Pharmacokinetics.pptx

 Pharmacokinetics:
 It is a branch of pharmacology
which deals with-
absorption
distribution
metabolism
and excretion
body
drug

Process of drug absorption (for oral
drug)
Drug orally given

GIT

Disintegration (to form granules )
into small molecules

Dissolution into the aqueous media

Absorption

Drug absorption
 Movement of the drug from its site of administration to
systemic circulation by crossing biological membrane.
 Why drugs should be transported?
In order to reach its site of action and for producing
biological functions.
 So, for absorption, drug needs crossing of the cell
membrane.
•Fastest route of absorption→ Inhalation
•Movement of the drug from one side of the biological
membrane to the other is called “Bio-transport”

Drug absorption
 Cell membrane consists of-
Lipid bilayer with
Integral membrane proteins

Drug absorption
• Lipid layers have “tight junction”
 Only lipid soluble substances can diffuse through it…..
 Large Water soluble substances can’t cross through tight lipid
layer.
Drug transport processes
Simple diffusion Specialized transport Pinocytosis
Also called as passive
diffusion/non-ionic
diffusion
Two types-
•Active transport
• Facilitated diffusion
 Most of the drugs (>90%) are absorbed by simple
diffusion.

Simple diffusion
occurs Through-
A- Aqueous channel
For small molecules (150-200
MW)
B- cell membrane
For large molecules (most
of the drugs >200MW)
 Only lipid soluble drugs can
cross by this process.
Filtration is passage of drugs
through aqueous pores present
in the membranes or through
paracellular spaces
•Most lipid soluble drugs readily move
across membranes (lipid diffusion)
•Drug moves across membranes
according to concentration
gradient(higher →low conc.)
•No carrier is involved
•Rate of transport is directly
proportional to conc. gradient

Facilitated diffusion:-
 Carrier mediated without energy consumption against concentration
gradient(higher to lower) but doesn’t required energy so called
facilitated transport
 Transfer due to absorption of other molecule which facilitate
movement of drug molecule
 It can be inhibited
e.g.-glucose is transported along with
sodium in direction of
Concentration gradient by GLUT-4
Specialized Transport

• Carrier mediated with energy consumption
• Involves specific carrier protein
• Involves energy expenditure
• Drugs can move against concentration gradient
 E.g.- absorption of
iron using transferrin
from gut.
Active Transport
Lower conc Higher conc

Pinocytosis
• Dugs trap into cells by pseudopods and formed
vesicles contains lysosome which converts
drugs into active form.
• It also required cellular energy
e.g.-
Insulin
T3 and T4 in thyroid

Factors influencing drug absorption
Physiochemical factors:
Lipid solubility of drug
 Degree of ionization
(polarity)
 Particle size of drug
 pKa of the drug
Salt form of the drug
Drug disintegration &
dissolution rate
Host factors or Biological
factors
Surface area
 Motility of GIT
 Blood supply at the
absorptive area
 Presence of other Substances
 Disease state
 Destruction of drug in GIT
 Surrounding Medium pH

 Lipophilic drugs easily cross membrane
 Lipophobic/hydrophilic drugs have problem crossing
membrane
 This is a major source of variation in drug diffusion or
absorption.
Lipid solubility of drug

 Less ionization more absorption & vice versa
 Only a non-ionized (non polar) drugs diffuses across the
membrane.
Non polar drugs are lipid soluble.
Polar drugs are water soluble, they can’t cross the biological
membrane.
The more ionized a drug→→ more water Soluble→Less
absorption
The less ionized a drug→→more lipid Soluble →More
absorption
DEGREE OF IONIZATION (POLARITY)

Drug absorption:-
C
E
L
L
M
E
M
B
R
A
N
E
Ionized Molecule
(water soluble)
Non-Ionized Molecule
(lipid soluble)

Particle size:-
The absorption of the drug can be increased by
increasing the particle surface area by micronization.
16
Smaller the
drug particle
Greater the
surface area

 pKa: is the pH where the concentration of ionized
and non-ionized drug form is equal.
Degree of ionization (polarity) depends on the pKa
of drug (and pH of body fluid).
 If pKa of a drug is equal to pH of the media, then…
“50% of the drug are ionized & 50% are non-ionized”
Drug pKa

SALT FORMATION OF A DRUG:
Salt of weak acid and weak
bases have much higher
aqueous solubility than the
free acid or base.
18

Disintegration & dissolution rate of drug
Rapid Disintegration- more absorption
Rapid Dissolution- more absorption

Surface area
The more absorptive surface area, the more absorption
Surface area of intestine is far greater than the SA of
stomach, so more drug absorption takes place in Intestine

Motility of GIT
- Drugs are better absorbed in normal GIT movement
- Diarrhea - ↓↓absorption
Blood supply at the absorptive area
- The more circulation
- the more maintenance of concentration gradient
- The more absorption

drugs given orally, food can increase or decrease the
absorption.
E.g.-
hypolipidemic drugs like the statins with food- are better
absorbed
Iron when given with milk has decreased absorption.
Vitamin C enhances the absorption of iron.
Milk decreases the absorption of tetracyclines.
Presence of other Substances

DISEASE STATE
• GI Disease:- disease such as malabsorption affect
the absorption of drugs
• Disorders such as hepatic cirrhosis influence bio-
availability mainly of drugs that undergo
considerable first-pass hepatic metabolism e.g.
Propranolol
• Cardiovascular disease also affect the absorption
of drugs

Destruction of drug in GIT
In GIT, there are gastric HCl, enzymes etc.
So, drugs may be destroyed in GIT before absorption
Example:
Benzyl penicillin is destroyed by gastric HCL
Insulin is destroyed by proteolytic enzymes

 Acidic drug better absorbed in acidic media.
 Basic drug better absorbed in basic media.
Acidic drugs (Aspirin) are better absorbed in stomach
(in acidic media)
and
Basic drugs (Diazepam) are better absorbed in intestine
(in alkaline media)
Effect of Surrounding Medium pH
on Drug Absorption

Continue……….
Acidic drug better excreted in basic media.
Basic drug better excreted in acidic media
 In case of acidic drug poisoning alkalization done to
promote excretion of that drug.
and
 In case of basic drug poisoning acidification done to
promote excretion of that drug.

Bioavailability (BA)
Bioavailability is the fraction or percentage of administered drug that
reach to the systemic circulation in unchanged form.
Or
Bioavailability refers to the rate and extent of absorption of a
drug from dosage form
If 100 mg of drug A is administered orally & 60 mg
reaches in systemic circulation-
then the oral bioavailability of drug A is 60%

 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.
 BA→ Measured by its concentration-time curve in blood or by its
excretion in urine.

Biovailability
Time (h)
5 10
AUC – area under the curve
F – Bioavailability
Plasma
concentration
(mcg/ml)
F=
Amount of drug in the plasma after oral dose
Amount of drug in the plasma after IV dose

First pass Metabolism(pre-systemic elimination/first
pass effect)
-when drugs are administered orally they have to pass via gut wall,
portal vein, liver and systemic circulation. During this passage certain
drug get metabolized and are removed or inactivated before they
reach the systemic circulation.
e.g.-lignocaine(liver),isoprenaline(gut wall)
Where ? (Site)
 Liver
 Gut wall
 Gut Lumen
Result ?
Low Bioavailability
Short duration of action (t ½).

First-pass metabolism
can occur with orally
administered drugs.

Some example of drugs with high first
pass metabolism
Alprenolol
Glyceryl trinitrate
Hydrocortisone
Isoprenaline
Lignocaine
Morphine
Neostigmine
Pentazocine
Pethidine
Propranolol
Salbutamol
Testosterone
Verapamil

How to avoid first pass effect:-
1.Increase the dose of orally administered drug as
propranolol and nitro-glycerine
2.Change the route of administration: The drug may be given
iv as benzyl penicillin and lidocaine

1st pass Elimination – Metabolism in liver
Buccal cavity
Stomach
Intestine
Rectum
Portal
vein
Vena
cava
internal hemorrhoid
vein

Factors influencing oral bioavailability of drug:
1st pass hepatic metabolism
+
Factors influencing drug absorption

Bioequivalence (BE)
 Two preparations of a drugs are consider Bioequivalence when-
“There is no significant difference in the rate and extent of
bioavailability between two different preparations of same drug”
Based on plasma conc. Achieved if two or more dosage forms of
same drug achieved the same BA they are called bioequivalent.

If two different drugs produce the same
therapeutic or clinical response they are called
therapeutic equivalent.
e.g.-imipramine and fluoxetine produce the same
effect for the treatment of endogenous
depression

“ The response produced by the two or more brand of a
generic drug is same they are called clinically equivalent.”
e.g.-if the response produced by 500mg calpol & 500mg
crocin same—they are clinically equivalent
500mg
500mg

 Drug distribution: refers to the reversible transfer of a drug
between the blood and the extra vascular fluids and tissues of the
body (for example, fat, muscle, and brain tissue).
DRUG DISTRIBUTION

Significance :-
Pharmacological action of drug depends upon its
concentration at the site of action
Thus distribution plays important role in
 Onset of Action
 Intensity of Action
 Duration of Action

STEPS IN DRUG DISTRIBUTION
 Permeation of Free Drug through capillary wall & entry in to
Interstitial fluid.
 Permeation of drugs from Interstitial fluid to ICF through
membrane of tissue cell.

The physico-chemical properties of the drug
Binding to plasma proteins
Special barriers
Blood flow
Binding to tissue proteins
Disease states
The factors affecting Distribution/ tissue permeability
of a drug:

I. Physicochemical Properties of the Drug:-
Drugs molecular weight (< 500 to 600 Da) easily
cross the capillary membrane to penetrate into the
extracellular fluids (except in CNS) because
junctions between the capillary endothelial cells are
not tight.
Passage of drugs from the ECF into the cells;
 molecular size
 degree of ionization and
 lipophilicity

Molecular weight:-
• Mol wt less then 500 to 600 Dalton easily pass
capillary membrane to extra cellular fluid.
• High molecular weight drugs (heparin) can’t
cross the capillary membrane & remains in
plasma

Degree of ionization
 More dissociation….less crossing of
membranes
Blood is slightly alkaline (pH 7.4)
Acidic low pKa drugs will be ionized more &
less crossing of membranes
Basic low pKa drugs will be ionized less &
more crossing of membranes

Lipid solubility
• Lipid Soluble drugs (non-ionized) can cross
easily the membranes & available everywhere
• Water Soluble drugs (ionized) can’t cross the
cell-membrane, and so remains in mostly ECF

-:Transportation of Drugs:-
•Drugs are transported in the circulating blood in
two forms: free form and bound form (plasma
proteins).
•Free form of drugs is pharmacologically active,
diffusible, and available for metabolism and
excretion.

Plasma Protein Binding(PPB)
• PPB→ It acts as drug reservoir
• Plasma consists of
– ~90% water,
– ~8% plasma proteins
– ~2% other organic or inorganic species.
• Many drugs bind to the plasma proteins as they have low water
solubility.
• Acidic & neutral drugs binds to basic protein- plasma albumin
e.g.- warfarin, Penicillins, Sulfonamides, Tolbutamide, Salicylic
acid.
• Basic drugs binds to acidic protein αı acid glycoprotien
e.g- Propranolol, Lignocain, Quinidine
• It ↓distribution of drug

Dru
g
Enters
circulation
Binds to plasma protein (Acidic drugs to
albumin, basic drugs to α1 acid
glycoprotein)
Bound form (Pharmacologically inactive,
acts as a ‘temporary store’ of the drug)
Free form
(Pharmacologically
active)

Plasma Protein Binding
Free drug  Bound drug
Always equilibrium
 This equilibrium will
always be maintained
whatever might be the amount
of the drug in circulation at
any time.

DRUG DISTRIBUTION
 Bound drugs remain as
reservoir of drugs.
When free drug concentration
is decreased then bound drugs
become free and maintains the
equilibrium.
 Only free drugs are active,
metabolized & excreted.
Alb
um
in

Clinical importance
 Highly protein bound drugs restricted to the vascular
compartment
 In case of poisoning, Highly protein bound drugs are difficult to
remove by dialysis
 Prolongs the Duration of action.
e.g.-sulphadiazine is less PPB & has duration of action-6hr.
Whereas sulphadoxine is high PPB. Duration of action- 1week.
 PPB is capacity limited and saturable process
e.g.-Liver diseases, ureaemia: Hypoalbuminemia--therapeutic
dose may become toxic-plasma albumin levels are low.so there
will be an increase in free form of the drug which can lead to drug
toxicity
 PPB-delays the metabolism of drug
 More than one drug can bind to the same site on albumin and
can lead to displacement interactions.

•It occur between two or more drugs that bind to
same plasma protein site
•If one drug is binding to such a site, then
administration of second drug having higher
affinity for the same site results in
- Displacement of first drug from its binding site.
Drug displacement interactions

Drug Displacement
Plasma Tissue
Drug A
protein bound
Drug A
free
Drug A
free
Drug B
Drugs A and B both bind to the same plasma protein

• Generally, In many cases, the impact of interactions
is minimal
•In some instances a slight displacement of a drug will
result in marked increase in its biological activity.
Example:-
Administration of phenylbutazone to a patient on
warfarin therapy results in displacement of warfarin
from its binding site.
The enhanced concentration of free warfarin may
cause severe hemorrhagic episodes

 e.g- Phenylbutazone, Salicylates & Sulfonamides displaces
Tolbutamide → hypoglycemia
 Salicylates,Indomethacin,Phenytoin & Tolbutamide
displaces Warfarin → haemorrhage.
 Sulfonamides & vitamin K
displace endogenous
ligands like bilirubin→
kernicterus in neonates
58

PHYSIOLOGICAL BARRIERS TO DRUG
DISTRIBUTION
• simple capillary endothelial barrier
• Blood brain barrier
• Blood CSF barrier
• Placental barrier

 All drugs unionized molecular size less than 600D diffuse through
the capillary endothelium to interstitial fluid
 Only drugs that bound to that blood components can’t pass through
this barrier because of larger size of complex
Simple capillary endothelial barrier

Blood brain barrier
• The capillary boundary that is present between the
blood and brain is called blood–brain
barrier(BBB)
• Only the lipid-soluble and unionized form of drugs
can pass through BBB and reach the brain,
• e.g. barbiturates, diazepam, volatile anaesthetics,
amphetamine, etc.
• Lipid-insoluble and ionized particles do not cross
the BBB, e.g. dopamine and aminoglycosides.

Blood brain barrier – contd.
 BBB is lipoidal and limits the entry of non-lipid soluble drugs
(amikacin, gentamicin, neostigmine etc.).
(Only lipid soluble unionized drugs penetrate and have action on the
CNS)
 Efflux carriers like P-gp (glycoprotein) present in brain capillary endothelial
cell (also in intestinal mucosal, renal tubular, hepatic canicular, placental and
testicular cells) extrude drugs that enter brain by other processes.
(Inflammation of meningitis of brain increases permeability of BBB)
 Example:-
 In normal conditions:- penicillin G has poor penetration through BBB,
 but its penetrability increases during meningitis and encephalitis
 Dopamine (DA) does not enter brain, but its precursor levodopa does. This
is used latter in parkinsonism.

65
Blood CSF Barrier :
Epithelial cells joined by tight junctions
allows non ionised lipid soluble drugs

Placental barrier:
•The maternal and foetal blood vessels are separated by a
layer of trophoblastic cells that together constitute the
placental barrier.
•Drug safe in pregnancy are-
1.Water soluble 2.Large MW. 3.Protein bound drug
•E.g.-
•Phenobarbital being a highly protein bound anti-epileptic
drug safe to use in pregnancy.

•However, restricted amounts of lipid insoluble drugs,
especially when present in high concentration or for long
periods in maternal blood gain access to the fetus by non-
carrier mediated processes.
•Thus, the placental barrier is not as effective as the blood-
brain barrier
•So care must be taken while administration of all types of
drugs during -Pregnancy

Other barriers:
• The prostrate, testicles, and globe of eyes
• contain barriers that prevent drug penetration to
tissues.
• Lipid soluble drugs→ can penetrate and reach
these structures freely, whereas water-soluble
drugs entry is restricted.

Blood Flow and Organ Size:-
•The rate of blood flow to tissue capillaries
varies widely as a result of unequal distribution
of drugs to various organs.
•The drug distribution to a particular organ or
tissue depends on the size of the tissue (tissue
volume) and tissue perfusion rate (volume of
blood that flows per unit time per unit volume of
the tissue).

•Highly perfuse tissues such as lungs, kidneys, liver,
heart, adrenals, and brain are rapidly equilibrated
with lipid soluble drugs.
•Muscle and skin are moderately perfuse, so they
equilibrate slowly with the drug present in blood.
•Adipose tissues, bones and teeth being poorly
perfuse, take longer time to get distributed with the
same drug.

Redistribution:
Highly lipid soluble drug such as thiopentone
upon IV administration immediately gets
distributed to the area of high blood flow such
as brain and causes GA. Immediately within
few minutes it diffuse across the BBB and into
the blood and into the less perfused tissue such
as muscle, adipose tissue. This is called
redistribution.
Resulted- Termination of Drug effect

Redistribution:
•Termination of drug effect after withdrawal of a
drug usually is by metabolism and excretion
•But also may result from redistribution of the
drug from its site of action into other tissues or
sites.
•Redistribution is a factor in terminating drug
effect primarily when a highly lipid-soluble drug
that acts on the brain or cardiovascular system is
administered rapidly by intravenous injection.

Example:-
Use of the IV anesthetic thiopental, a highly
lipid-soluble drug. Because blood flow to the
brain is so high, the drug reaches its maximal
concentration in brain within a minute of its
intravenous injection.
After injection is concluded, the plasma
concentration falls as thiopental diffuses into
other tissues, such as muscle.

Tissue Binding
•Many drugs accumulate in tissues at higher
concentrations than those in the extracellular fluids
and blood called localization.
•Tissue binding of drugs (cellular constituents);
Proteins, phospholipids, or nuclear proteins and
generally is reversible or some case irreversible
(covalent chemical bonding)

Tissue binding
Drugs may also accumulate in specific organs or get bound to
specific tissue constituents, e.g.:
• Heart and skeletal muscles – digoxin (to muscle proteins)
• Liver – chloroquine, tetracyclines, digoxin
• Kidney – digoxin, chloroquine
• Thyroid gland – iodine
• Brain – isoniazid, acetazolamide
• Retina – chloroquine (to nucleoproteins)
• Iris – ephedrine, atropine (to melanin)
• Bones and teeth – tetracyclines, heavy metals (to
mucopolysaccharide of connective tissue)
• Adipose tissues – thiopental, minocycline

•Important in distribution from two viewpoints:
Firstly, it increases the apparent volume of
distribution (in contrast to plasma protein binding
which decreases it)
Secondly it results in localisation of a drug at a
specific site in the body produce local toxicity.
Examples:
 Aminoglycoside antibiotic causes Nephro and
vestibular toxicity.

Paracetamol and chloroform metabolites
causes hepatotoxicity.
Tetracyclines, fluoride (infants or children)
causes permanent brown-yellow discoloration of
teeth.
Chlorpromazin, Chloroquine leads retinopathy.

Disease States:
Distribution characteristics of several drugs are
altered in disease states.
Examples:-
In meningitis and encephalitis, the blood-brain
barrier becomes more permeable and the polar
antibiotics like penicillin-G, which do not normally
cross it, gain access to the brain.

In hypoalbuminaemia, plasma protein binding of
drugs may be reduced and high concentration of
free drugs may be attained.
In congestive heart failure or shock the perfusion
rate to the entire body decreases, which affect
distribution of drugs.

Apparent Volume of Distribution (aVd)
Definition: Apparent Volume of distribution is defined as the
volume that would required to accommodate all the drugs in the
body, if the concentration was the same as in plasma
or
• Expressed as: in Liters
aVd =
Total amount of drug in body
Concen. Of drug in plasma
Volume into which a drug appears to distribute with a concentration equal to its
plasma concentration

• Drugs with high molecular weight (e.g. heparin) or Highly
bound to plasma protein (e.g. warfarin) are largely
restricted to the vascular compartment→ aVd is low
• If aVd of a drug is about 14–16 L, it indicates that the drug
is distributed in the ECF, e.g. gentamicin, streptomycin, etc.
• Small water-soluble molecules like ethanol are distributed
in total body water—aVd is approximately 42 L.
• Fat: Lean body mass ratio—highly lipid-soluble drugs get
distributed to the adipose tissue. If the ratio is high, the
volume of distribution for such a drug will be higher and fat
acts as a reservoir for such drugs

• Hemodialysis is effective→ in drugs having low Vd &
low plasma protein binding
• Hemodialysis is ineffective→ in high Vd e.g.
Chloroquine(maximum vd-1500L), digoxin
• Hemodialysis is ineffective→ in high PPB drug e.g.-
BZD,Warfarin,CCB,β-blockers,lignocaine
• If aVd → less than 5L means drug is retained in
vascular compartment

Importance
aVolume of
distribution
(aVd)
Retention Examples
< 5 L Vascular compartment Heparin, Insulin,
Warfarin
Aprox.15 L Extracellular
compartment
streptomycin
>20 L
>42 L
Intracellular
compartment
Localization in tissues
Ethanol , Phenytoin
Digoxin, Chloroquine

Factors affecting Vd
• Lipid solubility (lipid : water partition
coefficient)
• pKa of the drug
• Affinity for different tissues
• Blood flow
• Plasma protein Binding

Importance
• Predict whether the drug reside in blood or tissue
• Predict protein binding of drugs. Drugs with high
PP binding less Vd and vice versa
• Vd more than body volume means drugs are
widely distributed and localized in tissues
• Total amount of drug present in the body can be
determined
• Loading dose can be calculated

METABOLISM
or
BIOTRANSFORMATION

Definition
• Chemical alteration of drug in the body.
• Aim:- To convert non-polar lipid soluble compounds to polar lipid
insoluble compounds to avoid reabsorption
• Most hydrophilic drugs are less biotransformed and excreted
unchanged – streptomycin, neostigmine
• Biotransformation is required for protection of body from toxic
metabolites
• SITES
Primary site – Liver
Others – Kidney, Intestine, Lungs, Plasma…

Drug Biotransformation
Lipophilic / hydrophobic drug (to enter cells) to hydrophilic
metabolites.
Advantages
• Termination of drug action - (↓ toxicity)
• Reduced lipophilicity
• Renal / biliary excretion ↑ - (↓renal reabsorption)

CONSEQUENCES
• A) Drug inactivation-(inactive or less active)
Active drug→→→Inactive metabolite
Most common type of Metabolic transformation
E.g.-Morphine, Chloramphenicol, Paracetamol, Lignocaine
• B) Active drug to Active metabolite- active metabolite
Effect is due to parent drug and its active metabolite

Examples-
Phenyl butazone - Oxyphenbutazone
Diazepam - Desmethyl diazepam
Digitoxin - Digoxin
Amitriptyline - Nortriptyline
Procainamide - N Acetyl procainamide
Codeine - Morphine
Spironolactone - Canrenone
Allopurinol - Alloxanthine

C) Inactive drug (Prodrug) - Active drug
Prodrugs are inactive drugs which need biotransformation in the body to
form active metabolites
 Advantage:-
 To improve bioavailability
e.g.- Levodopa----------Levodopa------------------ Dopamine
 Less toxicity
 Prolong the duration of Action-e.g.-Phenothiazine-short duration of
action-ester of phenothiazine(fluphenazine)-longer duration of action
 To improve the taste-
e.g.-Clindamycin-has bitter taste so clindamycin palmitate suspension for
pediatric use to improve taste
 To provide site specific drug delivery:
e.g.-
Methenamine--------------Formaldehyde(acts as a urinary antiseptics)
BBB
Dopa decarboxylase
Acidic pH of urine

Disadvantages:-
1.Prodrugs can not be used for emergency
situations as onset of action is delayed
2.Prodrugs can not be activated to achieved
desired therapeutic concentration in liver
disease/damage as they are mainly activated in
liver

Prodrug Active form
Proguanil Cycloguanil
Prednisone Prednisolone
Bacampicillin Ampicillin
Sulfasalazine 5-Amino salicylic acid
Cyclophosphamide Aldophosphamide
Mercaptopurine Methyl Mercaptopurine
Acyclovir Acyclovir triphosphate

D. Active Drug to Toxic metabolite:-
Drug Toxic Metabolite
Halothane Trifluoroacetic acid
Isoniazid Acetyl-hydrazine
Methoxyflurane Fluoride
Paracetamol NAPQI
(N-acetyl-p-benzo-quinoneimine)
Sulphonamides Acetyl derivatives

BIOTRANSFORMATION REACTIONS - 2 TYPES
 Drug metabolism reaction grouped into two phases-
• Phase I / Non synthetic / Functionalization:-
 Functionalization reactions
 introducing or unmasking a functional group (-OH, -NH2).
 Metabolite – active or inactive
 Little increase of water solubility
• Phase II / Synthetic / Conjugation:-
 An endogenous radical is conjugated such as glucuronic acid, sulfate,
acetate, or an amino acid.
 Metabolite is usually inactive (Morphine – M-6 glucoronide is
exception),Polar & water soluble

Phase-I Reactions
 Oxidation
 Reduction
 Hydrolysis
 Cyclization
 Decyclization
Phase II Reactions
Acetylation
Methylation
Conjugation
 Glucuronide
conjugation/Glucuronidation
 Sulfate
conjugation/sulphation
 Glycine conjugation
 Glutathione conjugation
Ribonucleotide / Ribonucleoside
synthesis

• Phase I –
• Oxidation:-
• Addition of oxygen/ negatively charged radical or removal
of hydrogen/ positively charged radical.
• Oxidation is the main process of metabolism
• E.g.:-Phenytoin, phenobarbitone, pentobarbitone, propranolol
• Reduction:- Removal of oxygen or addition of hydrogen is known as
reduction
Drugs-Chloramphenicol, methadone
• Hydrolysis: Breakdown of the compound by addition of water is
called hydrolysis.
• This is common among esters and amides.
• E.g.-Esters—procaine, succinylcholine
• Amides—lignocaine, procainamide

• Cyclization: Conversion of a straight-chain compound
into ring structure.
• e.g.-Proguanil
• Decylization: Breaking up of the ring structure of the
drug.
• e.g.-Phenobarbitone, phenytoin
At the end of phase I, the metabolite may be active or
inactive.
Phase II Reactions
Glucuronide conjugation/Glucuronidation:-carried out
by UDP- glucuronyl transferase enzyme

e.g.-Piroxicam, chloramphenicol, metronidazole,
Aspirin
 Compounds with a hydroxyl or carboxylic acid group are
easily conjugated with glucuronic acid which is derived
from glucose
 Glucuronidation- ↑ molecular weight of the drug which
favors its excretion in bile.
Acetylation:-
 Compounds having amino or hydrazine residue are
conjugated with the help of acetyl coenzyme-A.
 e.g sulfonamides, isoniazid, dapsone, hydralazine.

• Methylation: The amines and phenoles can be
methylated by methyl transferases
• e.g. adrenaline, histamine, nicotinic acid
• Sulfate conjugation: The phenolic compound and
steroids are sulfated by sulfotransferases.
• e.g. Chloramphenicol, methyldopa, adrenal and sex
steroids.
• Glycine conjugation: Salicylates, nicotinic acid and
other drugs having carboxlic acid group are
conjugated with glycine.

• Glutathione conjugation:- This is carried out by
glutathione-S-transferase
• e.g. Paracetamol
• Not all drugs undergo phase I and phase II
reactions in that order.
• In case of isoniazid (INH), phase-II reaction
followed by phase I reaction.
• Drug-Metabolizing Enzymes:-

E.g.,-Monooxigenases, cytochrome P450,
epoxide hydrolases etc are microsomal
enzymes

Percentage of Drugs Metabolized by
CYP Enzymes
CYP 1A2
14%
CYP 2C9
14%
CYP 2C19
11%
CYP2D6
23%
CYP2E1
5%
CYP 3A4-5
33%

Hofmann elimination
Inactivation of the drug in the body fluids by
spontaneous molecular re arrangement without any
enzymatic action.
e.g. Atracurium.

MICROSOMAL ENZYME INDUCTION
• Repeated administration of certain drugs increases the synthesis of
microsomal enzymes. This is known as enzyme induction.
• The drug is referred to as an enzyme inducer
• Consequences:-
 ↑ rate of metabolism of other drugs→ resulted ↓ drug plasma
concentration(Cp) & ↓Intensity of action→ therapeutic failure
 E.g.-Rifampicin ×Oral contraceptives(OCP)-Rifampicin
induces the drug-metabolizing enzyme of oral contraceptives
resulted contraceptive failure.
↑rate of metabolism of its own (Autoinduction)-may lead to
development of drug tolerance
 e.g.-carbamazepine, rifampicin (enhances their own
metabolism)

Enzyme induction can lead to toxicity.
 Eg: Alcoholics more prone to hepatotoxicity of paracetamol
due to↑ production of metabolic product NAPQI (N-acetyl
para-aminobenzoquinoneimine)
Enzyme induction can also be beneficial.
 Eg: To treat neonatal jaundice (phenobarbitone in neonatal
jaundice—phenobarbitone induces glucuronyl transferase
enzyme; hence bilirubin is conjugated and jaundice is
resolved)
Enzyme inducers like phenytoin & phenobarbitone can
precipitate porphyria by ↑rate limiting enzyme of porphyrin
synthesis i.e. δ-ALA (δ-aminolevulenic acid) synthetase &
precipitate Acute intermittent porphyria

E.g.-
• Griseofulvin
• Phenytoin
• Rifampicin
• Smoking
• Carbamazepine,chronic alcohol,cyclophosphamide
• Phenobarbitone
• Isoniazide
• Tolbutamide
• Exception:-
• All barbiturate are enzyme inducers except secobarbital
• Ritonavir is an enzyme inhibitors but with chronic
administration(repeats) – acts as an inducer

MICROSOMAL ENZYME INHIBITION
• Certain drugs inhibit the activity of drug-metabolizing
enzymes and are known as enzyme inhibitors
• Enzyme inhibition is a rapid process as compared to enzyme
induction(4-7 days)
• Consequences
 Increase in the plasma concentration of drug
 Precipitate toxicity of the drug
 can be therapeutically beneficial. Eg: aversion of alcohol with
Disulfiram
Enzyme Enzyme inhibitors Clinical
Application
Drug Whose metabolism
is inhibited
Acetylcholine esterase Ecothiophate Glaucoma Succinylcholine,procaine
Aldehyde
dehydrogenase
Disulfiram Chronic
alcoholism
Alcohol,phenytoin,warfarin
Xanthine oxidase Allopurinol Gout Azathioprine,6MP

• Valproate, verapamil
• Ketoconazole
• Cimetidine
• Ciprofloxacin
• Erythromycin
• INH
• Sulfonamides
• Disulfiram
• Diltiazem
• Allopurinol, amiodarone
Enzyme Inhibitors Name

EXCRETION OF DRUGS
Excretion is defined as the process where by
drugs or metabolites are irreversibly
transferred from internal to external
environment through renal or non renal route.
Excretion of unchanged or intact drug is
needed in termination of its pharmacological
action.
The principal organ of excretion are
kidneys.

TYPES OF EXCRETION
1. RENAL EXCRETION
2. NON RENAL EXCRETION
 Pulmonary excretion.
 Biliary excretion.
 Salivary excretion.
 Mammary excretion.
 Skin / Dermal excretion

Renal Excretion-process
 Glomerular Filtration
 Tubular Secretion
 Tubular Reabsorption

Glomerular Filtration
 Normal GFR – 120 ml/min
 Glomerular capillaries have pores larger than usual
 Glomerular membrane is fenestrated→ so both water & lipid soluble
drugs filtered (Means GFR does not depends on polarity)
 The kidney is responsible for excretion of all water soluble
substances
 It is non selective, unidirectional process
 Only free drugs are filtered, except those that are bound to plasma
proteins
 Molecular wt. <20,000
 Drug conc in plasma-(less Conc.-less readily filtered)
 Glomerular filtration of drugs depends on their plasma protein
binding and renal blood flow - Protein bound drugs are not filtered !
 Driving force for GF is hydrostatic pressure of blood flowing in
capillaries.

Tubular secretion
 Carrier mediated, capacity limited, saturable process
 Site:-proximal tubule of nephron(PCT).
 Requires energy for transportation of compounds against
concentration gradient-Active process
 Unaffected by pH & protein binding
 Dependent on renal Blood flow(BF)
 Two types of transporters
Organic acids/anions transport(OAT) Organic bases or cations(OCT)
e.g. penicillin, salicylates, Probenecid &
endogenous substances like Uric acid.
e.g. Morphine, Quinine & endogenous
amines like choline, histamine
Bidirectional process Bidirectional process
 Therapeutic Advantage:- Probenecid is used to block renal tubular secretion of
some acidic drugs (e.g. penicillin) and thus prolong its duration
 Therapeutic Disadvantage:- probenecid inhibits renal tubular secretion of
nitrofurantoin thus decreases its efficacy in urinary tract infections (UTIs)

 Usually by diffusion-Passive process
 Depends upon :-
Lipid solubility:- ↑Lipid solubility-↑reabsorption
Degree of Ionization-more ionization- more excretion
 pH of the renal tubular fluid
 Basic drugs in acidic urine – ionize – less reabsorption -
e.g. morphine, Amphetamine
 Acidic drugs in alkaline urine – ionize – less reabsorption
- e.g. barbiturates, salicylates,Methotrexate
 This principle is utilized for facilitating elimination of
drugs in poisoning
Tubular reabsorption

 Sodium bicarbonate is used to alkalinize urine
 Ascorbic acid is used to acidify urine.
• Acidification of urine (in basic drug poisoning)
– Give Ammonium chloride or Vitamin C
– Urine acidified in Morphine,
Amphetamine poisoning
• Alkalinization of urine
(in acidic drug poisoning)
– Give Sodium bicarbonate or Acetazolamide
– Urine alkalinized in Barbiturate, Aspirin poisoning

Polar drug= water soluble
Non polar drug = lipid soluble

Non-renal / extra-renal excretion
• excretion by routes other than renal route, called as
extra-renal or non-renal routes of drug excretion.
• E.g.-
•Biliary excretion.
•Pulmonary excretion
•Salivary excretion
•Mammary excretion
•Skin/Dermal excretion
•Gastrointestinal excretion

 Is an active process-An important system for the secretion
of bile & excretion of drugs
 Greater the polarity better the excretion-metabolites are
more excreted via bile’s.
 Involving High Molecular weight (>350) drugs including
glucuronide conjugates
 Drugs excreted in bile & not reabsorbed- this drugs
eliminated in faeces
• E.g.-
colchicine, quinidine,
erythromycin, ampicillin,
cefoperazone, chlorpromazine

Enterohepatic circulation
• “The phenomenon of drug cycling between the intestine and the liver.”
• The cycle in which the drug is absorbed, excreted into the bile, & reabsorbed
in duodenum
• Certain drug metabolites (particularly Glucuronides) are excreted through
the bile and delivered to the intestine where these metabolites are
deconjugated or hydrolyzed releasing the parent active drug again. This free
drug is then reabsorbed and the cycle is repeated.
• E.g. Thyroxine
Morphine
Chloramphenicol
Rifampicin
Oral contraceptives
Indomethacin
Result:-
Increased t1/2- OCP,DDT
Prolongation of drug action-Rifampicin
121

122
Intestine
free
drug
glucuronide
conjugate
bacterial
glucuronidase
blood
portal
vein
free
drug
glucuronide
conjugate
Liver
bile
duct
Enterohepatic Recirculation

Molecular weight Influencing
Secretion Of Drugs In Bile:
123
Mol. Wt. Excretion pattern
< 300 Daltons Urine, < 5% in bile
>500 Daltons Bile, <5% in urine
300-500 Both urine and bile

Pulmonary Excretion
 Gaseous and volatile substances such as general anesthetics
(Halothane) are absorbed through lungs by simple diffusion.
Factors effecting Pulmonary excretion-
 Pulmonary blood flow,
 Rate of respiration
 Solubility of substance effect.
 Intact gaseous drugs are excreted but not metabolites.
• Alcohol which has high solubility in blood and tissues are excreted
slowly by lungs.
e.g. general anesthetics - halothane, nitrous oxide etc.
alcohol – excreted slowly through lungs. 125

GASTROINTESTINAL EXCRETION
 Water soluble and ionized from of weakly acidic and
basic drugs are excreted in GIT.
 Example are nicotine and quinine

Excretion through body secretions
 Quantitatively unimportant
 May be of some clinical significance
 Tears:- less significant
 Sweat:- LMW compounds are excreted may cause dermatitis,
discoloration
e.g., electrolytes, chloramphenicol, rifampicin
 Keratin precursor cells:- Griseofulvin
 Hair follicles:- Arsenic, Mercury, Iodides

Saliva:-
1. May reflect plasma conc. considered for drug estimation
(noninvasive method)
2. A/E : ulceration, taste disturbance, saliva, effects on gums &
teeth.
e.g., Iodide, lithium, phenytoin, Metronidazole

Drug excretion in milk
• Is of much concern
• Causes harmful effect on suckling infant
• Highly PB -> less secreted in milk
• Milk is slightly acidic, hence basic drugs tend to get conc in milk

Drugs contraindicated during lactation
• Most anti-cancer drugs
• All radio pharmaceuticals (RA isotopes)
• Antimicrobials:-
• Tetracyclines
• Chloramphenicol
• Sulphonamides
• Quinolones
• Isoniazid (INH)
• Hormones:- corticosteroids
• OC-Pills , bromocriptine, diuretics

Drug Elimination
Metabolism:-
conversion of one chemical
entity to another.
Excretion:-
Loss of drug or its
metabolites

Elimination
The pharmacokinetic parameter which gives a
quantitative measure of drug elimination is
named…..
Clearance

DRUG CLEARANCE(CL)
“Theoretical volume of plasma from which the drug is
completely removed in unit time”
• Alternatively defined as the rate of drug elimination divided
by the plasma drug concentration
• The units of clearance-vol/time (mL/min, L/hr.)
CL =
 So, If
A. CL>GFR-means Drug actively secreted into tubules
B. CL<GFR-means Drug has been absorbed
Rate of elimination
Plasma Concentration(Cp)

Why is clearance important?
• Clearance determines:
– Maintenance dose
– Loading dose
– Peak onset of action
– Duration of action of drug

Plasma t1/2 or Plasma half-life
“The plasma half life of drug is the time taken for its plasma
concertation to be reduced to half of its original value”
 Time required for 50% reduction in plasma conc
Dimensions - t1/2 – time (hr, min, day)
t1/2 =0.7×
Vd
CL
Where,
Vd = Volume of distribution
CL = clearance
E.g.-Plasma t/2 of lignocaine is 1 hr.
and is 4 hr. for aspirin
Plasma half-life of a drug after single intravenous injection
α-phase(Distribution)
-rapid decline
β-phase (elimination)
#T1/2 usually calculated due to β-phase

• Drug takes 4 ½ - 5 half lives for total elimination
» Indicative of overall duration of action
» Determines frequency of administration
• Plasma t½ may not always truly reflect DOA
» When no clear correlation b/w pl.conc & action
» Prodrug
» Highly conc at target tissue
» Hit & run drugs
Plasma t1/2-

Importance of half-life:-
Determine the duration of drug action
Determine the frequency of drug
administration
Estimate the time required to reach the
steady state
for calculating loading dose
 for calculating maintenance dose

Rate and pattern of drug elimination follow
three type of elimination
1. First order kinetics– Most of the drugs follow
first order kinetics
2. Zero order kinetics– Phenytoin, Alcohol obeys
zero order kinetics
3. Mixed order kinetics

Order of Elimination Kinetics
• Constant fraction of drug is
eliminated at constant interval
• Clearance,aVd remains constant
• Rate of elimination vary with
plasma concentration
• Nearly complete elimination in
4-5 half lives-remain constant
1st half life-50%,
2nd t1/2- 50+ 25 = 75%
3rd t1/2- 50+ 25 +12.5= 87.5%
4th t1/2- 50+ 25 +12.5 + 6.25= 93.75
5th t1/2- 50+ 25 +12.5 + 6.25+ 3.125= 96.875%
 If dose is doubled, the duration
is prolonged for one half life
 E.g.-Most of drugs follow
• Constant amount of drug is
eliminated at constant interval
• Clearance is never constant
• Rate of elimination remains
constant
• No relation with half life-
• If dose is doubled, the duration
is prolonged for so many times,
not related to half life
• E.g.-alcohol, phenytoin
First order kinetics/Linear/Non-
Saturated kinetics:-
Zero order /Exponential/
Curvilinear/saturable
kinetics:-

First order kinetics Zero order kinetics
On arithmetic scale
On log scale

• It is a dose dependent kinetics-where Low dose- follow 1st
order kinetics & High doses obeys zero order kinetics
• because metabolizing enzymes or the elimination process
get saturated
• Results in increase in plasma concentration
disproportionately with increase in dose
• Half life changes with dose
• Needs proper monitoring and maintenance of dose
 Drug follows-
Warfarin ,Theophylline, Tolbutamide, Phenytoin, Digoxin, Dicumarol,
Alcohol
Mixed order kinetics/ Michaelis Menten kinetics

Dosing schedule
• Drugs having very short t1/2→ to achieve desired
therapeutic effect-administration of drug by constant i.v.
infusion
• E.g.-noradrenaline-1-2min,dopamine-5min,oxytocin-3-
5min
• Drug having long t1/2-and high Vd→ in (only in
emergency condition) to achieve desired therapeutic
effect- administration of drug by loading dose followed by
maintenance dose
• E.g.- digoxin-40hr, diazepam-40hrs, chlorquine-40hrs

Loading dose
• For drugs with long half-lives, the time to reach steady state
might be long. It takes about 5 half- lives to reach steady
state.
• In a such cases the plateau can be achieved by administering
a dose that gives the desired steady- state. Such an initial/
first dose is called as Loading dose.
• A large initial dose or series of such doses given at the
beginning of treatment to rapidly achieve a therapeutic
concentration in the body
• Loading dose = Vd x Target Concentration
(so loading dose is mainly depends on Vol. of distribution)

Maintainance Dose
 After the loading dose is given the another dose is
given to maintain the steady- state drug conc. Or
plateau, Such dose is known as maintenance dose.
 i.e. maintain the response of drug by replacing drug lost
during dosing interval.
Maintainance dose = clearance(CL) x plasma conc(Cp)
 (Maintenance dose is mainly depends on Clearance)

Example
• Lignocaine-T1/2- more than1hr.
• So it takes more than 4–6 h to reach the target
concentration.
• In life-threatening condition:- like ventricular
arrhythmias after MI
• Initially:- a large dose of lignocaine has to be given to
achieve desired plasma concentration quickly.(Loading
dose)
• Once it is achieved, it is maintained by giving the drug as
an intravenous infusion.(Maintenance Dose)

0
1
2
3
4
5
6
7
0 5 10 15 20 25 30
Time
Plasma
Concentration
Repeated doses –
Maintenance dose
Therapeutic level
Single dose –
Loading dose

Therapeutic Drug Monitoring(TDM)
 Monitoring drug therapy by measuring plasma
concentration of a drug is known as therapeutic drug
monitoring (TDM)
 Useful in:-
1. Drugs with narrow therapeutic index, e.g. lithium,
digoxin, phenytoin, aminoglycosides, etc.
2. Drugs showing wide interindividual variations, e.g.
tricyclic antidepressants.
3. To ascertain patient compliance.
4. For drugs whose toxicity is increased in the presence of
renal failure e.g. aminoglycosides.
5. To check the bioavailability.

6. In patients who do not respond to therapy without any
known reason.
 Not useful in:-
1.Easy measurable response
A. Blood pressure measurement for antihypertensives.
B. Blood sugar estimation for antidiabetic agents.
2. Drugs producing tolerance, e.g. opioids.
3. Drugs whose effect persists longer than the drug itself, e.g.
omeprazole.
4. If TDM is expensive

Fixed Dose Combination
 It is the combination of two or more drugs in a fixed dose ratio in a
single formulation
 Some of the examples of WHO-approved FDCs are:
 Levodopa + carbidopa for parkinsonism.
 Isoniazid + rifampicin + pyrazinamide for tuberculosis.
 Ferrous sulphate + folic acid for anaemia of pregnancy.
 Sulphamethoxazole + trimethoprim for cotrimoxazole.
 Amoxicillin + clavulanic acid in Augmentin.
 Oestrogen + progesterone as oral contraceptive

Methods of prolonging the drug action
• When to prolong ?
– To reduce frequency of administration
– To increase patient compliance
– To avoid large fluctuations
– To maintain the drug effect throughout
• When not to prolong?
– If required for short duration
– If they are already long acting
• How to prolong ?
1.Administration of large dose
2.Pharmacokinetic manipulation
3.Pharmaceutical level

• Administration of large dose:-
 Only applicable for drug with high safety margin.E.g.-
Penicillin-G
• Pharmacokinetic manipulations:-
 Absorption:-
 By decreasing the vascularity of the absorbing surface-
achieved by adding a vasoconstrictor to the drug, e.g.
adrenaline with Lignocaine
 Distribution:- By ↑PPB of the drug, e.g.
sulphadiazine(t1/2-6 hr. but Sulphadoxine-1week due to
highly protein bound
 Metabolism:-
 By inhibiting drug metabolism→↑duration of Action. E.g.-
Anticholinesterases (physostigmine and neostigmine)
prolong the duration of action of acetylcholine by inhibiting
cholinesterases.

 Chemical modification ( ethinyl group to estradiol)
 Excretion:-By delaying renal excretion of the drug by
tubular secretion , e.g. penicillin/cephalosporins with
probenecid
 At Pharmaceutical level:-
 Modification of molecular structure e.g.-various
benzodiazepines
 Modifying the formulations-
Oral-By using sustained release preparations/controlled
released :- These preparations consist of drug particles that
have different coatings dissolving at different intervals of
time.
Advantages:-
o Prolongs the duration of action of the drug

o ↓↓frequency of administration
o improves patient compliance,
o e.g. Tab.diclofenac has a duration of action of 12 h, whereas
diclofenac sustained-release preparation has a duration of action
of 24 h.
Parental:-
 By decreasing the solubility of the drug: By combining it with
a water-insoluble compound.
For example,
– Injection penicillin G has a duration of action of 4–6 h.
– Injection procaine penicillin G: It has a duration of action of
12–24 h.
 By combining the drug with a protein, e.g. protamine zinc
insulin– the complexed insulin is released slowly from the site of
administration, thus prolonging its action

• By esterification: Esters of testosterone, e.g. testosterone
propionate and testosterone benzoate are slowly absorbed
following intramuscular administration resulting in
prolonged action.
• Injecting the drug in oily solution, e.g. depot progestins
(depot medroxyprogesterone acetate)
• Pellet implantation: e.g. norplant for contraception
• Topical:-
 Long acting preparation such as Transdermal patch of
nitroglycerine & hyoscine

Question Paper:-
1.Write a short note on:-
A. Factors affecting drug absorption (5M)
B. Microsomal enzyme induction (4M/5M/2.5M)
C. Bioavailability (4M)
D. Redistribution of drugs (with example) (5M)
E. Kinetics of Elimination (5M)
F. Plasma t1/2 & its clinical significance (5M)
G. Prodrugs(2.5M/5M)
H. Zero-order kinetics of Drug elimination (5M)
I. First pass Metabolism (2.5/M)
II. Method to prolong the drug action(5M)
3.Explain why:-
A. Aspirin is better absorbed in acidic environment of the stomach
4.Discuss the following:-
1.Utility of Pharmacokinetic study with suitable example.?

Pharmacokinetics.pptx

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