m pharm 2nd sem biopharm topic introduction to pharmacokinetic, pharmacodynamic and drug interactions

1. INTRODUCTION TO PHARMACOKINETICS AND PHARMACODYNAMICS, DRUG INTERACTION
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ADVANCED BIOPHARMACEUTICS
ASSIGNMENT
TOPIC - INTRODUCTION TO
PHARMACOKINETICS AND
PHARMACODYNAMICS, DRUG
INTERACTIONS
SUBMITTED BY
NISHA YADAV
2134852
M PHARM PHARMACEUTICS
2ND
SEMESTER
SUBMITTED TO
DR. KIRAN RAO

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Introduction to Pharmacokinetics and
pharmacodynamics, drug interactions
PHARMACOKINETICS
It is the study of those rate processes involved in the absorption,
distribution, metabolism and excretion of drugs and their relationship
to pharmacological, therapeutic or toxic response in animals or
humans.
Or
It is concerned with the ADME of drugs as elicited by the plasma drug
concentration-time profile and its relationship with the dose, dosage
form and frequency and route of administration. In short, it is the sum
of all the processes inflicted by the body on the drug.
Absorption- The process of movement of drug from its site of
administration to the systemic circulation is called as absorption.
Drug disposition- Together the process of distribution and elimination
is known as drug disposition.

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Distribution- The movement of drug between one compartment and
the other (generally blood and the extravascular tissues) is referred to
as distribution.
Elimination is defined as the process that tends to remove the drug
from the body and terminate its action. Elimination occurs by two
processes-
a. biotransformation (metabolism)- which usually inactivates the
drug,
b. excretion- which is responsible for the exit of drug/metabolites
from the body.
PHAMACODYNAMICS
It is concerned with the biochemical and physiologic effects of the drug
and its mechanism of action. It is characterized by the concentration of
drug at the site of action and its relation to the magnitude of effects
observed.
e.g.-Adrenaline ---- interaction with adrenoceptors ---- G-protein
mediated stimulation of cell membrane bound adenylyl cyclase -----
increased intracellular cyclic 3',S'AMP ---- cardiac stimulation, hepatic
glycogenolysis and hyperglycaemia, etc.
DRUG INTERACTION
Drug interactions are said to occur when the pharmacological activity
of a drug is altered by the concomitant use of another drug or by the
presence of some other substance. The drug whose activity is affected
by such an interaction is called as the object drug and the agent which
precipitates such an interaction is referred to as the precipitant.
Drug interactions include –
 Drug-drug interactions.
 Food-drug interactions, for example, inhibition of metabolism of
several drugs by grapefruit juice.

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 Chemical-drug interactions, for example, interaction of a drug
with alcohol, tobacco or environmental chemicals.
 Drug-laboratory test interaction, for example, alteration of
diagnostic laboratory test results by the presence of drug.
 Drug-disease interactions, for example, worsening of disease
condition by the drug.
Factors Contributing to Drug Interactions
 Multiple drug therapy
 Multiple prescribers
 Multiple pharmacological effects of drug
 Multiple diseases/predisposing illness
 Poor patient compliance
 Advancing age of patient
 Drug related factor
PHARMACOKINETIC DRUG INTERACTIONS
These interactions are those in which the absorption, distribution,
metabolism and/or excretion of the object drug are altered by the
precipitant and hence such interactions are also called as ADME
interactions. The resultant effect is altered plasma concentration of the
object drug.
ABSORPTION

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The interaction may result in a change in the rate of absorption (an
increase or a decrease), a change in the amount of drug absorbed (an
increase or a decrease) or both. Several mechanisms may be involved
in the alteration of drug absorption from the GIT. In general, drugs that
are not absorbed completely/rapidly are more susceptible to changes in
GI absorption.
1. Instability
Penicillin, erythromycin, cephalosporin and so on ----- stomach is
the prime area for drug degradation (hydrolysis) ----- decreased
possibility for absorption.
2. Complexation and adsorption
Tetracycline, fluoroquinolones like ciprofloxacin, penicillamine ----
- undergo complexation in the presence of calcium, magnesium,
aluminium, iron, zinc, bismuth ions ------- formation of poorly
soluble and unabsorbable complex -----thereby decrease the
absorption.
Cephalexin, sulphamethoxazole, trimethoprim, warfarin, and
thyroxine ---- undergo complexation in presence of cholestyramine
----- reduced absorption due to adsorption and binding.
3. Dissolution rate
Tetracycline hydrochloride capsules when coadministered with
sodium bicarbonate ------ tends to neutralize the acid salt and either
decrease the dissolution rate or precipitate tetracycline.
4. Physiology
Object drug Precipitant drug Influence on object
drug
Alteration of GI pH
Sulphonamides,
aspirin
Antacids Enhanced dissolution
and absorption rate
Ferrous sulphate Sodium bicarbonate,
calcium carbonate
Decreased
dissolution and hence
absorption

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Ketoconazole,
tetracycline, atenolol
Antacids Decreased
dissolution and
bioavailability
Alteration of Gut Motility
Aspirin, diazepam,
levodopa, lithium
carbonate,
paracetamol,
mexiletine
Metoclopramide Rapid gastric
emptying; increased
rate of absorption
Levodopa, lithium
carbonate, mexiletine
Anticholinergics
(atropine)
Delayed gastric
emptying; decreased
rate of absorption
Alteration of GI Microflora
Digoxin Antibiotics
(erythromycin,
tetracycline)
Increased
bioavailability due to
destruction of
bacterial flora that
inactivates digoxin in
lower intestine
Oral contraceptives Antibiotics
(ampicillin)
Decreased
reabsorption of drugs
secreted as
conjugates via bile in
the intestine
DISTRIBUTION
Competitive displacement, which results when two drugs are capable
of binding to the same site on the protein, causes the most significant
interactions.
Greater risk of interactions exists when the displaced drug is highly
protein bound (more than 95%), has a small volume of distribution and
has a narrow therapeutic index (e.g. tolbutamide, warfarin and
phenytoin), and when the displacer drug has a higher degree of affinity
than the drug to be displaced.

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In such situations, displacement of even a small percent of drug results
in a tremendous increase in the free form of the drug, which precipitates
increased therapeutic or toxic effects.
Competitive Displacement Interactions
Displaced drug(s) Displacer(s)
Anticoagulants
(warfarin)
Phenylbutazone,
chloral hydrate,
salicylates
Increased clotting
time; increased risk
of haemorrhage
Tolbutamide Sulphonamides Increased
hypoglycaemic effect
Methotrexate Sulphonamides,
salicylic acid
Increased
methotrexate toxicity
Phenytoin Valproic acid Phenytoin toxicity
METABOLISM
Major problems arise when one drug either induces or inhibits the
metabolism of another drug.
The influence of enzyme inducers and inhibitors become more
pronounced when drugs susceptible to first-pass hepatic metabolism
are given concurrently. The metabolic pathway usually affected is
phase I oxidation.
Enzyme inducers reduce the blood level and clinical efficacy of co-
administered drugs but may also enhance the toxicity of drugs having
active metabolites.
In contrast to enzyme induction, which is usually not hazardous,
enzyme inhibition leads to accumulation of drug to toxic levels and
serious adverse effects may be precipitated.
Enzyme Induction

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Corticosteroids,
oral contraceptives,
coumarins,
phenytoin,
tolbutamide,
tricyclic
antidepressants
Barbiturates Decreased plasma levels;
decreased efficacy of
object drugs
Corticosteroids,
oral contraceptives,
theophylline,
cyclosporine
Phenytoin Decreased plasma levels;
decreased efficacy of
object drugs
Oral
contraceptives, oral
hypoglycaemics,
coumarins
Rifampicin Decreased
plasma levels; decreased
efficacy of object drugs
Enzyme Inhibition
Tyramine rich food
(cheese, liver, yeast
products)
MAO inhibitors
(phenelzine,
pargyline, etc.)
Enhanced absorption of
unmetabolised tyramine;
increased pressor
activity; potentially fatal
risk of hypertensive crisis
Drugs that undergo
extensive first-pass
hepatic metabolism
(e.g. propranolol,
calcium channel
blockers, etc)
Grapefruit juice Enhanced absorption of
drugs; increased risk of
toxicity
Folic acid Phenytoin Decreased absorption of
folic acid due to
inhibition of an enzyme
responsible for its
absorption
Tricyclic
antidepressants
Chlorpromazine,
haloperidol
Increased plasma half-
life of tricyclics;
increased risk of sudden
death from cardiac
disease in such patients

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Coumarins Metronidazole,
phenylbutazone
Increased anticoagulant
activity; risk of
haemorrhage
Oral
hypoglycaemics
Phenylbutazone,
sulphaphenazole,
chloramphenicol
Hypoglycaemia may be
precipitated
Alcohol Disulphiram,
metronidazole,
tinidazole
Disulphiram like
reactions due to increase
in plasma acetaldehyde
levels
AZT,
mercaptopurine
Xanthine oxidase
inhibitors
(allopurinol)
Increased toxicity of
antineoplastics
Alcohol,
benzodiazepines,
warfarin,
phenytoin,
theophylline,
phenobarbital
Cimetidine Increased blood levels of
object drugs
EXCRETION
Excretion pattern can be affected by alteration in GFR, renal blood
flow, passive tubular reabsorption, active tubular secretion and urine
pH.
An interesting pharmacokinetic interaction that results due to the
pharmacodynamic drug effect is between thiazide diuretics and lithium.
Owing to the influence of former on the renal tubular transport of
sodium, the lithium ions are retained in the body resulting in its toxicity.
Changes in Active Tubular Secretion
Penicillin,
cephalosporin,
nalidixic acid, PAS,
methotrexate,
dapsone
Probenicid (acid) Elevated plasma
levels of acidic drugs;
risk of toxic reactions

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Procainamide,
ranitidine
Cimetidine (base) Increased plasma
levels of basic object
drugs; risk of toxicity
Acetohexamide Phenylbutazone Increased
hypoglycaemic effect
Changes in Urine pH
Amphetamine,
tetracycline,
quinidine
Antacids, thiazides,
acetazolamide
Increased passive
reabsorption of basic
drugs; increased risk
of toxicity
Changes in Renal Blood Flow
Lithium bicarbonate NSAIDs (inhibitors
of prostaglandin
synthesis; the latter
control renal blood
flow partially by
vasoconstriction)
Decreased renal
clearance of lithium;
risk of toxicity
PHARMACODYNAMIC DRUG INTERACTION
Those in which the activity of the object drug at its site of action is
altered by the precipitant. Such interactions may be direct or indirect.
a. Direct pharmacodynamics interactions
In which drugs having similar or opposing pharmacological effects
are used concurrently
 Antagonism:- The interacting drugs have opposing actions,
e.g. acetylcholine and noradrenaline have opposing effects on
heart rate.
 Addition or Summation:- The interacting drugs have similar
actions and the resultant effect is the sum of individual drug
responses, e.g. CNS depressants like sedatives, hypnotics, etc.
Additive drug combinations
Aspirin + paracetamol as analgesic/antipyretic

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Nitrous oxide + halothane as general anaesthetic
Amlodipine + atenolol as antihypertensive
Glibenclamide + metformin as hypoglycaemic
Ephedrine + theophylline as bronchodilator
 Synergism or Potentiation:- It is enhancement of action of one
drug by another, e.g. alcohol enhances the analgesic activity of
aspirin.
Potentiaion drug combinations
Acetylcholine + physostigmine Inhibition of break down
Levodopa + carbidopa/
benserazide
Inhibition of peripheral
metabolism
Adrenaline + cocaine/
desipramine
Inhibition of neuronal uptake
Sulfamethoxazole +
trimethoprim
Sequential blockade
Antihypertensives ( enalapril+
hydrochlorothiazide)
Tackling two contributory factors
Tyramine + MAO inhibitors Increasing releaseable CA store
b. Indirect pharmacodynamics interactions
In which both the object and the precipitant drugs have unrelated
effects but the latter in some way alters the effects of the former
for example:- salicylates decrease the ability of the platelets to
aggregate thus impairing the haemostasis if warfarin induced
bleeding occurs.
https://www.slideshare.net/saiadiseshu/pharmacokinetics-and-
pharmacodynamics-of-biotechnology-drugs-monoclonal-
antibodies-proteins-and-peptide-oligo-nucleotides link for module
protein n left topics