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PHARMACOLOGY- PART II
DEEPTHI P.R.
1st YEAR MDS
DEPT.OF CONSERVATIVE DENTISTRY & ENDODONTICS
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CONTENTS
Mechanism of drug Detoxication in the Body. Intolerance, Tolerance, Cumulative action,
Synergism, Antagonism. Dosage, Classification of Drugs
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MECHANISM
OF DRUG
DETOXICATIO
N IN THE
BODY
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CONTENTS
Fate of a drug
Reactions:
synthetic
non- synthetic
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FATE OF A DRUG
Changes that drug undergoes & its ultimate
elimination
Alteration of a drug within a living organism:
biotransformation
Metabolism: detoxication process
3 possible fates after absorption:
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FATE OF A DRUG
I. Metabolic transformation by enzymes
Microsomal/ cytosolic/ mitochondrial
Inactivate an active drug
Activate a prodrug
Generate active metabolites of an active drug
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FATE OF A DRUG
II. Spontaneous change into other substances
No enzymes
III. Excretion unchanged
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FATE OF A DRUG
Less polar, lipid soluble more polar, water
soluble: excretion by kidneys
Already polar & soluble: excreted as such-
aminoglycosides
Activation/ inactivation/ modification
Reactions:
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Non synthetic/ Phase I/
Functionalization
Oxidation
Reduction
Hydrolysis
Cyclization
Decyclization
REACTIONS
Synthetic/ Phase II/
Conjugation
Glucuronide conjugation
Acetylation
Methylation
Sulfate conjugation
Glutathione conjugation
Ribonucleoside/ nucleotide
synthesis
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REACTIONS
Phase I reactions: OH-, NH2, SH-, COO- into
drugs: water soluble & less active
Initial stages: active & more toxic products also
formed
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REACTIONS
Tissues metabolising drugs: liver
Enzymes : drug metabolism- liver microsomes- sER
Esterases, amidases, glucuronyl transferases:
catalyse oxidative & reductive reactions
Variety of enzymes- CYP450 system : absorbs light
maximally at 450nm
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REACTIONSDrugs – barbiturates: enzyme induction- rapid metabolism of
substrate drugs
Enzyme induction: kidney, gut, plasma, skin, lung
Non microsomal enzymes & intestinal microfloral enzymes : MAO,
alcohol dehydrogenase, xanthine oxidase
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Animal species &
strain
Age & sex
Genetic determinants
Nutritional status
Altitude & temperature
FACTORS AFFECTING DRUG METAB OLISM
Route & duration of
admn
Environmental
determinants: pollutants
Drug interactions
(inducers & inhibitors)
Disease- hepatic/ renal
damage
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PHASE I REACTIONS
OXIDATION
Hydroxylation: salicylic acid to gentisic acid
Dealkylation: phenacetin to p-acetaminophenol
Deamination: amphetamine to benzyl-methyl-ketone
REDUCTION
Microsomal enzymes- halothane & chloramphenicol
Non microsomal enzymes: chloral hydrate, disulfiram,
nitrites
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PHASE I REACTIONS
HYDROLYSIS
Esterases: microsomal/ non microsomal/ microfloral
Pethidine, procaine, acetyl choline
CYCLIZATION
Ring structure from a straight chain compound: proguanil
DECYCLIZATION
Opening up of ring structure – cyclic drug molecule:
barbiturates, phenytoin
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SYNTHETIC REACTION
Conjugation/ transfer reactions
Drug/ Phase I metabolite + endogenous
substance conjugates
Inactivation
large molecules: bile
small molecules: urine
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SYNTHETIC REACTION
GLUCURONIDE CONJUGATION
Chloramphenicol, aspirin, paracetamol
Bilirubin, steroidal hormones, thyroxine
MW: excretion in bile
reabsorbed
Enterohepatic cycling: duration of action- OCPs
hydrolysis
Gut bacteria
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ACETYLATION
Sulfonamides, isoniazid, PAS,
hydralazine,
Genetic polymorphism: slow
& fast acetylators
METHYLATION
Adrenaline, histamine,
nicotinic acid, methyldopa,
captopril
SYNTHETIC REACTION
GLYCINE CONJUGATION
Minor pathway-
Salicylates
GLUTATHIONE
CONJUGATION
Highly reactive
intermediates: inactivated-
paracetamol
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SYNTHETIC REACTION
RIBONUCLEOSIDE/ NUCLEOTIDE SYNTHESIS:
Activation of purine & pyrimidine antimetabolites in cancer
chemotherapy
SULFATE CONJUGATION
Chloramphenicol, methyldopa, adrenal & sex steroids
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ENZYMES OF INTERMEDIARY
METABOLISM
Alcohol: alcohol dehydrogenase
Allopurinol: xanthine oxidase
SCh & procaine: plasma cholinesterase
Adrenaline: mono amino oxidase
Majority: microsomal & non microsomal drug metabolising enzymes
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TOLERANCE
INTOLERANCE
CUMULATIVE
ACTION
SYNERGISM
ANTAGONISM
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TOLERANCE
Requirement of higher dose of a drug to produce a
given response
Refractoriness: loss of therapeutic efficiency – a
form of tolerance
Types:
Natural
Acquired
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NATURAL TOLERANCE
Innate/ congenital tolerance
Species/Racial/ individual: inherently less sensitive
to the drug
Rabbits: atropine
Black races : mydriatics
Some individuals: hyporesponders –
alcohol, β-blockers
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ACQUIRED TOLERANCE
Repeated administration: in initially responsive
Seen with most drugs: significant in CNS
depressants
Opiates, barbiturates, nitrites, xanthines
Not with: atropine, sodium nitroprusside, digitalis,
cocaine
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TISSUE TOLERANCE
Develops unequally: different effects of same drug
Sedative action of chlorpromazine: not to
antipsychotic
Analgesic & euphoric action of morphine & not
constipating & miotic actions
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CROSS TOLERANCE
Tolerance to pharmacologically related drugs
Alcoholics: barbiturates & general anesthetics
Partial: morphine & barbiturates
Complete: morphine & pethidine
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APPARENT/ PSEUDO TOLERANCE
Confined to oral administration of drug
Taking small amounts of poisons orally: render
immunity to oral poisons
Mucosal changes in GIT: prevents systemic
absorption of poison
Can occur through other routes
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1. Pharmacokinetic/ Drug
disposition tolerance:
Changes in absorption,
distribution, metabolism &
excretion: effective
concentration at the site of
action reduced
Barbiturates,
carbamazepine, amphetamine
MECHANSIM OF DEVELOPMENT OF TOLERANCE
2.Pharmacodynamic/
Functional/Cellular tolerance:
Target tissue changes-
Decrease in drug receptors/
down regulation or weakening
of response effectuation
Alcohol, barbiturates,
nitrates, morphine
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Acute tolerance
Doses of a drug are
repeated in quick
succession: marked
reduction in response
Ephedrine, nicotine
TACHYPHYLAXIS
Slow dissociation of drug
from receptor: reduced
intrinsic activity; continued
blockade
Unidentified ‘adaptive
response’ of tissue/
compensatory homeostatic
adaptation
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Rare in clinical
practice: repeated admn
in quick succession not
customary
Faster
Drug effect cant be
obtained with increased
dose
TA C H Y P H Y L A X I S V S T O L E R A N C E
More common
Slower development
Original effect obtained
with increasing dose
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REVERSE TOLERANCE
Sensitisation
Intermittent dosing schedule
Greater response seen for a given dose than after
an initial dose
Repeated daily administration of cocaine/
amphetamine: gradual increase in motor activity
with constant dose
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DRUG INTOLERANCE
‘Failure to tolerate’: Appearance of toxic effects of
a drug in an individual at therapeutic doses
Low threshold to the action of a drug
Single tablet of chloroquine: vomiting & abdominal
pain
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DRUG INTOLERANCE
Also used: any Adverse Drug Reaction (ADR)
DRUG INTOLERAN
CE
QUANTITATIVE
AUGMENTEDPREDICTABLE
TYPE A
QUANLITATIVE BIZZARE
UNPREDICTABLE
TYPE B
IDIOSYNCRASY
ALLERGY
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Dose related &
predictable :
pharmacological actions
Preventable &
reversible
Hyper response to the
main action: insulin
hypoglycemia
TYPE A ADR
Less common, not dose-
related, more serious,
require drug withdrawal
Idiosyncrasy: genetic/
unknown mechanism
Allergy: Immunological-
type I, II, III, IV
TYPE B ADR
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IDIOSYNCRASY
Genetically determined abnormal reactivity:
uncharacteristic reaction with drug
Due to individual peculiarities
Chloramphenicol: non- dose related serious
aplastic anemia
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ALLERGY
Type I/ Anaphylactic reactions:Urticaria angioedemabronchospasm anaphylactic shock
Type II/ Cytolytic reactions:Thrombocytopenia agranulocytosisaplastic anemia hemolysis SLE
Type III/ retarded, Arthus reaction:Rashes, serum sickness, polyateritis nodosa, SJS
Type IV/ Delayed hypersensitivity reactions:Contact dermatitis, rashes, fever, photosensitisation
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Immediate stoppage of
offending drug
Mild rxns: self
subsiding
Antihistamines: type I
rxns & skin rashes
TREATMENT OF ALLERGYAnaphylactic shock/ laryngeal
angioedema:
Patient in reclining position, O2
admn at high flow rate, CPR
Inj. Adrenaline 0.5mg (0.5 ml of 1
in 100 solution) im
chlorpheniramine 10-20 mg i.m/
slow i.v
i.v. hydrocortisone sodium
succinate 100-200 mg- severe/
recurrent cases
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Penicillins
Cephalosporins
Sulfonamides
Tetracyclines
Quinolones
AntiTB drugs
Phenothiazines
DRUGS CAUSING ALLERGY FREQUENTLY
Salicylates
Carbamazepine
Allopurinol
ACE inhibitors
Methyldopa
Hydralazine
Local anesthetics
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CUMULATIVE ACTION
Repeated admn. Of slow excreted drug: high
concentration- toxicity
Digoxin, emetine, heavy metals
Cumulative effect desired: phenytoin in epilepsy
Passive cumulation: remain deposited in bones without
toxic effects- LEAD;Toxic: once in blood
Liver & kidney impairment : non- cumulative drugs also
cumulate
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SYNERGISM
Greek: syn- together; ergon- work
Action of one drug facilitated by the other
Both may have action in same direction
Given alone: one inactive, still enhance the other
when together
2 types : additive & supraadditive
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Additive:
Effect of 2 drugs: same
direction- adds up 1+1=2
Combination- better
tolerated than higher dose
of individual drug
Aspirin + Paracetamol-
analgesic/ antipyretic
SYNERGISM
Supraadditive
The effect of the combination
> individual effects 2+2=5
prolongation of duration of
action of one – time
synergism
Levodopa + Carbidopa/
benserazide- inhibition of
peripheral metabolism
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ANTAGONISM
Phenomenon of opposing actions of two drugs on the same
physiological system
Effect of drugs A+B< effect of drug A + effect of drug B
One is inactive & decreases the effect of the other
Physical
Chemical
Physiological/ Functional
Receptor
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ANTAGONISM
Physical:
Physical property
Charcoal adsorbs alkaloids: poisoning
Chemical:
Chemical reaction of 2 drugs: inactive product
KMnO4 + alkaloids- gastric lavage in poisoning
Chelating agents + toxic heavy metals
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Physiological/ functional
Different receptors/
mechanisms- opposite
effects on same function
Opposing
pharmacological actions
Glucagon & insulin on
blood sugar level
ANTAGONISM
Receptor:
Antagonist drug blocks the
receptor action of agonist
Specific & profound
pharmacological effect
Antagonists: selective
Competitive/ non
competitive
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COMPETITIVE ANTAGONISMEquilibrium type/ Reversible
Antagonist chemically similar to agonist: competes
for same binding site
No response
Reversible:
concentration of both
ACh & atropine: muscarinic
Adrenaline & prazosin: α
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COMPETITIVE ANTAGONISM
Partial agonist: competes with full agonist-
submaximal response
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NONCOMPETITIVE ANTAGONISM
Antagonist inactivates the receptor : effective complex with the
agonist not formed
3 ways:
Combination with same binding site: firm, not displaced by higher
agonist concentration
Combination at a different site/ allosteric site: prevent
characteristic
change by agonist
Change induced in agonist binding site: reactivity abolished
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NONCOMPETITIVE ANTAGONISM
ACh & papaverine: smooth muscle
Ach & decamethonium : NMJ
Reversible/ irreversible effect
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SIGNIFICANCE OF ANTAGONISM
Correcting adverse effects: chlorpromazine &
benzhexol
Treating drug poisoning: morphine with naloxone
Predicting drug combinations which would reduce
drug efficacy: penicillin & tetracycline inferior to
penicillin alone in pneumococcal meningitis
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DOSAGE
CLASSIFICATIO
N OF DRUGS
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CONTENTSDose
Fixed dose ratio combinations
Factors necessitating dose modification
- body size
- age
- sex
- race &genetics
- pathological states
- other drugs
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DRUG DOSAGE
‘DOSE’
The appropriate amount of a drug needed to
produce a certain degree of response in a patient
Qualified in terms of the chosen response:
Aspirin: 0.3- 0.6g - headache
60-150mg - antiplatelet action
3-5g – rheumatoid arthritis
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DRUG DOSAGE
Prophylactic/ Therapeutic/ Toxic dose
Inherent potency & pharmacokinetic properties :
dose
Recommended doses: ‘average’ patient
Individual patients: differ from this
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Standard dose:
Same dose appropriate
for most: minor variations
& wide safety margin
OCPs, Penicillin,
chloroquine, mebendazole
DRUG DOSAGE
Regulated dose:
Finely regulated & easily
measured body function –
modified
Dosage adjusted :
measurement of parameter
Antihypertensives
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Target level dose:
Response: not measurable
Certain plasma levels of
drug : achieved
Facilities unavailable: crude
adjustments – observing
patient at long intervals
Antidepressants,
antiepileptics, digoxin, lithium
DRUG DOSAGE
Titrated dose:
Dose: maximal therapeutic
effect cant be given: adverse
effects
Compromise between
submaximal therapeutic effect
& tolerable side effects
Anticancer drugs, levodopa,
steroids
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Convenience & better
patient compliance
Synergistic combinations
Elimination &
counteraction of side
effects
Ensures single drug is not
administered: AIDS, TB
FIXED DOSE RATIO COMBINATIONS: ADVANTAGES & DISADVANTAGES
All components may not
be needed
Dose needs adjustment &
individualising
Time course of action of
components: different
Cause of adverse effect:
doubtful
Contraindication to one
component: whole
preparation
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FACTORS MODIFYING DRUG ACTION
Different pharmacokinetic handling of drugs
Variations in number/ state of receptors
Variations in neurogenic/ hormonal tone
Genetic/ non genetic factors modify drug action:
quantitatively
qualitativelyMost factors cause such
change: dealt by adjustment of drug dosage
Less common: precludes the
use of the drug in the patient
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FACTORS NECESSITATING DOSE MODIFICATION
Body size:
Average adult dose: medium built
Individual dose= x avg adult dose
Individual dose = x avg adult dose
BW (kg) 70
BSA(m2)
1.7
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FACTORS NECESSITATING DOSE MODIFICATION
Age:
Child dose= x adult dose-----------(Young’s
formula)
Child dose = x adult dose-----------(Dilling’s
formula)
Age Age +12
Age 20
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Low GFR, immature tubular
transport: gentamicin,
penicillin
Inadequate hepatic drug
metabolizing system:
chloramphenicol- gray baby
syndrome
Permeable blood brain barrier
Faster drug metabolism than
in adults after 1st year
PHYSIOLOGICAL DIFFERENCES FROM ADULTS REQUIRING
CAUTION:
Growth
Suppression –
corticosteroids
Stunting of stature:
androgens
Discoloration of teeth:
tetracycline
Dystonic reactions:
phenothiazines
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FACTORS NECESSITATING DOSE MODIFICATION
Elderly:
Drug doses reduced: GFR~ 75% -50 years &
~50%- 75 years
Reduction in hepatic drug metabolism: oral
bioavailability
Intolerant to digitalis
Reduced responsiveness of β receptors
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FACTORS NECESSITATING DOSE MODIFICATION
Sex:
Females: doses on lower side of the range
Changes altering drug disposition in pregnancy:
GI motility: delayed absorption of oral drugs
plasma albumin levels: fraction of acidic drugs and basic
drugs
RBF: faster elimination of polar drugs
Induction of hepatic enzymes: faster metabolism
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Race:
Blacks require higher
& mongols lower
concentrations of
atropine & ephedrine to
dilate their pupil
FACTORS NECESSITATING DOSE MODIFICATION
Genetics:
Dose of a drug- same effect: 4-6
fold variation
Pharmacogenetics: the study of
genetic basis for variability in
drug response
Pharmacogenomics: the use of
genetic information to guide the
choice of drug & dose on an
individual basis
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I. GI diseases:
Coeliac disease- Absorption
of amoxicillin
cephalexin & cotrimoxazole
achlorhydria aspirin
absorption
PATHOLOGICAL STATES
II. Liver diseases:
serum albumin: more free form
of diclofenac, warfarin
Dose reduction needed:
lidocaine, morphine, propanolol
Normal doses of CNS
depressants: toxic in cirrhotics
Oral anticoagulants: marked
PT
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PATHOLOGICAL STATES
III. Renal diseases
Maintenance dose of drugs excreted unchanged &
partly unchanged: reduced or dose interval prolonged
Free form of acidic drugs : reduction in albumin level
CNS depressants : more due to permeability of BBB
Pethidine: seizures
Urinary antiseptics: systemic toxicity
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PATHOLOGICAL STATES
Antimicrobials needing dose reduction
Even in mild failure Only in severe failure
Aminoglycosides Cotrimoxazole
Cephalexin Carbenicillin
Ethambutol Cefotaxime
Vancomycin Norfloxacin
Amphotericin B Ciprofloxacin
Acyclovir Metronidazole
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IV. Congestive heart failure
Decreased absorption
from GIT: procainamide,
hydrochlorothiazide
Loading doses and dosing
rates of lidocaine reduced
Compensated heart; more
sensitive to digitalis
PATHOLOGICAL STATES
V. Thyroid disease:
Clearance of digoxin- roughly
parallels thyroid function
Hypothyroid: more sensitive
to digoxin, morphine, CNS
depressants
Hyperthyroid: prone to
arrhythmic action of digoxin
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PATHOLOGICAL STATES
VI. Others:
Schizophrenics tolerate large doses of
phenothiazines
Head injury patients: respiratory failure- normal
doses of morphine
MI patients: prone to digitalis & adrenaline
induced arrhythmias
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FACTORS NECESSITATING DOSE MODIFICATION
Other drugs:
Concurrent administration of inhibitors of hepatic
microsomal enzymes: (macrolides, chloramphenicol,
cimetidine, metronidazole)- dose reduction of drugs
metabolised: (azathioprine, warfarin, theophylline)
Propanolol: lidocaine, morphine, verapamil,
imipramine & self metabolism- reduction in hepatic blood
flow
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FACTORS NECESSITATING DOSE MODIFICATION
Enzyme inducers: barbiturates, phenytoin, carbamzepine-
failure of antimicrobial therapy with metronidazole,
doxycycline, chloramphenicol
contraceptive failure
Paracetamol toxicity at lower doses: toxic metabolite
Oral anticoagulants, hypoglycemics, antiepileptics,
antihypertensives: dose adjustment
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CLASSIFICATION OF DRUGS
Single, rational classification system: not possible
Requirements of chemists, pharmacologists,
doctors differ
Categorised according to the convenience of the
discussing group
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I. BODY SYSTEM:
Alimentary
Cardiovascular
ANS, PNS, CNS
Respiratory system
Renal system
Blood & blood formation
CLASSIFICATION OF DRUGS
II. THERAPEUTIC USE:
Receptor blockers
Enzyme inhibitors
Carrier molecules
Ion channels
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CLASSIFICATION OF DRUGS
III. MODE/ SITE OF ACTION:
Molecular interaction: glucoside, alkaloid, steroid
Cellular site: loop diuretic, catecholamine uptake inhibitor
IV. MOLECULAR STRUCTURE:
Glycoside
Alkaloid
Steroid
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en. wikipedia.org
ANATOMICAL THERAPEUTIC CHEMICAL (ATC) CLASSIFICATION SYSTEM
Controlled by the WHO Collaborating Centre for Drug Statistics
Methodology (WHOCC)
First published in 1976
Drugs into different groups: the organ or system on which they
act and/or their therapeutic and chemical characteristics
Same drug: more than one code
Eg: Aspirin- A01AD05 - local oral treatment,
B01AC06 - antiplatelet,
N02BA01 – analgesic, antipyretic
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en. wikipedia.org
ANATOMICAL THERAPEUTIC CHEMICAL (ATC) CLASSIFICATION SYSTEM
drugs are classified into groups at 5 different levels
First levelthe anatomical main group and consists of one letter.
14 main groups
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Code ContentsA Alimentary tract and metabolism
B Blood and blood forming organs
C Cardiovascular system
D Dermatologicals
GGenito-urinary system and sex hormones
HSystemic hormonal preparations, excluding sex hormones and insulins
J Antiinfectives for systemic use
LAntineoplastic and immunomodulating agents
M Musculo-skeletal system
N Nervous system
PAntiparasitic products, insecticides and repellents
R Respiratory system
S Sensory organs
V Various
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en. wikipedia.org
ANATOMICAL THERAPEUTIC CHEMICAL (ATC) CLASSIFICATION
SYSTEM
Second level
the therapeutic main group and consists of two digits.
Eg: G03 Diuretics
Third level
the therapeutic/pharmacological subgroup and
consists of one letter.
Example: G03C High-ceiling diuretics
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en. wikipedia.org
ANATOMICAL THERAPEUTIC CHEMICAL (ATC) CLASSIFICATION SYSTEM
Fourth level
the chemical/therapeutic/pharmacological subgroup
and consists of one letter.
Eg: G03CA Sulfonamides
Fifth level
the chemical substance and consists of two digits.
Eg: G03CA01 Furosemide
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BIBLIOGRAPHY
Pharmacology & Pharmacotherapeutics- Satoskar,
Bhandarkar, Rege: 9th edition
Essentials of Medical Pharmacology- Tripathi, 6th edition
Clinical Pharmacology- Bennett, Brown- 9th edition
Textbook of Dental Pharmacology- Sharma, Sharma,
Gupta
en. Wikipedia.com
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THANK YOU!!!!