechanisms: A) Ligand binds to the extracellular domain of a ligand-gated ion channel. B) Ligand binds to a domain of a transmembrane receptor, which is coupled to a G protein. C) Ligand binds to the extracellular domain of a receptor that activates a kinase enzyme. D) Lipid-soluble ligand diffuses across the membrane to interact with its intracellular receptor. (A) Ligand gated ionic channel receptors: They are membrane receptors located on the gate of ionic channels. Binding of ligand to the receptor will lead to conformational change in the receptor and change in cell membrane permeability to ions.  (A.Ch) + Nicotinic receptors Na+ influx depolarization. GABA + GABAA receptors  Cl- influx  hyperpolarization Milliseconds between binding of the ligand and cellular response e.g.Acetylcholine (B) G. protein-coupled receptors and second messenger: They are cell surface receptors which facilitate binding of guanosine triphosphate (GTP) to specific proteins located on the cytoplasmic surface of plasma membrane known as G- protein which regulates the activity of membrane enzymes and ion channels The G-protein is a membrane protein comprising three subunits (α, β, Ɣ) G-protein either: -regulate intracellular 2nd messenger (α-subunits with GTPase activity) or- control opening of ion channel (β, Ɣ- subunits) There are different Gα subunits (Gαs -Gαi - Gαq) i. Adenyl cyclase (A.C) is regulated via Gαs ( c-AMP) and Gαi (c-AMP) ii. Phospholipase C activated via Gαq responsible for generation of IP3 (inositol triphosphate) and DAG (diacylglycerol) to regulate free calcium concentration. - Adrenaline + β-receptors → Gαs-protein → ++ A.C. →  cAMP concentration - Adrenaline + α-2 receptors → Gαi-protein → -- A.C. →  cAMP concentration Few seconds - minutes between binding of the ligand and cellular response: (C) Enzyme (Tyrosine kinase)-linked receptors: They are polypeptide receptors consisting of an extracellular ligand-binding domain (to which insulin or growth hormone bind). It is connected to cytoplasmic enzymatic domain containing tyrosine kinase enzyme. Which when activated will phosphorylate and activate: i. Signal transducer → Non-genomic actions → Seconds – Minutes e.g. hypoglycemia of insulin. ii. Activator of transcription that will separate from the receptor to cross the nuclear membrane and modulate gene transcription → Genomic actions → Hours e.g. anabolic effect of insulin and growth hormone. (D) intracellular receptors (DNA linked receptors): They are cytosolic or nuclear receptors that modulate the transcription of genes in the nucleus leading to change in protein synthesis. e.g. Lipid soluble ligands (steroid hormones, thryoxine, vit. D) + Intracellular receptors → DNA transcription → mRNA → change in protein synthesis. Delayed long-lasting effect (hours between binding of the ligand and cellular response).