2. CONTENTS
Mechanism of drug Detoxication in the Body.
Intolerance, Tolerance, Cumulative action, Synergism, Antagonism.
Dosage, Classification of Drugs
5. 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:
6. 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
7. FATE OF A DRUG
II. Spontaneous change into other substances
No enzymes
III. Excretion unchanged
8. 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:
10. REACTIONS
Phase I reactions: OH-, NH2, SH-, COO- into drugs: water
soluble & less active
Initial stages: active & more toxic products also formed
11. 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
13. FACTORS AFFECTING DRUG
METABOLISM
Animal species & strain
Route & duration of admn
Age & sex
Environmental determinants:
Genetic determinants
Nutritional status
Altitude & temperature
pollutants
Drug interactions (inducers &
inhibitors)
Disease- hepatic/ renal
damage
14. 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
15. 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
16. SYNTHETIC REACTION
Conjugation/ transfer reactions
Drug/ Phase I metabolite + endogenous substance conjugates
large
molecules:
bile
Inactivation
small
molecules:
urine
17. SYNTHETIC REACTION
GLUCURONIDE CONJUGATION
Chloramphenicol, aspirin, paracetamol
Bilirubin, steroidal hormones, thyroxine
hydrolysis
MW: excretion in bile
Gut bacteria
Enterohepatic cycling: duration of action- OCPs
reabsorbed
19. SYNTHETIC REACTION
RIBONUCLEOSIDE/ NUCLEOTIDE SYNTHESIS:
Activation of purine & pyrimidine antimetabolites in cancer chemotherapy
SULFATE CONJUGATION
Chloramphenicol, methyldopa, adrenal & sex steroids
20.
21. E N Z Y M E S O F I N T E R M E D I A RY
M E TA B O L I S M
Alcohol: alcohol dehydrogenase
Allopurinol: xanthine oxidase
SCh & procaine: plasma cholinesterase
Adrenaline: mono amino oxidase
Majority: microsomal & non microsomal drug metabolising enzymes
22.
23. 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
24. 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
25. 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
26. 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
27. CROSS TOLERANCE
Tolerance to pharmacologically related drugs
Alcoholics: barbiturates & general anesthetics
Partial: morphine & barbiturates
Complete: morphine & pethidine
28. A P PA R E N T / P S E U D O
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
29. MECHANSIM OF DEVELOPMENT OF
TOLERANCE
1. Pharmacokinetic/ Drug
2.Pharmacodynamic/
disposition tolerance:
Functional/Cellular tolerance:
Changes in absorption,
Target tissue changes-
distribution, metabolism &
Decrease in drug receptors/ down
excretion: effective concentration
regulation or weakening of
at the site of action reduced
response effectuation
Barbiturates, carbamazepine,
Alcohol, barbiturates, nitrates,
amphetamine
morphine
30. TACHYPHYLAXIS
Acute tolerance
Slow dissociation of drug
Doses of a drug are repeated
from receptor: reduced intrinsic
in quick succession: marked
activity; continued blockade
reduction in response
Unidentified ‘adaptive
Ephedrine, nicotine
response’ of tissue/
compensatory homeostatic
adaptation
31. TACHYPHYLA X IS
VS
Rare in clinical practice:
TOLERANCE
More common
repeated admn in quick
succession not customary
Faster
Drug effect cant be obtained
Slower development
with increased dose
Original effect obtained with
increasing dose
32. 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
33. 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
34. DRUG INTOLERANCE
Also used: any Adverse Drug Reaction (ADR)
DRUG
INTOLERANCE
QUANTITATIVE
AUGMENTED
PREDICTABLE
TYPE A
IDIOSYNCRASY
ALLERGY
QUANLITATIVE
BIZZARE
UNPREDICTABLE
TYPE B
35. TYPE A
ADR
TYPE B
ADR
Dose related & predictable :
Less common, not dose-
pharmacological actions
related, more serious, require
Preventable & reversible
drug withdrawal
Hyper response to the main
Idiosyncrasy: genetic/
action: insulin hypoglycemia
unknown mechanism
Allergy: Immunological- type
I, II, III, IV
36. IDIOSYNCRASY
Genetically determined abnormal reactivity: uncharacteristic
reaction with drug
Due to individual peculiarities
Chloramphenicol: non- dose related serious aplastic anemia
40. CUMULATIVE ACTION
Repeated admn. Of slow excreted drug: high concentrationtoxicity
Digoxin, emetine, heavy metals
Cumulative effect desired: phenytoin in epilepsy
Passive cumulation: remain deposited in bones without toxic effectsLEAD;Toxic: once in blood
Liver & kidney impairment : non- cumulative drugs also cumulate
41. 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
42. SYNERGISM
Additive:
Supraadditive
Effect of 2 drugs: same
The effect of the combination >
direction- adds up 1+1=2
individual effects 2+2=5
Combination- better tolerated
prolongation of duration of
than higher dose of individual
action of one – time synergism
drug
Levodopa + Carbidopa/
Aspirin + Paracetamol-
benserazide- inhibition of peripheral
analgesic/ antipyretic
metabolism
43. 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
44. 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
45. ANTAGONISM
Physiological/ functional
Receptor:
Different receptors/
Antagonist drug blocks the
mechanisms- opposite effects on
same function
Opposing pharmacological
receptor action of agonist
Specific & profound
actions
pharmacological effect
Glucagon & insulin on blood
Antagonists: selective
sugar level
Competitive/ non competitive
46. COMPETITIVE
ANTAGONISM
Equilibrium type/ Reversible
Antagonist chemically similar to agonist: competes for same
binding site
No response
Reversible:
concentration of both
ACh & atropine: muscarinic
Adrenaline & prazosin: α
48. 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
50. 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
51.
52. CONTENTS
Dose
Fixed dose ratio combinations
Factors necessitating dose modification
- body size
- age
- sex
- race &genetics
- pathological states
- other drugs
53. 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
54. DRUG DOSAGE
Prophylactic/ Therapeutic/ Toxic dose
Inherent potency & pharmacokinetic properties : dose
Recommended doses: ‘average’ patient
Individual patients: differ from this
55. DRUG DOSAGE
Standard dose:
Regulated dose:
Same dose appropriate for
Finely regulated & easily
most: minor variations & wide
measured body function –
safety margin
modified
OCPs, Penicillin, chloroquine,
mebendazole
Dosage adjusted :
measurement of parameter
Antihypertensives
56. DRUG DOSAGE
Target level dose:
Titrated dose:
Response: not measurable
Dose: maximal therapeutic effect
Certain plasma levels of drug :
cant be given: adverse effects
achieved
Compromise between submaximal
Facilities unavailable: crude
therapeutic effect & tolerable side
adjustments – observing patient at
effects
long intervals
Antidepressants, antiepileptics,
digoxin, lithium
Anticancer drugs, levodopa,
steroids
57. FIXED DOSE RATIO COMBINATIONS:
A D VA N T A G E S & D I S A D VA N T A G E S
Convenience & better patient
compliance
All components may not be
needed
Dose needs adjustment &
Synergistic combinations
individualising
Elimination & counteraction
Time course of action of
of side effects
components: different
Ensures single drug is not
Cause of adverse effect: doubtful
administered: AIDS, TB
Contraindication to one
component: whole preparation
58. FAC T O R S M O D I F Y I N G D RU G
AC T I O N
Different pharmacokinetic handling of drugs
Variations in number/ state of receptors
Variations in neurogenic/ hormonal tone
Genetic/ non genetic factors modify drug action:
quantitatively
Most factors cause
such change: dealt by
adjustment of drug
dosage
qualitatively
Less common:
precludes the use of
the drug in the
patient
59. FAC T O R S N E C E S S I TAT I N G
D O S E M O D I F I C AT I O N
Body size:
Average adult dose: medium built
Individual dose= BW (kg) x avg adult dose
70
2
Individual dose = BSA(m ) x avg adult dose
1.7
60. FAC T O R S N E C E S S I TAT I N G
D O S E M O D I F I C AT I O N
Age:
Age
Child dose= Age +12 x adult dose-----------(Young’s
formula)
Child dose = Age x adult dose-----------(Dilling’s
20
formula)
61. PHYSIOLOGICAL DIFFERENCES FROM
A D U LT S R E Q U I R I N G C A U T I O N :
Low GFR, immature tubular
Growth
transport: gentamicin, penicillin
Suppression – corticosteroids
Inadequate hepatic drug
Stunting of stature:
metabolizing system:
androgens
chloramphenicol- gray baby syndrome
Discoloration of teeth:
Permeable blood brain barrier
tetracycline
Faster drug metabolism than in
Dystonic reactions:
adults after 1st year
phenothiazines
62. FAC T O R S N E C E S S I TAT I N G
D O S E M O D I F I C AT I O N
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
63. 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
RBF: faster elimination of polar drugs
Induction of hepatic enzymes: faster metabolism
and basic drugs
64. FAC T O R S N E C E S S I TAT I N G
D O S E M O D I F I C AT I O N
Race:
Genetics:
Blacks require higher &
Dose of a drug- same effect: 4-6
mongols lower concentrations
fold variation
of atropine & ephedrine to dilate
Pharmacogenetics: the study of genetic
their pupil
basis for variability in drug response
Pharmacogenomics: the use of genetic
information to guide the choice of
drug & dose on an individual basis
65. PATHOLOGICAL STATES
I.
GI diseases:
II. Liver diseases:
serum albumin: more free form of
Coeliac disease- Absorption of
amoxicillin
cephalexin & cotrimoxazole
achlorhydria aspirin
absorption
diclofenac, warfarin
Dose reduction needed: lidocaine,
morphine, propanolol
Normal doses of CNS depressants:
toxic in cirrhotics
Oral anticoagulants: marked
PT
66. 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
67. 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
68. PATHOLOGICAL STATES
IV. Congestive heart failure
V. Thyroid disease:
Decreased absorption from
Clearance of digoxin- roughly
GIT: procainamide,
hydrochlorothiazide
Loading doses and dosing rates
of lidocaine reduced
parallels thyroid function
Hypothyroid: more sensitive to
digoxin, morphine, CNS depressants
Compensated heart; more
Hyperthyroid: prone to arrhythmic
sensitive to digitalis
action of digoxin
69. 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
70. FAC T O R S N E C E S S I TAT I N G
D O S E M O D I F I C AT I O N
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
71. FAC T O R S N E C E S S I TAT I N G
D O S E M O D I F I C AT I O N
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
72. CLASSIFICATION OF DRUGS
Single, rational classification system: not possible
Requirements of chemists, pharmacologists, doctors differ
Categorised according to the convenience of the discussing group
73. CLASSIFICATION OF DRUGS
I. BODY SYSTEM:
II. THERAPEUTIC USE:
Alimentary
Receptor blockers
Cardiovascular
Enzyme inhibitors
ANS, PNS, CNS
Carrier molecules
Respiratory system
Renal system
Blood & blood formation
Ion channels
74. 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
75. 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
76. ANATOMICAL THERAPEUTIC CHEMICAL (ATC)
CLASSIFICATION SYSTEM
drugs are classified into groups at 5 different levels
First level
the anatomical main group and consists of one letter.
14 main groups
en. wikipedia.org
77. Code
Contents
A
Alimentary tract and metabolism
B
Blood and blood forming organs
C
Cardiovascular system
D
Dermatologicals
G
Genito-urinary system and sex hormones
H
Systemic hormonal preparations, excluding
sex hormones and insulins
J
Antiinfectives for systemic use
L
Antineoplastic and immunomodulating
agents
M
Musculo-skeletal system
N
Nervous system
P
Antiparasitic products, insecticides and
repellents
R
Respiratory system
S
Sensory organs
V
Various
78. 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
79. 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
en. wikipedia.org