Author of Lecture: Hilmer, Sarah (Dr.) Title of Lecture: Clinical Pharmacology (Problem 17, Lecture 1, 2009) COMMONWEALTH OF AUSTRALIA Copyright Regulations 1969 WARNING This material has been reproduced and communicated to
you by or on behalf of the University of Sydney pursuant to Part VB of the Copyright Act 1968 (the Act). The material in this communication may be subject to copyright under the Act. Any further reproduction or communication of this material by you may be the subject of copyright protection under the Act. Do not remove this notice Clinical Pharmacology Dr Sarah Hilmer BScMed(Hons) MBBS(Hons) FRACP PhD [email protected] Head of Department, Clinical Pharmacology, RNSH
Staff Specialist, Geriatric Medicine, RNSH Associate Professor, Northern Clinical School Clinical Pharmacology Lectures 1. Pharmacokinetics I Absorption & Distribution 2. Pharmacokinetics II Metabolism & Excretion 3. Pharmacodynamics 4. Individualising drug therapy 5. Quality use of medicines
Acknowledgements NIH Fundamentals of Clinical Pharmacology http://www.cc.nih.gov/training/training/ principles/info.html Professor Evan Begg Christchurch, New Zealand http://www.icp.org.nz Definitions Pharmacology Study of drugs and their actions in living
organisms Clinical Pharmacology Study of drugs in humans Includes drug Discovery Development Use
Evaluation History Only relatively recent emphasis on drug therapy and rational prescribing. a surgeon who uses the wrong side of the scalpel cuts his own fingers and not the patient; if the same applied to drugs they would have been investigated very carefully a long time ago. Rudolph Buchheim, 1849 Established first laboratory of experimental pharmacology
www.chem.ut.ee PHARMACEUTICAL PROCESS Is the drug getting into the patient? PHARMACOKINETIC PROCESS Is the drug getting to its site of action? PHARMACODYNAMIC PROCESS Is the drug producing the required pharmacological effect? THERAPEUTIC PROCESS Is the pharmacological effect being translated into a therapeutic (or toxic) effect?
Pharmacokinetics What your body does to the drug The quantitative analysis of the time course of drug: Absorption Distribution Metabolism Excretion Pharmacokinetics Improves Drug Dose Selection Traditional:
Look up usual dose in MIMS/AMH Memorise usual dose Improved: Individualise dosing Apply pharmacokinetics and the target concentration strategy Useful when drug has a low therapeutic index and pharmacokinetics account for much of the interpatient variability in response Target Concentration Strategy Estimate Initial Dose -Target level
-Loading dose -Maintenance dose Begin therapy Assess therapy -Patient response -Drug level Refine dose estimate and Adjust dose Tozer and Rowland, 2006
Absorption Site of administration to plasma Depends on route of administration Administration Cross lipid barriers/ cell walls Distribute Cellular target Movement of drugs across cell
membranes Fulton, UCSF Routes of Administration 2006 Twentieth Century Fox Film Corporation Oral Absorption Passive non-ionic diffusion Majority of drugs Specialised transporters
Large neutral amino acid transporter L-dopa, Methyldopa, Baclofen Oligopeptide transporter (PEPT-1) Amino beta lactams, ACE inhibitors Monocarboxylic acid transporter Salicylic acid, pravastatin Oral (enteral): absorption from mouth, stomach and small intestine Stomach: minority Small Intestine: majority
Passive > Active Rate ~ 75% in 1-3 hours. Depends on: Motility eg diarrhoea decreases absorption Blood flow Food enhance or impair Particle size and formulation Physico-chemical factors
Unionised Lipid soluble Rate of gastric emptying rate limiting step Gastric Emptying Rate Affects Paracetamol Absorption Gastric emptying is: -Delayed by propantheline -Stimulated by metaclopramide
Nimmo et al., Br Med J, 1973 Effects of Food on Oral Drug Absorption Poor acid stability: prolonged gastric exposure degradation eg erythromycin, azithromycin, isoniazid Require acid environment eg itraconazole, ketoconazole Fat or bile acids enhance absorption eg tacrolimus, carbamazepine
Bind to fibre, reducing absorption eg digoxin Bind to calcium (chelate), reducing absorption eg tetracyclines, quinolones Formulation Rate of disintegration of tablet Tablet compression Bulk excipients Rate of dissolution of drug particles in intestinal fluid
Particle size: smaller dissolve quicker Modified Release Reduce frequency of oral administration eg morphine, nifedipine, paracetamol extend Deliver contents to site of action eg mesalazine: pH sensitive coating 5-ASA released in distal small bowel and colon Routes of Administration 2006 Twentieth Century Fox Film Corporation
Sublingual Administration From blood vessels at base of tongue Lipid soluble drugs only nitroglycerin Small surface area potent drugs only Avoids first pass metabolism Rapid absorption: minutes Routes of Administration
2006 Twentieth Century Fox Film Corporation Rectal Formulations Avoid first pass metabolism Erratic absorption because of rectal contents Acceptable to patients? Useful if unable to take oral medications
eg paracetamol, oxycodone, NSAIDS Useful if unable to get IV access eg diazepam in status epilepticus Direct effect on large bowel eg corticosteroids in Inflammatory Bowel Disease Routes of Administration 2006 Twentieth Century Fox Film Corporation Parenteral: Intravenous
Direct delivery to plasma no absorption required Rapid effect Avoids first pass metabolism Risks: infection, embolism Parenteral: Intramuscular - Low water solubility drugs - Slow release - eg depot fluphenazine in oil to slow diffusion - Painful
Parenteral: Subcutaneous - Insoluble suspensions - Slow, even absorption Subcutaneous Insulins Ultra-short and short acting: soluble (clear) Intermediate acting: large crystals (cloudy) Long acting:
Insulin glargine: Soluble in acid (clear in vial) Insoluble at body pH After injection crystals form and insulin is absorbed slowly. Insulin detemir: Fatty acid attached to insulin molecule. Complex binds albumin in the s/c space and in plasma. Insulin gradually dissociates from albumin and can then diffuse into blood stream to reach tissue insulin Rcs. Routes of Administration
2006 Twentieth Century Fox Film Corporation Inhaled Medications Formulations: Powders Aerosol solutions Nebulised solutions Delivery to bronchioles ~10% Depends on type of inhaler and how used Local effects
eg oral candida Some systemic absorption Salbutamol: tremor Corticosteroids: osteoporosis Ipratropium bromide: anticholinergic dry mouth in 15% patients Routes of Administration 2006 Twentieth Century Fox Film Corporation Topical: Intranasal Formulations Direct therapeutic effect
Sodium chromoglycate for rhinitis Systemic effect Sumatriptan in migraine (vomiting) Local toxicity Cocaine necrosis of nasal septum Saddle-nose deformity Villa, J Can Dent Assoc, 1999 Routes of Administration
2006 Twentieth Century Fox Film Corporation Topical: Eye Drops Absorption through conjunctival sac epithelium Local effects in eyes with minimal systemic effects Some systemic absorption eg timolol for glaucoma may precipitate bronchospasm in asthma Routes of Administration
2006 Twentieth Century Fox Film Corporation Topical: Cutaneous Administration Local effect on skin Steroids Slow systemic absorption (patch) Lipid soluble drugs only Oestrogen Opioids Fentanyl, Buprenorphine 77 year old woman found dead Applied heating pad over fentanyl patch,
which was also site of her pain Increased fentanyl absorption due to heat Possible application of 2nd patch without removing 1st First pass metabolism of oral drugs Lilver Gut First Pass Metabolism in Gut Lumen Gastric acid inactivates benzylpenicillin
Proteolytic enzymes inactivate insulin First Pass Metabolism in Gut Wall Monoamine oxidase metabolises monoamines Irreversible MAO inhibitors + amine-containing foods Tyramine not metabolised by MAO in gut wall enters systemic circulation releases NAd from stores in nerve endings causing hypertensive crisis Microsoft Clip Art First Pass Metabolism in Gut Wall
CYP 3A4 Plasma Simvastatin Concentration (ng/ml) Blocked by grapefruit juice Many drugs inducers, inhibitors, substrates Administration of 40mg Simvastatin with Water Grapefruit juice Lilja et al., Br J Clin Pharmacology, 1994
First Pass Metabolism in Gut Wall P-glycoprotein (enterocytes to gut lumen) Interactions b/w inhibitors (eg verapamil, macrolides) and substrates (eg digoxin) Administration of 0.75mg digoxin with placebo clarithromycin Rengelshausen et al., Br J Clin Pharmacol, 2003
Hepatic First Pass Metabolism Reduced amount of parent drug Metabolites More water soluble - facilitates excretion Activity Decreased Increased: Pro-drugs Inactive precursors, metabolised to active metabolites eg cyclophosphamide, simvastatin, ramipril, perindopril Reduced first pass metabolism reduced bioavailability of pro-drugs Oral availability
http://www.icp.org.nz/html/oral_availablity.html Bioavailability: the % of an ingested dose of a drug that enters systemic circulation www.icp.org.nz Bioavailability: implications for oral and parenteral dosing High bioavailability, dose same for IV and po routes eg metronidazole, fluconazole, amoxicillin
Low bioavailability, lower dose for parenteral than po routes eg morphine: 10 mg s/c or IM = 30 mg po Bioavailability after oral administration of different formulations Burkitt, Australian Prescriber, 2003 Bioequivalence Pharmaceutically equivalent and equal systemic bioavailability
Generics must be bioequivalent to innovator (80-125%) Phenytoin toxicity outbreak (Australia 1968) Inert excipient changed: CaSO4 to lactose Increased solubility and systemic availability Change in phenytoin excipients results in epidemic toxicity F Bochner, Proc Aust Assoc Neurol, 1973 AUC A > B: Therapeutic Significance?
9 8 serum concentration 7 6 5 Drug A 4
Drug B 3 2 1 0 0 5 10 15
20 Time after drug administered (hours) 25 AUC A > B: B Ineffective 9 8 serum concentration
7 6 5 Drug A 4 Drug B MEC 3
2 1 0 0 5 10 15 20
25 Time after drug administered (hours) MEC = Minimum Effective Concentration AUC A > B: Equally Effective 9 8 serum concentration 7
6 5 Drug A 4 Drug B 3 2 1
MEC 0 0 5 10 15 20
25 Time after drug administered (hours) MEC = Minimum Effective Concentration Bioavailability of Thyroxine (T4) Agents that reduce bioavailability of oral thyroxine may need to dose T4: Drugs that decrease absorption of oral T4:
cholestyramine soy bean formulations sucralfate ferrous sulfate Drugs that increase hepatic metabolism of T4 phenobarbitone carbamazepine rifampicin Stockigt; Aust Prescr 1996;19:47
Effect of route of Administration on Plasma Concentration http://www.icp.org.nz/html/dose.html Drug Binding and Distribution Protein Binding Reversible and rapid Depends on [free drug], affinity for binding sites, [protein] Protein binding Many drugs bind to plasma proteins
Albumin (acidic drugs, eg warfarin, NSAIDs) Alpha-1 acid glycoprotein (basic drugs, eg quinine) Lipoproteins (basic drugs) Globulins (hormones) Only free drug can bind to receptors Clinical implications of changes in protein binding Changes in protein binding Disease and nutrition Protein binding displacement interactions
eg valproate displaces phenytoin increases free phenytoin, compensate with increased clearance Clinically relevant effects if >90% of drug is protein bound eg phenytoin, warfarin Small volume of distribution High protein binding, low clearance drug plasma concentration
[Free drug] depends on clearance of free drug [Total drug] depends on protein binding 100 90 80 70 60 50 40 30 20 10 0
Same drug Same dose Same clearance free bound 1 2 patient Birkett et al., 1979
Tissue Binding Body Fat Lipid soluble drugs Stable reservoir eg anaesthetics Bone Adsorption onto bone-crystal surface Reservoir slow release eg tetracyclines, heavy metals Distribution: body fluid compartments
Plasma Water 5% Interstitial Water 16% Intracellular Water 35% Transcellular
Water 2% Fat 20% Free drug can move between compartments. Depends on: - permeability - binding - pH partition - fat:water partition Apparent distribution volumes of
some common drugs Volume Compartment (L/kg body weight) Vd Examples (L/kg body weight) 0.05 0.05-0.1
Plasma 0.1-0.2 0.2 Extracellular fluid 0.55 Total body water 0.4-0.7
Diazepam Morphine Digoxin Apparent Volume of Distribution (Vd) Vd: volume of fluid required to contain the total amount of drug in the body at the same concentration as that in the plasma Vd = amount of drug in body plasma concentration
Loading dose = Vd x desired plasma concentration Apparent volume of distribution http://www.icp.org.nz/html/volume_of_distribution.html Gentamicin Absorption Oral: <1% - highly polar cation, disease Topical: large wound/burn/ulcer IMI: rapid, peak 30-90 mins, shock Distribution Apparent Vd 25% lean body weight (~ECF)
Loading dose = Vd x desired plasma concentration = 0.25 L/kg x 12-20 mg/L = 3-5 mg/kg Apparent Vd increases in sepsis ? higher loading dose Adjust interval or maintenance dose in renal impairment clearance next lecture! High concentrations in renal cortex and endolymph/perilymph inner ear toxicity Barriers to Drug Distribution Blood brain barrier Only lipid soluble drugs can enter brain and
CSF Leaky in disease eg penicillin in meningitis Placenta Allows passage of lipid and some water soluble drugs - eg opioids, antiepileptics Enzymes in placenta inactivate some drugs Pharmacokinetics II
Quiz Metabolism Excretion Pharmacokinetic drug interaction case
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