Pharmacokinetics & Its clinical importance

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:
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
4

From mouth:
 Lipid soluble basic/neutral drugs absorbed.
 1st pass metabolism bypassed.
eg. Isosorbide dinitrate given sublingually
5

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.
9

Absorption via Lungs:
 Simple diffusion.
 Rapid---> large surface area, high vascularity.
 Absorption increases due to +ve pressure.
 First pass metabolism avoided.
 eg. Salbutamol spray.
10

Absorption via Topical Sites:
 Poor absorption in intact Skin.
 Mucous membrane  Highly vascular.
 Ophthalmic drop  Cornea
eg: Nitroglycerin patch, pilocarpine
containing ocular inserts.
11

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?
12

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 Tourniquet
13

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]
16

Calculation of AUC:
a. By Planimeter.
b.Cut & Weight Method.
c. Trapezoid rule.
17

Fig: Parameters of Bioavailability
18

Factors Influencing Absorption & Bioavailability:
19
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

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.
21

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.
23

• 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.
24
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 complex
25

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]
26

Clinical Importance of Plasma Protein Binding:
1. Plasma α1-AGP = acute phase reactant protein.
Increases in MI, Crohn’s disease etc. Binding of
basic drug increases. eg. Propanolol
2. Highly protein bound drugs
i) Restricts to vascular compartment and have
lower Vd.
ii) Difficult to remove by Dialysis
3. In diseases causing hypoalbuminemia therapeutic
dose can lead to higher conc. of drug.
27

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
28

Volume of distribution: It has physiological meaning, &
related to the Body Water.
29

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
30

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.
31

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.
33

Redistribution of Drugs:
 Typical mode of drug distribution
observed with highly Lipid-soluble
drugs.
eg: Anaesthetic effect of Thiopentone is
rapid but effect get terminated due to
redistribution in muscle and fat.
34

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.
36

Biotransformation:
• Enzyme catalysed biochemical
transformation.
• Within Living organism
• Occurs mainly in LIVER.
37

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
39

Drug Metabolising Enzymes:
i) Microsomal Enzymes
ii) Non-microsomal Enzymes
iii) Non-enzymatic Biotransformation
40

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. CYP2D6
41

ii)Non-Microsomal Enzymes:
 Present in Cytoplasm, Mitochondria of hepatic
cells & Plasma.
 Catalyse Phase II reactions (except Glucuronide
conjugations).
Eg. Monoamine oxidase, Transferase.
42

iii) Non-enzymatic Biotransformation:
 No involvement of any enzyme action
 Drugs metabolized in Plasma through
Molecular Rearrangement.
Eg. Atracurium (Hoffmann Elimantion)
43

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. CYP2D6
44

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.
45

CYP overview:
CYP3A4, 3A5,
50%
CYP2D6, 30%
CYP2C8,2C9, 10%
Micellaneous,
10%
46

CYP3A4 & CYP3A5:
 50 % of drugs are metabolised.
 Present in Liver, intestine, kidney.

47
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
48

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.
49

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.
50

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
51

Non Microsomal Oxidations (CYP Independent):
 Cytoplasmic Oxidations (dehydrogenations):
eg. Alcohol
Alcohol dehydrogenase
Acetaldehyde
Aldehyde dehydrogenase
Acetic Acid.
C2H5OHCH3CHOCH3COOH
 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.
54

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.
55

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.
58

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.
60

Routes of Elimination:
Major Routes Minor Routes
Renal Milk
Biliary Skin
Fecal Hair
Alveolar Sweat & Saliva
62

Renal Excretion:
 Most important organ for Elimination.
 Free drugs (eg. Frusemide, gentamicin)
 Drug Metabolites.
63

Processes that determine renal excretion:
i. Glomerular filtration.
ii. Active tubular Secretion.
iii. Passive tubular reabsorption.
64

Factors of Glomerular filtration:
i. Molecular size.
ii. Plasma protein binding
iii. Renal Blood Flow.
65

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
66

Tubular Reabsorption:
 Passive diffusion.
 Factors :
Lipid solubility.
Ionisation constant (pKa)
pH of Urine.
Clinical Importance:
Alkalisation of Urine in Salicylate or barbiturate
poisoning.
67

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.
69

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.
70

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.
71

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.
72

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.
73

Kinetics of Drug Elimination:
 First order kinetics.
 Zero order kinetics.
 Mixed order kinetics.
74

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.
75

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 remain
constant 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.
77

(contd.)
 After a single dose, about 97% of the drug gets
eliminated after 4-5 half-lives (t ½) interval.
 Steady state Concentration:
78

(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
81

 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 plotted
against time, the resultant “plasma fall-out
curve” is steeply linear, but if logarithm of
plasma 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 plasma
concentrations are plotted against time, the
resultant curve remains linear in the beginning
(zero order) and then become predominantly
exponential ( 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 [t½ 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

Pharmacokinetics & Its clinical importance

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Pharmacokinetics & Its clinical importance