Pharmacology Introduction - Level 2 PDF

Pharmacology introduction - level 2 Dr/ Butheina Al-Amrani General pharmacology Mid exam 30 marks Practical exam 20 marks Final exam 50 marks Total 100 marks Lectures 1. Pharmacokinetics and pharmacodynamics 2. Autonomi...

Pharmacology introduction - level 2 Dr/ Butheina Al-Amrani General pharmacology Mid exam 30 marks Practical exam 20 marks Final exam 50 marks Total 100 marks Lectures 1. Pharmacokinetics and pharmacodynamics 2. Autonomic nervous system 3. Antibacterial and antifungal drugs 4. Autocoids Reference  2 [TYPE THE DOCUMENT TITLE] Pharmacology: The study of the effects of drugs on the function of living organisms. Drug : It is an active chemical that is used for diagnosis, prevention, treatment of a disease. Drug nomenclature A drug generally has three categories of names: (a) Chemical name It describes the substance chemically, e.g: N-(4-hydroxyphenyl)ethanamide. (b) Non-proprietary name It is the name accepted by scientific authority : acetaminophene (c) Proprietary (Brand) name It is the name assigned by the manufacturer: Paracetamol, Panadol, Amol, Adol and Paramol Pharmacology Pharmacodynamics Pharmacokinetics What the drug does to the body What the body does to the drug ADME: Mechanism of action Pharmacological action Absorption Adverse effect Distribution metabolism excretion 2 Pharmacology introduction - level 2 Dr/ Butheina Al-Amrani Pharmacokinetics I. Absorption: the uptake of drug through biological membranes Mechanisms of absorption of drugs from the Gastrointestinal tract: 1. Passive diffusion: passive (no force needed) absorption of a drug with the concentration gradient 2. Facilitated diffusion: Drugs enter the cell through specialized transmembrane carrier proteins, moving with concentration gradient 3. Active transport: drug entry by Energy-dependent active transport and moving drugs against a concentration gradient  4 [TYPE THE DOCUMENT TITLE] 4. Endocytosis and exocytosis : Endocytosis involves engulfment of a drug by the cell membrane and transport into the cell. Exocytosis is the reverse of endocytosis Factors Affecting Absorption Are: 1. Area of absorbing surface 2. Vascularity of the absorbing surface 3. pH 4. contact time absorption surface 5. Expression of P-glycoprotein Influence of pH Most drugs are weak acids or weak bases, i.e. their ionization is pH dependent (contrast strong electrolytes that are nearly completely ionized at acidic as well as alkaline pH). Unionizes drugs are absorbed while ionized drugs are not absorbed BIOAVAILABILITY: is the total proportion of the drug that reaches the systemic circulation from the site of administration Bioavailability of drug injected I.V. (intravenous ) is 100% Bioavailability = plasma concentration X 100 Total drug concentration 4 Pharmacology introduction - level 2 Dr/ Butheina Al-Amrani Example 1 100 mg of drug X is given orally, 70mg was absorbed to the systemic circulation What is the bioavailability of this drug ? Example 2 10 mg of drug Y is given I.V. What is the bioavailability of this drug ? What is the amount of the drug in blood ? Factors that influence bioavailability 1. First-pass metabolism 2. Solubility 3. Drug form 4. Chemical stability Bioequivalence Two drug formulations are bioequivalent if they show comparable bioavailability and similar times to achieve peak blood concentrations. Therapeutic equivalence Two drug formulations are therapeutically equivalent if they are pharmaceutically equivalent with similar clinical and safety profiles. II. DISTRIBUTION: Factors that influence DISTRIBUTION 1. Total body water 2. Binding to plasma and tissue proteins 3. Blood flow 4. Capillaries permeability  6 [TYPE THE DOCUMENT TITLE] Volume Of Distribution volume of distribution (Vd) : is the apparent volume in which drug is distrusted in all body tissue assuming the drug is uniformly distributed and the body behaves as a single homogeneous compartment. Vd = dose administered I.V.\ plasma concentration. Drugs that have a volume of distribution 42, the drug is thought to be distributed in tissues more than extracellular compartment 6 Pharmacology introduction - level 2 Dr/ Butheina Al-Amrani Example 1. If 10 mg of drug is injected into a patient and the plasma concentration is C = 1 mg/L what is the Vd? 2. A 40-year-old male patient (70 kg) was recently diagnosed with infection involving methicillin-resistant S. aureus. He received 2000 mg of vancomycin as an IV loading dose. The peak plasma concentration of vancomycin was reported to be 28.5 mg/L. what is The apparent volume of distribution ? 3. 10 mg of drug X is given to a patient. After eqlibrium the plasma concentration was 1mg/ml. What is the volume of distribution of this drug Redistribution: Highly lipid-soluble drugs get initially distributed to organs with high blood flow, i.e. brain, then its redistributed to other organs blood-brain barrier : The capillary endothelial cells in brain have tight junctions and lack large intercellular pores called blood-brain barrier. Only lipid-soluble drugs are able to penetrate the central nervous system. Passage across placenta: Cross of drugs from the mother to the fetus through placenta III. BIOTRANSFORMATION (Metabolism) : Biotransformation means chemical alteration of the drug in the body (i) Inactive → active (ii) Active → another active drug (iii) Activate → inactive drug Biotransformation reactions can be classified into: 1) Nonsynthetic/Phase I/Functionalization reactions a) Oxidation b) Reduction c) Hydrolysis (2) Synthetic/Conjugation/ Phase II reactions a) Glucuronide conjugation b) Acetylation c) Methylation d) Sulfate conjugation e) Glycine conjugation f) Glutathione conjugation  8 [TYPE THE DOCUMENT TITLE] Microsomal enzymes: These are located on smooth endoplasmic reticulum in liver, also in kidney, intestinal mucosa and lungs. They metabolize almost all drugs For example of microsomal enzyme : cytochrome P 450 Microsomal enzyme inhibition cause :- 1. Increase effect of drugs that are inactivated by metabolism 2. Decrease effect of the drugs that are activated by metabolism. Microsomal enzyme induction cause:- 1. Decreased effect of drugs that are inactivated by metabolism 2. Increased effect of drugs that are activated by metabolism. 3. Tolerance 4. Intermittent use of an inducer may interfere with adjustment of dose of another drug prescribed on regular basis, e.g. oral anticoagulants, oral hypoglycaemics, antiepileptics, antihypertensives. First Pass Metabolism All orally administered drugs are exposed to drug metabolizing enzymes in the liver (where they first reach through the portal vein). IV. Elimination removal of the drug from systemic circulation through any route Urine Feaces Hepatic metabolism Renal elimination Clearance (CL): estimates the amount of drug cleared from the body per unit of time. It depends on glomerular filtration rate (GFR) CL= 0.693 x Vd/ t1/2 Site of drug renal elimination Glomerular filtration : depend on Glomerular filtration rate (GFR) may diminish significantly in renal disease Proximal tube secretion Distal tube reabsobtion : some non-ionized non conjugated drug may return back to system circulation this may be decrease for acidic drug by alkalization of urine Total body clearance CL total = CLhepatic + CLrenal + CLpulmonary + CL other First order kinetics The rate of elimination is directly proportional to the drug concentration, CL remains constant 8 Pharmacology introduction - level 2 Dr/ Butheina Al-Amrani Zero order (linear) kinetics The rate of elimination remains constant irrespective of drug concentration, CL decreases with increase in concentration; or a constant amount of the drug is eliminated in unit time Plasma half-life: The Plasma half-life (t1\2) of a drug is the time taken for its plasma concentration to be reduced to half of its original value. Example The volume of distribution and clearance determined of the drug X are 40 L and 2.0 L/hour, respectively. what is the most likely half-life of the drug ? Therapeutic Window (index) The therapeutic window is the safe range between the minimum therapeutic concentration and the minimum toxic concentration of a drug. Drug indication: The basis for initiation of a treatment for a disease or of a diagnostic test Drug contraindication: Any special symptom or circumstance that delay the use of a remedy Over-the-counter (OTC) medication that can be purchased without a medical prescription Off-label use The use of pharmaceutical drugs for an unapproved indication or in an unapproved age group, dosage, or route of administration  10 [TYPE THE DOCUMENT TITLE] Drug dosage regimen 1. Continuous infusion regimens With continuous IV infusion, the rate of drug entry into the body is constant. Most drugs exhibit first-order elimination, Following initiation of a continuous IV infusion, the plasma concentration of a drug rises until a steady state (rate of drug elimination equals rate of drug administration) is reached, at which point the plasma concentration of the drug remains constant. The steady-state plasma concentration (Css) is directly proportional to the infusion rate. 2. Multiple IV injections\ oral When a drug is given repeatedly at regular intervals, the plasma concentration increases until a steady state is reached 10 Pharmacology introduction - level 2 Dr/ Butheina Al-Amrani Maintenance dose: Drugs are generally administered to maintain a Css within the therapeutic window. It takes four to five half-lives for a drug to achieve Css. The dosing rate can be determined by knowing the target concentration in plasma (Cp), clearance (CL) of the drug from the systemic circulation, and the fraction (F) absorbed (bioavailability) Dosing rate = (Target C plasma ) CL F Loading dose: the dose administered to achieve the desired plasma level rapidly followed by a maintenance dose to maintain the steady state Loading dose = Vd x Css F Pharmacodynamics Pharmacodynamics is the study of drug effects on the body (mechanism of action, pharmacological action and adverse effects) Drugs produce their effects by interacting with a discrete target biomolecule, which usually is a protein. RECEPTOR = It is defined as a macromolecule or binding site located on the surface or inside the cell that recognize the drug and initiate the response to it. Ligand Any molecule which attaches selectively to particular receptors or sites Effect of drug on receptor 1.Agonist An agent which activates a receptor to produce an effect a. partial agonist b. full agonist 2. Antagonist An agent that prevents the action of an agonist on a receptor, but does not have any effect of its own -Competitive antagonism (equilibrium type) The antagonist is chemically similar to the agonist, competes with it and binds to the same site to the exclusion of the agonist molecules. -non Competitive antagonism The antagonist competes with the drug on different binds site.  12 [TYPE THE DOCUMENT TITLE] 3. Combined Effect Of Drugs (SYNERGISM) When the action of one drug is facilitated or increased by the other. Synergism can be: a. Additive : drugs A + B = effect of drug A + effect of drug B b. Potentiation: effect of drug A + B > effect of drug A alone + effect of drug B alone Receptor groups: four major categories, a) ion channels : eg GABA receptor, Nicotinic receptor b) G protein : α and β receptor c) enzymes : insulin receptor d) Intracellular : steroid receptor Desensitization of receptors Repeated or continuous administration of an agonist may lead to decease in the responsiveness of the receptor Dose-Response Relationship The effect of the drug on a receptor depend on the concentration of the drug. As the concentration of the drug increase the response of the receptor increase. until all the receptors are occupied , the response reach maximum effect. The response effect will be plateau with increase of drug concentration 12 Pharmacology introduction - level 2 Dr/ Butheina Al-Amrani Potency: a measure of the amount of drug necessary to produce an effect of a given magnitude Efficacy: This is the ability of a drug to illicit physiologic response when it interacts with a receptor. Efficacy is measured by (Emax) Adverse Drug Effects 1. Side effects These are unwanted but often-unavoidable pharmacodynamics effects that occur at therapeutic doses. 2. Secondary effects/ secondary infection / superinfections Suppression of bacterial flora by drug cause growth of opportunistic pathogens for example: Corticosteroids activates latent tuberculosis Antibiotics cause diarrhea 3. Toxic effects Excessive pharmacological action of the drug due to overdosage or prolonged use. 4. Idiosyncrasy The drug interacts with some unique feature of the individual due to genetic mutation and produces the uncharacteristic reaction. 5. Drug allergy It is an immunologically mediated reaction 14 [TYPE THE DOCUMENT TITLE] 6. Drug dependence Drug dependence is a state in which use of drugs for personal satisfaction 7. Drug withdrawal reactions Sudden stop of the drug results in adverse effects. 8. Teratogenicity Drug cause fetus abnormalities when administered to the pregnant mother. 9. Carcinogenicity It refers to capacity of a drug to cause genetic defects and cancer respectively. 14