Applied pharmacology

SENEZA Celestin, MD, Mmed
Consultant Anesthesiologist/CHUB
APPLIED PHARMACOLOGY:
Introduction

Pharmacology?
 Pharmacology studies the effects of drugs and how
they exert their effects:
 Acetylsalicylic acid (ASA) can reduce inflammation, pain
and fever inhibit the action of a human cell membrane
enzyme known as cyclooxygenase (COX) , which is
responsible for the synthesis of a number of inflammatory
mediators
 Penicillin cures certain bacterial infections by disrupting
the synthesis of cell walls in susceptible bacterial strains

Pharmacology?
 Pharmacokinetics
 It is what the body does to the drug
 How the body absorbs, distributes, metabolizes, and
excretes drugs
 Pharmacodynamics
 Is what the drug does to the body
 Study the mechanisms by which drugs work
 Clinical interactions of drugs

PHARMACOKINETICS
 Process for a drug to reach the target organ at a
concentration sufficient to have a therapeutic effect
 A successful drug should have an ability to cross
physiologic barriers that other foreign substances do not
have
 This is possible through:
 Drug absorption
 Use of distribution systems with the body to reach the
target organ at a sufficient concentration
 The drug’s ability to reach the target is limited also by:
 Metabolism: enzymatic degradation
 Excretion: drug eliminated from the body

PHARMACOKINETICS
A bsorption
D istribution
M etabolism
E limination
“The journey of medication through the
body”

GI Absorption
Blood
Renal
excretion
Pharmacokinetics
Extracellular
compartment
of tissues
Oral ingestion

Injection site
BLOOD
TISSUESLIVERKidney
ABSORPTION
ELIMINATION
ADME

Pharmacokinetics
Routes of Drug Administration
 Oral (per os, p.o.)
 Inhalation:vapors, gases, smoke
 Mucous membranes
 Intranasal (sniffing)
 Sublingual
 Rectal suppositories
 Injection (parenteral)
 intravenous (IV)
 intramuscular (IM)
 subcutaneous (SC)
 intraperitoneal (IP; nonhumans only)
Transdermal

Factors affecting absorption of
drugs
Factors related to drugs:
1. Lipid water solubility:
LWS coefficient is the ratio of dissolution of drug in lipid as
compared to water. Greater the LWS coefficient, more is the lipid
solubility of drug and greater is the absorption.
2. Molecular weight
Smaller the molecular size of drug, rapid is the absorption
3. Degree of Ionization
Different drugs are either Acid or basic and are present in ionized
or unionized form. Acid drugs are better absorbed from acid area.
4. Physical form
Drugs may exist as solids, gases and liquids.
Gases are rapidly absorbed than the liquids while liquids are
rapidly absorbed than solids
5. Formulation, particle size etc

drugs
Factors related to the Body:
1.Area of absorptive surface:
Most of the drugs are given orally bcz of largearea of
absorptive surface,so that the greater absorption
occurs. Intestinal resection decreases the surfaces area
leading to a decreased absorption.
2.Vascularity:
More the vascularity, more is the rate of absorption.
3. pH:
Acidic pH favors acidic drugs absorption while basic pH
is better for basic drugs.
4. Presence of other substances:
Eg: Vit C enhances the absorption of Iron

drugs
5. GI mobility
6. Functional integrity of absorptive surface: edema
7.Diseases: Diarrhea, malabsorptive sd etc

Absorption
Biological membranes:
 All human cells are limited by a lipid bilayer
membrane→ passive diffusion +++ for non polar
small molecules
 Facilitated diffusion: Transmembrane carrier proteins
for bigger molecules
 Active transport: needs energy
 Endocytosis: some drugs bind to specific cells and form
vesicles form which drugs are released into the cell

Absorption
Central Nervous System:
 Well insulated from foreign substances
 Blood-brain barrier: tight junctions prevent passive
diffusion
 Drugs acting into in the CNS:
 Sufficiently small and hydrophobic to cross the mbne
or use existing transport proteins in the BBB
 BBB bypassed using intrathecal drug infusion

Absorption
BIOAVAILABILITY
 The fraction of administered drug that reaches
the systemic circulation
 Depends on:
 Route of administration
 Chemical form of drug
 Patient’s specific factors (eg: GI and hepatic
transporters and enzymes)

ABSORPTION
Bioavailability
The fraction of the dose of a drug (F) that enters
the general circulatory system,
F= Amount of drug that enters systemic circulation
Dose administered
F = AUC/Dose

BIOAVAILABILITY
SerumAntibioticConcentration
0
2
4
6
8
10
0 1 2 3 4 5 6 7 8
Time (hours)
(mcg/mL)
9 10 11 12
Dose
Dose
Concentration present for
50% of dosing interval (6 h if
given q12h)
Area under
curvePeak
serum
conc.

Bioavailability
Plasma
concentration
Time
IV
oral
Bioavailability =
AUCORAL
AUCIV

ABSORPTION
Different routes of administration of drugs
 Enteral: weak barriers, but acid (gastric) and basic
(duodenal) can ↓bioavailability, easy, no risk of
bloodsteram infection
 First pass hepatic metabolism: ↓bioavailability
 Parenteral (IV, IM, SC, IT): rapid delivery, pain, infection,
irreversible
 For IV drugs: bioavailability = 1.0
 Mucous membrane: rapid delivery, no first pass, low
infection, direct delivery to affected tissue
 Transdermal: simple, painless, excellent for continuous
administration. Requires highly lipophilic drug, may be
irritating

ABSORPTION
Clinical example of FIRST PASS Metabolism :
Morphine
 Undergoes extensive first pass metabolism
 Oral bioavailability is 30 – 50 %
 Oral dose not comparable with IV dose

Distribution
1. Definition:
 Distribution is the process of delivering a drug from the
bloodstream to the tissues of the body
 It is a reversible transfer of drug between one
compartment (blood) to another (extra vascular tissue)
 Plasma concentration: poor measure of tissue
concentration
 Distribution affects the duration of action of the drug

Distribution
2. 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

FACTORS AFFECTING DISTRIBUTION OF
DRUGS
1. Tissue Permeability of Drugs
 Physicochemical Properties of drug like:
• Mol.size, pKa, o/w Partition Coefficient
 Physiological barriers to diffusion of drugs
• Simple Capillary Endothelial Barrier
• Simple Cell Membrane Barrier
• Blood Brain Barrier
• Blood-CSF Barrier
• Blood Placental Barrier
• Blood Testis Barrier
2. Organ/tissue size and perfusion rate
3. Binding of drugs to tissue components.
 binding of drug to blood components
 binding of drug to extra cellular components

FACTORS AFFECTING DISTRIBUTION OF
DRUGS
4. Miscellaneous:
 Age:
 Total body water
 Fat content
 Skeletal muscles
 Organ composition
 Plasma protein content
 Pregnancy
 Obesity
 Diet
 Disease states

METABOLISM
Definition
 Chemical alteration of drug in the body.
 Non polar lipid soluble compounds are made polar lipid
insoluble, so that they are easily excreted.
 SITES
 Primary site – Liver
 Others – Kidney, Intestine, Lungs, Plasma

METABOLISM
Drug Biotransformation : convert lipophilic /
hydrophobic drug (to enter cells) to hydrophilic
metabolites.
Advantages
 Termination of drug action - (↓ toxicity)
 Reduced lipophilicity.
 Renal / biliary excretion ↑ - (↓renal reabs)

METABOLISM
Absorbed drugs – 3 changes
Metabolic changes by Enzymes
( Microsomal, Cytoplasmic, Mitochondrial)
Spontaneous Molecular rearrangement –
HOFMANN ELIMINATION
Excreted unchanged (highly polar drugs) -
Aminoglycosides,Methotrexate,Neostigmine

METABOLISM
CONSEQUENCES
A) Drug inactivation - inactive or less active
Propranolol,Pentobarbitone,Morphine,Chloramphenicol,Parac
etamol,Ibuprofen,lignocaine
B) Active drug to Active metabolite- Active metabolite
Effect is due to parent drug and its active metabolite
C) Inactive drug (Prodrug) - Active drug
Prodrugs are inactive drugs which need BT in the body to form
active metabolites.
ADV
More stable
Better BA
Less toxicity
Eg: Levodopa - Dopamine
Enalapril - Enalaprilat

METABOLISM
TYPES
Biotransformation reactions - 2 types
 Phase I / Non synthetic / Functionalization
 A functional group is generated
 Metabolite – active or inactive
 Phase II / Synthetic / Conjugation
 An endogenous radical is conjugated
 Metabolite is usually inactive

METABOLISM
Phase I Reactions Phase II Reactions
 Oxidation
 Reduction
 Hydrolysis
 Cyclization
 Decyclization
 Glucuronide
conjugation
 Acetylation
 Methylation
 Sulfate conjugation
 Glycine conjugation
 Glutathione
conjugation
 Ribonucleotide /
Ribonucleoside
synthesis

INHIBITION OF DRUG
METABOLISM
 One drug can inhibit the metabolism of another drug
 ↑ in circulating levels of slowly metabolized drug
 Prolongation or potentiation of its effects
Consequences
 Precipitate toxicity of the object drug.
 can be therapeutically beneficial. Eg: aversion of
alcohol with disulfiram, Reversal of SKM paralysis
of d-tc by neostigmine
e.g:Valproate,Ketoconazole,Cimetidine,Ciprofloxacin,Er
ythromycin,INH
Code – Vitamin K cannot cause enzyme inhibition.

MICROSOMAL ENZYME
INDUCTION
 Inducers of enzymes that mediate the phase I
reaction enzymes (eg: Barbiturates)
Drugs, insecticides, carcinogens will induce the
synthesis of microsomal enzyme proteins
Accelerated metabolism and reduced
pharmacological response
Consequences
 Drug- drug interactions
 Can lead to toxicity. Eg: Alcoholics more prone to
hepatotoxicity of paracetamol due to↑ production of
NABQI
 Decreased duration of action.
EG:Griseofulvin,Phenytoin,Rifampicin,Smoking,Carbam

First Pass Metabolism
Presystemic metabolism/ First pass effect
Metabolism of a drug during its passage from the site
of absorption into the systemic circulation.
 ↓BA
 ↓therapeutic response
SITES
 Gut wall
 Gut lumen
 Liver (major site)
 Lungs
 Skin

Attributes of drugs with FPM
 Oral dose is higher than sublingual or parenteral.
 Oral BA is increased in patents with severe liver
 disease.
 Drugs with FPM usually have short plasma t1/2.
 Oral BA is increased if another drug competing
with it in first pass metabolism is given
concurrently. Eg: CPZ & Propranolol

ELIMINATION
Clearance
 Factor that predicts the rate of elimination in
relation to the drug concentration
Rate of elimination = CL x C
CLsystemic = CLliver + CLkidney + CLother
Rate of elimination
Plasma concentration (C)
Clearance (CL) =

ELIMINATION
Effect of disease processes
 Disease processes can alter the elimination of a
drug:
 Hepatic failure
 Renal failure

Renal failure
Time
PlasmaConcentration
Normal renal function
Renal insufficiency

RENAL EXCRETION:
• Most important organ for Elimination.
• Free drugs (eg. Furosemide,gentamicin)
• Drug Metabolites
PROCESSES THAT DETERMINE RENAL
– Glomerular filtration.
– Active tubular Secretion.
– Passive tubular reabsorption.
FACTORS OF GLOMERULAR FILTRATION:
• Molecular size.
• Plasma protein binding
• Renal Blood Flow

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.

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.

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.

Half-Life
It is defined as the time required for drug blood levels
to be reduced by 50%.
Factors affecting half-life
 Decreased:
 Ageing (decreased muscle and off course Vd)
 P450 induction
 Increased:
 Obesity ( adipose tissue and Vd)
 P450 inhibition
 Cardiac failure
 Hepatic failure
 Renal failure

PHARMACODYNAMICS
Pharmacodynamics is the study of drug effects.
 Wanted effects of drugs
 Side effects
 Clinical Interactions with other drugs:
 Synergy
 Antagonism
 Addition

Pharmacodynamics
Drug-receptor interactions
 2 properties determine the nature of a drugs
pharmacological effect:
 Affinity
 Refers to how well a drug binds to its receptor
 Intrinsic activity or efficacy
 refers to the magnitude of effect the drug has once bound to the
receptor

PHARMACODYNAMICS
Definitions
 Agonist: Mimic actions of neurotransmitter at same
site
Affinity for receptor
Intrinsic activity
 Antagonist: Block actions of neurotransmitter at
same site
 Affinity for receptor
 NO intrinsic activity

PHARMACODYNAMICS
Agonists
 Full agonist
 Drug that generates a maximal response from a
receptor (Emax)
 Demonstrates high affinity & high intrinsic activity
 Partial agonist
 Fails to achieve maximal effect even in high dose
 Demonstrates reduced intrinsic activity

PHARMACODYNAMICS:
Agonists
Log dose
Response
Full Agonist
Partial Agonist
Emax
Dose
Response

PHARMACODYNAMICS
Antagonists
 Reversible
 Competitive
 The effect of the antagonist can be overcome by increasing the
concentration of the agonist
 The 2 molecules are competing for the same receptor
 Non-competitive
 Do not bind to the same site on the receptor as the agonist
 Effect results from preventing receptor activation through
conformational distortion
 Effect cannot be overcome by increasing the concentration of
agonist
 Irreversible
 Irreversibly bind to the receptor
 Increasing agonist concentration will not overcome the blockade

PHARMACODYNAMICS
Antagonists
Log dose
Response
Full Agonist
Agonist in presence of
competitive antagonist
Emax
Log dose
Response
Full Agonist
Full agonist + non-competitive or
irreversible antagonist
Emax

PHARMACODYNAMICS
Other factors affecting pharmacological
response:
 Receptor down-regulation / up-regulation
 Receptor desensitization
 Change to affinity / maximal response
 Tachyphylaxis
 Genetic variations

Drug potency and efficacy
Drug potency which refers to the amount of
drug needed to produce a certain response.
Drug efficacy refers to the maximal response
that can be elicited by the drug.

Drug potency and efficacy
 Drug B is less potent but
equally efficacious as drug A.
 Drug C is less potent and
less efficacious than drug A.
 Drug D is more potent than
drugs A, B, & C, but less
efficacious than drugs
 A & B, and equally
efficacious as drug C.

Combined effect of Drugs
 Synergism:
When the action of one drug is facilitated or increased by
the other, they are said to be synergistic.
 Additive Synergism
 The effect of the two drugs is in the same direction and
simply adds up:
 Effect of drugs A + B = effect of drug A + effect of drug
B.

Applied pharmacology

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