drug detoxication, tolerance, intolerance, combined effects, dosage, classification
TRANSCRIPT
PHARMACOLOGY- PART II
DEEPTHI P.R.
1st YEAR MDS
DEPT.OF CONSERVATIVE DENTISTRY & ENDODONTICS
CONTENTS
Mechanism of drug Detoxication in the Body. Intolerance, Tolerance, Cumulative action,
Synergism, Antagonism. Dosage, Classification of Drugs
MECHANISM
OF DRUG
DETOXICATIO
N IN THE
BODY
CONTENTS
Fate of a drug
Reactions:
synthetic
non- synthetic
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:
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
FATE OF A DRUG
II. Spontaneous change into other substances
No enzymes
III. Excretion unchanged
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:
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
REACTIONS
Phase I reactions: OH-, NH2, SH-, COO- into
drugs: water soluble & less active
Initial stages: active & more toxic products also
formed
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
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
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
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
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
SYNTHETIC REACTION
Conjugation/ transfer reactions
Drug/ Phase I metabolite + endogenous
substance conjugates
Inactivation
large molecules: bile
small molecules: urine
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
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
SYNTHETIC REACTION
RIBONUCLEOSIDE/ NUCLEOTIDE SYNTHESIS:
Activation of purine & pyrimidine antimetabolites in cancer
chemotherapy
SULFATE CONJUGATION
Chloramphenicol, methyldopa, adrenal & sex steroids
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
TOLERANCE
INTOLERANCE
CUMULATIVE
ACTION
SYNERGISM
ANTAGONISM
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
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
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
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
CROSS TOLERANCE
Tolerance to pharmacologically related drugs
Alcoholics: barbiturates & general anesthetics
Partial: morphine & barbiturates
Complete: morphine & pethidine
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
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
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
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
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
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
DRUG INTOLERANCE
Also used: any Adverse Drug Reaction (ADR)
DRUG INTOLERAN
CE
QUANTITATIVE
AUGMENTEDPREDICTABLE
TYPE A
QUANLITATIVE BIZZARE
UNPREDICTABLE
TYPE B
IDIOSYNCRASY
ALLERGY
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
IDIOSYNCRASY
Genetically determined abnormal reactivity:
uncharacteristic reaction with drug
Due to individual peculiarities
Chloramphenicol: non- dose related serious
aplastic anemia
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
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
Penicillins
Cephalosporins
Sulfonamides
Tetracyclines
Quinolones
AntiTB drugs
Phenothiazines
DRUGS CAUSING ALLERGY FREQUENTLY
Salicylates
Carbamazepine
Allopurinol
ACE inhibitors
Methyldopa
Hydralazine
Local anesthetics
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
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
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
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
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
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
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
COMPETITIVE ANTAGONISM
Partial agonist: competes with full agonist-
submaximal response
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
NONCOMPETITIVE ANTAGONISM
ACh & papaverine: smooth muscle
Ach & decamethonium : NMJ
Reversible/ irreversible effect
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
DOSAGE
CLASSIFICATIO
N OF DRUGS
CONTENTSDose
Fixed dose ratio combinations
Factors necessitating dose modification
- body size
- age
- sex
- race &genetics
- pathological states
- other drugs
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
DRUG DOSAGE
Prophylactic/ Therapeutic/ Toxic dose
Inherent potency & pharmacokinetic properties :
dose
Recommended doses: ‘average’ patient
Individual patients: differ from this
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
CLASSIFICATION OF DRUGS
Single, rational classification system: not possible
Requirements of chemists, pharmacologists,
doctors differ
Categorised according to the convenience of the
discussing group
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
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
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
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
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
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
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
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
THANK YOU!!!!