Principle of Pharmacology. Higher Diploma in Nursing Year 1 Pathophysiology and Pharmacology
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1 Principle of Pharmacology Higher Diploma in Nursing Year 1 Pathophysiology and Pharmacology
2 Speaker Dr Edgar Liu PhD in Pharmacology Program Director of Pharmaceutical Studies in HKU SPACE Contact:
3 Topics to cover in this session Absorption, distribution, bio-transformation and elimination of drugs Drug interactions Drug tolerance and dependency
4 What is Pharmacology? Greek: pharmakon the Science that deals with the fate of drugs in the body and their actions on the body
5 Drug Nomenclature Chemical name N-(4-hydroxyphenyl)acetamide Generic name (or official name) Paracetamol / acetaminophen Trade name Panadol, tylenol.etc. Common name
6 Sources: Integrated Pharmacology, 3 rd edition. Mosby 2006
7 Definitions used in pharmacology Pharmacokinetics: how the body absorbs, distributes, metabolizes and excretes drugs Pharmacodynamics: how the body responds to drugs: the interaction between drug and receptor Pharmacogenetics: how genetics alters responses to drugs Pharmacoeconomics: cost-effectiveness of drug treatments
8 Pharmacokinetics bsorption istribution etabolism limination
9 Sources: Kalant and Roschlau Principles of Medical Pharmacology, 1998 Oxford
10 Routes of drug administration Topical (e.g. eye, skin) Sublingual Oral (p.o. per os) Rectal mucosa (suppositories) Pulmonary epithelium (inhalation) Injection subcutaneous (s.c.) intramuscular (i.m.) intravenous (i.v.) intra-arterial (i.a.) intrathecal (i.t.) intraperitoneal (i.p.)
11 Drug dosage Commonly used: mg, ml (cc) Frequency: qd: once daily bd (or bid): twice daily tds (or tid): three times daily qds (or qid) : four times daily
12 Drug formulation Tablets, capsules, solutions and suspensions Controlled-release formulation Patches Ointments, creams Injectable solutions Suppositories Inhalers
13 Medication order Standing order The patient is to receive the prescribed drug on a regular basis. e.g. Aricept 10mg PO qd Single order To administer the drug one time only. e.g. Valium 10mg IV at 9:00pm PRN order To administer the drug as needed. e.g. Demerol 100mg IM q4h PRN for pain STAT order A one-time order given as soon as possible e.g. Losec 40mg IV STAT
14 Site of absorption p.o. : stomach, small intestine inhalation: pulmonary epithelium sublingual epithelium injection: blood circulation rectal mucosa
15 Factors affecting absorption Chemical properties: Chemical nature Lipid partition coefficient (permeability) Physical properties: Drug formulations Gastric motility ph at the absorption site Ingestion with or without food Area of absorbing surface
16 Examples in absorption in G.I. 1) A tertiary amine Highly impermeable Highly permeable 2) An acid Highly permeable Highly impermeable
17 Oral drug absorption When the drug is administered in dissolved solution: easiest to be absorbed
18 Pathways of Drug Distribution DRUG DOSAGE Absorption Binding to: serum proteins tissue fat, proteins Free drug in extracellular water Excretion DRUG at the site of action metabolites
19 Volume of distribution 70 kg man Blood volume: 4-5 L Total body water: 50-70% of weight = ~40 liters 40 L = extracellular + intracellular (13L) (27L) Plasma concentration = Mass (g) / Volume of distribution (L)
20 Simple calculation A 70kg lean man takes 15g of alcohol: Total body water= 70% of weight = 50L Concentration of drug in TBW = 15g/50L = 0.3g/L Since alcohol does not bind to plasma proteins, and plasma contains 93% water Conc. in plasma = 0.28 g/l Conc. in blood = 0.24 g/l (conversion factor 1.16)
21 i.v. injection Vd = Dose /C 0 C 0 log conc. 5min time
22 Tissue and plasma protein binding Tissues: fat and protein e.g. DDT stored in fat Plasma protein binding e.g. diazepam or propanolol (over 90% bound) - albumin protein: acidic drug - globulin protein: basic drug A + A
23 Importance of plasma protein binding free drug conc., pharmacological activity clearance by glomerular fitration in kidney Prolong half life of drug in the body Highly protein bound drug interactions Competition binding with endogenous substance e.g. bilirubin, fatty acids
24 Tissue distribution of halothane Vessel-rich group Conc. of halothane in each tissue group Time
25 Blood brain barrier Only capillaries in the body that have their intercellular spaces completely occluded. Only lipid-soluble drugs normally get into the cerebral spinal fluid (CSF) from the blood Once the drug get to CSF, they can permeate into the brain cells freely.
26 Metabolism (or biotransformation) Background Intake may contain traces of potential toxic chemicals Conversion of lipid-soluble xenobiotics into more polar and water soluble products more efficient excretion
27 Drug biotransformation Phase I Parent Drug Excrete d Product Phase II reactions Major site: liver Other sites: gastrointestinal tract, lungs, skin and kidney
28 Phase I reactions Oxidation, reduction and hydrolysis
29 Phase II reactions Coupling of a drug or drug metabolite with an endogenous substance Epoxide hydration, glucuronidation, glutathione conjugation, sulphation, acetylation, methylation, glycine conjugation
30 Biotransformation of paracetamol in liver
31 Cytochrome P450 system as a monooxygenase: to incorporate one atom of oxygen into the drug substrate Multiple isoforms of cytochrome P450 system Overall: RH + O 2 + NADPH + H + ROH + H 2 O + NADP +
32 Cytochrome P450 superfamily
33 Common P450 cytochromes CYP isoforms CYP 1A2 Drug substrates Caffeine, tricyclic antidepressants CYP 2D6 Beta blockers, class I antiarrhythmics, antidepressants (TCA, SSRI, SNRI), antipsychotics CYP 3A4 acetaminophen, codeine, cyclosporin A, diazepam, erythromycin, statins, calcium channel blockers, steroids, antidepressants and carcinogens
34 Importance of drug metabolism (1) First pass effect: - lower the oral bioavailability of drugs Most of the drugs (given orally): less than 100% bioavailable. Admin. Dose >> actual free drug in blood
35 Importance of drug metabolism 2. Activation - An inactive precursor (pro-drug) can be converted into a pharmacologically active drug e.g. L-dopa to dopamine (Parkinson s) sulfasalazine to 5-aminosalicylic acid (5-ASA)
36 Importance of drug metabolism 3. Individual difference - Impaired enzyme functions may result in poor detoxification, leading to overdose toxicity 4. Drug-drug interaction
37 Elimination Drugs are excreted from the body by: Kidneys (urine) Intestinal tract (bile and feces) Lungs (exhaled air) Breast milk Sweat
38 - Drugs are eliminated regardless of how it is administered Time course of drug concentration following i.v. injection
39 Order of elimination Zero-order: rate independent of the conc. of drug First-order: rate dependent of the conc. of drug
40 C 0 /2 C=C 0 e -kt Time course of drug concentration following i.v. injection t 1/2 Half life elimination t 1/2 = 0.693/k where k is the elimination constant Slope = - k/2.303 log 10 C=log 10 C 0 -kt/2.303
41 Sample calculation 10mg dose of a drug (i.v.) Its plasma concentration is recorded repeatedly The logarithms of the conc. have been plotted against times (hr) A straight line: slope: and intercept: k= ( ) = hr -1 C 0 = antilog = = 2mg/L t 1/2 = 0.693/k = 0.693/0.173 = 4.0 hrs Volume of distribution = 10mg/2mg/L = 5L
42 Duration of Drug Action proportional to half life of elimination Pharmacological effect is attained if the conc. of the drug in the central compartment is higher than a minimal threshold the duration is extended by one half life if the dose is doubled.
43 Effect of doses on the duration of drug action i.v. administration oral administration
44 Common phenomenon: Why we should keep taking the drug three/ four times a day even the half life of the drug is more than 18 hours?
45 maintenance dose (i.v.) maintenance dose (i.v.) loading dose (i.v.) Initial dose = maintenance dose, the desired concentration range is reached not immediately. Loading dose >> maintenance dose, the desired range is reached immediately
46 Clearance A quantitative measure characterizing the rate of removal of drugs from the body, as a result of ADME. Cl = kv d (where k is the elimination constant, V d is the volume of distribution) (ml/min) The amount of drug in the body at any time is V d C; therefore the rate of elimination is a function of V d C, which is kv d C
47 At steady state, the rate of input (Q) is equal to the rate of elimination Q = k V d C ss where C ss is the steady state conc. = Cl C ss Rate of input C ss Rate of elimination
48 Calculation of the rate of drug infusion (i.v.) Given: 70kg man C ther = 2.0mg/L t 1/2 = 80 min V d = 49 L (70% of BW for TBW) k = / 80min = min -1 Desired infusion rate = kvc = = 0.85mg/min Clearance = kv = 0.43 L/min Loading dose = VC ss = 49 2 = 98mg
49 Calculation of the rate of drug oral intake multiplied by bioavailability factor F Bioavailability factor F = AUC (oral) AUC (i.v.) Drug conc. in plasma following a single i.v. injection Drug conc. in plasma following a single oral administration
50 Drug interactions
51 Drug interactions Most notable in elderly, due to polypharmacy, multiple diseases Patients with chronic disorders or chronic use of drugs: hypertension, diabetes Specific drug classes: e.g. anticoagulants
52 Classification of Drug Interactions Consequence: beneficial or adverse Site: external or internal Mechanism: pharmacodynamic, pharmacokinetic, physiological
53 Consequence Beneficial: Enhancing therapeutic effectiveness; or Lowering toxicity or side effect e.g. cancer therapy, infection, hypertension therapy Adverse: Reducing therapeutic effectiveness; or Increasing toxicity or side effect e.g. antidepressants + alcohol vasodilator + beta blocker
54 Site of interaction External: Physicochemical incompatible: precipitation or inactivation may occur if the drugs are mixed Internal: Receptor level DNA, RNA, Cell membrane E.g. metoprolol blocks β1-adrenoceptor agonists, such as isoproterenol
55 Mechanism of pharmacodynamic interaction Response related Barbiturates + alcohol: death rate due to enhancing the CNS effects (hynopsis) Hydralazine: peripheral resistance β-blockers: can block reflex tachycardia induced by fall in peripheral resistance Overall, augmenting the antihypertensive effect of hydralazine
56 Pharmacokinetic interaction Drugs may affect ADME, therefore affecting the conc. of other drugs e.g. antacids affects absorption of other drugs Effect Decreased drug level or action Increased drug level or action Antacid component Al(OH) 3 Mg(OH) 2 Aspirin Aspirin Chlorpromazine Chlordiazepoxide Isoniazid Cimetidine Propanolol Digoxin Tetracycline Tetracycline Vitamin A Levodopa Levodopa Quinidine Quinidine Dicumarol Sulfonamides
57 Drugs affecting absorption and distribution Changes in gastrointestinal motility gastric emptying intestinal motility Serum protein binding Highly bound drugs may be displaced by other high bound drugs: higher level of free drug (may become toxic) ; faster action; shorter half life
58 Drugs affecting biotransformation of other drugs Cytochrome P450 enzymes Drugs may induce enzymes: Increases the rate of biotransformation of other drugs Increases the rate of production of metabolites Increases hepatic clearance Decreases the drug half life Decreases serum total and free drug concentrations Decreases pharmacological effect e.g. phenobarbital affects biotransformation of warfarin
59 Drugs affecting biotransformation of other drugs Drugs may inhibit enzymes: Decreases the rate of biotransformation of other drugs Decreases the rate of production of metabolites Decreases hepatic clearance Increases the drug half life Increases serum total and free drug concentrations Increases pharmacological effect e.g. ethanol affects the biotransformation of propranolol, amitriptyline, diazepam.etc.
60 Examples of drugs and specific isoforms of cytochrome P- 450 which require adjustment of medication to prevent metabolic interaction
61 Notable drug-drug interactions Alcohol affect absorption and metabolism of many drugs e.g. anti-anxiety drugs, antidepressants (dangerous), narcotics, sleeping pills, antihistamines etc.
62 Notable drug-drug interactions Contraceptives may interact with barbiturates, antibiotics, asthma medicine
63 Notable drug-drug interactions NSAIDs NSAIDs impair control of coagulation in patients on oral anticoagulant therapy e.g. aspirin on effect of warfarin NSAID counteracts hypotensive effect by diuretics
64 Notable drug-drug interactions Anticoagulant: interacts with antibiotics, aspirin, anticonvulsants, antidepressants, antifungal drugs, NSAIDS.
65 Notable drug-nutrient interactions Grapefruit juice Naringen in converted to naringenin, and it appears to be the inhibitor of CYP3A4, CYP1A2 and CYP2A6. affects calcium channel blockers, statins, cyclosporine, caffeine
66 Drug tolerance and dependency
67 Tolerance Need for increased amounts of the drug to achieve the desired effect, or markedly decreased effect with the same amount of the substance
68 Pharmacodynamics: Drug action on receptors
69
70 A graph of dose-response curve
71 Mechanism of tolerance Reduction of the number of receptors Reduction in the affinity of drugs on receptors Increase in receptor internalization
72 More drug is needed to produce the same response
73 Example of tolerance Use of analgesics (e.g. morphine) Use of hypnotics (e.g. benzodiazepines) Use of alcohol
74 Drug dependence Use of larger amount, over a long period, than intended Tolerance developed Withdrawal syndrome occur if the administration stops Unsuccessful effort to cut down and control its use Spending of a great deal of time/money getting and using the substance, or recovering from its effects Continuation of the use despite having persistent or recurrent physical or psychological problems.
75 Substance (drug) dependence Common motives: REWARDING Producing pleasure Relieving displeasure Winning approval of the user s peers (friends, working partners, spouse)
76 Common drug dependence Benzodiazepines (anxiolytics, hypnotics) Ethanol Opioids (morphine, heroin, fentanyl) Cocaine Amphetamines (methamphetamine, ecstasy) Nicotine (tobacco in cigarettes, cigars) Caffeine
77 Consequence of drug dependence Risk of overdose Risk of dangerous drug-drug interactions: effects on CNS Liver or kidney or lung damage Personal problem: economic, familial, social
78 Treatment of Drug Dependence The goal: to stop the undesired drug-taking response from continuing to be self-reinforcing Psychological and social therapy Pharmacotherapy: Use of specific blockers Non-specific blockade of reinforcement (e.g. antidepressants) Substituting a less reinforcing and legally available drug (e.g. methdone) Aversive agents to produce an unpleasant effect (e.g. disulfiram)
79 End
Principle of Pharmacology. Higher Diploma in Nursing Year 1 Pathophysiology and Pharmacology
Principle of Pharmacology Higher Diploma in Nursing Year 1 Pathophysiology and Pharmacology Speaker Dr Edgar Liu PhD in Pharmacology Program Director of Pharmaceutical Studies in HKU SPACE Contact: edgar.liu@hkuspace.hku.hk
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