Pharmacokinetics

&

Its Clinical Importance

Presenter:

Dr. Bijoy Bakal

Pharmacokinetics:

• It deals with the

»Absorption

»Distribution

»Metabolism of DRUGS.

»Excretion

• It is a branch which deals with “ What the

BODY DOES to the DRUG.2

Absorption:

3

Absorption:

A drug can be absorbed from the following sites:

1. GI tract Mouth

Stomach

Intestine

Large Intestine or Colon

2. Parenteral Sites : iv> im> sc

3. Lungs.

4. Topical Sites. eg. Eye drops.

Sublingual Rectal Oral

Rate of absorption, fastest to lowest

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From mouth:

Lipid soluble basic/neutral drugs absorbed.

1st pass metabolism bypassed.

eg. Isosorbide dinitrate given sublingually

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Stomach:

Lipid soluble acidic/neutral drugs absorbed.

Drug undergo First pass metabolism after

absorption.

6

Intestine:

Lipid soluble basic/neutral drugs absorbed.

eg. Morphine.

Major site of absorption.

First-pass effect.

Enterohepatic circulation- Drug secreted in

intestine through bile are reabsorbed back. eg.

Ezetimibe, Morphine.7

Large intestine or Colon:

Basic/ Neutral Drugs absorbed.

Absorption from External Haemorrhoidal

vein have minimal first-pass effect.

8

Parenteral Sites:

Complete absorption, rapid distribution.

Absorption following i.m., s.c. – passive

diffusion.

i.v.> i.m.>s.c.

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Absorption via Lungs:

Simple diffusion.

Rapid---> large surface area, high vascularity.

Absorption increases due to +ve pressure.

First pass metabolism avoided.

eg. Salbutamol spray.

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Absorption via Topical Sites:

Poor absorption in intact Skin.

Mucous membrane Highly vascular.

Ophthalmic drop Cornea

eg: Nitroglycerin patch, pilocarpine

containing ocular inserts.

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Absorption and its Clinical importance:

• Do we need to increase/facilitate the

Absorption of a Drug?

• Do we need to delay the Absorption of a

Drug?

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Facilitate Absorption Delay Absorption

1. Adding Hyaluronidase

to injection fluid.

1. Using Appropriate

dosage forms. Eg. S/c

implants, Retard tablets

2. Changing Physical

Characteristics of Drugs

2. Increase local blood

flow by hot fomentation

3. Adding a

Vasoconstrictor Drug or

applying a Tourniquet13

Bioavailability:

Rate and extent to which the active concentration

of the drug is available at the desired site of

action after non-vascular route of administration.

It is an absolute term.

AUC (oral)

Drug Bioavailability(%) = -------------- x 100

AUC (iv)14

Equivalence: Comparison of two brand products of the same

drug with a set of established standards.

It is a relative term.

It can be of several types:

Bioequivalence.

Chemical Equivalence.

Clinical Equivalence.

Therapeutic Equivalence.15

Measurement of Bioavailability:

From the plasma conc.-time curve we get:-

1. Cmax

2. Tmax

3. AUC [expressed in mg-hr/ml]

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Calculation of AUC:

a. By Planimeter.

b. Cut & Weight Method.

c. Trapezoid rule.

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Fig: Parameters of Bioavailability18

Factors Influencing Absorption & Bioavailability:

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Pharmaceutical Factors Pharmacological factors

Particle Size Gastric Emptying & Motility

Salt Form GI Disease

Crystal Form Food & other substance

Water of Hydration First pass effect

Nature of Excipients & Adjuvants Drug-Drug Interactions

Degree of Ionization Pharmacogenetic Factors

Drug Distribution:

After absorption of a drug it may:-

Reversibly attached with its site of action.

Bound to plasma Proteins.

Accumulate in various storage sites.

Enter into tissues.

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Barriers to Drug Distribution:

• Blood-Brain Barrier [BBB] (by glial cells)

• Blood-CSF and CSF-Brain Barrier.

• Placental Barrier.

22

Clinical Importance of The Barriers:

• BBB Protects brain tissue from toxic substances.

• Inflammatory conditions like cerebral meningitis alter permeability of BBB

Drugs like Penicillin, Chloramphenicol exhibit increased permeability.

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• CSF-Brain barrier permeable to drug molecules

If drug given by intrathecal route it reach the brain

in sufficient concentrations.

eg: Penicillin in Brain Abscess.

• Hypoxia increases permeability of drugs through

placental barrier.

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Clinical Importance of The Barriers (contd):

Special Compartments for Drug Distribution:

Cellular Reservoir. eg. Digoxin

Fat as Reservoir. eg. Thiopentone

Transcellular Reservoir. eg. Chloramphenicol in aqueous

humour

Bones & Connective Tissue as Reservoir. eg. Griseofulvin

in Keratin precursor cells.

Plasma protein binding as Drug Reservoir.

Free Drug + Protein Drug-Protein complex25

Important proteins that contribute

to Drug Binding:

1) Plasma Albumin. [acidic drugs]

2) α1-Acid Glycoproteins (α1-AGP). [basic drug]

3) Tissue Proteins & Nucleoproteins. [drugs with high

aVd]

4) Miscellaneous Binding Proteins. [thyroxin to α

globulin, antigens to gamma globulins]

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Clinical Importance of Plasma Protein Binding:

1. Plasma α1-AGP = acute phase reactant protein.Increases in MI, Crohn’s disease etc. Binding ofbasic drug increases. eg. Propanolol

2. Highly protein bound drugs

i) Restricts to vascular compartment and havelower Vd.

ii) Difficult to remove by Dialysis

3. In diseases causing hypoalbuminemia therapeuticdose can lead to higher conc. of drug.

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4. Displacement interactions increase free drug

concentration (of the displaced drug) causing

adverse effects.

Displacement is significant when:-

Clinical Importance (contd.)

Displaced drug is more than 95% protein bound

Displaced drug with extensive protein bounding but lower aVd

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Volume of distribution: It has physiological meaning, & related to the Body Water.

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The volume of each of these compartments can be determined by use of specific markers or tracers.

The intracellular fluid volume can be determined as the difference between total body water and extracellular fluid.

Physiological Fluid Compartments the

Markers Used Approximate volume (liters)

Plasma Evans Blue 4

Extracellular fluid Inulin 14

Total Body Water D2O 42

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Apparent Volume of Distribution (aVd):

aVd = Total amount of drug in body (mg/kg)_

Conc. Of the Drug in the Plasma (mg/L)

It is the total space which should apparently be

available in the body to contain the known

amount of the drug.

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Drugs which bind selectively to Plasma proteins

e.g. Warfarin have Apparent volume of

distribution smaller than their Real volume of

distribution. Vd between 6 to 42 liters.

Drugs which bind selectively to Extravascular

Tissues: e.g. Chloroquine have Apparent volume

of distribution larger than their Real volume of

distribution. Vd greater than 42 liters.

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Redistribution of Drugs:

Typical mode of drug distributionobserved with highly Lipid-solubledrugs.

eg: Anaesthetic effect of Thiopentone israpid but effect get terminated due toredistribution in muscle and fat.

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Metabolism:

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Metabolism:

• Drug molecules are processed by enzymes

evolved to cope with natural compounds

• Drug may have actions increased or

decreased or changed

• Not constant - can be changed by other

drugs.

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Biotransformation:

• Enzyme catalysed biochemical

transformation.

• Within Living organism

• Occurs mainly in LIVER.

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Biotransformation results in formation of:

An inactive metabolite from an active drug.

eg: Phenobarbitone to hydroxyphenobarbitone

Active metabolite from prodrug.

eg: L-dopa to dopamine.

Active metabolite from an equally active drug.

eg: Codeine to morphine.38

First pass metabolism:• It means drug metabolism occurring before

the drug enters the systemic circulation.

• Results is decreased bioavailability.

• Decreased therapeutic response.

Bypass First pass metabolism:• IV route

• Sublingual route

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Drug Metabolising Enzymes:

i) Microsomal Enzymes

ii) Non-microsomal Enzymes

iii) Non-enzymatic Biotransformation

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i) Microsomal Enzymes:

Primarily present in LIVER.

Also present in intestinal mucosa, lungs, kidney.

Principal enzyme is Cytochrome P -450.

Non-specific in action.

Concerned primarily with Phase I reactions [&

Phase II Glucuronyl conjugations]

Eg. CYP2D641

ii)Non-Microsomal Enzymes:

Present in Cytoplasm, Mitochondria of hepatic

cells & Plasma.

Catalyse Phase II reactions (except Glucuronide

conjugations).

Eg. Monoamine oxidase, Transferase.

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iii) Non-enzymatic Biotransformation:

No involvement of any enzyme action

Drugs metabolized in Plasma through

Molecular Rearrangement.

Eg. Atracurium (Hoffmann Elimantion)

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CYP: Haemoproteins

In reduce form combine with CO whose product’s absorption peak at 450.

Classification of CYP:

Families designated by numbers. Eg. 1,2,3,4 etc.

Subfamilies by letters A,B, C, D etc.

Another number is added, indicating specific isoenzymes.

Eg. CYP2D644

CYP (contd.):

In humans 12 CYPS responsible for drug metabolism

CYP1A1, CYP1A2, CYP1B1, CYP2B1,

CYP2A6,CYP2B6,CYP2C8,CYP2C9,CYP2C19,CYP2D6,

CYP2E1, CYP3A4,CYP3A5.

Most important of CYPs for drug metabolism are

belong to 3 subfamilies CYP3A,CYP2D, CYP2C.

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CYP overview:

CYP3A4, 3A5, 50%

CYP2D6, 30%

CYP2C8,2C9, 10%

Micellaneous, 10%

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CYP3A4 & CYP3A5:

50 % of drugs are metabolised.

Present in Liver, intestine, kidney.

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Inducers: Inhibitors:Barbiturates Ketoconazole

Rifampicin Erythromycin

Phenytoin Verapamil

Carbamazepine Diltiazem

Ritonavir

CYP2D6: Metabolise 25-30% commonly used drugs.

Inhibitors: Quinidine & Fluoxetine

Inducers: Unknown

Exhibit Genetic Polymorphism.

CLINICAL IMPORTANCE:

Some person may be genetically deficient to CYP2D6.

Such persons are poor responders to analgesic action of Codeine.

They are unable to metabolise Codeine to Morphine

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Chemical Pathways of Drug Biotransformation:

1) Phase I Reactions

- Degradative reactions

- Introduction of new group

2) Phase II Reactions

- Conjugation reactions

- Originally contains NH2, OH, COOH reactive group.

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Phase I Reactions:a) Oxidations [uses enzyme oxidases]

1) Microsomal Oxidations (CYP dependent)

2) Non Microsomal (CYP Independent)

b) Reductions

1) Microsomal Reductions

2) Non-Microsomal Reductions.

c) Hydrolysis

1) Microsomal Reductions

2) Non-Microsomal Reductions.

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Microsomal Oxidations (CYP dependent) :

Aliphatic Hydroxlations:

Eg: Pentobarbitone to hydroxypentobarbitone.

R.CH2.CH3 R.CHOH.CH3

Aromatic Hydroxlations:

N-,O- & S-Dealkylation.

N- & S- Oxidation.

Deamination

Desulfurisation

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Non Microsomal Oxidations (CYP Independent):

Cytoplasmic Oxidations (dehydrogenations):

eg. Alcohol

Alcohol dehydrogenase Acetaldehyde

Aldehyde dehydrogenase

Acetic Acid.

C2H5OHCH3CHOCH3COOH

Microsomal Oxidations.

Plasma Oxidative Process.52

Phase II Reactions:

Conjugations Reactions

Types - i) Microsomal.

ii) Non- microsomal.

Enzymes used:

UDP Glucuronyl Transferase

N-acetyl Transferase

Sulfotransferase (in cytosol)

Eg. Drug + UDPGA Drug glucuronide + UDP

Drugs like Morphine, Diazepam, Aspirin etc.53

Enzyme Induction:

Several drugs induce growth of smooth ER.

Leads to enhance microsomal enzyme

activity.

Accelerated metabolism.

Decrease pharmacological response.

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Clinical Importance of Enzyme Induction:

1.Clinical consequence of increases drug metabolism:

a) Decreased plasma levels & decrease therapeutic effect.

b) Decreased drug effect if metabolite is inactive.

c) Increased drug effect if metabolite is active.

Eg. OCP & Rifampicin Unwanted Pregnancy.

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Clinical Importance of Enzyme Induction: (contd.)

2. Drug toxicity.

eg. Ethanol drinkers have more probability of

developing drug toxicity.

3. For therapeutic benefit.

Eg. For Rx neonatal jaundice phenobarbitone is

used in pregnant mother or in new born.56

Enzyme Inhibition:

One drug may inhibit metabolism of another drug

Increase in circulating levels of slowly metabolised

drug.

Prolongation & Potentiation of effects.

Enzyme inhibition can be either

Hepatic Microsomal Mixed function oxidase

Enzyme with specific functions. Eg Xanthine oxidase.57

Clinical Importance of Enzyme Inhibition:

1) Potentially adverse Consequences:

* Theophylline co-administered with Chloramphenicol Nausea, Tremors, Vomiting.

* Dicumarol with Cimetidine Increased bleeding tendency.

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Clinical Importance of Enzyme Inhibition: (contd.)

2) Therapeutically beneficial Consequences:

* Increased accessibility of L-dopa in brain

when given with Carbidopa .

* Aversion to alcohol after prior disulfiram

therapy. Further conversion of acetaldehyde to

acetic acid prevented vomiting, nausea

headache etc.59

Factors Affecting Drug Metabolism:

Age

Sex

Species

Race

Genetic Variation

Nutrition and Diet

Disease

Drug-drug Interactions.

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Drug Elimination:

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Routes of Elimination:

Major Routes Minor Routes

Renal Milk

Biliary Skin

Fecal Hair

Alveolar Sweat & Saliva

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Renal Excretion:

Most important organ for Elimination.

Free drugs (eg. Frusemide, gentamicin)

Drug Metabolites.

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Processes that determine renal excretion:

i. Glomerular filtration.

ii. Active tubular Secretion.

iii. Passive tubular reabsorption.

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Factors of Glomerular filtration:

i. Molecular size.

ii. Plasma protein binding

iii. Renal Blood Flow.

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Tubular Secretion:

Non-selective Active transport

Two independent carrier systems For acidic drug (eg. Penicillin, salicylic acid)

For basic drugs (eg. Morphine)

Clinical Importance:

Weakly acidic drug (salicylic acid) interfere with secretion of Uric Acid

Increase plasma Uric acid Level

Precipitates GOUT

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Tubular Reabsorption:

Passive diffusion.

Factors :

Lipid solubility.

Ionisation constant (pKa)

pH of Urine.

Clinical Importance:Alkalisation of Urine in Salicylate or barbiturate poisoning.

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Biliary Excretion & Enterohepatic circulation:

Drugs excreted in Bile:-Quinine, Colchicines,

Corticosteroids.

Some drugs secreted through bile but after being

delivered to intestine, are reabsorbed back and

the cycle is repeated. Eg: Digitoxin.

Other drugs with enterohepatic circulation:

Morphine, Chloramphenicol, Tetracycline etc.68

Clinical Importance of Biliary excretion and

Enterohepatic circulation:

In morphine poisoning Gastric lavage is done

to prevent Enterohepatic Circulation.

Rifampicin drug action is prolonged.

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Fecal Elimination:

Orally ingested drug not absorbed in Gut

eg. MgSO4, Neomycin, Certain purgatives

Drugs excreted in bile & not absorbed from intestinal tract.

eg. Erythromycin, Corticosteroids.

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Alveolar Excretion:

Gases & Volatile liquids

eg: General Anaesthetics, Ether, Alcohol

Depends on partial pressure in the blood.

Eucalyptus oil and garlic oil eliminated through

expectoration.

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Elimination through Breast Milk:

May cause unwanted effect in Nursing infant.

Drugs transferred to breast milk according to pH

partition principle.

Basic drugs not ionised at plasma alkaline pH, get

accumulated in Milk.

Eg: Chloramphenicol, Tetracycline, Morphine etc.

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Excretion through Skin, Hair, Sweat & Saliva:

Griseofulvin is secreted through keratin

precursor cells.

Arsenic, Mercury salts & Iodides Hair

Follicles.

Iodine, KI, Li & Phenytoin Saliva.

Amines & Urea derivatives Sweat.

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Kinetics of Drug Elimination:

First order kinetics.

Zero order kinetics.

Mixed order kinetics.

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First order kinetics: Majority of the drugs follow this type of

elimination.

A constant fraction of the drug is eliminated at a constant interval of time.

eg: Plasma concentration declining at a rate of 50% per two hours:

100 µg/ ml 50 µg/ml 25 µg/ ml

12.5 µg/ml and so on.

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First order kinetics: (contd.) The rate of drug elimination is directly

proportional to the plasma concentration.

eg: 200-> 100-> 50-> 25-> 12.5 so on.

The t ½ of any drug would always remainconstant irrespective of the dose.

76

First order kinetics: (contd.)

Plasma concentration is plotted against time , the

resultant “ plasma fall-out curve” curvilinear,

Log of plasma concentration are plotted against

time , the resultant curve linear.

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(contd.) After a single dose, about 97% of the drug gets

eliminated after 4-5 half-lives (t ½) interval.

Steady state Concentration:

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(1st order kinetics:contd)

If the dose of the drug is doubled, its duration

of action is prolonged for one more half-life.

The “log plasma concentration fall-out curve” of

a drug having high aVd, exhibits 2 slopes.

• An initial rapid declining phase due to distribution

(called as α phase)

• Later linearly declining phase due to elimination

(called as β phase) 79

fig : α AND β-PHASE OF DRUG CLEARANCE

80

Zero Order Kinetics:

A constant or a fixed quantity of drug is

eliminated per unit time.

Ethyl alcohol exhibit zero order at virtually all

plasma concentrations.

For eg: if plasma concentration falls at a rate of

25 µg per hour then 50 25 nil

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The rate of elimination is independent of the

concentration of the drug in the plasma. So

increasing the dose does not result in a

proportionate rise in the extent of elimination.

100 75 50 25 Nil

The t ½ of a drug following zero order is never

constant.

Zero Order Kinetics: (contd.)

82

If such a fall in plasma concentration is plottedagainst time, the resultant “plasma fall-outcurve” is steeply linear, but if logarithm ofplasma concentration are plotted against time ,then the curve becomes curvilinear.

83

Mixed Order Kinetics/ Saturation Kinetics / Michaelis-Menten Kinetics:

Dose-dependent kinetics where smaller doses

are eliminated by first order kinetics but as the

plasma concentration reaches higher values ,the

rate of drug elimination becomes zero order.

Phenytoin, warfarin, digoxin, dicumarol.

84

After a single dose administration, if the plasmaconcentrations are plotted against time, theresultant curve remains linear in the beginning(zero order) and then become predominantlyexponential ( curvilinear i.e. first order).

Fig : Plasma concentration fall-out curve in mixed order kinetics.85

Clinical Importance:

Drugs having very short half-life are given by

constant i.v. infusion to maintain steady state

concentration.

For drugs having longer t ½, with high Vd & slow

rate of clearance also are cumulative in nature. To

reach steady state Loading dose given

Maintenance dose.

Loading dose= Desired plasma conc. x aVd.86

Digoxin , 0.25 mg given/24 hour, 5 days a week,

considering its nature of accumulation.

Lignocaine in cardiac arrhythmia- loading dose

given irrespective of shorter t ½.

Loading dose also necessary in case of certain

antibiotics to keep the plasma conc. higher than

MIC.

87

Fixed-Dose Drug Combination:

Rationale fixed-drug formulation of two drugs can

be advantageous.

The drug should have equal t ½. Eg. Cotrimoxazole

(Sulfamethoxazole [t ½ 11 hr]) & Trimethoprim [t ½ 10 hr] )

Ratio of dose depends on aVd & plasma conc. Of

individual drug. eg. t ½ & aVd of Amoxycillin (1-2hr;

0.21 L/kg) matches with t ½ & aVd of Clavulanic acid

(1-1.5hr; 0.20 L/kg ).88

Advantage of Fixed-dose formulation:

Convenient dose schedule.

Better patient compliance.

Enhanced effect.

Minimal side effect.

89

Disadvantage of Fixed-dose formulation:

Dose of component drug can’t be

adjusted independently.

Difficult to identify which component

cause harmful or beneficial effect.

90

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