PHARMACOLOGY: PRELIMINARIES o Disadvantages: unsuitable for oily substances;
Romie Solacito, MLS3C bolus injection may result in adverse effects;
INTRODUCTION most substances must be slowly injected; strictly Pharmacology – the body of knowledge concerned aseptic techniques needed with action of chemical on biologic systems Subcutaneous – depends on drug diluents: aqueous Drugs – any substances that brings about a change in solution – prompt; depot preparations – slow and biologic function through its chemical actions sustained Pharmacy – the science of Identification, selection, o Advantages: suitable for slow-release drugs; preservation standardization, compounding, and ideal for some poorly soluble suspensions dispensing of medical substance. o Disadvantages: Pain or necrosis if drug is Pharmacodynamics – the study of the biological irritating; unsuitable for drugs administered therapeutic effects of drugs; what the drug does to large volumes the body Intramuscular – depends on drug diluents: Aqueous Pharmacokinetics – deals with the proper selection solution – prompt; depot preparation – slow and and use of drugs for the prevention and treatment of sustained disease o Advantages: Suitable if drug volume is Toxicology – it’s the science of poison; substance moderate; suitable for oily vehicles and certain that cause harmful, dangerous or fatal symptoms in irritating substances; preferable to intravenous if living substance. patient must self-administer Factors that influences proper dose of a drug: o Disadvantages: Affects certain lab tests (creatine o Age kinase); can be painful; can cause intramuscular o Pharmacogenetics haemorrhage (precluded during anticoagulation o Body Weight therapy) o Body Surface Area Transdermal/Patch – Slow and sustained o Sex o Advantages: Bypasses the first-pass effect; o Pathologic State convenient and painless; ideal for drugs that are o Tolerance lipophilic and have oral bioavailability; ideal for o Concomitant drug therapy drugs that are quickly eliminated from the body o Time and condition of administration o Disadvantages: Some patients are allergic to o Dosage form and route of administration patches, which can cause irritation; drug must be highly lipophilic; may cause delayed delivery of PHARMACOKINETICS drug to pharmacological site of action; limited to Route of Drug Administration drugs that can be taken in small daily doses Oral – Variable; affected by many factors Rectal – Erratic and variable o Advantages: safest and most common, o Advantages: partially bypasses first-pass effect; convenient, and economical route of bypasses destruction by stomach acid; ideal if administration drug cause vomiting; ideal in patients who are o Disadvantages: Limited absorption of some vomiting, or comatose drugs; food may affect absorption; patient o Disadvantages: Drugs may irritate the rectal compliance is necessary; drugs nay be mucosa; not a well-accepted route metabolized before systemic adsorption. Inhalation – Systemic absorption may occur; this is not always desirable Intravenous – absorption not required o Advantages: can have immediate effects; ideal if o Advantages: Absorption is rapid: can have dosed in large volumes; suitable for irritating immediate effects; ideal for gases; effective for substances and complex mixtures; valuable in patients with respiratory problems; dose can be emergency situations; dosage titration titrated; localized effect to target lungs: lower permissible; ideal for high molecular weight doses used compared to that with oral or proteins and peptide drugs. parenteral administration; fewer systemic side effects o Disadvantages: Most addictive route (drug can be enter the brain quickly); patient may have difficulty regulating dose; some patients may have difficulty using inhalers Sublingual – Depends on the drugs: Few drugs (i.e. nitroglycerin) have rapid, direct systemic adsorption; most drugs erratically or incompletely absorbed o Advantages: Bypasses first-pass effect; bypasses destruction by stomach acid; drug stability maintained because the pH of saliva relatively neutral; may cause immediate pharmacological effects e. Expression of P-glycoprotein o Disadvantages: Limited to certain types of drugs; f. Route of administration limited to drugs that can be taken in small doses; may lose part of the drug dose if swallowed
Transport Processes – mechanism of drug movement
across cell membrane
1. Passive Transport/Diffusion – most dominant;
movement of particles from higher concentration to lower concentration; non-energy requiring; factors affecting the processes: surface area, concentration, thickness, and diffusion coefficient (permeability) – g. Bioavailability – measure the rate and extent of particle size and liposolubility drug entry into the systemic circulation. Two 2. Carrier-Mediated Transport – Utilize carrier proteins methods of determining Bioavailability: features: selectivity, subject to Cumulative Urinary Excretion competition/inhibition and saturability. Types: Drug Plasma Concentration: uses time data, a. Facilitated Diffusion – along a concentrated and most commonly used gradient h. Factors that influence bioavailability: b. Active Transport – energy requiring First-pass hepatic metabolism c. Convective Transport – solvent-drag movement Solubility of drug 3. Endocytosis/Picocytosis/Exocytosis – Cell drinking, Chemical instability vesicle mediated, not requiring to be in aqueous Nature of the drug formulation solution, energy requiring, and ADEK 2. Distribution – the process of drug movement from Drug Pathway the systemic circulation to the different body compartments and into the site of Action 1. Absorption – rate and extent of drug entry into the a. Affected by two physiologic parameters systemic circulation. Factors influencing absorption Cardiac output – volume pumped by the heart a. Effects of pH on drug absorption per minute b. Blood flow to the absorption site Regional blood flow – fraction of cardinal c. Total surface area available for absorption output d. Contact time at the absorption surface b. Two distribution parameters: High Gastric Emptying Time, Low Gastric Protein binding – binding of drugs to plasma Emptying Rate = Low Rate of Absorption proteins and tissues Binding to plasma proteins Binding to tissues proteins Volume of distribution – hypothetical volume of the body fluid necessary to dissolve a given dose of drug or amount of drug to a Hepato-biliary Excretion concentration equal to the plasma Pulmonary Excretion (Application: estimated loading dose) 3. Metabolism – Sites: Liver (major), intestine, blood Dose-Time Relationship plasma (esterases), and kidneys (dihydropeptidases) Half Life – the time taken for the concentration of a. Exceptions: drug in the blood or plasma to decline to half of Prodrug – inactive drug introduce to the body original value or the amount of drug in the body to to make active. be reduced by 50%. Allopurinol – Alloxanthine Loading Dose – one or series of doses that may be Enalapril – Enalaprilat given at the onset of therapy with the aim of Chloramphenicol palmitate – achieving the target concentration rapidly. Chloramphenicol Maintenance Dose – the rate of drug administration Active metabolites is adjusted such that the rate of input equals to rate Benzodiazepine Diazepam – Oxazepam loss Toxic Metabolites Paracetamol – NAPQI (Hepatotoxicity)/N- PHARMADYNAMICS acetyl-p-benzoquinone Imine General Mechanism of Drug Action b. Objective: to make the drug polar, inactive, Receptor (i.e. antagonist, agonist) excretable form Physical (i.e. sunblock) c. First Pass Metabolism – initial metabolism that Chemical (i.e. hyperacidity) happens before the drug reaches the systemic Physiological (i.e. antibiotic, dimercaprol) circulation d. Enzyme Inducers – stimulate expression of Receptor - Like a dynamite metabolizing enzymes If drug is prodrug? efficacy and toxicity Single Transduction: o The drug – receptor complex If the parent drug is active with inactive o Receptor State metabolite? Efficacy o Major Receptor Families If with toxic metabolite? Toxicity A. Ligand – Gated Ion Channels (i.e cholinergic nicotinic e. Enzyme Inhibitors – Reduce expression of receptor) metabolizing enzymes B. G Protein – Coupled Receptors (i.e. Beta f. Genetic Polymorphism – genetic differences in adenoreceptors) expression of enzymes C. Enzyme – Linked Receptors (i.e. Insulin Receptors) g. Categories for enzyme expression: D. Intracellular Receptors (i.e. Steroid Receptors) Extensive Metabolizers – produce normal/adequate amount of enzymes Dose Response Relationship Ultra-Rapid Metabolizers – produce more than Graded dose – response relations the normal amount of enzymes o Potency – measure of the amount of drug Poor Metabolizers – Produces less than the necessary to produce an effect of a given normal amount of enzymes magnitude. 4. Elimination (Output) – Final loss of drug from the o Efficacy – the magnitude of response of a drug body; elimination = metabolism + excretion. causes when it interacts with a receptor; a. Minor: dependent on the number of drug-receptor Gastrointestinal Excretion complexes formed and the intrinsic activity of Skin – through sweat the drug. Mammary Excretion o Intrinsic Activity - its ability to activate the b. Major: receptor and cause a cellular response Renal excretion – renal excretion processes Filtration Tubular Secretion o NOTE: Efficacy is a more clinically useful Enzyme induction – during metabolism is characteristic that the drug potency, since a drug accelerated and is cause of therapeutic with greater efficacy is more therapeutically b. failure. (i.e. of enzyme inducers: Effect of Drug Concentration on Receptor Binding phenobarbital, phenytoin, carbamazepine, rifampicin, and St. John’s Wort) Drug + Receptor = Drug Receptor Complex – Biologic Enzyme Inhibition – by this biotrans of drugs effect is delayed and is cause of increased The Relationship of Drug Binding to Pharmacology intensity, and sometimes toxicity. (i.e. Effect cimetidine, Flucazole, Erythromycin, Ketoconazole, grapefruit juice.) The magnitude of the response is proportional o Interaction during Excretion – some drugs to the amount of receptors bound or occupied interact with others of the site of excretion; The Emax occurs when all receptors are bound probenecid and penecilin interaction The binding of the drug to the receptor exhibits Pharmacodynamics no cooperativity o Drug Synergism Intrinsic Activity Additive Effects – equivalent to the summation of their individual 1. Full Agonist – mimic endogenous substances; drug pharmacological action A + B = AB binds to a receptor and produces a biological Potentiation Effects – the net effect of response that mimics the response to the two drugs used together is greater than endogenous ligand. the sum of individual effects AB > A + B 2. Partial Agonist – cannot produce the same o Drug Antagonism – opposing actions of two maximum efficacy as a full agonist drugs on the same physiological system 3. Inverse Agonist – reverse the activity of receptor, o Importance of drug antagonism and exert the opposite pharmacological effect of Correcting adverse effects of drugs agonist. Treating drug poisoning 4. Antagonists – binds to a receptor with high affinity Predicting drug combinations which but possess zero intrinsic activity; can decrease the reduce drug efficacy. effect of an agonist when present by blocking the o Types of Antagonism drug’s ability to bind to the receptor; bind allosteric Based on bond formation: site to change the structure Reversible Drug Interaction Irreversible Based on surmountability: Drug Incompatibility – Serious loss of potency that Competitive occurs between an infusion fluid and a drug that is Non-Competitive added to it Based on mechanism: Pharmaceutical – drug in compatibility – serious loss Pharmacologic Antagonism of potency that occurs between an infusion fluid and Physiologic Antagonism a drug that is added to it. Chemical Antagonism Pharmacokinetics o Interaction drug absorption – drug may interact in the gastrointestinal tract resulting in either decreased or increased absorption o Interaction during distribution – a drug which is extensively bound to plasma protein can be displaced from its sites by another drug or displacement from other tissue binding sites. o Interaction during Biotransformation: