Beruflich Dokumente
Kultur Dokumente
Dr. D. K. Brahma
Department of Pharmacology
NEIGRIHMS, Shillong
What is Pharmacokinetics
how the human body act on the drugs?
ics
Concentration at the
site of action
Effect
The Pharmacokinetic Process
The Pharmacokinetic Process
Biological Membrane - image
Drug Transportation
Drug molecules can cross cell membrane
by:
Passive Diffusion
Protein – mediated transport (carrier mediated)
Facilitated Transport
Active trnsport
Primary
Secondary
Passive transport (down hill
movement)
Most important Mechanism for most of the Drugs
Majority of drugs diffuses across the membrane in the direction of
concentration gradient
No active role of the membrane
Proportional to lipid : water partition coefficient
Lipid soluble drugs diffuse by dissolving in the lipoidal matrix of
the membrane
Characteristics
Not requiring energy
Having no saturation
Having no carriers
Not resisting competitive inhibition
Passive transport
Affecting factors :
the size of molecule
lipid solubility
polarity
degree of ionization
the PH of the environment
such as: fluid of body
fluid in cell
blood, urine
Remember
The drugs which are Unionized, low polarity
and higher lipid solubility are easy to
permeate membrane.
The drugs which are ionized, high polarity
and lower lipid solubility are difficult to
permeate membrane.
pH Effect
Most of drugs are weak acids or weak bases.
The ionization of drugs may markedly reduce their
ability to permeate membranes.
The degree of ionization of drugs is determined by
the surrounding pH and their pKa.
Henderson–Hasselbalch Equation
Vena
Intestine cava
Portal
vein
Rectum
Buccal and Rectal – bypasses liver
Vena
cava
Absorption – contd.
Intravenous administration has no
absorption phase
According to the rate of absorption:
Inhalation→Sublingual→Rectal→intramusc
ular→subcutaneous→oral→transdermal
Example – Nitroglycerine:
IV effect – immediate, SL – 1 to 3 min and
per rectal – 40 to 60 minute
Bioavailability
Bioavailability refers to the rate and extent of absorption of
a drug from dosage form as determined by its
concentration-time curve in blood or by its excretion in
urine. It is a measure of the fraction (F) of administered
dose of a drug that reaches the systemic circulation in the
unchanged form
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.
Bioequivalent
Practical Significance – low safety margin drugs
Biovailability - AUC
AUC – area under
the curve AUC p.o.
Plasma concentration
(mcg/ml)
F = ------------
F – bioavailability x 100%
AUC i.v.
0 5
Time (h) 10 1
5
Biovailability – contd.
MTC
MEC
2. Distribution of Drugs
It 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
Movement of drug - until equilibration between
unbound drug in plasma and tissue fluids
Volume of Distribution (V)
Definition: 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
Expressed as: in Liters
Dose administered IV
V=
Plasma concentration
Volume of Distribution (V)
• Phase I or Non-synthetic –
metabolite may be active or
inactive
• Phase II or Synthetic –
metabolites are inactive
(Morphine – M-6 glucoronide is
exception)
Phase I - Oxidation
Most important drug metabolizing reaction –
addition of oxygen or (–ve) charged radical or
removal of hydrogen or (+ve) charged radical
Various oxidation reactions are – oxygenation or
hydroxylation of C-, N- or S-atoms; N or 0-
dealkylation
Examples – Barbiturates, phenothiazines,
paracetamol and steroids
Phase I - Oxidation
Involve – cytochrome P-450 monooxygenases (CYP), NADPH and Oxygen
More than 100 cytochrome P-450 isoenzymes are identified and grouped
into more than 20 families – 1, 2 and 3 …
Sub-families are identified as A, B, and C etc.
In human - only 3 isoenzyme families important – CYP1, CYP2 and CYP3
DOPA-
Levodopa (DOPA)
decarboxylase
Dopamine
Phase I - Hydrolysis
This is cleavage of drug molecule by taking up of a molecule of
water. Similarly amides and polypeptides are hydrolyzed by
amidase and peptidases. Hydrolysis occurs in liver, intestines,
plasma and other tissues.
Examples - Choline esters, procaine, lidocaine, pethidine, oxytocin
Esteras
Ester + H20 e
Acid + Alcohol
Phase I – contd.
Cyclization: is formation of ring structure
from a straight chain compound, e.g.
proguanil.
Decyclization: is opening up of ring
structure of the cyclic molecule, e.g.
phenytoin, barbiturates
Phase II metabolism
Conjugation of the drug or its phase I metabolite with an endogenous substrate -
polar highly ionized organic acid to be excreted in urine or bile - high energy
requirements
acid.
Ribonucleoside/nucleotide synthesis:
activation of many purine and pyrimidine
antimetabolites used in cancer chemotherapy
Factors affecting Biotransformation
Factors affecting biotransformation
Concurrent use of drugs: Induction and inhibition
Genetic polymorphism
Pollutant exposure from environment or industry
Pathological status
Age
Enzyme Inhibition
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 – quinidine
Some enzyme inhibitors – Omeprazole,
metronidazole, isoniazide, ciprofloxacin and
sulfonamides
Microsomal Enzyme Induction
CYP3A – antiepileptic agents - Phenobarbitone,
Rifampicin and glucocorticoide
CYP2E1 - isoniazid, acetone, chronic use of alcohol
Other inducers – cigarette smoking, charcoal broiled
meat, industrial pollutants – CYP1A
Consequences of Induction:
Decreased intensity – Failure of OCPs
Increased intensity – Paracetamol poisoning (NABQI)
Tolerance – Carbmazepine
Some endogenous substrates are metabolized faster – steroids, bilirubin
4. Excretion
Organs of Excretion
Excretion is a transport procedure which the
prototype drug (or parent drug) or other metabolic
products are excreted through excretion organ or
secretion organ
Hydrophilic compounds can be easily excreted.
Routes of drug excretion
Kidney
Biliary excretion
Sweat and saliva
Milk
Pulmonary
Bile duct
Hepatic Excretion
Drugs can be excreted in Intesti Portal
bile, especially when the are
conjugated with – glucuronic nes vein
Acid
Weak acids ionized more and are less reabsorbed in alkaline urine
Time
CL = RoE/C
t1/2 = In2/k
In2 = natural logarithm of 2 (0.693)
k = elimination rate constant = CL / V
t1/2 = 0.693 x V / CL
Plasma half-life
50 + 25 + 12.5 +
1 half-life …………. 50% 6.25 = 93.75
Repeated Dosing
At steady state, elimination = input
Cpss = dose rate/CL
Dose Rate = target Cpss x CL
In oral administration
Dose rate = target Cpss x CL/F
In zero order kinetics: follow Michaelis Menten
kinetics
RoE = (Vmax) (C) / Km + C
Vmax = max. rate of drug elimination, Km = Plasma
conc. In which elimination rate is half maximal
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 measurable 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
Summary – Must Know
Definition of Pharmacokinetics
Transport of Drugs across Biological Membrane – different
processes with example
Factors affecting absorption of drugs
Concept of Bioavailability
Distribution of Drugs – Vd and its concept
Biotransformation Mechanisms with examples
Enzyme induction and inhibition concept and important examples
Routes of excretion of drugs
Orders of Kinetics
Definition and concept of drug clearance
Definition of half life and platue principle