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PHARMACOKINETICS

INTRODUCTION
The subjects of ‘Drugs’ is as old as disease because illness has
been man’s heritage from the beginning of his existence
...

A Drug is any substance used for the purpose of diagnosis,
prevention, relief or cure of a disease in man or animals
...


Pharmacology is defined as the detailed study of drugs,
particularly their actions on living animals, organs or tissues
...
Pharmacology
covers many fields such as:
v Pharmacodynamics
v Pharmacokinetics
v Therapeutics
v Toxicology
Pharmacodynamics
is the quantitative study of the biological and therapeutic effects
of drugs ( what the drug does to the body)
...


Pharmacokinetics is the study of absorption, distribution,

metabolism and excretion of drugs and their relationship to
pharmacologic response (what the body does to the drug)
...

Bioavailability describes the fraction (F) of a dose (D) of a drug that
enters systemic circulation
...

Bioavailability is therefore determined by the degree of drug
absorption
...

Before a drug can act within the body, it must be absorbed into the
blood stream which carries it to its site of action
...

The route of administration largely determines the latent period
between administration and onset of action
...
g
...
t
...
g
...
t
...
This is referred to as ‘’first-pass effect or presystemic
elimination”
...
e
...
nitroglycerin tablet placed under the
tongue acts within 2-5 minutes
...
g
...
g
...

The rate of absorption from SC or IM sites depends largely on two
factors; solubility of the drug and the blood flow through the
region
...
The more the blood vessels in the subcutaneous area,
the larger the diameter of blood vessels and the greater the rate of
absorption
...


IV route completely by-passes absorption processes, since the drug
is introduced directly into the blood stream
...

Factors Affecting Oral Drug Absorption and its Bioavailability
v Physical properties of the drug (liquids, solids, crystalloids,
colloids , lipid or water solubility )
v Nature of the dosage form ( particle size, disintegration time,
type)
v Physiological factors
v Pharmacogenetic factors
v Disease state

Physiological Factors
I
...

II
...
e
...
salicylates and barbiturates
Ø Basic Drugs are not absorbed in the stomach until they reach the
alkaline environment of the small intestine in unionized form
...
e
...

pethidine and ephedrine
...

Streptomycin, neomycin, mecamylamine, sulfaguanidine e
...
c
...

III
...
t
...
t
...
Absorption of fat soluble vitamins
is reduced by liquid paraffin
...
Enterohepatic circulation: Increases the bioavailability of a drug
...
g
...
Area of the absorbing surface and local circulation:
Drugs can be absorbed better from the small intestine than
from stomach because of the larger surface area of the former
...

VI
...
e
...
propranolol
...


Absorption of drugs from the GIT follows the laws of transfer
of molecules across the biological membrane
...

v PASSIVE DIFFUSION: Bidirectional movement of
molecules occurs down the concentration gradient, without
the input of energy
...

Highly lipid soluble drugs can thus be absorbed by this process
regardless of the pH of the medium
...
Many
inorganic ions such as Na, K, Ca and chloride need active transport through
the respective ion channels
...

A few synthetic drugs are also absorbed by active transport e
...

Majority of the drugs are however not absorbed by active transport
...
g
...


Facilitated diffusion is a special example of carrier mediated
transport, not requiring an input of energy
...
g absorption of cyanocobalamin from the gut
...
Aminoglycoside antibiotics enter the
proximal tubule of the kidney by this mechanism
...
The total body area or body fluid to which a drug is
distributed is known as apparent volume of distribution ( Vd)
Compartments where drugs are distributed are:
v Total body water- Small water-soluble molecules e
...
g
...
g
...
g
...
g
...
In such a situation,
the amount of drug may have to be increased
...
In this case, a normal dose of a drug may lead to
higher concentration in body fluids
...
Assists enteral absorption
II
...
Causes prolong levels of free drug
IV
...
Delays excretion
VI
...
g
...
The drug is made more hydrophilic
II
...

However, this is not always so, and sometimes the metabolites are
as active or more active than the original drug
...
Such
prodrugs remain inactive until they are metabolised in the body to
the active form
For example, levodopa is metabolised to active dopamine, while
methyldopa is metabolised to more active α-methylnoradrenaline

• Majority of drugs , however, are metabolised by the enzymes
resulting in their activation, inactivation and modification
...
Oxidation
II
...
Hydrolysis
IV
...
Microsomal oxidation
involves the introduction of hydroxyl group into the drug molecule
or an alkyl or amino group may be removed e
...
conversion of
phenacetin to active compound to p-acetaminophenol (dealkylation)
or of amphetamine to benzyl-methyl-ketone (deamination)
Oxidation can also be catalysed by non-microsomal oxidative
enzymes e
...
alcohol dehydrogenase oxidize alcohol to aldehyde,
aldehyde dehydrogenase converts aldehyde to carboxylic acid,
Xanthine containing drugs like caffeine, theophylline and
theobromine are oxidized by xanthine oxidase to uric acid
A mitochondrial enzyme monoamine oxidase (MAO) causes
oxidative deamination of substances like adrenaline, 5-HT and
tyramine while diamine oxidases endogenously metabolise
histamine

Reduction: Many halogenated compounds and nitrated aromatic
compounds are reduced by the microsomal enzymes e
...
halothane
and chloramphenicol
Drugs like chloral hydrate and disulfiram are reduced by nonmicrosomal enzymes
Hydrolysis: This is usually carried out by enzymes ‘esterases’ that
hydrolyse (split with addition of water) the esters
...
Drugs
like Ach, procaine, atropine and neostigmine e
...
c
...
After such
inactivation, large molecules are eliminated in the bile while
smaller molecules are excreted in the urine
Phase II or Conjugation reactions are;
I
...
Sulphate conjugation or sulphation
III
...
Glutathione Conjugation
V
...
Methylation

Glucuronic acid conjugation : Glucuronides are produced by the
combination of hydroxyl, carboxyl or amino group of drug molecule with
glucuronic acid catalysed by uridyl-diphosphate-glucuronide transferase
Compounds like morhine (morhine -3-glucuronide), PABA, salicylic acid ,
paracetamol, chloramphenicol, phenol e
...
c
...
Phenols, alcohol, aromatic amines, thiols and paracetamol
undergo this pathway of metabolism
Amino acid (Glycine Conjugation) : This reaction depends on the
availability of CO-enzyme A, glycine and glycine-N-acyclase
...
e
...

Acetylation: Acetylation reaction are common for aromatic amines and
sulfonamides and requires acetyl-COA and N-acetyl transferase
...

There is a bimodal distribution of acetylating ability of individuals
...
In the case of INH, slow
acetylators come down with serious reactions such as peripheral
neuropathy
Methylation: Mainly involves endogenous compounds metabolism and
catalysed by methyltransferases which include phenylethanolamine-Ntransferase (noradrenaline), imidazole-N-methyl transferase (histamine),
catechol-O-methyltransferase (catechols) and S-methyltransferase (thiols)
Epinephrine and norepinephrine are metabolised to metanephrine and
normetanephrine respectively
...
Animal Species and strain
II
...
Genetic endowment
IV
...
Route and duration of drug administration
VI
...
Presence of disease

Renal excretion is ultimately responsible for elimination of most of
the drugs and/or their metabolites
The main route of excretion of drugs and their metabolites is the
urine followed by the faeces (for unabsorbed orally administered
drugs)
Some gaseous or volatile general anaesthetics are eliminated
through the lungs
Drugs may be removed through secretions, such as sweat and milk
Some drugs excreted into the bile are reabsorbed from the intestine
(enterohepatic circulation) thus prolonging the effects of such
drugs

Lipid- soluble drugs are not readily excreted until they are metabolised to
more polar compounds
The processes which contribute to the elimination of drugs from the urine are;
§ Glomerular filtration
§ Active tubular secretion
§ Passive tubular reabsorption
Changes in renal function generally affect all three processes to a similar
extent
Unionized drugs which are well absorbed are filtered at the glomerulus, but
they can diffuse back from the lumen of the renal tubule into the cells lining
the tubules
...
Therefore, great care must
be taken when administering certain drugs like aminoglycosides,
coumarin anticoagulants and potassium salts
Protein binding reduces amount of drug available for filtration the
glomerulus but may be available for secretion by the proximal renal
tubule
...
g
...
g
barbiturates and salicylates; while weak bases are quickly excreted
in an acidic urine e
...
g
when probenecid is co-administered with penicillins, they compete
for tubular secretion and probenecid is secreted instead of
penicillins, prolonging the stay of penicillins in circulation, hence
prolonging their duration of action
2/22/23

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In neonates, renal function is low compared with body mass but matures rapidly
within the first few months after birth
During adulthood, there is a low decline in renal function , approximately 1%
yearly

v
v
v
v
v
v

In elderly patients, a substantial degree of functional renal impairment may be
present
Other Sites of Drug Excretion and Examples of Drugs They Excrete
Lungs: Volatile GAs , alcohol and paraldehyde
Skin: Arsenic, mercury e
...
c
Bile: Novobiocin, erythromycin, phenolphthaleine (undergo enterohepatic
circulation)
Intestines: cascara, senna, heavy metals e
...
c
...
t
...


Biological Half-Life
It is the time taken for one-half (50%) of the administered concentration of a
drug to be removed from the body
...
5%) and four half-life (93
...
3 or 4 Half-lives are required to reach steady state
It gives an idea how long it takes a drug to be eliminated from the body e
...

50% of drug remain after 1 half-life, 25% remain after 2 half-life, 12
...
25% after 4 half-life
...
This is important in
drug toxicity
It may also be used to estimate an appropriate dosing interval

MCQ QUIZ
• Which of the following is NOT a pharmacokinetic
process?
• A
...
Excretion
• C
...
Receptor binding
• Which of the following formulas defines
bioavailability?
• A
...
Plasma concentration of unbound drug ÷ total
plasma drug concentration
• C

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