pharmacokinetics overview

DRUG PHAMACOKINETICSBy Amad Islam

LIFE HISTORY OF DRUG

Dosage Regimen

Concentration in Plasma

Concentration at the site of action

AbsorptionDistributionMetabolismExcretion

Pharmacokinetics

Pharmacodynamics

Effect

DEFINATION Pharmacokinetics is the study of drug

absorption, distribution within body, and drug elimination over time.

Pharmacokinetics is the quantitative study of drug movement in, through and out of the body. Intensity of effect is related to concentration of the drug at the site of action, which depends on its pharmacokinetic properties.

WHAT THE BODY DOES TO THE DRUG

ABSORBTION OF DRUG

ABSORBTION OF DRUGAbsorption is the transfer of a drug from its site

of administration to the blood stream.

Most of drugs are absorbed by the way of passive transport Intravenous administration has no absorptionInhalation→Sublingual→Rectal→intramuscular→subcutaneous→oral→transdermal

ABSORBTION OF DRUGFactors affecting absorption Drug properties:

lipid solubility, molecular weight, and polarity etc

Blood flow to the absorption site Total surface area available for absorption Contact time at the absorption surface Affinity with special tissue

ABSORBTION OF DRUGPoints to Remember The drugs which are Unionized, low polarity,

small molecule and higher lipid solubility are easy to permeate membrane(Absorb).

Acidic drugs re absorbed are largely unionized in stomach and absorbed faster while basic drugs are absorbed faster in intestines.

Letrozole is highly Lipid

Solouble and Basic Compound so

easily completely absorbed by G.I.T.

Doxorubicin HCL is Highly water

soluble and Large molecule so

difficultly absorbed by G.I.T.

ABSORBTION OF DRUGBioavailabilityIt is measure of the fraction (F) of administered dose of a drug that reaches the systemic circulation in the unchanged form.

It refers to the rate and extent of absorption. 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.

ABSORBTION OF DRUGLorelin (Leuprorelin Acetate) is sophisticated PLGA microspheres. So, Bioavailability by subcutaneous administration is comparable to that by intravenous administration.

ABSORBTION OF DRUG Bioequivalence is a term used to assess the

expected in vivo biological equivalence of two proprietary preparations of a drug. If two products are said to be bioequivalent it means that they would be expected to be, for all intents and purposes, the same.

BIOAVAILABILITY - AUCPl

asm

a co

ncen

tratio

n (m

cg/m

l)

Time (h)0 5 10 15

AUC p.o.F = ------------ x 100% AUC i.v.

AUC – area under the curveF – bioavailability

DISTRIBUTION OF DRUG

DISTRIBUTION OF DRUGSIt is the passage of drug from the circulation to

the tissue and site of its action.

The extent of distribution of drug depends on its lipid solubility, ionization at physiological pH (dependent on pKa), extent of binding to plasma and tissue proteins and differences in regional blood flow, disease like CHF, uremia, cirrhosis

DISTRIBUTION OF DRUGSVolume of Distribution (V)Apparent Volume of distribution is defined as the volume that would accommodate all the drugs in the body, if the concentration was the same as in plasma

DISTRIBUTION OF DRUGS Plasma Protein Binding

Most drugs possess physicochemical affinity for plasma proteins. Acidic drugs bind to plasma albumin and basic drugs to α1-glycoprotein The clinical significant implications of PPB are:a) Highly PPB drugs are largely restricted to the vascular compartment and tend to have lower Vd.b) The PPB fraction is not available for action.c) There is an equilibration between PPB fraction of drug and free molecules of drug.(d) High degree of protein binding makes the drug long acting, because bound fraction is not available for metabolism, unless it is actively excreted by liver or kidney tubules.

Plasma Protein Binding of Oxaliplatin is >90%.

So 10% of 85mg/m2 is administered in to achive Peak plasma concentration of 1.21mcg/mL.(least effective conc)

• Plasma Protein Binding of Leuprorelin Acetate is 43% to achive Mean peak plasma of 54.5 µg/L occur within 1 to 3 hours

DISTRIBUTION OF DRUGSBarriers of Distribution

Blood Brain Barrier(BBB) limits the entry of non-lipid soluble drugs in Brain and CSF.

Placental Barrier(PB) Only lipid soluble Drugs can penetrate – limitation of hydrophilic drugs.

METABOLISM OF DRUG

METABOLISM OF DRUGSIt is the 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 - CLASSIFICATION

2 (two) Phases of Biotransformation:

• Phase I or Non-synthetic – metabolite may be active or inactive

• Phase II or Synthetic – metabolites are inactive (Morphine – M-6 glucoronide is exception)

METABOLISM OF DRUGSEnzyme InhibitionOne drug can inhibit metabolism of other – if utilizes same enzyme However not common because different

drugs are substrate of different CYPs Some enzyme inhibitors – Omeprazole,

metronidazole, isoniazide, ciprofloxacin and sulfonamides

EXCREATION OF DRUG

EXCRETION OF DRUG Excretion is a transport procedure which the

prototype drug (or parent drug) or other metabolic products are excreted through

excretion organ or secretion organ

Routes of drug excretion• Kidney• Biliary excretion• Sweat and saliva• Milk• Pulmonary

EXCRETION OF DRUG Hepatic ExcretionDrugs can be excreted in bile, especially when the are conjugated with

– glucuronic AcidRenal Excretion Acidic urine

alkaline drugs eliminated acid drugs reabsorbed

Alkaline urine acid drugs eliminated alkaline drugs absorbed

KINETICS OF ELIMINATION Clearance: The clearance (CL) of a drug is the theoretical volume of

plasma from which drug is completely removed in unit time. Ability of organs of elimination (e.g. kidney, liver) to “clear” drug from

the bloodstream Plasma half- life time taken for its plasma concentration to be reduced to

half of its original value – 2 phases rapid declining and slow declining.

t1/2 = In2/k

Half Life of Oxaliplatin – 391 hrs……… Dose frequency 12 cycles of 2

weeks

KINETICS OF ELIMINATION First Order Kinetics (exponential): Rate

of elimination is directly proportional to drug concentration, CL remaining constant Constant fraction of drug is eliminated per unit

time Zero Order kinetics (linear): The rate of

elimination remains constant irrespective of drug concentration CL decreases with increase in concentration Alcohol, theophyline, tolbutmide etc.

EXCRETION - THE PLATUE PRINCIPLERepeated dosing:

• When constant dose of a drug is repeated before the expiry of 4 half-life – peak concentration is achieved after certain interval• Balances between dose administered and dose interval

WHY DO WE DO IT?

DRUG SAFETY AND EFFECTIVENESS Not all people respond to a similar dose of a drug in the exact

same manner, this variability is based upon individual differences and is associated with toxicity. This variability is thought to be caused by: Pharmacokinetic factors contribute to differing concentrations

of the drug at the target area. Pharmacodynamic factors contribute to differing physiological

responses to the same drug concentration. Unusual, idiosyncratic, genetically determined or allergic,

immunologically sensitized responses.

TARGET LEVEL STRATEGY Low safety margin drugs (anticonvulsants,

antidepressants, Lithium, Theophylline etc. – maintained at certain concentration within therapeutic range

Drugs with short half-life (2-3 Hrs) – drugs are administered at conventional intervals (6-12 Hrs) – fluctuations are therapeutically acceptable

Long acting drugs: Loading dose: Single dose or repeated dose in

quick succession – to attain target conc. Quickly Loading dose = target Cp X V/F

Maintenance dose: dose to be repeated at specific intervals

MONITORING OF PLASMA CONCENTRATION Useful in

Narrow safety margin drugs – digoxin, anticonvulsants, antiarrhythmics and aminoglycosides etc

Large individual variation – lithium and antidepressants

Renal failure cases Poisoning cases

Not useful in Response mesurable drugs – antihypertensives,

diuretics etc Drugs activated in body – levodopa Hit and run drugs – Reseprpine, MAO inhibitors Irreversible action drugs – Orgnophosphorous

compounds

PROLONGATION OF DRUG ACTION By prolonging absorption from the site of

action – Oral and parenteral By increasing plasma protein binding By retarding rate of metabolism By retarding renal excretion