Pharmacokinetics

Dr. Mizanur Rahman

Pharmacokinetics
• Pharmakon means drug, kinein means move.
• It is the branch of pharmacology which deals
with
• Absorption
• Distribution
• Metabolism &
• Excretion of drugs
• What the body does to the drug
 Pharmacokinetics
• Absorption • Pharmacokinetic principles
• Distribution • Bioavailability
• Half life
• Biotransformation • Volume of distribution
• Enzyme induction
• Clearance
• Enzyme inhibition
• First pass metabolism • Dosage regimens
• Elimination
• Entero-hepatic circulation
Overview
What is our target
Estimate Initial Dose
- Target level
- Loading dose
- Maintenance dose

Begin therapy

Assess therapy
- Patient response
- Drug level

Refine dose estimate and

Adjust dose
Absorption of drug
• The process by which drug enters into the systemic circulation
from the site of administration ( except intravenous and
intraarterial route)through biological barrier.
Administration

• Barrier for drugs

Cross lipid barriers/ cell walls
• Lipid bilayer of cell membrane
• Blood brain barrier/ Blood placental barrier
Distribute

Cellular target
 Absorption of drug
• Sites of absorption
• Alimentary tract
• Skin
• Respiratory membrane
• Capillary wall for IM /Subcutaneous route
• Process of absorption
• Simple diffusion
• Active transport
• Facilitated transport / diffusion
• Ion paired transport
 Absorption of drug
Factors influence absorption
• Factors related to drug Factors related to site
• Lipid solubility • Surface area of absorption
• Size of the drug • Vascularity
• Degree of ionization • Gastric empty rate
• Concentration of drug • PH of the environment
• Formulation of drug • Peristalsis
• Physical state of drug
• GIT disease
• Excipient used
• Presence of food in gut
• Presence of 2nd drug
• Presence of other substance
• Route of administration
• Availability of carrier or energy for
specialized transport
 Formultablet
ation
• Rate of disintegration of 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
 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
Distribution of Drug
Fundamental factors Pathological factors
• Physio-chemical property of drug
 Cardiac output
• Solubility
• Ionization  Liver disease
• size
 Renal disease
• Plasma protein binding of drug
 Malnutrition
• Cellular binding of drug
Physiological factors
• BBB
• BPB
• Regional blood flow
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
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
Bioavailability
• Means the fraction of administered drug available in
unchanged form in the systemic circulation from the site of
absorption.
• 2 phase
• Rising phase & Falling phase
Bioavailability
Factors modifying bioavailability of drug
• Route of administration
• Dose of the drug
• Dosage formulation of a drug
• Size of the drug
• Solubility
• PH of the drug and PK of the media
• Character of the excipient
• First pass metabolism
• Surface area of gut
• Gut motility
• Blood flow
• Interaction with food and 2nd drug
 Distribution: body fluid compartments

Plasma Interstitial Intracellular Transcellular

Water Water Water Water
5% 16% 35% 2%

Fat
20%

Free drug can move between compartments. Depends on:

- permeability
- binding
- pH partition
- fat:water partition
Volume of distribution
• The volume of fluid into which drug appears to be distributed in the body in
a conc. equal to that in plasma is called volume of distribution.
• Volume of Distribution = Amount of drug in the body
Plasma Concentration of drug

• Apparent volume of distribution is the theoretical volume that would

have to be available for drug to disperse in if the concentration
everywhere in the body were the same as that in the plasma or serum
• Significance of high Vd and low Vd.
It is the volume apparently necessary to contain the amount of
drug homogeneously at the concentration found in the blood,
plasma, or water.

Drugs with very high volumes of distribution have much higher

concentrations in extravascular tissue than in the vascular
compartment, ie, they are not homogeneously distributed.

Drugs that are completely retained within the vascular compartment,

on the other hand, have a minimum possible volume of distribution
equal to the blood component in which they are distributed.
Clearance
• Clearance relates the rate of elimination to the plasma concentration.
• Ability of organs of elimination (e.g. kidney, liver) to “clear” drug from
the bloodstream.
• Volume of fluid which is completely cleared of drug per unit time.
• Units are in L/hr or L/hr/kg

• Clearance = Rate of elimination of drug

plasma drug concentration
• Clearance is constant for a drug. It depends on drug and condition of
organ of elimination of that drug of the patient.
 Clearance
• Zero Order Elimination • First Order Elimination
• [drug] decreases linearly • [drug] decreases
with time exponentially w/ time
• Rate of elimination is • Rate of elimination is
constant proportional to [drug]
• Rate of elimination is • Plot of log [drug] or
independent of [drug] ln[drug] vs. time are
• No true t 1/2 linear
• t 1/2 is constant regardless
of [drug]
Clearance
 Rate of elimination =
clearance x plasma drug conc.
 VD is a theoretical Volume
and determines the loading
dose.
 Clearance is a constant and
determines the maintenance
dose.
Half life
• Time required by a drug to come its ½ from its peak plasma
concentration (or during a constant infusion).
• Half life is constant
for a drug.

• T½= 0.693 x Vd
CL
Half life
• Factors that can affect half life.
• Significance of long / short half life.
• Therapeutic advantage and disadvantage.
• Importance
• Give gross idea about pharmacokinetics & pharmacodynamics
• Duration of action
• Frequency of administration & dosage schedule
• Give an idea about dosing required for steady state conc. of
drug in blood.
Steady-State
• Rate in = Rate Out
• Steady-state occurs after a drug has been given
for approximately 4 – 5 elimination half-lives.
• At steady-state the rate of drug administration
equals the rate of elimination and plasma
concentration - time curves found after each
dose should be approximately superimposable.
Accumulation to Steady State
100 mg given every half-life
194 … 200
187.5
175

150

100

87.5 94 97 … 100

75

50
Dosage regimens
• A dosage regimen is a plan for drug administration over a period of time.
• An optimal dosage regimen results in the achievement of therapeutic level
of a drug in the blood without exceeding the minimum toxic concentration.
• Therapeutic dose : dose which produce optimum therapeutic effect.
• ED 50 : dose produce desired pharmacological effect in 50% test animal.
• Toxic dose
• TD 50
• Lethal dose
Therapeutic Index : ratio of TD 50 (or LD 50) to ED 50.

This is a measure of a drug’s safety

A large number = a wide margin of safety
A small number = a small margin of safety
Dosage regimens
• Therapeutic window : safe range between minimum effective
therapeutic dose / concentration and minimum toxic dose /
concentration.
• Also a safety indicator.

• Drugs with narrow therapeutic windows require smaller and more

frequent doses or a different method of administration
• Drugs with slow elimination rates may rapidly accumulate to toxic
levels….can choose to give one large initial dose, following only
with small doses
Dosage regimens
• Maintenance dose : Dose required to maintain desired therapeutic effect.
• Maintenance dose
= CL x Desired plasma concentration
Bioavailability
• Here desired plasma con. is avg. steady state concentration.
• Maintenance dose will be in mg/hr so for total daily dose will need multiplying
by 24
• The number of dose to be given per day is determined by half life of the
drug and therapeutic window.
• Maintain drug conc. above minimum therapeutic level at all time.
• Low therapeutic window → frequent dosing.
Dosage regimens
Loading dose : If therapeutic concentration must be achieved
rapidly and Vd is large lording dose may be needed.

• Loading dose = Vd X Desired plasma concentration

Bioavailability
Adjustment of dose when elimination is impaired:
• Corrected dose = average dose x Patient CCR
100 ml/min
• CCR = (140 – age) X body wt. in Kg x 0.85 in case of female
72 x S. creatinine
Biotransformation of drug
• Chemical alteration of drug in a living body which bring
about alteration of lipid solubility of the drug & its
biological activity
• Aims / Result
• Sites
• Pro-drug
• Phases
• Phase I
• Phase II
Biotransformation of drug
Phase I / Non synthetic phase:
• Usually converts parent drug to a more polar metabolites by introducing or
removing a functional group. No new product.
• Fate
• Cellular Site
• Microsomal
• Non-microsomal
• Requirement
• Cyt. P 450
• NADPH
• Enzymes
• O2
Biotransformation of drug
Phase II / Synthetic phase:
• Parent drug or Phase I metabolites conjugates with endogenous substance
( glucoronic acid, amino acid) to yield a drug-conjugates complex which are
polar and readily excretable through the kidney.
• Fate
• Polar group add
• Biological activity terminate
• Excrete out.
• Enzymes
• Microsomal- Glucuronidation
• Non-microsomal-Sulfation, Amino acid conjugation, Acetylation, Methylation.
Factors modifying biotransformation
re-systemic metabolism

Age  Pathological condition

Sex  Environmental condition
Race  Enzyme induction
Nutritional factor  Enzyme inhibitor
Genetic factors
Slow acetylator
Rapid acetylator
 Metabolism
• Pre-systemic metabolism
• Hepatic first pass metabolism.

Liver

Gut
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
Enzyme Induction
• It is the process of increasing synthesis and activity of hepatic
microsomal enzymes by repeated administration of inducing
drug/agents results in increased metabolism of the inducer and also
co-administered drugs.
• Mechanism:
• Increase synthesis of microsomal enzyme.
• Increase the rate of metabolism by 2-4 folds.
Enzyme Induction : Significance
• Therapeutic failure of the primary drug.
• OCP + Rifampicin
• Development of tolerance
• Phenobarbitone
• Increase metabolism of drug to toxic metabolite.
• Metabolism of endogenous substance
• Rifampicin + Steroid
• Antiepileptic drug + Vit D
• Variation of Individual drug response
Enzyme Inhibition
• Inhibition of drug bio-transforming enzyme.

• Significance:
• Drug Toxicity
• Cimetidine + Warfarin results Hemorrhage
• Decrease cost of therapy
• Cyclosporine + Ketoconazole
Drug Excretion
• Major Routes
• Kidney
• Hepato-biliary process
• GIT
• Lungs
• Minor Routes
• Skin
• Saliva
• Breast milk
• Tear
• Hair/Nail
Elimination by the Kidney
1. Glomerular filtration
• Molecular Weight.
• Plasma protein binding
• Concentration of drug
• Renal blood flow
• GFR
• Polarity of drug
2. Active tubular secretion

3. Tubular reabsorption
• Lipid solubility of drug
• Degree of PH
• acidification/ alkalization of urine.
• Acidic drug –Acidic urine : Less polar-More reabsorption-less excretion. Vise
versa
Elimination by the Liver
• Metabolism - major
1) Phase I and II reactions

2) Function: change a lipid soluble to more

water soluble molecule to excrete in kidney

3) Possibility of active metabolites with same

or different properties as parent molecule

• Biliary Secretion – active transport, 4 categories

The Enterohepatic Shunt
Drug Liver

Bile Bile formation

duct
Biotransformation;
Hydrolysis by glucuronide produced
beta glucuronidase
gall bladder

Portal circulation

Gut
Prolongation of Drug Action
• Change of route
• SR/Spansule capsules
• Modification of formulation
• SC/IM/Transdermal Patch
• Increase plasma protein binding
• Reducing rate of distribution
• Adrenalin +Local anesthesia
• Reducing rate of metabolism
• Chemical modification/Enzyme inhibitor
• Reducing renal excretion
• Penicillin + Probencid
 Pharmacokinetics
• Absorption • Pharmacokinetic principles
• Distribution • Bioavailability
• Half life
• Biotransformation • Volume of distribution
• Elimination • Clearance
• Order Of kinetics
• Dosage regimens