pharma_final_modified_part1_1_153d94e1aea8f47c955895612af47975.pdf

Pharmacology I (0201330 & 0201335) Dr. Luay Alessa Dr. Elham Abusharieh Faculty of Pharmacy Al-Zaytoonah University of Jordan Brief Description This course is designed to discuss the basic concepts of drugs activity, pharmacodynamics and pharmacokinetics. In addition, the basic and clinical pharm...

Pharmacology I (0201330 & 0201335) Dr. Luay Alessa Dr. Elham Abusharieh Faculty of Pharmacy Al-Zaytoonah University of Jordan Brief Description This course is designed to discuss the basic concepts of drugs activity, pharmacodynamics and pharmacokinetics. In addition, the basic and clinical pharmacology of drugs acting on autonomic nervous and cardiovascular systems will be introduced. It will cover the pharmacodynamics, pharmacokinetics, and the clinical uses of those drugs. Type of Assessment Course Book Information Evaluation Midterm Exam 30% Participation / Practical Applications 20% Final Exam 50% Supportive Learning Resources Subject Learning Style* Pharmacokinetics (Absorption and distribution) Lecture Pharmacokinetics (Metabolism and elimination) Lecture Drug-receptor interactions and Pharmacodynamics Lecture Dose-response curve and types of agonists and antagonists Lecture The autonomic nervous system: Cholinergic agonists Lecture The autonomic nervous system: Cholinergic antagonists Lecture The autonomic nervous system: Adrenergic agonists Lecture The autonomic nervous system: Adrenoceptor antagonists Lecture Diuretic drugs Lecture Antihypertensive drugs Lecture Antihypertensive drugs Antianginal Drugs Lecture Lecture Drugs for Heart Failure Antiarrhythmics Lecture Lecture Introduction to Pharmacology Definition of Pharmacology ➢Pharmacology the study of substances that interact with living systems through chemical processes, especially by binding to regulatory molecules and activating or inhibiting normal body processes. ➢Drugs are any substance that bring about a change in biological function through its chemical actions. ➢Drugs may be endogenously synthesized within the body (e.g. hormones) or may be chemicals not synthesized in the body, (i.e. xenobiotics) or natural substances. ➢Poisons may be drugs and drugs are poisons in overdose. Poisons have harmful effects. Drug-Body Interactions ➢The interactions between a drug and the body are conveniently divided into two classes: 1- The actions of the body on the drug are called pharmacokinetic (PK) processes. 2- The actions of the drug on the body are termed pharmacodynamic (PD) processes. Pharmacokinetics “Examines the movement of the drug through the body” The four major processes are: Absorption Distribution Metabolism ADME Excretion Routes of Drug Administration ➢ The route of administration determined primarily by the: is 1. Properties of the drug water or lipid solubility, ionization, etc. 2. Therapeutic objectives Rapid onset of action, long-term administration, local or systemic). Routes of Drug Administration Enteral routes (delivery through GIT) -Oral - Buccal & sublingual - Rectal Parenteral (injection) - Intravenous - Intramuscular -Subcutaneous Others neither through GIT nor Injection - Oral inhalation - Intranasal - Intrathecal - Topical - Transdermal Enteral routes (delivery through GIT): 1. Oral ADVANTAGES: ✓ Safe (risk of systemic infections is minimal) DISADVANTAGES: ➢ The drug should be formulated properly to be ✓ Convenient (easily self-administered) absorbed through the gastrointestinal tract. ✓ Economic ➢ Drugs can undergo first-pass metabolism. ✓ Toxicities or overdose may be overcome with antidotes. First-pass effect ➢ Drugs absorbed from the gastrointestinal tract enter the portal circulation and pass through the liver. ➢ In liver, the drugs may be exposed to metabolism before reaching the general blood circulation. ➢ This process may limit the bioavailability and reduce efficacy (decrease drug concentration in the circulation). Enteral routes (delivery through GIT): 2. Sublingual and Buccal: ➢ Sublingual: placement of the drug under the tongue where it dissolves in salivary secretions. ➢Buccal: placement of the drug between the gum (between the teeth and the mucous membrane of the cheek). Mucosal (local), Transmucosal (systemic) ➢Because of its high permeability and rich blood supply, the sublingual mucosa route gives fast absorption (faster than buccal), a rapid onset of action and overall high bioavailability. ➢ ADVATAGES: ✓Drug (highly hydrophobic) diffuses into the capillary network that supplies the oral mucosa and enters directly the systemic circulation. ✓Rapid absorption ✓Convenience ✓Avoidance of the harsh gastro-intestinal environment and first-pass metabolism Enteral routes (delivery through GIT) 3. Rectal ➢ADVANTAGES: ✓Bypasses the portal circulation by >50% , low first pass metabolism (because the lower hemorrhoidal veins are not connected to the portal system). ✓Avoiding gastrointestinal enzymes and harsh condition ✓Useful if the drug induces vomiting when given orally, if the patient is already vomiting, or if the patient is unconscious. ➢DISADVANTEDES: ✓Irritant to the rectal mucosa ✓Absorption is sometimes incomplete!! Parenteral (injection) occurs from routes outside the GIT: ➢ADVANTAGES : ✓Introduces drugs directly into the systemic circulation (IV). ✓Used for drugs that are poorly absorbed from the gastrointestinal tract. ✓Used for treatment of unconscious patients. ✓Rapid onset of action ✓Highest bioavailability 100% for IV route (VERY IMPORTANT)!!! ✓Avoidance of first-pass metabolism and harsh gastrointestinal tract environments ➢DISADVATAGES ✓These routes are irreversible ✓May cause fear, pain, tissue damage and infections. Parenteral (injection) occurs from routes outside the GIT The three major parenteral routes are intravascular (IV) (intravenous or intra- arterial), intramuscular (IM), and subcutaneous (SC). 1. Intravenous (IV) ✓The most common parenteral route ✓Rapid effect ✓Maximal control over the circulating levels of the drug ➢May induce hemolysis!!!! (adverse effect or action of drug) by the too-rapid delivery of high concentrations of drug to the plasma and tissues. Therefore, the rate of infusion must be carefully controlled (some drugs need rapid injection e.g. adenosine while others slow injection e.g. vancomycin) . Parenteral (injection) occurs from routes outside the GIT 2. Intramuscular (IM) ✓Can be aqueous solutions or oily and may be formulate as specialized depot preparations. ✓Absorption of drugs in depot preparations is slow with long duration of action ( e.g Progesterone depot preparation as contraceptive, given one injection every 3 months) ✓Onsets of action is slower, but duration may be longer than IV. ✓Factors alter the rate of blood flow to the site of IM injection may affect the onset and duration of drug action. Parenteral (injection) occurs from routes outside the GIT 3. Subcutaneous (SC): ✓The layer of skin directly below the dermis and epidermis, collectively referred to as the cutis. ✓Needs absorption ✓Slower than the IV and IM routes - Subcutaneous tissue has few blood vessels - Minimizes the risks associated with intravascular injection ✓Absorption may be retarded by incorporating a vasoconstrictor such as epinephrine to the drug solution (Less blood flow = slow absorption) ✓Used for non–irritant drugs Other Routes of Drug Administration : 1. Oral inhalation ✓May reach systemic circulation ! Depends on the particle size of the drug. ✓Rapid absorption of the drug through the large surface area of the respiratory tract and pulmonary epithelium ✓Local application in pulmonary diseases (Asthma) ✓Avoidance of hepatic first-pass metabolism ✓Drugs usually are gases or volatile liquids, those that can be dispersed in an aerosol, or dry powders 2. Intranasal ✓Administration of drugs directly into the nose for either local or systemic effects. ✓The nasal cavity is covered by a thin mucosa which is well vascularised >> drug can be transferred directly to the systemic blood circulation without firstpass hepatic. ✓Examples: Nasal decongestants (local effect) 3. Intrathecal ✓Introduces drugs directly into the cerebrospinal fluid. ✓Overcome the blood brain barrier (BBB). ✓Used to treat central nervous system (CNS) infection and cancer. ✓ DISADVANTAGES: Painful ! 4. Topical ✓Is used when a local effect of the drug is desired For example, cream directly to the skin or eye drops 5. Transdermal ✓Application of drugs to the skin, usually via a transdermal patch. ✓Drug is delivered across the skin for systemic distribution, achieving systemic effects ✓The physical characteristics of the skin at the site of application may affect the rate of absorption (diseases!!!) Pharmacokinetics Examines the movement of the drug through the body The four major processes are: Absorption Distribution Metabolism ADME Excretion Absorption of Drugs ✓ Is the transfer of a drug from its site of administration to the systemic bloodstream circulation. ✓Transport of a drug from the gastrointestinal tract/ or the movement of drugs in the body this need absorption, transfer through biological membrane ✓ Depending on the physicochemical properties of the drug , it may be absorbed from the gastrointestinal tract or through body biological membrane by one of the following processes: 1. Simple diffusion 2. Facilitated diffusion 3. Active transport 4. Endocytosis and Exocytosis Absorption of Drugs 1. Simple diffusion (passive) ✓ Drug moves along its concentration gradient, from high to low concentration. ✓ Doesn’t require energy (passive) ✓Doesn’t require a carrier protein. ✓The rate of diffusion is dependent on the lipid-water partition coefficient ( physiochemical properties) ✓ Lipid-soluble drugs cross the cellular membranes (lipid bilayer) easier. ✓ Most of the drug's gain absorbed by simple passive diffusion. 2. Facilitated diffusion ✓ Drugs needs transmembrane carrier proteins that facilitate the passage of large molecules through the cellular membrane. ✓ The drugs move according to their concentration gradient (high to low) ✓ Does NOT require energy ✓ Saturable even increase concentration the rate of absorption will not increase. ✓ Can be inhibited by other substances (because of carrier) ✓ Example is ethacrynic acid 3. Active transport ✓Involves specific carrier proteins (saturation & inhibition) ✓Drugs should be sufficiently resembling the endogenous substances that are the normal substrate for the particular carrier system (a.a carriers, e.g L-dopa) ✓Active transport is energy-dependent and is driven by the hydrolysis of adenosine triphosphate (ATP). ✓Drugs move against a concentration gradient that is, from a region of low drug concentration to higher drug concentration. ✓Saturable and can be inhibited. 4. Endocytosis and Exocytosis ✓Transport large-sized drugs ✓Endocytosis involves engulfment of a drug molecule by the cell membrane and transport into the cell by pinching off the drug-filled vesicle (e.g. vitamin B12+ Intrinsic factor). ✓Exocytosis is the reverse of endocytosis and is used by cells to secrete many substances. Factors Influencing Absorption rate and efficiency 1) pH ✓Most drugs are either weak acids or weak bases, they capable of ionization ✓A drug passes through membranes more readily if it is uncharged (unionized) ✓ Thus, for a weak acid, the uncharged HA can permeate through membranes, and A-can not ✓For a weak base, the uncharged form B, penetrates through the cell membrane, but BH+ does not. ✓The effective concentration of the permeable form (uncharged) of each drug at its absorption site is determined by the relative concentrations of the charged and uncharged forms ✓The ratio between the two forms is, in turn, determined by the pH at the site of absorption and by the strength of the weak acid or base ,which is represented by the pKa. Factors Influencing Absorption rate and efficiency ✓ The pKa : a measure of the strength of the interaction of a compound with a proton. The lower the pKa of a drug, the more acidic it is. Conversely, the higher the pKa, the more basic is the drug. ✓ The relationship of pKa and the ratio of acid-base concentrations to pH is expressed by the Henderson-Hasselbalch equation: ✓ Pka=PH, 50% charged and 50% uncharged ✓ Weak acids drugs are mostly uncharged in acidic pH, while basic drugs are uncharged in basic pH >>> increasing absorption. (increase unionized form so increase absorption) ✓ Acidic drugs are absorbed from the stomach (can be e.g Aspirin, but mainly absorbed from intestine). ✓ The duodenum is a major site of basic drug absorption because of the presence of large concentration of uncharged form as well as the large absorptive surface of duodenum ( and jejunum, and ileum Factors Influencing Absorption rate and efficiency 2) Blood flow to the absorption site - The higher blood flow, the higher is absorption. (IMPORTANT!) - Blood flow to the intestine is much greater than the flow to the stomach (also for other routs such as S.C, IM) 3) Total surface area available for absorption - The upper intestine has larger surface area (villi & microvilli) for drug absorption than that of the stomach; thus, higher absorption capacity than the stomach. 4) Contact time (transit) at the absorption surface - Increasing contacting time of the drug at the absorption site (stomach or intestine) increases the amount of drug absorbed (transient time) - Food delays transporting drugs from stomach to intestine >> delay the rate of absorption of the drugs in intestine. - Diarrhea causes too rapid drug movement through the GI tract. So, shortening contacting time of the drugs at the site of absorption and decreasing drug absorption. Factors Influencing Absorption rate and efficiency 5) Expression of P-glycoprotein ( Genetically) ✓P-glycoprotein is a transmembrane transporter protein that contributes to pumping drugs out of the cell , This can cause: ✓Decrease drug absorption through GI tract. ✓Reducing thereby their intracellular therapeutic concentration and consequently reducing their efficacy. ✓Decrease crossing the BBB. ✓P-glycoprotein pumping needs energy to pump the drugs. 6) The route of administration. -For IV route, (No absorption, the total dose of drug reaches the systemic circulation); while other routes need absorption process and thus lower bioavailability. Factors Influencing Absorption rate and efficiency 7) Chemical characteristics of the drug (lipophilicity) 8) The dosage form (pharmaceutics) 9) The health status - Inflammation increase absorption (vasodilation) increase blood flow so increase absorption Bioavailability ➢ Is defined as the percentage of the administrated dose of drug that reaches the systemic circulation. ➢OR the fraction of unchanged drug reaching the systemic circulation following administration by any route. ➢For example, if 100 mg of a drug are administered orally and 70 mg of this drug are absorbed unchanged, the bioavailability is 0.7 or seventy percent. ➢Depends on the rout of administration, thus, it is a measure of the drug’s absorption rate and extent . ➢Factors influencing bioavailability 1. First-pass hepatic metabolism ( oral>> rectal) 2. Extend of absorption which can be affected by a) Chemical instability (degradation of drug in low stomach pH) b) Solubility of the drug (hydrophobic drugs are absorbed more) c) Nature of drug dosage form and formulation ➢ IV route of drug administration has the highest bioavailability 100%. Why? For a drug administered orally, bioavailability may be less than 100% for two main reasons—incomplete extent of absorption and first-pass elimination Bioavailability Bioequivalence (is a measure of pharmacokinetic (PK)) ➢Two related drug products are considered to be bioequivalent when: 1) Comparable bioavailability ( close to each other) 2) Similar time to achieve maximum blood concentration ( after giving drug time for highest plasma concentration). ➢Two related drugs with a significant difference in bioavailability are said to be bioinequivalent Therapeutic equivalence (is a measure of pharmacodynamic (PD), must be : ➢Two similar drug are therapeutically equivalents when they have comparable efficacy and safety. ➢Therapeutic Equivalence = Bioequivalence ( bioavailability& time of highest conc.) + Pharmaceutical Equivalence ( same drug conc., same dosage form, same active ingredient, same rout of administration) ➢This means that therapeutic equivalence necessitates bioequivalence, but the opposite is not true. They are pharmaceutical equivalents in that they, (a) contain identical amounts of the same active drug ingredient in the same dosage form and route of administration. ➢Drugs are considered to be therapeutic equivalents and thus suitable for substitution (generic equivalents). Pharmacokinetics “Examines the movement of the drug through the body” The four major processes are: Absorption Distribution Metabolism ADME Excretion Drug Distribution ➢Is the process by which a drug reversibly leaves the bloodstream and enters the interstitium (extracellular fluid) and/or the cells of the tissues. ➢ Drug distribution depends on: 1) Blood flow>> drug distribution 2) Capillary permeability >> drug distribution 3) Degree of binding of the drug to plasma protein >> drug distribution (plasma albumin) 4) The relative hydrophobicity of the drug (lipophilic) >> drug distribution (Drug properties) Volume of distribution (Vd) ➢The volume of distribution is a hypothetical volume of fluid into which a drug is dispersed. (calculation) ➢It is useful to compare the distribution of a drug with the volumes of the water compartments in the body Example 1: if patient had an 420mg IV dose of drug A, and the plasma concentration was found to be 10mg/L when measured, what would be the Vd of Drug A?? Vd=420/10= 42L (ideal, homogenous distribution along all body fluids) Example 2: if patient had an 420mg IV dose of drug B, and the plasma concentration was found to be 5mg/L when measured, what would be the Vd of Drug A?? Vd=420/5= 84L (High, Most of drug distributed ino the tissues) Example 3: if patient had an 420mg IV dose of drug C, and the plasma concentration was found to be 20mg/L when measured, what would be the Vd of Drug A?? Vd=420/20= 21L (Low, Most of drug in the plasma) Volume of distribution (Vd) 1) Plasma compartment If the drug is large and ionized, it can’t cross to the tissues. So, the drug is trapped in the plasma. 2) Extracellular fluid If the drug has low molecular weight but hydrophilic, it will distribute to the interstitial fluid and plasma. 3) Total body water If the drug has low molecular weight and lipophilic, it can cross the cellular membrane and distribute intracellular fluid. Also, it can distribute to the interstitium through slit junctions. Both compartments constitute 60% of total body weight. Special case: Pregnancy!! The fetus may take up drugs and increases the volume of drug distribution, especially when the drug is highly lipophilic. Binding of the drugs to the plasma proteins ➢Drugs molecules may bind to plasma protein (usually albumin). ➢Since albumin is alkalotic, acidic and neutral drugs will primarily bind to albumin. ➢Basic drugs will bind to the acidic alpha-1 acid glycoprotein. ➢Bound drugs are pharmacologically inactive. Only free unbound drug is: a) Active b) Can enter the cell and act on the targets c) Available for elimination ➢If two drugs bind to plasma protein are administrated at same time, competition at the binding site may occur and may displace the bound drug. Result: increasing of free drug concentration >> increasing the pharmacological and toxic effects and may increase the elimination ➢Binding of drugs to plasma protein decreases the Vd! Why? Pharmacokinetics “Examines the movement of the drug through the body” The four major processes are: Absorption Distribution Metabolism ADME Excretion Drug Metabolism ➢Drugs may be eliminated without metabolism (e.g. aminoglycosides) or metabolized then eliminated. ➢The liver is the major site for drug metabolism. ➢ Drug metabolism can occur in other tissues, such as the kidney (insulin) and the intestines (catecholamines). ➢The metabolism is needed to convert the lipophilic drugs to more polar (which can be eliminated outside the body) and may be less or in-active, terminating their therapeutic effects. ➢Drug metabolism may also activate the drug (e.g. pivamplicillin to ampicillin) ➢The drug which is inactive and is converted to active form in the body is called prodrug. Kinetics of Drug Metabolism ➢Drug metabolism is mediated by enzymes which: 1) Follow Michaelis-Menten equation. 2) Are saturable. 3) The rate of drug metabolism is linear when drug concentration is below the Km value. 4) The rate of drug metabolism is non-linear when drug concentration is above the Km and near the Vmax value. Km is a constant refers to the affinity of the enzyme to metabolize the drug. Km is the concentration of the drug at half of the maximum metabolism rate (Vmax). Kinetics of Drug Metabolism First-order kinetics (or linear kinetics): ✓The metabolism of most drugs follow first order kinetics. ✓The concentration of drug is below its Km value. ✓The rate of drug metabolism is directly proportional to the concentration of the drug. ✓Constant fraction of drug is metabolized per unit of time. Zero-order kinetics ( or non-linear kinetics): ✓The concentration of drug is above its Km value. ✓The rate of drug metabolism doesn’t depend on the drug’s concentration. ✓A constant amount of drug is metabolized per unit time. ✓Only some drugs follow zero-order kinetics, such as Aspirin, ethanol and phenytoin. Kinetics of Drug Metabolism (first order) linear Km Vmax Metabolism rate (µM /min/mg) Saturation (zero order) nonlinear Drug concentration (µM) Drug Metabolism Reactions of metabolism ➢Lipid-soluble agents are metabolized in the liver via two general sets of reactions, called Phase I and Phase II. ➢Phase I Phase I reactions function to convert lipophilic molecules into more polar molecules by introducing or unmasking a polar functional group, such as OH or NH2. ❑ Phase I reactions usually involve reduction, oxidation, or hydrolysis. Drug Metabolism CYP450s ➢The Phase I reactions most frequently involved in drug metabolism are catalyzed by the cytochrome P450 (CYP450) system. ➢CYP450s oxidize many endogenous and exogenous compounds. ➢CYP450 enzymes exhibit considerable genetic variability among individuals and racial groups. Relative contribution of cytochrome P450 (CYP) isoforms to drug biotransformation. Drug Metabolism (CYP450s) CYP450 Inducers ➢ The expression of CYP450 enzymes can be induced; increasing in the amount of enzyme. (example: Phenytion, Rifampicin, Smoking) ➢ Induction of CYP450 enzymes increases drug metabolism and this consequently decreases its concentration and activity (if the metabolite is inactive). CYP450 Inhibitors ➢ Some drugs, food and chemicals inhibit CYP450 enzyme activity and consequently drug metabolism. ➢ Inhibition of CYP450 activity results in decreased drug metabolism and hence increasing drug plasma concentration, activity and toxicity. ➢ Example: Clarithromycin and grapefruit inhibit CYP3A4.( substrate : statins, Paracetamol, diazepam, cyclosporin) Drug Metabolism Phase II: ➢This phase consists of conjugation reactions ➢ A subsequent conjugation reaction with polar endogenous substrate, such as glucuronic acid, sulfuric acid, acetic acid, or an amino acid. ➢ Increasing of drugs polarity to be excreted by the kidneys. ➢ Phase II drug metabolism usually inactivate the drug. However, in few limited cases, phase II drug metabolism such as morphine. Pharmacokinetics “Examines the movement of the drug through the body” The four major processes are: Absorption Distribution Metabolism ADME Excretion Drug Excretion ➢- Removal of the drug from the body occurs via a number of routes, the most important being through the KIDNEY into the urine. ➢- Other routes include the bile, intestine, lung, or milk in nursing mothers. Drug Excretion Renal elimination of a drug Excretion of drugs in the urine involves three processes: 1) Glomerular filtration 2) Proximal tubular secretion 3) Distal tubular reabsorption 1) Glomerular filtration: - Drugs enter the kidney through renal arteries. - The functional unit of the kidney is the nephron (components of the nephron include Bowman's capsule, Proximal Tubule, Loop of Henle, Distal Tubule and the Collecting Duct). ➢Factors effect glomular filtration: 1. Low molecular weight drugs are filtered in Bowman's capsule (glomerular filtrate). 2. Free drug (not bound to albumin) flows into Bowman's space as part of the glomerular filtrate. 3. Lipid solubility and pH don’t influence the passage of drugs into the glomerular filtrate. 4. Pressure : filtration from higher ( capillary ) to lower pressure 2) Proximal tubular secretion: ➢Drugs that were not transferred into the glomerular filtrate leave the glomeruli through efferent arterioles, which divide to form a capillary plexus surrounding the nephric lumen in the proximal tubule. ➢Secretion primarily occurs in the proximal tubules by two energyrequiring active transport (carrier-requiring) systems: 1. Anion transport mechanism: anions (for example, deprotonated forms of weak acids) and 2. Cations transport mechanism (for example, protonated forms of weak bases). Examples: Penicillin (weak acid), some NSAIDS, some Diuretics ✓Each of these transport systems shows low specificity and can transport many compounds ✓Competition between drugs for these carriers can occur within each transport system (for example, probenecid for hyperuricemia compete with penicillin). ✓These transporters are saturable and can be inhibited ✓Premature infants and neonates have an incompletely developed tubular secretory mechanism and, thus, may retain certain drugs in the body 3) Distal tubular reabsorption: - As a drug moves toward the distal convoluted tubule, its concentration increases. - The drug, if uncharged and still lipid-soluble, may diffuse (by passive or facilitated diffusion) out of the nephric lumen, back into the systemic circulation. ➢Factors this reabsorption: 1. Ionization (unionized easier reabsorbed) 2. PH ✓ Metabolized drugs by phase I and II metabolism reactions are polar and charged which cannot back-diffuse out of the kidney lumen. ✓ Manipulating the pH of the urine to increase the ionized form of the drug in the kidney lumen may minimize the amount of back-diffusion and drug reabsorption. 3) Distal tubular reabsorption: • As a general rule, weak acids can be eliminated by alkalinization of the urine, whereas elimination of weak bases may be increased by acidification of the urine. This process is called ion trapping. ✓For example, a patient presenting with phenobarbital /Aspirin (weak acid) overdose can be given bicarbonate, which alkalinizes the urine and keeps the drug ionized, thereby decreasing its reabsorption. ✓If overdose is with a weak base, such as cocaine, acidification of the urine with NH4Cl leads to protonation of the drug and an increase in its clearance. Drug Clearance ➢Clearance of the drug from the plasma is expressed as the volume of plasma from which all drug appears to be removed in a given time (mL/min). ➢The total body clearance of the drug is equal to: CL total = CL hepatic + CL renal + CL pulmonary + CL other Half-Life Half-life (t1/2) is the time required to change the amount of drug in the body by one-half during elimination. Half-life is useful because it indicates the time required to attain 50% of steady state—or to decay 50% from steady-state conditions—after a change in the rate of drug administration. Elimination half life (t1/2): the time taken for plasma concentration to reduce by 50%. After 5 half lives, elimination is 97% complete( nearly 100%). Q-What is the difference between (PK) half-life and (PD) half-life of the same drug? • Pharmacokinetic half life (PK t 1/2 ): time to have 50% decrease in the level of the drug in plasma • Pharmacodynamic half life (PD t 1/2 ): time to 50% decrease in the effect of the drug • Drug with Vd high , so most of drug distributed into the tissue, in cells not in plasma ,( because of irreversible binding, enzyme binding ) give effect more, so PD t 1/2 >>>PK t1/2 . Half-Life ✓Patient take the drug and stopped take the drug ✓After 5 half lives, elimination is 97% complete( nearly 100%). ✓Time need to get all the drug out of the body= t1/2 X 5 ✓Example: plasma half life : 1hr, 10hr, 5hr, what time needed to get all drug out of body???? 100% 50% 25% 12.5% 6.25% 3.125% Half-Life ✓Patient started drug and continue ✓ Until reach steady state, constant as doses are taken in same regimen ✓ Give max. effect of drug and needed effect ✓ Drug eliminated ( get out) = drug enter (taken by the patient) ✓ Two processes are working on the drug at the same time ✓ Time needed to reach steady state (SS) is 5 half time ✓ Following repeated administration of a drug, a steady-state is reached when the quantity of drug eliminated in the unit of time equals the quantity of the drug that reaches the systemic circulation in the same unit of time. Q- What is the difference between half-lives of zero-order and first-order kinetics? First order elimination pharmacokinetic Zero order Elimination pharmacokinetic Constant fraction % of drug eliminated per unit time Constant amount of drug eliminated per unit time Rate of elimination is proportional to drug concentration (increase drug conc. will increase rate of elimination) Rate of elimination is independent on drug concentration Half life remains constant Half life is not constant Most of drugs follow first order kinetic Less drugs follow zero order kinetics ✓Most 1st order pharmacokinetic ✓<<5% zero order pharmacokinetic Effect of Vd on drug half-life and elimination ➢ Drug elimination depends on the amount of drug delivered to the liver or kidney. ➢If a drug has a large Vd, most of the drug is in the extraplasmic space and is unavailable to the excretory organs (liver, kidney,..). Less elimination ➢Therefore, any factor that increases Vd can increase the half-life (decreasing the elimination rate) and extend the duration of action of the drug. ➢Disease states can affect both physiologically related primary pharmacokinetic parameters: volume of distribution and clearance. Pharmacodynamic The actions of the drug on the body are termed pharmacodynamic (PD) processes. How does the drug act? I- Action on cell membrane: a. Action on specific receptors e.g. adrenaline on adrenoceptors. b. Interference with some ion channels e.g. calcium channel blockers. c. Inhibition of membrane bound enzymes and pumps e.g. membrane bound ATPase by cardiac glycosides. II. Action on metabolic process within the cell: a. Enzyme Inhibition e.g. monoamine oxidase by phenelzine. b. Inhibition of transport processes that carry substances across cells e.g. blockade of anion transport in the renal tubule cells by probenecid. c. Incorporation into larger molecules e.g. fluorouracil incorporation in mRNA in place of uracil. d. In the case of antimicrobial agents by altering process unique to micro organisms, e.g. inhibition of bacterial cell wall by penicillin. III.Action outside the cell: a. Direct chemical interaction e.g. antacids b. Osmosis e.g. magnesium sulfate as laxative, mannitol as diuretic. Drug-Receptor Interactions and Pharmacodynamics: Some Rules (1) Affinity is a measure of the strength of attraction between a receptor and its ligand. ▪ This depends on how much the ligand fit the binding sites and the strength of binding. ▪ The receptor's affinity for binding a drug determines the concentration of drug required to form a significant number of drug-receptor complexes (the higher the affinity is the higher ability to bind more receptors that gives higher action). (2) The molecular size, shape, and electrical charge of a drug determine how much the drug fits in the binding site of the receptor and the strength of the bond between the drug and the receptor. ▪ Changes in the chemical structure of a drug can dramatically increase or decrease a new drug's affinities for different classes of receptors, with resulting alterations in therapeutic and toxic effects. Drug-receptor binding (Affinity) ▪ The affinity of drugs binding to the receptor is measured by Kd (dissociation constant), (i.e., the value of Kd can be used to determine the affinity of a drug for its receptor) ▪ Affinity describes the strength of the interaction (binding) between ligand and receptor. The higher the Kd value, the weaker the interaction and the lower the affinity, and vice versa. (3) Drugs that bind and stimulate the receptor to produce a signal is called agonist. Some drugs and all hormones and neurotransmitters, regulate the function of receptor macromolecules as agonists. D + R <----------> ( DR ) <------------> ( DR ) * -------> biological effect or response (4) Other drugs function as pharmacologic antagonists; i.e., they bind to receptors but do not activate generation of a signal; consequently, they interfere with the ability of an agonist to activate the receptor. Thus, Its effect on a cell or in a patient depends entirely on it preventing the binding of agonist molecules and blocking their biologic actions. ▪ The magnitude of drug response is proportional to the number of drug-receptor complexes. ▪ Drug-receptor binding alters the biological response without creating effects de novo. Chemistry of receptors and ligands ➢Interaction of drug with receptor involves formation of chemical bonds, most commonly electrostatic and hydrogen bonds as well as weak interactions involving van der Waals forces). ➢These bonds are important in determination of the selectivity of the drug’s binding to the receptor (key-lock model), because the strength of these noncovalent bonds is related inversely to the distance between the interacting atoms. ➢Therefore, the successful binding of a drug requires an exact fit of the ligand atoms with the complementary receptor atoms. ➢The bonds are usually reversible, except for a handful of drugs (for example, the nonselective alpha-receptor blocker Phenoxybenzamine, and acetyl cholinesterase inhibitors in the organophosphate class) that covalently bond to their targets (irreversible and strong and longer duration of time). Major Receptor Families ➢ Pharmacology defines a receptor as any biologic molecule to which a drug binds and produces a measurable response. Thus, enzymes and structural proteins can be considered to be pharmacologic receptors. However, the richest sources of therapeutically exploitable pharmacologic receptors are proteins that are responsible for transducing extracellular signals into intracellular responses. ➢ These receptors may be divided into four families: 1) ligand-gated ion channels, 2) G protein coupled receptors, 3) enzyme-linked receptors, and 4) intracellular receptors. The type of receptor a ligand will interact with depends on the nature of the ligand. Hydrophilic ligands interact with receptors that are found on the cell surface (families 1, 2, and 3). In contrast, hydrophobic ligands can enter cells through the lipid bilayers of the cell membrane to interact with receptors found inside cells (family 4). ➢ ➢ ➢ ➢ ➢ ➢ 1. Transmembrane ligand-gated ion channels ➢Responsible for regulation of the flow of ions across cell membrane. ➢The response of these channels to the ligands (drugs) is very rapid (milliseconds). ➢Examples: Nicotinic and gamma-aminobutyric acid (GABA) receptors. ➢Nicotinic receptors regulates sodium influx (Excitation) (depolarization) ➢GABA receptors regulate chloride influx (Inhibition) (hyperpolarization). 2. Transmembrane G protein–coupled receptors ➢ G protein-coupled receptor consists of: 1. Single peptide that has seven membrane-spanning regions 2. G protein ➢ G protein has 3 subunits : α (binds to guanosine triphosphate GTP), β and γ subunits. ➢ Binding of the ligand to the receptor activates the receptor. Then, GTP replaces GDP on the α subunit>> causing dissociation of the α-GTP complex from the βγ complex. ➢ The two dissociated complexes then interact with other cellular effectors, usually an enzyme and ion channel causing changing of the concentration of the second messengers. Example : β adrenergic receptors — Slower in action than ligand-gated ion channels. Second messengers ➢Are essential in conducting and amplification signals coming from G-protein coupled receptor. ➢Further activate other effectors in the cell. ➢Type of second messengers inside the cell. 1) The α-GTP activates adenylyl cyclase. Activated adenylyl cyclase produces the second messenger cyclic adenosine monophosphate (cAMP). 2) G protein activates phospholipase C which is responsible for the generation of 2 other second messengers: inositol 1,4,5-triphosphate (IP3) and diacylglycerol (DG). 3) G protein receptor can activate guanylyl cyclase, which converts GTP to cGMP, a second messenger. 3. Enzyme-linked receptors ➢Having cytosolic enzyme activity as an integral component of their structure or function. ➢Binding of ligand to the extracellualr domain of the receptor activates or inhibits this cytosolic enzyme activity. ➢Duration of responses to stimulation of these receptors is of minutes to hours. ➢ This cascade of activations results in multiplication of the initial signal. ➢Examples: Epidermal growth factor, atrial natriuretic peptide and insulin. 4. Intracellular receptors ➢Differs from the previous receptors in that the receptor is entirely intracellular. ➢The ligand must diffuse into the cell to Ligand should be hydrophobic (sufficient lipid solubility) to diffuse into the cell and interact with the receptor. ➢Binding of the ligand to the receptor causes activation; because of dissociation of small repressor peptide. ➢The activated ligand–receptor complex binds to specific DNA sequences and regulates gene expression (DNA>RNA>Protein). ➢Duration of response is long (hours to days). ➢Example: steroid hormones. Some characteristics of receptors (1) Amplification of signals ▪ Receptors amplify the duration and intensity of the signals. ▪ For example: Activated G protein persists longer duration of time than the original ligand-receptor complex. Binding of the ligand to the receptor lasts for few milliseconds but subsequent activated G protein persists for hundreds of milliseconds. ▪ Increasing the intensity by interaction of the ligand-receptor complexes with many Gproteins and each G-protein activates many enzyme molecules and each enzyme molecule catalyzes the synthesis of many second messenger molecules. ▪ We can find this phenomenon mainly in (enzyme-linked receptor.....followed by Gprotein............the least in ion channel) (2) Desensitization of receptors and tolerance ▪ ▪ Repeated or continuous administration of an agonist (or an antagonist) may lead to changes in the responsiveness of the receptor, to prevent potential damage to the cell. When repeated or continuous administration of an agonist results in a diminished effect, the phenomenon is called tolerance. If it happens rapidly the it is called tachyphylaxis (=rapid tolerance). (3) Up- and down-regulation of the receptors A. B. C. The receptors are down regulated >> decreased total number of available receptors when subjected to an agonist and this may lead to tolerance. The receptors are up-regulated when subjected to an antagonist and this may exaggerate activity to an agonist Desensitization and down-regulation are among the causes of tolerance Dose-Response Relationships ➢ ➢ ➢ 1. 2. ➢ A. B. An agonist is defined as an agent that can bind to a receptor (affinity) and elicit a biologic response (efficacy or intrinsic activity). Antagonist has affinity only. The magnitude of the drug effect depends on the drug concentration at the receptor site, which in turn is determined by: the dose of drug administered by factors characteristic of the drug pharmacokinetic processes. Types of Dose-response relations Graded dose-response relations Quantal dose-response relations Dose-Response Relationships A. ▪ ▪ Graded dose-response relations: The relationship between dose and response is continuous. The response is a graded effect, meaning that the response is continuous and gradual. ▪ This contrasts with a quantal response, which describes an all-or-nothing response (discussed later). ➢ Two important properties of drugs can be determined by graded dose–response curves: Potency Efficacy 1. 2. Rectangular hyperbola Dose-Response Relationships (1) Potency ➢ Is a measure of the amount of drug necessary to produce an effect of a given magnitude. ➢ The concentration of drug producing 50% of the maximum effect (EC50) is usually used to determine potency. ➢ The lower the EC50, the higher the potency Sigmoid (S) shaped Dose-Response Relationships (2) Efficacy (intrinsic activity) ➢ Efficacy is the ability and magnitude of a drug to elicit a physiologic response when it interacts with a receptor. ➢ It is dependent on the number of drug–receptor complexes formed and on the efficiency of coupling of receptor activation to cellular response. ➢ The magnitude of the response is proportional to the amount of receptors bound or occupied. ➢ Maximal response or effect of the drug (Emax) describes its efficacy. ➢ The Emax occurs when all receptors are bound. ➢ Drug efficacy is more important than potency. The drug with greater efficacy is more therapeutically beneficial than one that is more potent. • Drugs A and B are said to be more potent than drugs C and D • Pharmacologic potency of drug A is less than that of drug B, • Drug A has a larger maximal efficacy Emax than B • Drugs A, C, and D in have equal maximal efficacy (Emax) • Potency of a drug B >A>C>D Receptor ligands: 1. Agonists 2. Antagonists 3. Partial agonists Partial agonists have intrinsic activities which are greater than zero but less than that of full agonist. ▪ ▪ ▪ Even if all the receptors are occupied, partial agonists cannot produce the same Emax as that of a full agonist. Interestingly, a partial agonist may have an affinity that is greater than, less than, or equivalent to that of a full agonist. A unique feature of the partial agonist is that may act as a blocker of the full agonist !!!! As the number of receptors occupied by the partial agonist increases, the Emax would decrease until it reached the Emax of the partial agonist . 4. Inverse agonists ➢ They are substances that can bind and stimulate receptors but, in a manner, to give effects opposite to the effects of the same receptor's agonist (pimavanserin, serotonin receptor inverse agonist). ➢ Produce a response below the base-line response measured in the absence of drug. Types of drug antagonism (drug decrease the action of another drug or endogenous ligand) 1. Pharmacological antagonism: — An antagonist (or partial agonist) decreases the action of an agonist. — Depending on the mechanism, antagonists can be classified into: A. Competitive drug antagonist binds to the receptor and prevents the binding of the agonist. It is reversible antagonism. Examples: adrenaline : propranolol /acetylcholine : atropine B. Non-competitive antagonists 1. “allosteric, so called negative allosteric modulator” binds to another site than where the agonist binds, thereby decreasing its activity. 2. It may also bind irreversibly to the same binding site of its agonist ligand. Example: adrenaline : phenoxybenzamine Competitive antagonist decreases the potency of the agonist without decreasing efficacy (Emax). while non-competitive antagonist decreases the efficacy of the agonist. Irreversible Antagonist (non- competitive) Competitive Antagonist Emax decrease Emax the same EC50 the same Shift potency to the right (EC50 increase) Curves not parallel Curves parallel 2. Functional (physiological) antagonism: ▪ It acts at separate receptor, initiating effects that are functionally opposite those of the agonist. Example: histamine induces bronchoconstriction through acting on histamine receptor on the lung while epinephrine induces bronchodilation by acting on the beta receptor of the lung itself. ▪ The 2 involved drugs may be both agonists, both antagonists or one agonist and the another one is antagonist 3. Chemical antagonism: It binds with another drug and renders it inactive. Example: heparin : protamine Quantal Dose-Response Relationships ➢ It involves the relationship between the dose of the drug and the proportion of a population that responds to it. ➢ Quantal responses means for does not. any individual the drugs effect either occurs or it ➢ Graded responses can be transformed to quantal responses by designating a predetermined level of the graded response as the point at which a response occurs or not. ➢ Quantal dose–response curves of the population responds. ➢ Quantal dose–response curves are useful for determining doses to which most are useful for determining: 1. Doses to which most of the population responds. 2. The therapeutic index (TI) of a drug Therapeutic index ➢ The therapeutic index (TI) of a drug is the ratio of: the dose that produces toxicity in half the population (TD50) to the dose that produces a clinically desired or effective response in half the population (ED50): TI = TD50 /ED50 ➢ The ➢ TI is a measure of a drug’s safety: Larger TI value indicates a wide margin between doses that are effective and toxic (the higher TI value is more safer) ➢ The therapeutic index is determined by measuring the frequency of desired response, and toxic response, at various doses of drug. ➢By convention, the doses that produce the therapeutic effect and the toxic effect in fifty percent of the population are employed; these are known as the ED50 and TD50, respectively. Optimisation of dose ➢The goal of drug therapy is to achieve and maintain concentrations within a therapeutic response window while minimizing toxicity and/or side effects. ➢Drug regimens are administered as a maintenance dose and may require a loading dose if rapid effects are warranted. ➢For drugs with a defined therapeutic range, drug concentrations are subsequently measured, and the dosage and frequency are then adjusted to obtain the desired levels. ➢Sometimes rapid obtainment of desired plasma levels is needed (for example, in serious infections or arrhythmias). Therefore, a “loading dose” of drug is administered to achieve the desired plasma level rapidly, followed by a maintenance dose to maintain the steady state. ➢A loading dose is most useful for drugs that have a relatively long half-life. ➢Disadvantages of loading doses include increased risk of drug toxicity and a longer time for the plasma concentration to fall if excess levels occur. Adverse drug reaction (ADRs) Adverse drug reactions (ADRs) are unwanted drug effects that have considerable economic as well as clinical costs as they often lead to hospital admission, prolongation of hospital stay and emergency department visits The chance of having an adverse reaction can be described as: 1. Very common – this means that 1 in every 10 people taking the medicine are likely to have the adverse reaction 2. Common – this means that between 1 in 10 and 1 in 100 people may be affected 3. Uncommon – this means that between 1 in 100 and 1 in 1,000 people may be affected 4. Rare – means that between 1 in 1,000 and 1 in 10,000 people may be affected 5. Very rare – means that fewer than 1 in 10,000 people may be affected. ➢ The traditional pharmacological classification of ADRs includes: Type A: Augmented pharmacologic effects - dose dependent and predictable Type B: Bizarre effects (or idiosyncratic) - dose independent and unpredictable Type C: Chronic effects (chlorpromazine> tardive dyskinesia) Type D: Delayed effects (diethylstilbosterol>clear cell adenocarcinoma Type E: End-of-treatment effects (prednisolone>addison crisis) Type F: Failure of therapy Type G: Genetic reactions (sulfonamides >hemolytic anemia in G6PD deficiency.