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dr. Prajogo Wibowo, M. Kes
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The phases of drug delivery
1. Drug administration phase
Enteral, Parenteral, etc.
2. Pharmacokinetic phase
Absorption, Distribution, Metabolism,
Excretion
3. Pharmacodynamic phase
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Time of drug administration is determined by
properties of drug 1. Sensitive againts gastric pH/ gastric irritating
drug (e.g. NSAIDs)
2. The absorption interfered by food (e.g.
ampicillin)
3. Modify gastrointestinal physiology (e.g.
atropine)
4. Possibility of drug interaction (e.g.paracetamol with phenobarbital)
5. Fluctuation of gastrointestinal tract
secretion (e.g. antacide with tetracycline)
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Pharmacokinetics describes actions of thebody on drugs, including the principles of
drug absorption, distribution, biotransformation
(metabolism), and excretion.
Pharmacodynamics deals with the study of the
biochemical and physiological effects of
drugs on the body and their mechanisms of
action, includes the principles of receptor
interactions, mechanisms of therapeutics and
toxic action, and close-response relationships.
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Absorption is movement of drug from its
site of administration to systemic
circulation.
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The rate and efficacy of absorption depend on
Route of administration-The intravenous route is
most effective
Blood flow-Highly vascularized organs such as the
small intestine have the the greates absorbing ability
Surface area available-Absorption of a drug is directly
proportional to the surface area available
Solubility of a drug-The ratio of hydrophilic to
lipophilic properties (partition coefficient) that a drug
has will determine whether the drug can permeate cell
membranes.
Drug-drug interactions-When given in combination,
drug can either enhance or inhibit one anothers
absorption
pH-A drugs acidity or alkalinity affects its charge, which
affects absorption.
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Most drugs are weak acids or bases that
are present in solution as both the
nonionized and ionized species. The
nonionized molecules usually are morelipid-soluble and can diffuse readily
across the cell membrane. In contrast,
the ionized molecules usually are unableto penetrate the lipid membrane
because of their low lipid solubility.
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The site of absorption for oral administration is in small intestine,
(except alcohol is in stomach)
Factors affecting gastrointestinal absorption 1. Gastrointestinal motility has a large effect (e.g. loperamid: decrease,
metoclopramide: increase)
2. Gastrointestinal contain-A meal is often slowly absorbed, but there
are some exceptions.
3. Drug formulated-Particle size and formulation have major effects on
absorption. Therapeutic drugs are formulated pharmaceutically to produce
desired absorption characteristic. There are many drug forms (tablet,
capsule, matrix tablet, enteric coated tablet, coated tablet with delayed
release, drops, mixture, effervescent, solution, and suspension)
4. Physicochemical factors-drug interaction affect drug absorption.
Tetracyclin binds strongly to calcium therefore milk prevent its absorption.
Colestyramine binds several drugs.
5. Charateristic of drugs-Aminoglycoside (Streptomycin) is very poorly
absorbed because water soluble.
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Distribution:
The process by which a drug leaves the
bloodstream and enters the interstitium
or the cells of the tissues.
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Factors affecting drug distribution: 1. Circulation (blood flow)
2. Capillary structure (barrier)
- Central Nervous System (Blood BrainBarrier)
- Placenta barrier
- Testis barrier 3. Chemical structure of the drugs
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Metabolism can be defined as thealteration of the chemical structure of
the drug by enzyme.
The liveris the principal organ of drug
metabolism. Other tissues that display
considerably activity include the
gastrointestinal tract, the lungs, the skin,
and the kidneys.
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Factors affecting drug metabolism
Genetic factor-influence enzyme levels
Age & sex-The ability to metabolize drugs is lower in
neonatus and elderly patient.
Liver function-Alcoholic hepatitis, cirrhosis, acut viral,
hemochemochromatosis, and drug induced hepatitis may
impair drug metabolism
Diet & environmental factors-Charcoal-broiled food
(inducer), grape juice (inhibitor), cigarette smokers (inducer),
pesticide may induce or inhibit other drug metabolism
Drug interaction
drug inhibitor, reduced metabolism of other drugs
drug inducer, induced metabolism of other drugs or its own
metabolism
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1st pass metabolism
a condition in which the metabolism of
drug occurs before reaching the Site Of
Action (systemic circulation).
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Excretion
The procces by which a drug or metabolite is removed fromthe body
The routes of excretion
Renal urine is one ofthe most common routes ofexcretion
Fecal
Lung/respiration-primarily for anesthetic gases and vapors
Breast milk
Skin
Hair(e.g. arsen)
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TERMINOLOGY
Adverse Reaction
Unintended and unwanted effect occursat the doses normally given in man for
prophylactic, diagnostic, or therapeuticpurposes
Adverse Drug Reaction Monitoring
The systematic reporting, recording andevaluation of certain or all adversereaction to drug
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POST MARKETING SURVEILLANCE
(PMS)
ADR monitoring is only part of the
totally of post-marketing
surveillance which may providedata both on efficacy and safety
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NATIONAL MONITORING
CENTRE
The national centre for ADR monitoring is a
government agency or body to which
reports of suspected or proven ADRs can
be sent. The Centre evaluates the reportsin the light of all published and unpublished
data available to it and feeds back its
conclusions to the reporters and to health
professionals
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MONITOR
A monitor is a physician, pharmacist
or other designated health
professional who has agreed toundertake certain task in connection
with the reporting of original data to
the National Centre
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Classification of ADRs
(Etiological Basis)Reaction due to inherent anomalies
Acquired patient abnormalities
Anomalies of drug presentation andadministration
Drug interaction
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Classification of ADRs (Etiological Basis)
A. Reactions due to inherent
anomalies1. Drug allergy (hypersensitivity)
- Immunological mechanism
- Characteristic :
a. uncorrelated with the knownpharmacological properties
b. Predictable
c. Repeated exposure will cause
recurrences ofthe reactions
Included : skin rash, angioneurotic edema,serum sickness, and anaphylaxis or asthma
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Classification of ADRs (Etiological Basis)
A. Reactions due to inherent anomalies
2. Genetically determined ADRs :Reaction due to altered :
a. Pharmacokinetic handling of thedrug
b. Tissue responsiveness
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Classification of ADRs (Etiological Basis)
B. Acquired patient abnormalities
Due to the presence of intecurrent illness
which may unmask pharmacological effect
that are not apparent in normal
individuals, exp. : Hemorrhage of perforation in peptic
ulcers due to aspirin or corticosteroid
Hypoglycemia due to oral anti diabetes
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Classification of ADRs (Etiological Basis)
C. Anomalies of drug presentation
and administration Excessive response, alteration in
bioavailability or an inappropriate method of
administration
Potential sources of ADRs :
abnormalities of the drug : decomposition of
its active. Solubilizers, stabilizers, colourizers
in pharmaceutical preparations
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Classification of ADRs (Etiological Basis)
D. Drug Interaction
> 1 drug given at the same time
DI : unwanted effects and certain benefits
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The mechanism and
predisposing factors of ADRs :
Onset of reaction
Age
Pathophysiological
condition
Amount of drug
administered
Sex
Previous history of
allergy
Multiple drug
therapy
Racial or genetic
factors
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Mechanisms of Interaction
Direct physical or chemical interaction ofmore than one drug given concomitantly
Altered GI absorption, competition for proteinbinding sites or receptors
or metabolism of a drug by induction,activation, or inhibition of drug metabolismenzyme
Alteration of acid-base equilibrium, therebyinfluencing drug distribution and renalclearance
Alteration of hemodynamics or renal functionthat influences rates of renal excretion
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Reaction should be reported
ADRs previously unknown to the reporters
Serious or life-threatening ADRs
Cases of suspected dependence
Cases of suspected due to drug
interaction
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Methods of ADRs Monitoring
Incidental reporting
Systematic voluntary reporting
Intensive hospital monitoring
Record linkage
Mandatory or compulsory Monitoring
Limited Monitoring Release
Methods of
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Methods of
ADRsMSpontaneou
sR.
Simple & chip
Largepopulations
Rare & delayed
ADR
Incomplete
reportedFrequency
cant be
evaluated
Systematic
Valuntary
R.
Chip
Large
populations All
drugs
Early warning
Spread easily
Early warning
Is doubt
Low
Participate-on
Of health
professions
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Methods of ADRsM
IntensiveHospital
M.
Determine TheIncidence of
ADR
And risk factors
Large of costLimited population
Delayed ADR cant
be findRecord
linkage
May find chronic,
congenital, and
malignancy
ADRs
The tremendous
amount of data
Not identical
terminology
incomplete record
Methods of
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Methods of
ADRsM
Mandatory/Compulsor
y
M.
The reportexsist
(Rules)
Ideal for the
hospital
Accurate report isdoubted
Limited
Monitoring
Release
Frequency of
ADR can bedetermined
Limited of drug
and period/time
ALGORITM OF CAUSAL RELATIONSHIP
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ALGORITM OF CAUSAL RELATIONSHIPBETWEEN DRUGS AND ADRS
Onset of ADRs
afterAppropriate drug
use
Yes
DECHALLENGE
Yes
ADRs decrease
No Causal relationship
REMOTE
Causal relationship
REMOTE
No
NoCausal relationship
POSSIBLE
PROBABLE
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Yes
RECHALLENGE
Yes
ADRs
Appearing again
Yes
Causal Relationship
HIGHLY PROBABLE
PROBABLE
No
ADRs could not happened
because of clinical situation
Yes
Causal relationship
POSSIBLE
No
No