Clinical Pharmacokinetics Dr. Norul Badriah Hassan Jabatan Farmakologi Pusat Pengajian Sains Perubatan Universiti Sains Malaysia
Objectives 1. Drug-Response Relationship 2. Why we need to study pharmacokinetics? 3. Absorption 4. Sites of Drug Administration 5. Bioavailability and factors affecting bioavailability 6. Absorption in children and elderly 7. Distribution 8. Distribution in children and elderly 9. Metabolism 10. Metabolism in children and elderly 11. Excretion 12. Excretion in children and elderly
Pharmacokinetics • Study of the movement of drugs through the body. • Pharmacokinetics determine the time course of drug concentrations in serum or plasma as well as in tissues and body fluids
Pharmacokinetics
• Absorption • Distribution • Metabolism • Excretion
Dosage
Plasma Site of Concen. Action
Pharmacokinetics
what the body does to the drug
Effects
Pharmacodynamics
what the drug does to the body
Drug-Response Relationship Relationship between dose of a drug and response produced by that drug Generally if there is more dose, then there will be more drug-receptor complex and more response But when the maximum response is produced by the drug, then there will be no more increase of response even after administration of more dose.
Drug Concentration
Dose & Response
Therapeutic Window
Therapeutic Response
Adverse Effects
Dose-Response Relationship • Potency of A is more than B (less dose is needed to produce same response) • Efficacy of both same (max response same).
Pharmacokinetics
Why we need to study pharmacokinetics? • Compare and select appropriate drugs • Mode of administration • Dosage adjustment
Sites of Drug Administration • • • • • •
GI tract Artery Peripheral vein Muscle Subcutaneous tissue Lung
Bioavailability • Percentage or fraction of administered dose that reaches systemic circulation of patient.
Bioavailability = AUC (oral) AUC (intravenous)
Bioavailability 1. Dissolution
2. Absorption 3. Chemical form (e.g. salt) 4. Dosage form (tablet, solution) 5. Route of administration 6. Stability of active ingredient in GI tract 7. Extent of drug metabolism
Oral Bioavailability Destroyed in gut
Dose
Not absorbed
Destroyed by gut wall
Destroyed by liver
to systemic circulation
Oral bioavailability Drug Gentamicin Verapamil Lignocaine Propranolol Digoxin Phenytoin Valproate
Foral (%) <5 22 35 36 75 98 100
Plasma concentration-time relationship after a single oral dose
Effect of Food on Bioavailability Grapefruit juice: • increases bioavailability: ☻felodipine - 200% ☻nifedipine - 57%
☻verapamil - 36%
Effect of Food on Bioavailability Grapefruit juice: • Alter the pharmacokinetics of oral medications by different mechanisms: ☻ inhibit CYP3A4 irreversibly in intestinal apical enterocytes and hepatocytes. ☻ Inhibition of the P-glycoprotein in intestinal enterocytes. ↑ drug amount in systemic circulation. • This inhibitory effect can last up to 72 hours after final consumption of the grapefruit juice.
Effect of Food on Bioavailability • Other fruits which inhibit the CYP3A4 enzyme system: • Seville orange juice • Pimelo • common orange juice (30% of the inhibitory effect compared to grapefruit)
Drugs Known to Have Potentially Serious Interactions with Grapefruit Products Antiepileptics
Carbamazepine
Antidepressants
Sertaline, buspirone, clomipramine
Benzodiazepines
Diazepam
Calcium channel blocker
Felodipine, nifedipine, nimodipine, verapamil
Antiretroviral agents
Saquinavir, indinavir
Statins
Simvastatin, lovastatin, atorvastatin
Cytotoxic drugs
Cyclosporin, tacrolimus,
Antiarrhythmics
Amiodarone
Miscellaneous
Methadone, sildenafil Pillai et al, South Med J. 2009
Absorption in Children Infant- slower compared to older children and adults:
• Prolong GI emptying time • Unpredictable gastric peristalsis • Delayed time to peak concentrations
Absorption in Children •
Gastric pH values: 1 to 3 within 24 hours after birth neutral by 1 week of age slowly decline over 2 to 3 years to adult values.
• These changes may result in: greater absorption of basic drugs, e.g amoxicillin, erythromycin, and penicillin G. reducing absorption of weak acidic drugs, including phenobarbital.
Cmax
Distribution • Refers to transport of drugs to body compartment and the time required for the drug to reach those locations. • Vd : Volume of distribution (liters or L/kg).
Distribution Factors affecting drug transport: • • • •
Protein binding Body fluids Membrane transport/permeability Blood and tissue hemodynamics
Distribution Determinants of drug movement to maintain equilibrium: • Disease states • Drug lipid solubility • Characteristics of body tissues • Regional pH differences • Protein binding
Volume of Distribution A measure of the tendency of a drug to move out of the blood plasma to some other site.
Volume of Distribution C = D/V D V
V = D/C Total amount of the drug in the body
Concentration of a drug in the plasma
Volume of Distribution Vd (L/Kg) =Amount of drug (mg) Css (mg/L)
D V
Average population Vd = 1 L/kg Desired Plasma concentration = 15 mg/L Required loading dose = 15 mg/kg.
Drugs with extensive extraplasma distribution seem to have large Vd values.
Volume of Distribution Vd (L/Kg) =Amount of drug (mg) Css (mg/L)
D
D = 50 mg C = 2.5 mg/L
V
V = D/C = 50mg / 2.5mg/L = 20 Litres
Loading Dose As with infusions, a loading dose may be required to produce therapeutically effective blood levels without delay.
With loading dose (extra large initial dose)
Immediately effective treatment
Divided doses
Volumes of distribution (In litres for average 70 Kg adult)
Warfarin 7 Gentamicin 16 Theophylline 35 Cimetidine 140 Digoxin 510 Mianserin 910 Quinacrine 50,000
Small vol. Mainly in plasma little in tissues.
Medium volume. Similar concent in plasma and tissues Large volume. Mainly in tissues, little in plasma.
Steady state
Amount eliminated = 1 dose
Amount eliminated << 1 dose
Amount eliminated < 1 dose
36
Concentrations at Steady State Css,max = “Peak” Css (Average) Css,min = “Trough”
Free Vs Bound Drug • Drug bound to protein is inactive • Only unbound or free drug is pharmacologically active.
Free Versus Bound Drug Major drug binding proteins in serum: • Albumin, • 1-acid glycoprotein • Lipoproteins In uremia
↑ free drug concentration liver disease
hypoalbuminemia
Protein Binding of Commonly Monitored Therapeutic Drugs Drug
Protein Binding (%)
Protein Type
Amikacin
<5
No
Kanamycin
<5
No
Ethosuximide
0
No
Procainamide
10–15
Albumin
Theophylline
40
Albumin
Phenobarb
40
Albumin
Phenytoin
90
Albumin
Carbamazepine
80
Albumin
90–95
Albumin
Primidone
15
Albumin
Digoxin
25
Albumin
Quinidine
80
1-acid glycoprotein
Lidocaine
60–80
1-acid glycoprotein
98
Lipoproteins
Valproic acid
Cyclosporine
A. Dasgupta Handbook of Drug Monitoring Methods © Humana Press Inc., Totowa, NJ
Pathophysiological Conditions that Reduce Albumin Concentration Leading to an Increase in Free Fraction of Acidic Drugs Reduced Albumin Concentrations Uremia Pregnancy Intensive care unit patients Trauma patients Liver disease Hyperthyroidism Burn patient Elderly (> 75years) Cirrhosis Malnutrition AIDS patients A. Dasgupta Handbook of Drug Monitoring Methods © Humana Press Inc., Totowa, NJ
Distribution in Elderly Fat soluble (lipophilic) Increased Vd in older persons because they have greater fat stores. Longer time to reach a steady-state Longer elimination from the body.
Examples of fat-soluble drugs: diazepam, thiopental
Distribution in Elderly • Vd also influenced by protein binding. • Albumin is often decreased in older patients
• Higher proportion of drug is unbound (free) and pharmacologically active. • eg. ceftriaxone, diazepam, lorazepam, phenytoin, valproic acid, and warfarin.
Distribution in Children Total Body Water and Extracellular Fluid Volume •
Expanded total body water values relative to body weight are observed in newborns,infants, and children compared with adults: 80% total body weight in premature infants 70 to 75% in newborns 50 to 60% in adults •
Neonates and young infants also have a greater extracellular fluid compartment relative to body weight compared with adults.
•
For watersoluble drugs demonstrating distribution through total body water, larger doses will be required in infants to achieve comparable serum concentrations to those achieved in adults.
•
e.g aminoglycosides, penicillins, and cephalosporins,
Metabolism • Defined as chemical modification of a drug in a biologic environment. • Also referred as drug biotransformation or drug detoxification.
Metabolism • Liver - most common site of drug metabolism
• Metabolic conversion also can take place in: intestinal wall lungs skin kidneys other organs
Metabolism • Most drugs undergo metabolism. • Only few excreted unchanged in urine. e.g. Acetazolamide Penicillin G
First-Pass Effect • Some drugs may be extensively metabolised by the liver before reaching systemic circulation • First pass refers to metabolism by the liver as a drug passes through the liver via portal vein following absorption
Metabolism in Children • Both Phase I and II reactions mature over time. • Phase I reactions generally mature by 1 year of age.
• Phase II processes mature at a slower rate, • E.g - glucuronidation activity by 3 to 4 years of age. • CYP activity is present at 30 to 60% of adult values in infancy.
Metabolism in Elderly • Aging affects the liver by decreasing liver blood flow, liver size & mass. • Consequently, in the older patient the metabolic clearance of drugs by the liver may be reduced.
Excretion • Excretion refers to a drug’s final route(s) of exit from the body. • For most drugs, this involves elimination by the kidney as either the parent compound or as a metabolite or metabolites.
• Terms used to express excretion are drug’s half-life (t1/2) and its clearance.
Half-Life • A drug’s half-life is the time it takes for its plasma or serum concentration to decline by 50%, e.g. from 20 µg/mL to 10 µg/mL. • Expressed in hours. • Steady state is reached when the amount of drug entering the systemic circulation is equal to the amount being eliminated. • For a drug administered on a regular basis, 95% of steady state in the body is achieved after five half-lives of the drug.
Half-Life
Linear vs non-linear pk • First order kinetics = linear Rate of change in drug concentration is proportional to drug concentration
• Zero order kinetics = non-linear Michealis-Menten Equation- capacity limited kinetics
For most drugs [Expansion of the relevant part of the graph]
Elimination rate Graph would start to curve if we went to much higher concentrations and began to saturate the enzyme.
Drug concentration
For CERTAIN drugs Elimination rate
Highest concentrations actually seen in real therapeutic use. Too little to saturate the enzyme. Almost no curvature. Drug concentration
Linear kinetics (most drugs)
Non-linear kinetics (e.g. phenytoin)
Rate of eliminat’n
Rate of eliminat’n
Blood drug conc
Blood drug conc
NON-LINEAR KINETICS There are a small number of drugs where concentrations seen in real life use are high enough to saturate the eliminating enzymes.
Phenytoin - The only case of real clinical significance •Salicylates •Ethanol Theophylline may approach saturation but, in practice, it can be treated as following linear kinetics.
Factors Causing Non-Linear Kinetics Absorption • Poor aqueous solubility/slow dissolution (griseofulvin) • Site specific absorption along GI tract (phenytoin) • Carrier mediated absorption (riboflavin)
Factors Causing Non-Linear Kinetics Absorption • P-glycoprotein efflux in intestinal epithelial cells (cyclosporin A) • Saturable first pass effect by the intestine and/or liver (propranolol). • Dose/time-dependent changes in GI physiology including gastric emptying, GI motility & GI blood flow rate.
Factors Causing Non-Linear Kinetics Distribution • Non-linear plasma protein binding (valproic acid) • Carrier-mediated membrane transport (thiamine) • Non-linear tissue binding (prednisolone)
Factors Causing Non-Linear Kinetics Metabolism • Saturable metabolism (ethanol) • Product inhibition (dicoumarol) • Co-substrate depletion (acetaminophen)
• Nonlinear plasma protein binding (prednisolone) • Autoinduction
Factors Causing Non-Linear Kinetics Excretion • Nonlinear protein binding and/or glomerular filtration (naproxen) • Carrier-mediated tubular excretion (cimetidine)/reabsorption (riboflavin) • Carrier-mediated biliary excretion (iodipamide)
Excretion in Children •
Glomerular filtration function is dramatically reduced in newborns
•
Greater immaturity in premature infants when compared with fullterm infants
•
Increases in glomerular filtration rate (GFR) occur in the first weeks of life, reaching 50 to 60% of adult function by the third week of life, and adult values by 8 to 12 months of age.
•
By 3 to 6 years of life, GFR values exceed adult values.
•
Therefore, drugs dependent on glomerular filtration will show reduced drug clearance through early infancy, more evident in premature infants, and likely require dosage reduction.
•
During early childhood, higher daily doses are likely when corrected for weight and in comparison with adult doses because of increased GFR.
Clearance in the Elderly • Decline in renal function with age, even in the absence of renal disease • Increased Vd • Larger drug storage reservoirs • Decreased drug clearance • Prolong drug half-lives and lead to increased plasma drug concentrations in older people.
Creatinine in Elderly • Serum creatinine - not accurate reflection of creatinine clearance in elderly patients. • Decline in lean muscle mass cause reduced production of creatinine.
Acknowledgements • Dr. Mohd Suhaimi Ab Wahab • Dr. Ruzilawati Abu Bakar
Suggested Readings • Michael E. Winter, Basic Clinical Pharmacokinetics, 4th ed. Lippincott Williams & Wilkins, Philadelphia • Thomas N. Tozer & Malcolm Rowland, Introduction to Pharmacokinetics and pharmacodynamics: The quantitative basis of drug therapy. Lippincott Williams & Wilkins, Philadelphia
