I.

General Pharmacology
Objectives: After listening to the lecture (s), and studying the textbook the student should be able to: I Introduction to pharmacology: 1. Define and describe the concepts of: Pharmacology, Pharmacokinetics, Pharmacodynamics, Pharmacotherapeutics and Toxicology 2. Outline sources of drugs and drug nomenclature 3. Know sources of information and literature of pharmacology 4. List different dosage forms of drugs 5. Outline routes of drug administration with regard to advantages and disadvantages as well as the effect on the therapeutic outcome 6. Discuss the therapeutic vs. adverse effects of each drug class A) Pharmacokinetics: I. Principles and concept 1. Define pharmacokinetics 2. Write down major processes involved in pharmacokinetic (absorption, distribution, metabolism and excretion). 3. Define pharmacokinetic parameters and list factors influencing those (genetics, disease states, age, hepatic and renal function). 4. Estimate the values of the following pharmacokinetic parameters from the drug plasma concentration-time curve: peak concentration (Cmax) peak time (Tmax, half-life (t1/2), elimination rate constant (Ke), clearance (Cl), volume of distribution (Vd) and area under the plasma concentration-time curve (AUC). 5. Explain the importance of pharmacokinetics in drug therapy (drug of choice, dose & dosage regimen, therapeutic outcome, adverse drug reactions and drug interactions. II. The fate of drug in the body: absorption and distribution: 1. List and explain physicochemical factors in transfer of drugs across membrane (influence of pH and pKa) 2. Describe and compare drug absorption, bioavailability and routes of administration. 3. Anticipate the host and drug factors affecting absorption of drug (physicochemical properties of the drug, physiological and pathological conditions and exposure to xenobiotics)

4. Describe the process, consequence and significance of drug distribution, redistribution, plasma protein binding, tissue binding and placental transfer of drug with regard to factors affecting distribution and redistribution of drug (tissue perfusion, physicochemical properties of the drug, accumulation of drugs in tissues and its consequences. III. The fate of drug in the body: metabolism and excretion: 1. Define the terms: elimination, metabolism (biotransformation) and excretion. List the major biotransformation reactions resulting in drug metabolism (phase 1 and phase 2 reactions). 2. Identify the factors that can affect drug metabolism (nutritional, physiological, genetic and environmental effects, chemical effects, enzyme inhibition and induction) 4. Describe the different excretion routes and the mechanisms by which drug excreted from the body (hepatic excretion, and enterohepatic circulation, other excretion processes: lungs, milk, placenta, eggs, nails, hair, sweat, etc.) 5. Define the following terms: total clearance, renal clearance, hepatic clearance, biliary clearance and extraction ratio. B. Pharmacodynamics: 1. Define the following terms: agonist, partial agonist, inverse agonist and antagonist (competitive and irreversible, physiological and pharmacological antagonism) 2. Define terms being used in describing drug action: specificity, selectivity, efficacy, and potency 3. Describe the concept of drug receptors and its theories 4. Describe the molecular drug targets (membrane receptors, intracellular receptors enzymes, carriers, ion channels and etc.) 5. Explain the functional roles of the four receptor super families (Voltage- and receptor operated ion channels, G protein-linked receptors, Enzyme-linked receptors, and DNA-linked receptors 6. Describe factors that contribute to variation in drug responsiveness 7. Classify adverse drug reactions and explain how to reduce the risk of adverse drug reactions. Outline factors affecting adverse drug reactions (disease, dose, co-medications and genetic).

OCULAR DRUGS AND PHARMACOLOGY

OPTO-343 GENERAL PHARMACOLOGY

Frequently asked questions on general pharmacology Bioavailability (Biological availability) Q1: Definition, significance, calculation, and factors affecting bioavailability of drug: 1. Bioavailability is the percentage of drug released from a
formulation that becomes available for biological effect 2. It measures the rate and extent of drug transfer from its site of administration to the systemic circulation 3. It is calculated by comparison of the area under the serum concentration curve (AUC) after IVI with that observed when the same dose is given by another route 4. Factors affecting bioavailability include: a) Factors affecting GI absorption and b) first pass metabolism A. Factors affecting GI absorption: 1) Drug: molecular weight, lipophilicity, pKa, and stability in the gut contents. 2) Formulation: disintegration time and rate of dissolution 3) Patients: pH of the gut, gastric emptying rate, surface area available for absorption, presence of GI diseases and other drugs that can modify absorption of drugs 4) Food: food reduces the absorption of some drugs like penicillin-V, cephalexin, tetracyclines and aspirin while increases the absorption of another drugs as propranolol, diazepam and dicoumarol. B. First- pass effect (first-pass metabolism, presystemic elimination) is the metabolism of some drugs in a single

passage through the liver, gut wall or the lungs before reaching the systemic circulation. Q2: Mention some notes on first pass-effect? 1. Some drugs are extensively metabolized in their first-pass as propranolol and morphine 2. First-pass also occurs due to intestinal mucosal metabolism as isoprenaline and flurazepam 3. Pulmonary drug metabolism after aerosol inhalation can occur after isoprenaline administration 4. First-pass effect can be avoided by sublingual administration and to some extent by rectal administration

Q3: Define drug distribution? After a drug is absorbed, it will distribute between blood and tissues. The drug passes through the various body fluid compartments (plasma, interstitial fluid and intracellular fluid)

Q4: Define compartment Concept? The body can be represented as series of compartments that communicate reversibly with each other. A compartment is not a real physiologic or anatomic region but is considered as a tissue or group of tissues which have similar blood flow and drug affinity. Within each compartment the drug is considered to be uniformly distributed

Q5: Define One-compartment model?

The simplest pharmacokinetic model. It considers the body as a single homogenous compartment. I.e. any change in the plasma levels of the drug reflects proportional changes in tissue drug levels.

Q6: Define two-compartment model? It involves a central compartment and a more slowly equilibrating deeper peripheral compartment. It explains the biphasic fall in log plasma concentration seen after IVI.

Q7: Mathematical interpretation of drug distribution? Drug distribution is interpreted mathematically as the apparent volume of distribution (Vd)

Q8: Definition, calculation and importance of Vd? Vd is the apparent volume that would accommodate all drug in the body if its concentration throughout the body was the same as that in the plasma. It is not a real volume Vd = Amount of drug in the body / plasma concentration

Q9: What is the importance of Vd: 1. It is an estimate of the extent of extravascular tissue uptake of drugs. When Vd is small (frusemide 0.1 L/Kg) tissue uptake is limited. Large values (digoxin 7L/Kg) indicate extensive tissue distribution) 2. Vd is important to calculate the size of a loading and estimate the fluctuations in plasma levels during repetitive dosing

3. Drugs with high Vd are not amenable to dialysis because of extensive tissue distribution 4. Small Vd is favored by low lipid solubility, high degree of plasma protein binding and low level of tissue binding. The reverse is true

Q10. Mention factors affecting distribution of drugs? 1. Physicochemical properties of the drug as MW, polarity, lipophilicity 2. Size of the tissue and amount of its blood flow 3. Binding to plasma proteins like plasma albumin and Alpha1-acid glycoprotein. The bound portion is inactive, non diffusible, can't be metabolized or excreted. The free drug is active, diffusible and can be metabolized and excreted. The two fractions exist in equilibrium; when the free part is metabolized and/or excreted, another part is released from plasma proteins 4. Binding to cell and tissue constituents due to an affinity to some cellular constituents as chloroquine (concentrated in the liver because it is highly bound to nucleic acids) also can bind to retinal nucleoproteins. Arsenic is deposited in the skin and hair as it is bound to keratin. Iodides are concentrated in thyroid and salivary glands, calcium is deposited in bone due to its affinity to collagen, tetracyclines deposit in bone and teeth as they chelate with calcium

Q11: Mention the results of binding drug to plasma proteins? 1. Drugs with higher affinities to plasma proteins can displace drugs of lower ones. 2. It provides a reservoir as the bound part is in equilibrium with the free part

3. It prolongs the half life of the drug because the bound part is not metabolized or excreted 4. Binding of drug to plasma protein determines its Vd, penetration into tissues and secretion 5. Binding of a drug may facilitate drug absorption by reducing its free concentration in the plasma

The results of binding to plasma proteins (continued): 6. The concentration of free part of highly protein bound drugs may be too low to be effective against dangerous infections 7. When a drug that is extremely protein bound is given by IVI, the concentration of the free (active) drug will depend on the injection rate

Q12. Passage of drugs to CNS: 1. The glial cells are the blood brain barrier (BBB) 2. Lipid soluble drugs pass freely through the BBB as general anesthetics and other CNS depressants 3. Secondary and tertiary amines can pass while quaternary ammonium compounds cannot 4. Dopamine cannot penetrate easily into CSF, so in parkinsonism we give L-dopa instead of dopamine

Q13. Passage of drugs to the fetus: 1. Many drugs pass across the placental barrier by simple diffusion depending on their lipid solubility and their degree of ionization. Lipid soluble drugs pass readily to the fetus as hypnotics, narcotics, anesthetics, most antibiotics, cortisone

Q14: Examples of drugs that cross the placenta and can harm the fetus: 1. In early pregnancy (third to tenth weeks), drug-induced congenital anomalies may occur 2. Morphine can cause respiratory depression (asphyxia neonatorum) 3. Oral anticoagulants may initiate fatal hemorrhage in the newborn 4. Sulfonylurea may cause prolonged neonatal hypoglycemia 5. Aminoglycosides can cause eighth cranial nerve damage

Q15: Define prenatal therapy "Fetotherapy": A) Glucocorticoids reduce the incidence of respiratory distress syndrome B) Enzyme inducers as phenobarbitone given to the mother before labor enhance the ability of the newborn to conjugate bilirubin to prevent Kernicterus . However, phototherapy is now used instead C) Rho(D) immunoglobulin injected into the RH-negative mother to prevent the development of erythroblastosis fetalis D) Low dose aspirin (60-75 mg/day) for prophylaxis of uteroplacental insufficiency and pre-eclampsia

Q16: Define Biotransformation or metabolism? Changes that occur to drugs after absorption until excretion. Drug metabolism occurs mainly in the liver though also in other organs as intestinal lumen, lung, skin and kidney

Q17: What are the consequences of drug metabolism? 1. Abolishes the activity as with most drugs 2. Increases the activity as chloral hydrate to trichlorethanol, cyclophosphamide to various alkylating metabolites 3. Changes active drug to another active substance as codeine to morphine, propranolol to 4-hydroxypropranolol

Q18: What are types of biotransformation reactions? 1. Phase I (non-synthetic reactions) as oxidation, reduction, hydrolysis, usually converts the parent drug to a more polar metabolite. Non-synthetic reactions occur first and may be followed by synthetic reactions 2. Phase II (Synthetic reactions): the body add one of its constituents to the drug to form highly polar, rapidly eliminated conjugates (conjugation)

Q19: What are types of metabolizing enzyme systems? 1. Microsomal drug metabolizing enzyme systems 2. non-microsomal enzyme systems

Q20: What are microsomal drug metabolizing enzymes? Group of enzymes synthesized in the smooth part of the endoplasmic reticulum and concentrated mostly in the liver but also in many other tissues

Q21: What are the characters of MDMEs? 1. They contain the mixed function oxidase or monooxygenases. This oxidation reduction process require cytochrome P-450, cytochrome P-450 reductase, NADPH and molecular oxygen 2. They metabolize lipid soluble drugs into water soluble easily excreted metabolites 3. They metabolize drugs as well as some body constituents 4. They lack substrate specificity 5. They are not well developed in the newly born so drugs as chloramphenicol are highly toxic in early infancy

Q 22: What are characters of NMDEs? Specific enzyme systems that act on natural products present in the body and on water soluble foreign compounds as oxidases, peroxidases and dehydrogenases

Q23: What are the factors affecting biotransformation? 1. Species variation 2. Age: extremes of age are more susceptible to drug effects 3. Sex: estrogens inhibit while testosterone stimulates MES 4. Pathological factors: in liver disease, drug metabolism is depressed. In addition, the metabolism of some drugs is reduced in cases of heart failure, shock and with B-blockers that reduce hepatic blood flow 5. Environmental factors as tobacco smoking and pesticides

6. Drugs can stimulate (enzyme induction) or inhibit (enzyme inhibition) microsomal drug metabolizing enzymes. Enzyme induces as phenobarbitone, rifampin and phenytoin and enzyme inhibitors as cimetidine, chloramphenicol

Q24: Drug clearance (definition, calculation, and factors affecting drug clearance)? 1. Drug clearance is the volume of a fluid from which all drug is removed per unit time. It is a measure of the body's ability to eliminate drugs 2. Clearance (CL) = Rate of elimination / Drug concentration Elimination of drugs from the body involves two major processes: hepatic metabolism-biliary excretion and renal filtration-secretion. Total body clearance (CL) consists of renal clearance (Clr) and non-renal clearance (Clnr) 3. Factors affecting drug clearance: 1. Blood flow to the clearing organ 2. Binding of the drug to plasma proteins 3. Activity of the processes responsible for drug removal as hepatic enzymes, glomerular filtration and secretory processes

Q25: Define hepatic clearance and factors affecting it? Hepatic clearance = hepatic blood flow X extraction ratio (E) Hepatic clearance depends upon: 1. Intrinsic activity of metabolic enzymes and transport processes. 2. Free fraction of drug in the blood 3. Total effective hepatic blood flow

Q26: Define extraction ratio (E) Extraction ratio (E) is the proportion of drug removed by a single transit of blood through an organ E = arterial drug conc. venous drug conc. / arterial drug con When E is more than 0.6, clearance is flow-dependent as verapamil and morphine, when E is less than 0.2, clearance is enzyme-dependent as warfarin and theophylline and when E is between 0.2-0.6, clearance is both flow and enzyme dependent as acetaminophen and chloramphenicol

Q27: Define elimination half life (t1/2) The time required to reduce the plasma concentration of drug to half the initial concentration It is the relationship between apparent volume of distribution (Vd) and clearance (CL) Elimination half life = 0.693 Vd / CL

Q28: Define first order (linear or non-saturable) kinetics? Clearance is directly proportional to the concentration of the drug in the plasma. This means that a constant fraction or ratio of drug is eliminated per unit time as with most drugs Characteristics of first order kinetics: 1. Constant half life 2. AUC, Css and amount of drug excreted unchanged in urine, all are proportional to the dose 3. The composition of drug metabolites excreted is independent of the dose 4. The time required to reach Css is about 5 times the half life

Q29: define Zero order (non-linear) kinetics? Drug elimination occurs at a constant rate and independent of the amount of drug to be eliminated. This means that a constant amount of drug is eliminated per unit time as with ethanol clearance Characteristics of zero order kinetics? 1. Half-life increases with the dose 2. AUC, Css and renal clearance are not proportional to the dose 3. Composition of drug metabolites may vary with the dose

Q30: Adverse reactions of drugs (Definition and types)? Harmful effects of a drug occurring at doses used for therapeutic, prophylactic or diagnostic purposes and which call for reduction of dose, drug withdrawal and/or immediate treatment

Q31 what are types of adverse reactions? 1. Type A (side effects and over dosage toxicity) 2. Type B (hypersensitivity and idiosyncrasy) Adverse reactions include: A) Side effects: Unavoidable part of the pharmacologic actions of the drug used for a specific indication at therapeutic doses as sedation with antihistaminics B) Over dosage toxicity: occur at high doses and their incidence increases as the dose is increased as liver damage from paracetamol overdosage, ototoxicity from aminoglycosides C) Allergic reactions: adverse reactions that are not doserelated, usually induced by prior contact with drugs that act as antigens D) Drug abuse: the use for non-therapeutic purpose of drugs that act on the CNS leading to dependence Adverse reactions are due to many factors: 1. Some are related to the patient as age, sex, tendency to allergy, disease, personality and habits 2. Others are drug factors due to the drug itself or interactions between drugs

Q32: Define intolerance? A low threshold to the normal pharmacological action of a drug. It is the reverse of tolerance

Q33; Define idiosyncrasy? Inherent qualitatively abnormal reaction to a drug due to genetic abnormality as porphyria, favism.

Q34: Iatrogenic diseases (drug-induced diseases) A drug prescribed for a disease causes another disease as drug- induced asthma, peptic ulcer or parkinsonism

Q35: Define teratogenesis? Foetal abnormalities caused by some drugs when given early in pregnancy as cytotoxic drugs (abortion or foetal anomalies), tetracyclines (dental enamel hypoplasia)

Q36: Define potency and efficacy? Potency refers to the range of doses over which a drug produces increasing response. It is determined along the dose axis of the dose- response curve Efficacy is the capacity of the drug to produce maximal effect. It can be determined along the response axis of the doseresponse curve Clinically, efficacy is more important than potency Individuals vary in their response to a drug. They may be hyporeactive or hyperreactive in comparison to most individuals

Q37: What are factors modifying drug action? The main factor that can modify drug action is the dose. Other factors include age, sex, weight, race, pathological states, nutrition, pharmacogenetic defects, bioavailability, hypersensitivity, tolerance and tachyphylaxis, dependence and drug interactions The dose of the drug can be calculated according to the age, weight or surface area of the patient Dose for infants (less than 2 years) = adult dose X infant's surface area / 1.73 Young's rule: Dose for children = adult dose X age (years) / age + 12 Clark's rule: Dose for a child = adult dose X weight in pounds / 150 Percentage method: the dose is calculated as a percentage of adult dose: 1 month (10%), 1 year (25%), 3 years (33%), 7 years (50%), 12 years (75%) Method considering pharmacokinetic parameters: Loading dose = Vd/f X Css Maintenance dose = Cl/f X Css X T Weight: The dose is calculated according to the lean body weight. In the obese, lipid soluble drugs should be given in larger doses

Sex: Females are more susceptible to autonomic drugs as estrogens inhibit choline esterase. Certain drugs act specifically in women as progesterone and women respond differently to certain drugs as nitrous oxide leads to vivid dreams

Pathological states: 1. In sensitive patients, cholinomimetics, B-blockers can precipitate an asthmatic attack 2. Myxedematous patients cannot tolerate morphine 3. Morphine is dangerous in liver disease 4. Aminoglycosides accumulate in renal impairment 5. Absorption of iron salts is increased in iron deficiency anaemia

Nutrition: 1. Protein-deficient diet may decrease drug conjugation 2. Patients receiving MAO inhibitors should avoid diet containing tyramine as cheese, red wine, beans (Cheese reaction)

Pharmacogenetic defects (genetically determined variations that are revealed only by the effect of drug. Examples include: 1. Drug acetylating enzymes: two classes of people exist, the rapid and slow metabolizers. In the slow acetylators, the drug accumulates and produce toxic effects more than in the rapid acetylators as with isoniazid 2. Plasma pseudocholinesterase: succinylcholine apnoea may occur in patients deficient in ChE or having atypical enzyme (has a lower rate of activity and decreased affinity for succinyl choline

3. glucose-6-phosphate dehydrogenase: congenital deficiency of the enzyme renders RBCs readily hemolyzaed in presence of some oxidant drugs as antimalarials, antimicrobials 4. Porphyrias: increased levels of porphyrins and their precursors that can cause severe neurological disturbance and may cause death. Drugs causing porphyria include barbiturates (they increase the activity of ALA-synthetase enzyme. Haemin is an ALA-synthetase inhibitor obtained from RBCs, it can be used to ameliorate recurrent attacks of acute intermittent porphyria 5. Malignant hyperthermia: marked muscle rigidity and rise of temperature. It is a rare complication of anesthesia. The basic defect is reduced uptake or binding of calcium to the sarcoplasmic reticulum. Occurs with suxamethonium or halothane. Dantrolene can be used to treat this condition 6. Steroid-induced raised intraocular pressure in genetically predisposed persons 7. Acatalasia: deficiency of catalase enzyme which causes breakdown of hydrogenperoxide into water and oxygen. Affected persons develop severe ulcers in the mouth and suffer loss of teeth

Drug allergy: A drug, metabolite or a non-drug element in the formulation activates the immune system in an undesirable way that appears as drug allergy. It is dose independent and occurs in minority of patients. Cross allergy occurs within a group of drugs. The chief target organs of drug allergy include skin, respiratory tract, GIT, blood and blood vessels

Types of allergic reactions: 1. Type I reaction: immediate type (Anaphylactic): It is an IgEmediated reactions as anaphylaxis, asthma, urticaria and angioedema. Occurs with penicillin. 2. Type II reaction: It involves IgG or IgM antibodies., occurs as autoimmune hemolytic anaemia (methyldopa), thrombocytopenia (quinidine), agranulocytosis (chloramphenicol) 3. Type III reactions: Involves IgG and includes serum sickness, glomerulonephritis and pulmonary disease. Occurs with sulphonamides, penicillin. 4. Type IV reactions: Delayed type (cell-mediated): involves allergic contact dermatitis from topically applied drugs

Diagnosis of drug allergy: 1. History and type of reaction 2. Intradermal and conjunctival tests Measures against allergy: 1. Drug treatment as epinephrine, corticosteroids, antihistaminics 2. Desensitization or hyposensitization

Define tolerance and mention its mechanisms? Tolerance is an acquired resistance to the ordinary doses of drugs. It develops upon repeated administration and more drug is needed to produce the same effect. It disappears when the drug is stopped for sometime. Mechanisms of tolerance: 1. Increased metabolism due to enzyme induction 2. Development of antihormones (against insulin for example) 3. Decreased sensitivity of receptors 4. Reduced efficacy at receptor sites (e.g. opiates) 5. Down regulation of receptors (decreased number of receptors), occurs with B-agonists Cross tolerance: When one develops tolerance to a drug, he may also show tolerance to other drugs of the same group as members of opiods

Tachyphylaxis (acute tolerance): It is a rapid form of tolerance in which we cannot get the same response by increasing the dose. Ephedrine produces tachyphylaxis due to depletion of CA stores and may be due to down regulation

Drug interactions: Pharmacologic responses which cannot be explained by the action of one drug but are due to multiple drugs acting concurrently. Clinically important drug interactions occur with drugs that have a steep dose-response curve and a small therapeutic/toxic ratio. Examples are oral anticoagulants, oral hypoglycemics, antiarrhythmics. Drug interactions may result in antagonism or synergism

Antagonism: may be physiologic (as histamine/adrenaline), competitive (naloxone/morphine) or non-competitive (irreversible ChEIs) Synergism: may be in the form of summation 9additive effect) as alcohol and ether or potentiation (the combined effect is more powerful as trimethoprim-sulphonamide combination

Types (mechanisms) of drug interactions: 1. Pharmaceutical incompatibilities: occurring outside the body 2. Pharmacokinetic interactions: at sites of absorption, distribution. Metabolism and excretion 3. Pharmacodynamic interactions: at sites of action or nearby Mechanism of drug action: 1. Receptor-mediated mechanisms: involving interactions with particular receptors at specialized sites within the body 2. Non-receptor-mediated mechanisms

Receptors: specific cellular structures, protein in nature, which may be extracellular or intracellular. They interact, by a variety of chemical forces, with chemical transmitters or drugs (agonists) to trigger changes in activity which result in the final observed effect. They are blocked by other drugs (antagonists or blockers). They are characterized by sensitivity, selectivity and specificity

Drug receptor interaction can manifest itself in various ways: 1. Drug interacts with the receptor activating it resulting in a pharmacologic effect, i.e. it has affinity and efficacy. It is called an agonist (acetylcholine, epinephrine, norepinephrine) 2. Drug interacts with the receptor without activating it. i.e., it only occupies the receptor (affinity without efficacy). It is called a pure antagonist as naloxone 3. A drug may act as a partial agonist (agonist-antagonist), i.e., it interacts with the receptor activating it but not to the extent of that of a full agonist i.e., it produces a lower response, at full receptor occupancy, than do full agonists. It antagonizes the effect of a full agonist as nalorphine 4. A drug may bind receptors without effect. The receptors are called silent receptors. E.g., drug binding to plasma protein 5. A drug may attach to many receptors and have many actions as morphine, dopamine

Antagonists 1. Chemical antagonists: they chemically interact with the agonist away from the receptor site 2. Competitive antagonists: compete with agonists for the same recognition site of the receptors. Antagonism may be reversible or pseudoirreversble 3. Non-competitive antagonists: bind to an allosteric site on the receptor distinct from the agonist recognition site. Antagonism may be reversible or irreversible 4. physiological or functional antagonists: interfere with some process or processes subsequent to agonist activation of the receptor The antagonism is reversible when the antagonist binds reversibly to the receptor site. Irreversible antagonism occurs when the antagonist binds covalently to the receptor site and hence dissociates very slowly. Competitive antagonism is usually reversible. However, some competitive antagonists are also able to produce irreversible antagonism if they are tightly bound to the receptor and dissociate slowly. This better called pseudoirreversible antagonism Noncompetitive, irreversible and pseudoirreversible antagonism are defined as nonsurmountable antagonism as they don't regain the original response by addition of high agonist concentration

Characters of competitive antagonism: 1. Reversible 2. Compete with the agonist for the receptors 3. The duration of action is dependent on the relative plasma concentration of both agonist and antagonist 4. Causes parallel shift to the right in the dose-response curve with no change in maximal efficacy 5. Examples: B-blockers, atropine, naloxone

Characteristics of non-competitive antagonism: 1. Irreversible 2. Have high affinity for the receptors rendering them unavailable for agonist binding 3. The duration depends on the rate of turnover of the receptor molecules 4. Causes non-parallel shift in the dose-response curve and diminution of maximal response 5. Examples: phenoxybenzamine

Theories of Drug-Receptor Interaction: 1. Receptor occupation theory: Drug effect is proportional to the fraction of receptors occupied, and the maximum effect results when all receptors are occupied

2. Paton's rate theory: The stimulus provided by an agonist molecule is proportional to their rate of association and dissociation to and from receptors rather than to the proportion of the receptors occupied. Drugs that associate and dissociate rapidly are agonists. Those which dissociate slowly are antagonists.

3. Two-state model: The receptors exist in two interchangeable states, R1 which preferentially binds the agonist, and R2, to which the antagonist binds more readily. When an agonist combines with R1, more R2receptors change to the R1 configuration. The reverse occurs when an antagonist binds to R2. Partial agonists can combine with either receptor. Given alone, they interact with R1 state and produce an agonist response. However, in the presence of a full agonist, they interfere with its action both by competing for R1 sites and by binding to the R2 site causing more receptors to change configuration from R1 to R2.

Cellular receptors and their signaling mechanisms The receptors has two functions: ligand binding and message propagation. Hence, two functional domains should exist within the receptor; a ligand-binding domain and an effector domain. The effector domain of the receptor is linked to an effector system in order to generate its effects (Receptoreffector system).

Cellular signaling systems "Receptor Effector Systems": An individual receptor molecule may interact with closely associated cellular protein in order to generate its effect; this constitutes a receptor-effector system or cellular signaling system:

1. Agonist-gated ion channels: Receptors for fast neurotransmitters form ion-selective channels in the plasma membrane and convey their signals by altering cell membrane potential or ionic composition. Ligand binding and channel opening occur in milliseconds thus they are involved mainly in fast synaptic transmission. It includes nicotinic ACh receptors, GABA-A receptor and receptors for glutamate, aspartate and glycine

2. Agonist-regulated enzymes: 1. Receptors for peptide hormones such as insulin. The extracellular hormone-binding domain is connected to an intracellular protein kinase catalytic domain. 2. Receptors for ANP and EDRF: the intracellular domain is guanylyl cyclase that forms the second messenger cGMP 3. G-protein-coupled receptors: receptors for slow neurotransmitters as biogenic amines. These receptors interact with G proteins at their cytoplasmic face. The G protein is a trimer (, , and ). Agonist binding leads to dissociation of the subunit which regulates the activity of specific effectors. These effectors include: 1. Adenylyl cyclase (increases cAMP), phospholipase C (liberates diacylglycerol 'DAG" and inositol triphosphate "IP3", guanylate cyclase (increases cGMP) 2. Channels that are specific for calcium, potassium or sodium 3. Certain transport proteins 4. Trancriptional regulators: Steroid hormones enter the target cell and combines with intracellular receptor proteins associated with nuclear chromatin to activate or inhibit transcription of the nearby gene. This will modify protein production and thereby cause changes in the structure or function of the target tissue 5. Translational regulators: These bind to intracellular receptors and affect RNA secondary structure, its stability or translational efficiency.

END OF THE LECTURE