clinical pharmacokinetics
TRANSCRIPT
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ADIGRAT UNIVERSITY
COLLEGE OF MEDICINE AND HEALTH SCIENCES
department of pharmacy
CLINICAL PHARMACOKINETICS PREPARED BY : GROUP 2
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Group members
Name id.no1.Basa Ketema 1506/072. Brhane Gebrekidan 1509/073. Chaltu bokan 1510/074. Derbew Getaneh 1511/075. Etsay Haftom 1515/076. Mubarek Ahmedin 1530/07
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CLINICAL PHARMACOKINETICS
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OUTLINE Introduction to clinical pharmacokinetics Processes of pharmacokinetics 1. Absorption of drugs 2. Distribution of drugs 3. Metabolism of drugs 4. Elimination of drugs Applying pharmacokinetic principles
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Learning Objectives
Upon completion of the chapter, the students will be able to:
Define the following terms: clinical pharmacokinetics, and clearance, volume of distribution, half-life, bioavailability.
Calculate , a values of clearance, volume of distribution, and half-life .
Processes of pharmacokinetics
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Introduction
Definition Pharmacokinetics ; involves the study of absorption,
distribution, metabolism (biotransformation) and drug excretion over time.
-- refers on how the body acts on the drug Clinical pharmacokinetics; is the application of pharmacokinetic
principles to the safe and effective therapeutic management of drugs in an individual patient.
- - it is the discipline that describes the absorption, distribution, metabolism, and elimination of drugs in patients requiring drug therapy.
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The question could be asked-why bother about Pharmacokinetics ??????
To prevent, cure or control various disease states adequate drug doses must be delivered to the target tissues.
so that therapeutic yet NON – toxic levels are obtained
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Too much of a drug will result into toxic effects & too little will not result into the desired therapeutic effects.
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CONT…
Monitor medications with a narrow therapeutic index
Decrease the risk of adverse effects while maximizing pharmacologic response of medications
Know and apply drug administration routes.
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Pharmacokinetic paths cont..
Drug at the site of Administration
Drug in plasma
Drug & metabolites in urine, feces, or bile
1 . ABSORPTION(INPUT)
2. DISTRIBUTIONdrug in tissues
3. METABOLISM metabolites in tissues
4. ELIMINATION(OUTPUT)
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1. Absorption of drugs
Absorption Movement of drug from site of
administration to the systemic circulation.
Occurs after dissolution of a solid drug or administration of liquid drugs.
Route and site of administration affect
Rate …… and Extent of absorption
IV delivery – absorption is complete
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Mechanisms of drug absorption
There are 4 mechanisms by which drug molecules cross the cell
membrane/absorption/
Passive diffusion
Facilitated diffusion
Active transport
Bulk transport mechanisms
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Cont…
Characteristics Simple
diffusion
Facilitated
diffusion
Active transport
Incidence Commonest Less common Least common
Process Slow Quick Very Quick
Movement Along
concentratio
n gradient
Along
concentration
gradient
Against concentration
gradient
Carrier Not needed Needed Needed
Energy Not require Not required Required
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Bioavailability
The bioavailability of a drug is the fraction of the dose administered which is absorbed and reaches the systemic circulation.
Bioavailability of drug injected i.v. is 100%, but is frequently lower after oral ingestion, because:
The drug may be incompletely absorbed The absorbed drug may undergo first pass
metabolism in intestinal wall and/or liver or be excreted in bile.
For non I.V.: ranges from 0-100% (0 – 1)
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First-Pass Metabolism
Before the drug reaches the systemic circulation, the drug can be metabolized in the liver or intestine. As a Result, the concentration of drug in the systemic circulation will be reduced.
Drug Oral administration G.I.T. Portal circulation ⇒ ⇒ ⇒Liver ( First pass metabolism ) Systemic Circulation⇒ ⇒
Decreases Bioavailability Decreases Therapeutic Response
Can be bypassed if drug is given – - Parenterally ( i.v. Xylocaine in Arrhythmias ) Or- Sublingually ( Isosorbide dinitrate in Angina )
Vena cava
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Factors Affecting Drug Absorption and Bioavailability1. Physicochemical properties of the drug – Molecular shape (Physical state) – Particle size – Lipid solubility and unionized form of drug – Disintegration and dissolution time
-Formulation2. Route of drug administration3. pH and ionization4. Presence of other drugs5. Patient conditions eg. - Disease condition – Presence or absence of food … affect absorption from the GI
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2. DISTRIBUTION OF DRUGS
- Is a random movement drug molecules out of the central
compartment /systemic circulation/ in to the different body tissues
/fluid compartments
– Involves the delivery of drugs from the blood in to the target sites
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Factors Affecting Distribution of Drugs
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Physico-chemical properties of drugs Lipid solubility of the drug pKa of the drug(ionization at
physiological pH ) Degree of plasma protein.Physiological factors Rate of blood flowPresence of barriers BBB Placental barrier
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Drug - plasma protein binding
After entering the blood stream, drugs exist in two forms [plasma protein bound & unbound form].
Bound drugs are pharmacologically INACTIVE, only the FREE, UNBOUND drug can act on target sites in the tissues, elicit a biologic response & be available to the processes of elimination.
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CONT…
The major plasma proteins that bind drugs are
– Albumin
– α-acid glycoprotein
– Lipoproteins
– Globulin
– Hormone-binding factors
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The phenomenon of plasma protein binding is clinically important to
consider for drug with the following properties
– Drugs that are highly plasma protein bound (above 90% or so)
– Drugs with narrow therapeutic index
– Drugs with low excretion rate
– Examples, Warfarin, Phenytoin, Aspirin
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Redistribution
Termination of drug effect is due toBiotransformation and excretion, ….mostCircumstances. Redistribution of the drug from its site of action into
other tissues or sites. Highly lipid soluble drugs – distribute to brain, heart
and kidney etc. immediately followed by muscle and Fats.
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3. Metabolism of Drugs23
The liver is the principal(The major site) organ for drug metabolism.Drugs are often eliminated by biotransformation and or excretion into the URINE OR BILE.
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24cont… Chemical alteration of the drug in the body. Aim: to convert non-polar lipid soluble compounds
to polar lipid insoluble compounds to avoid reabsorption in renal tubules.
Most hydrophilic drugs are less biotransformed and excreted unchanged – streptomycin, neostigmine and pancuronium etc.
Biotransformation is required for protection of body from toxic metabolites
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Results of Biotransformation
1. Active drug and its metabolite to inactive.2. Active drug to active.3. Inactive drug to active/enhanced activity
(prodrug)4. No toxic or less toxic drug to toxic metabolites.
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Enzymes responsible for metabolism of drugs Biotransformations are enzymatic in nature
Microsomal enzymes:
• Located in the smooth endoplasmic reticulum of the liver, kidney & GIT.
• Cytochrome P450 monooxygenases, Dehydrogensase, Hydroxylase
and Glucuronyl transferase
• Inducible by drug,diet
Non-microsomal enzymes:
• Present in the cytoplasm and mitochondria
• Esterases, Amidases
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Biotransformation - Classification
2 (two) Phases of Biotransformation:
•Phase I or Non-synthetic – metabolite may be active or inactive,functionalizing. Unmasking/addition of polar functional group like OH, COOH.
• Phase II or Synthetic,conjugation – metabolites are inactive (Morphine – M-6 glucoronide is exception)
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Reactions of biotransformation 1. Phase IAlso called functionalizing reaction due to the addition and/or formation of new functional groups on to the parent drugResult in more REACTIVE and hydrophilic metabolites
Most (not all) phase I reactions are catalyzed by a family of
microsomal enzymes called CYP 450 which are found in the
liver.
Phase I metabolism may
– Increase
– Decrease ……..or
– leave unaltered the pharmacologic activity of the drug
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2. Phase II reactions Consist of conjugation reactions ( addition of polar
macromolecules to the drug molecule)
Usually Follow the phase I reaction (not always true)
Make the products of phase reaction more polar and water
soluble so that they can easily be excreted
Types of phase II reaction • Glucoronide conjugation (Glucoronidation)
• Acetyl conjugation (Acetylation) etc..
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Cont…Eg. Conjugation = addition of endogenous macromolecules to drug
molecules( substrates)
• Some drugs may undergo phase II reaction before undergoing
phase I reaction
–Isoniazide is first acetylated (phase II) and then is
hydrolyzed to isonicotinic acid (phase I)
• Phase II reactions are saturable as the conjugating
macromolecules can be exhausted
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Microsomal Enzyme Induction
Enzyme inducer is a type of drug that increases the
metabolic activity of an enzyme either by binding to
the enzyme and activating it, or by increasing the
expression of the gene coding for the enzyme E.g.,
microsomal enzymes (CYP450)
Increases metabolism of other drugs and sometimes
their own
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Enzyme Inhibition
Decreases the rate of drug metabolism, thereby increasing the amount of drug, leading to accumulation, extended pharmacological activity, and potential toxicity
One drug can inhibit metabolism of other – if utilizes same enzyme
However not common because different drugs are substrate of different CYPs
A drug may inhibit one isoenzyme while being substrate of other isoenzyme.
Some enzyme inhibitors – Omeprazole, metronidazole, isoniazide, ciprofloxacin and sulfonamides
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4. Drug Elimination Vs Excretion• Elimination and excretion both signify loss of the drug from
the body though they are two different phenomena
• Drug elimination is the irreversible loss of drug from the body
through two processes:
– Metabolism
– Excretion
• Metabolism involves enzymatic conversion of one chemical
entity to another within the body
• Excretion consists of removal from the body of chemically
unchanged drug or its metabolites
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Drug Excretion
The passage out of a systemically absorbed drug from the body
in the form of metabolites or unchanged drug
Main Routes of Excretion
Renal excretion (major organ)
Hepatobiliary excretion
Pulmonary excretion (for volatile/gaseous anaesthetics)
Minor Routes of Excretion
Saliva, sweat, milk, tears
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Enterohepatic circulation:
•Cycle in which a drug or metabolite is excreted in bile and then reabsorbed from the intestine either as the metabolite or after conversion back to the parent drug
Enterohepatic recirculation•The recirculation of highly conjugated drugs between the
liver-bile-and the GI
• Involves the release of free drug by the GI microflora and
free drug is reabsorbed back to the liver
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APPLYING PHARMACOKINETIC PRINCIPLES
By using1. A loading dose in one or a series of doses that may
be given at the onset of therapy with the aim of achieving the target concentration rapidly.
loading dose = desired concentration * VD
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Cont…
2. Maintenance dose- is a dose administered to
maintain the target concentration of a drug. The
dose is equivalent to the excreted amount.
DM = DL*(1- e-K*T)
3. Drug Half-Life—Time required for amount of drug
in the body/plasma conc. to decrease by 50%.
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Drug Half-Life
Elimination follows either First order kinetics or Zero order kineticsHalf-life (t1/2) is the time required for half of the initial concentration (or amount) of reactants to form products.The elimination rate constant (k) is the fraction of drug in the body which is removed per unit time
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Cont…
First order kinetics: Constant fraction of the drug is eliminated per
unit of time
Most common kinetics of elimination
Increase in dose, increases elimination
Increase in dose, t1/2 remains unaltered
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Cont…
Zero order kinetics:
Constant amount of the drug is eliminated per unit of
time
Rare: ethanol & high dose of phenytoin, aspirin,
dicoumarol
Increase in dose, no increase in elimination
Increase in dose, t1/2 is increased & chance of toxicity is
present
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cont…
Half-life in zero-order reaction• The half-life of zero-order reactions is directly proportional
to the initial concentration of the reactants. The zero-order rate constant, k1, has the units of (concentration)
time–1
Half-life in first-order reaction The half-life of first order reaction are independent of the initial
drug concentration, A0 .
The first-order rate constant, k1, has the units of time–1
0
01/2 2k
A t
12/1
693.0k
t
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Cont…
4. Clearance: The clearance (CL) of a drug is the theoretical volume of plasma from which drug is completely removed in unit time
- is fraction of the apparent volume of distribution from which drug is removed in unit time.
CL= Rate of elimination / Plasma Concentration of the drug
CL (total) = CL (renal) + CL (liver) + CL (other) CL total = k x Vd
CL = Rate of elimination (RoE)/C
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CONT….43
5. Bioavailability = AUC oral / AUC IV AUC: reflects the actual body exposure to drug after
administration of a dose of the drug This area under the curve is dependent on: • The rate of elimination of the drug from the
body • The dose administered
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Biovailability - AUC44
AUC – area under the curveF – bioavailability
AUC p.o.F = ------------ x 100% AUC i.v.
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6. Volume of distribution (Vd)Fluid volume that would be required to contain all of
the drug in the body at the same concentration measured
in the blood or plasma: Expressed as: in LitersRelates the amount of drug in the body to the concentration of
drug in blood or plasma.
-- Vd = [D]/[C]
» [D] = total concentration of the drug in the body
» [C] = concentration of the drug in the plasma
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REFERENCE1.GOLDMANIS CECIL MEDICINE 24TH EDITION
2.CLINICAL PHARMACOKINETICS AND PHARMACODYNAMICS CONCEPTS AND APPLICATION 4TH EDITION.
4.CLINICAL PHARMACOKINETICS SLIDE SHARE
5. MARTINS PHYSICAL PHARMACY AND PHARMACEUTICAL SCIENCES SIXTH EDITION
6. Pharmaceutical and clinical calculation 2nd edition
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for listening!!!
“If you want to explain any poison properly, what then is not a poison? All things are poison, nothing is without poison; the dose alone causes a thing not to be poison.”