Download - PHARMACOKINETICS
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PHARMACOKINETICS
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WHAT THE BODY DOES TO THE DRUG
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XENOBIOTIC
A compound to which the body is exposed that is foreign to the body.
Includes drugs, industrial and environmental chemicals
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Pharmacodynamics – concentration – effect
Graded response
Quantal response Pharmacokinetics – dose - concentration
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Routes of drug administrationRoutes of drug administration
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Routes of Administration
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PHARMACOKINETICS ABSORPTION
DISTRIBUTION
METABOLISM
EXCRETION
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ABSORPTION
Describes the rate and extent to which a
drug leaves its site of administration
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Pharmacokinetics
Absorption –the process by which the drug moves into the body from external source
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Drug Absorption Orally Rectually (drug embedded in a suppository,
which is placed in the rectum) Parenterally (given in liquid form by injection with
a needle and syringe) Inhaled –thru the lungs as gases, as vapors, or
as particulars carried in smoke or in an aerosol Absorbed through the skin Absorbed through mucous membranes (from
snorting or sniffing the drug, with the drug depositing on the oral or nasal mucosa)
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Drug Absorption -caveats
Orally
Drug must be soluble and stable in stomach fluid (not destroyed by gastric acids), enter the intestine, penetrate the lining of the stomach or intestine, and pass into the blood stream.
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Drug Absorption -disadvantages
May occasionally lead to vomiting and stomach distress.
How much of the drug will be absorbed into the bloodstream cannot always be accurately predicted because of the genetic differences between people and because differences in the manufacture of the drugs.
The acid in the stomach destroys some drugs.
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Drug Absorption -caveats
Rectually
Rarely used unless patient is vomiting, unconscious, or unable to swallow
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Drug Absorption -disadvantages
Rectually
Often irregular, unpredictable, and incomplete
Many drugs irritate the membranes that line the rectum.
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Drug Absorption
Parenterally
Intravenous –directly into a vein
Intramuscular –directly into muscle
Subcutaneous –just under the skin
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Drug Absorption
Parenterally
Often produces a more prompt response than does oral administration because absorption is faster.
Permits a more accurate dose because the unpredictable processes of absorption are bypassed.
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Drug Absorption -disadvantages
Parenterally Leaves little time to respond to an unexpected
drug reaction or accidental overdose.
Requires the use of sterile techniques.Once a drug is administers by injection, it
cannot be recalled.
Drugs that cannot become completely soluble before injection, cannot be injected intravenuously.
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Drug Absorption
Inhaled
Lung tissues have a large surface area with large blood flow, allowing for rapid absorption of drugs.
Relatively quick route to the brain.*
*May even have a faster onset of effect than drugs administered intravenously.
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Drug Absorption
Absorbed through the skin
Provides continuous,
controlled release of a drug
from a reservoir through a semipermeable membrane.
Potentially minimizes side effects associated with rapid rises and falls in plasma concentration of the drug contained in the patch.
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CHARACTERISTICS OF A DRUG FAVORING
ABSORPTION Low molecular size
Nonpolar
Uncharged
High lipid solubility
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MECHANISMS OF SOLUTE TRANSPORT ACROSS MEMBRANESPassive diffusion
Facilitated diffusion
Active transport
Endocytosis
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Passive Diffusion Concentration gradient Lipid-water partition coefficient Area, Thickness and Permeability
of the membrane Ionic, pH, charge gradient*
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Ionic Transport
pH gradient
Drug’s acid dissociation constant
(pKa)
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pKa – pH value at which one half of the drug is present in ionic form
pKa = pH + log (HA) (A-)
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Henderson-Hasselbalch equation
Calculates the ratio of non-ionized to ionized drug at each ph
pH = log [A-] + pka (Acid) [HA] or = log [B] + pKa (Base) [BH+] Ka = dissociation constant A = molar concentration of the acidic anion HA = molar concentration of the undissociated acid B = molar concentration of the basic anion HB = molar concentration of the undisscociated base
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1. Ionised drugs do not easily cross lipid 1. Ionised drugs do not easily cross lipid barriers such as the gut, placenta and barriers such as the gut, placenta and blood brainblood brain
2. Acidic drugs are well absorbed in the 2. Acidic drugs are well absorbed in the acidic medium of the stomach, basic drugs acidic medium of the stomach, basic drugs in the alkaline medium of the small bowelin the alkaline medium of the small bowel
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Un-ionized Ionized
Pharmacologic effect Active InactiveSolubility Lipids WaterCross lipid barriers Yes No(gastrointestinal tract,
blood-brain barrier, placenta)
Hepatic metabolism Yes No Renal excretion No Yes
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Drugs and ionisation: PractiseDrugs and ionisation: Practise
Acidic drugs (such as aspirin) will be Acidic drugs (such as aspirin) will be ionised in an alkaline urine and thus ionised in an alkaline urine and thus cannot be reabsorbed across the renal cannot be reabsorbed across the renal tubular membrane (alkaline diuresis)tubular membrane (alkaline diuresis)
pH trap (ion trapping) is significant for pH trap (ion trapping) is significant for some drugs, especially local some drugs, especially local anaesthetics in laboranaesthetics in labor
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Factors Affecting GI Absorption
Gastric Emptying Time
Intestinal Motility
Food
Formulation Factors
“First Pass Effect”
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PK DefinitionsPK Definitions
0 2 4 6 8 10 12
Time Postdose (hr)
100
1000
10000
Pla
sma
Co
nce
ntr
atio
n
3000
Cmax: Maximum concentration – may relate to some side effects
AUC: Area under the curve (filled area) = overall drug exposure
Cmin: minimum or trough concentrations: may relate with efficacy of HIV drugs
http://www.thebody.com/content/art875.html
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Drug Levels & ResistanceDrug Levels & Resistance
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BIOAVAILABILITY
Quantity of drug in systemic circulation
Quantity of drug administered
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BioavailabilityBioavailability
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BioavailabilityBioavailability
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BioavailabilityBioavailability
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Measuring bioavailabilityMeasuring bioavailability
time
LogConcentration
I.v. dose
Oral dose
AUC I.v.
AUC oral
Bioavailability =
AUC oral/AUC i.v.
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Bioavailability (f)
f = dose(IV) x AUC (PO)/dose(PO) x AUC (IV)
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DISTRIBUTION
Delivery of drug from systemic circulation to tissues
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Pharmacokinetics
Distribution –the drug is distributed throughout the body (including fetus)
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Distribution
The movement of drug from the blood to and from the tissues
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Drug Distribution4 Body Membranes that Affect Drug
Distribution
1. Cell membranes
2. Walls of the capillary vessels in the circulatory system
3. Brain-blood barrier
4. Placental barrier
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Drug Distribution1st Body Membrane that Affects Drug
Distribution Cell membranes
Permeable to small lipid (fatty) molecules
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Drug Distribution2nd Body Membrane that Affects Drug
Distribution Walls of the capillary vessels in the
circulatory systemDoes not depend on lipid solubility
Only drugs that do not bind to plasma proteins
pass through capillary pores.
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Drug Distribution3rd Body Membrane that Affects Drug
Distribution Brain-blood barrier
The rate of passage of a drug into the
brain is determined by two factors:
(1) the size of the drug molecule and
(2) its lipid (fat) solubility.
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Drug Distribution4th Body Membrane that Affects Drug
Distribution Placental barrier
Oxygen and nutrients travel from the
mother’s blood to that of the fetus,
while carbon dioxide and other waste
products travel from the blood of the
fetus to the mother’s blood.
Fat-soluble substances (including all
psychoactive drugs) diffuse rapidly and
without limitation.
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PATTERNS OF DRUG DISTRIBUTION Mainly in the vascular system
ex. Dextran, highly bound to plasma protein
apparent Vd = 3-5 L in adults (approx plasma volume)
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PATTERNS OF DRUG DISTRIBUTION Uniformly distributed throughout the body
water
ex.ethanol, sulfonamides
Vd = 30-50 L corresponding to total body water
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PATTERNS OF DRUG DISTRIBUTION Concentrated specifically in one or more
tissues that may or may not be the site of action
Vd – very large values
ex. Chloroquine – 1000x in the liver
Tetracycline – bone and developing teeth
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PATTERNS OF DRUG DISTRIBUTION Non-uniform distribution in the body
- highest concentrations usually in the liver, kidney and intestine
- distribution varies with lipid solubility, ability to pass thru membranes
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Factors Affecting Drug Distribution
Affecting Rate of Distribution Membrane Permeability Blood Perfusion Affecting extent of distribution Extent of plasma protein binding Regional differences in pH Lipid solubility Available transport mechanisms Intracellular Binding
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Membrane Permeability
Capillary permeability Renal capillary permeability
large pores Brain capillaries
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Blood Perfusion Rate
Greatest blood flow – brain, kidneys, liver and muscle
Highest perfusion rate – brain, kidneys, liver, heart
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Protein Binding
Extensive plasma protein binding – lower Vd; stay in central blood compartment
Slight change in the binding of highly bound drugs – significant change in clinical response
Only free drug are active
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Acidic drugs (e.g. barbiturates) bind to Acidic drugs (e.g. barbiturates) bind to albumin albumin
Basic drugs (e.g. opioids, local Basic drugs (e.g. opioids, local anaesthetics) bind to alpha 1 acid anaesthetics) bind to alpha 1 acid glycoproteinglycoprotein
The process is reversibleThe process is reversible Binding sites are non-selective for Binding sites are non-selective for
similar drugs and thus one can displace similar drugs and thus one can displace anotheranother
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Drugs Binding sites for acidic agents
Vit. C, salicylates, sulfonamides, barbiturates, penicillins, tetracyclines, probenecid
Albumin
Binding sites for basic agents
Quinine, Streptomycin, chloram, digitoxin, coumarin
Globulins, 1, 2, β1, β2
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Percent Unbound for Selected drugs
Drug % Unbound
Caffeine 90
Digoxin 77
Gentamicin 50
Theophylline 85
Phenytoin 13
Diazepam 4
Warfarin 0.8
Phenylbutazone 5
dicumarol 3
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? Volume of container? Volume of container
Injecteddose
10 mg.
Sampledconcentration
1 mg. l-1
Volume = injected dose/ sampled concentration = 10 litres
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? Volume of container? Volume of container
Injecteddose
10 mg.
Sampledconcentration
0.1 mg. l-1
Volume = injected dose/ sampled concentration = 100 litres
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Vd is proportional to body weight and Vd is proportional to body weight and thus, the loading dose can be based thus, the loading dose can be based on body weighton body weight
Varies with the very young, and very Varies with the very young, and very old old
Weight consideration
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Centralcompartment
Peripheralcompartment
Peripheralcompartment
K12
K21
K elim
Dose
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Central compartment
Intravascular space, highly perfused tissues
Rapid uptake of drug 75% of cardiac output; 10% of body mass Apparent volume can be calculated
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METABOLISM
Active Drug Inactive drug Active Drug Active or toxic
metabolite Inactive Prodrug Active drug Unexcretable drug Excretable
metabolite
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Pharmacokinetics
Metabolism –detoxification or breakdown of the drug into metabolites that no longer exert any effect
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Drug Metabolism
Side effects are results that are different from the primary, or therapeutic, effect, for which a drug is taken.
First-pass metabolism drug-metabolizing enzymes in either the cells of the GI tract or the liver can markedly reduce the amount of drug that reaches the bloodstream.
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BIOTRANSFORMATION
Phase I Phase II
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PHASE I
Modify the chemical structure of a drug
OXIDATION
REDUCTION
HYDROLYSIS
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Oxidative Reactions N- dealkylation – Imipramine, erythromycin O-dealkylation – Indomethacin,Codeine Aromatic hydroxylation – Phenytoin,
phenobarbital N- Oxidation – chlorpheniramine, Dapsone S- oxidation - Cimetidine, Omeprazole Deamination – Amphetamine, Diazepam
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HYDROLYSIS
Ester Hydrolysis – Procaine, aspirin, Succinylcholine
Amide Hydrolysis – Lidocaine, Indomethacin
Epoxide Hydrolysis - Carbamazepine
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REDUCTION
Nitro reduction – Chloramphenicol
Dehalogenation – Halothane
Carbonyl Reduction – Methadone, Naloxone
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PHASE II Conjugate a drug to large polar molecules to :
Inactivate a drug
Enhance drug’s solubility
Enhance excretion rate
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CONJUGATION REACTIONS
Glucoronidation – Acetaminophen, Morphine, Oxazepam
Sulfation – Acetaminophen, Steroids Acetylation – Sulfonamides, INH,
Clonazepam
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Metabolism
Induction – drugs can cause an increase in liver enzyme activity thus increasing metabolic rates of some drugs
ex. Phenobarbitone – induce metabolism of itself, phenytoin, warfarin
Inhibition – inhibit metabolism of other drugs
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Liver
Induction
Drug A induces the body to produce more of an enzyme to metabolized Drug B
This reduces the amount of Drug B and may lead to loss of Drug B’s effectiveness
Inhibition
Drug A inhibits the production of enzymes to metabolize Drug B
This increases the amount of Drug B in the body and could lead to an overdose or toxic effects
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Extraction ratio = Ci - Co/ CiExtraction ratio = Ci - Co/ CiCi may be calculated by determining the Ci may be calculated by determining the
percentage of a drug absorbed, and thus percentage of a drug absorbed, and thus reaching the liverreaching the liver
Co may be calculated from the bioavailability Co may be calculated from the bioavailability Effect on clearance when hepatic blood Effect on clearance when hepatic blood
flow falls (e.g. hepatic disease, decreased flow falls (e.g. hepatic disease, decreased cardiac output and hypovolaemia)cardiac output and hypovolaemia)
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Drug metabolism: Drug metabolism: Zero and first order kineticsZero and first order kinetics
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The rate constant is the fractional change The rate constant is the fractional change in concentration in unit timein concentration in unit time
It is expressed as the elimination rate It is expressed as the elimination rate constant k, in units of hconstant k, in units of h-1-1
Thus, if 10% of the drug is removed per Thus, if 10% of the drug is removed per hour, then the rate constant is 0.1hhour, then the rate constant is 0.1h-1-1
T1/2 = natural logarithm of 2 (0.693)/kT1/2 = natural logarithm of 2 (0.693)/k Thus, k of 0.1 = T1/2 of 6.93 hoursThus, k of 0.1 = T1/2 of 6.93 hours
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First order kinetics states that a fixed fraction First order kinetics states that a fixed fraction of the drug is metabolised in unit timeof the drug is metabolised in unit time
Or … the amount metabolised is proportional Or … the amount metabolised is proportional to the concentrationto the concentration
Or … amount metabolised = K * Or … amount metabolised = K * concentrationconcentration
K is the ‘clearance’ and has the unit of flow K is the ‘clearance’ and has the unit of flow (e.g. mls.min(e.g. mls.min-1-1 or litres.hr or litres.hr-1-1))
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Why do we need to know the drug Why do we need to know the drug clearance?clearance?
For effective drug therapy you need to For effective drug therapy you need to
be able to maintain the effective be able to maintain the effective
concentration (Ceff) that produces the concentration (Ceff) that produces the
desired effect desired effect Thus, we need to calculate the Thus, we need to calculate the
maintenance dose maintenance dose
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Why do we need to know the drug Why do we need to know the drug clearance?clearance?
Maintenance dose = clearance * Maintenance dose = clearance *
effective concentration (Ceff)effective concentration (Ceff)e.g. if clearance is 3 l.hre.g. if clearance is 3 l.hr-1-1 and Ceff is 10 and Ceff is 10
mg.lmg.l-1-1
Maintenance dose = 30 mg.hrMaintenance dose = 30 mg.hr-1-1
We can thus predict the effect of changes We can thus predict the effect of changes in clearance and Ceff on maintenance in clearance and Ceff on maintenance dosedose
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CLP =___rate of elimination (mg/min)______ plasma concentration of drug (mg/ml)
CLEARANCE
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Number of Percent of Drug Percent of Drug Half-lives Remaining Removed
0 100 01 50 502 25 753 12.5 87.54 6.25 93.755 3.125 96.875
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Number of Percent of final Half-times steady state concentration
0 01 502 753 87.54 93.755 96.875
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The context sensitive half lifeThe context sensitive half life
Definition:Definition:
The time for the plasma The time for the plasma concentration to fall by half concentration to fall by half following steady state infusion and following steady state infusion and constant blood levels.constant blood levels.
Usually after several hours infusion.Usually after several hours infusion.
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FACTORS AFFECTING DRUG METABOLISM
Genetic variation
Environmental determinants
Disease Factors
Age
Sex
Cultural
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Metabolism
Genetic –people have different amounts of enzymes that metabolize drugs
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Metabolism
Physiological –if more than one drug is present in the body, the drugs may interact with one another either in a therapeutically beneficial way or in a way that can adversely affect the patient.
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Metabolism
Environmental –current mood, stress, and past experience with drug can affect metabolism (and toxicity)
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RELATIVE HEPATIC CONTENT OF CYP ENZYMES
% DRUGS METABOLIZED BY CYP ENZYMES
ROLE OF CYP ENZYMES IN ROLE OF CYP ENZYMES IN HEPATIC DRUG METABOLISMHEPATIC DRUG METABOLISM
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CYP Enzyme Examples of substrates
1A1 Caffeine, Testosterone, R-Warfarin
1A2 Acetaminophen, Caffeine, Phenacetin, R-Warfarin
2A6 17-Estradiol, Testosterone
2B6 Cyclophosphamide, Erythromycin, Testosterone
2C-family Acetaminophen, Tolbutamide (2C9); Hexobarbital, S- Warfarin (2C9,19); Phenytoin, Testosterone, R- Warfarin, Zidovudine (2C8,9,19);
2E1 Acetaminophen, Caffeine, Chlorzoxazone, Halothane
2D6 Acetaminophen, Codeine, Debrisoquine
3A4 Acetaminophen, Caffeine, Carbamazepine, Codeine, Cortisol, Erythromycin, Cyclophosphamide, S- and R-Warfarin, Phenytoin, Testosterone, Halothane, Zidovudine
Adapted from: S. Rendic Drug Metab Rev 34: 83-448, 2002
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Adapted from: S. Rendic Drug Metab Rev 34: 83-448, 2002
Nutrition 1A1;1A2; 1B1, 2A6, 2B6, 2C8,9,19; 2D6, 3A4,5
Smoking 1A1;1A2, 2E1
Alcohol 2E1
Drugs 1A1,1A2; 2A6; 2B6; 2C; 2D6; 3A3, 3A4,5
Environment 1A1,1A2; 2A6; 1B; 2E1; 3A3, 3A4,5
Genetic Polymorphism
1A; 2A6; 2C9,19; 2D6; 2E1
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Pharmacokinetics
Elimination –metabolic waste products are removed from the body
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Elimination
Drugs leave the body through: Kidneys Lungs Bile Skin
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Elimination
Drugs leave the body through: Kidneys:1) Excrete most of the products of body
metabolism2) Closely regulate the levels of most of the
substances found in body fluids• Psychoactive drugs are often reabsorbed out of the kidneys, so the liver has to enzymatically transform the drugs so with minimal reabsorption they can exit in urine.
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Elimination
Drugs leave the body through: Bile
After most psychoactive drugs are processed by the liver they are usually less fat soluble, less capable of being reabsorbed, and therefore capable of being excreted in urine.
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Elimination
Drugs leave the body through: Lungs
Only occurs with highly volatile or gaseous agents
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Elimination
Drugs leave the body through: Skin
Small amounts of a few drugs can pass through the skin and be excreted in sweat.
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Processes That Determine Urinary Excretion of Drug
1. Glomerular filtration
2. Tubular secretion
3. Tubular reabsorption
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Drug excretion: Role of the Drug excretion: Role of the KidneysKidneys
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Drug excretion: Role of the Drug excretion: Role of the KidneysKidneys
Glomerular filtration (GFR)Glomerular filtration (GFR)clearance = fraction unbound (FU) * clearance = fraction unbound (FU) *
GFRGFRif TOTAL renal clearance = the above, if TOTAL renal clearance = the above,
then the drug is principally excreted by then the drug is principally excreted by filtration (e.g. gentamicin) ANDfiltration (e.g. gentamicin) AND
clearance is proportional to GFRclearance is proportional to GFR
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Drug excretion: Role of the KidneysDrug excretion: Role of the Kidneys Passive tubular reabsorptionPassive tubular reabsorption
clearance is clearance is less thanless than FU * GFR (due to FU * GFR (due to reabsorption)reabsorption)
e.g. aspirin and amphetamine (effect of e.g. aspirin and amphetamine (effect of pH of urine)pH of urine)
Active tubular secretion (ATS)Active tubular secretion (ATS)clearance is clearance is greater thangreater than FU * GFR (due FU * GFR (due
to secretion)to secretion)e.g. penicillin (inhibited by probenecid), e.g. penicillin (inhibited by probenecid),
digoxin (inhibited by quinidine)digoxin (inhibited by quinidine)
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Renal Factors that Affect Urinary Drug excretion
Glomerular filtration rate Tubular fluid pH Extent of back-diffusion of unionized form Extent of active tubular secretion of the
compound Extent of tubular reabsorption
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ADME - Summary
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CLINICAL PHARMACOKINETICS
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CLP =___rate of elimination (mg/min)______ plasma concentration of drug (mg/ml)
CLEARANCE
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Clearance First Order Kinetic – constant fraction of
the drug in the body is eliminated
Saturation Kinetics – constant amount of drug is eliminated per unit time
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CLEARANCE:Clinical Utility
Determines the maintenance dose (DM) required to achieve the target plasma conc at steady state
DM(mg/h) = Tconcn (mg/L) x Clearance (L/h)
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Volume of Distribution
Actual volume in which drug molecules are distributed within the body
Vd = D/CO
Co = D/Vd
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VOLUME OF DISTRIBUTION:Clinical Utility
Used to determine the loading dose (LD)
LD = Css x Vd
(mg) (mg/L) (L)
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HALF-LIFE
Time it takes for plasma concentration or the amount of drug in the body to be reduced by 50%
t1/2 = (0.693 x Vd) / Cl
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HALF-LIFE:Clinical Utility
Determines how long it takes to reach steady state after multiple dosing
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CSS = Bioavailability x Dose Interval x Cl
STEADY STATE CONCENTRATION
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Initial Concentration
Initial concentration = Loading Dose Vd
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Dosing Rate
Dosing rate = Target conc’n x Cl / F
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Oral Digoxin is to be used as maintenance dose to gradually digitalize a 69 kg patient with congestive heart failure.
A steady state plasma concentration of 1.5 ng/ml is selected as an appropriate target. Based on the patient’s renal function, the clearance of digoxin is computed at 1.6/ml/min/kg or 110ml/min.
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How should the drug be given in this patient? Given:
Cl – 1.6ml/min/kg
F – 70%
Target conc’n = 1.5ng/ml
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Dosing rate = 1.5ng/ml x 1.6ml.min/kg/0.7