This document discusses various concepts related to pharmacology including the fate of drugs in the body, drug metabolism, tolerance, intolerance, synergism, and antagonism. It provides details on the three main fates of drugs after absorption which are metabolic transformation, spontaneous chemical changes, and excretion unchanged. It also describes the two phases of drug metabolism and various metabolic reactions including conjugation. Factors affecting drug metabolism and development of tolerance are summarized. The mechanisms and types of tolerance, intolerance, synergism, antagonism, and cumulative effects are defined.

1. PHARMACOLOGY- PART
II
DEEPTHI P.R.
1st YEAR MDS
DEPT.OF CONSERVATIVE DENTISTRY & ENDODONTICS

2. CONTENTS
 Mechanism of drug Detoxication in the Body.
 Intolerance, Tolerance, Cumulative action, Synergism, Antagonism.
 Dosage, Classification of Drugs

4. CONTENTS
 Fate of a drug
 Reactions:
synthetic
non- synthetic

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:

9. REACTIONS
Non synthetic/ Phase I/
Synthetic/ Phase II/ Conjugation
Functionalization
 Glucuronide conjugation
 Oxidation
 Acetylation
 Reduction
 Hydrolysis
 Cyclization
 Decyclization
 Methylation
 Sulfate conjugation
 Glutathione conjugation
 Ribonucleoside/ nucleotide
synthesis

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

12. REACTIONS
 Drugs – 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

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

18. SYNTHETIC REACTION
ACETYLATION
 Sulfonamides, isoniazid, PAS, h
ydralazine,
 Genetic polymorphism: slow &
GLYCINE CONJUGATION
 Minor pathway- Salicylates
GLUTATHIONE
fast acetylators
CONJUGATION
METHYLATION
 Highly reactive intermediates:
 Adrenaline, histamine, nicotinic
inactivated- paracetamol
acid, methyldopa, captopril

19. SYNTHETIC REACTION
RIBONUCLEOSIDE/ NUCLEOTIDE SYNTHESIS:
 Activation of purine & pyrimidine antimetabolites in cancer chemotherapy
SULFATE CONJUGATION
 Chloramphenicol, methyldopa, adrenal & sex steroids

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

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

37. ALLERGY
Type I/
Anaphylactic
reactions:
Urticaria
angioedema
bronchospasm
anaphylactic shock Type II/ Cytolytic
reactions:
Thrombocytopenia
agranulocytosis
aplastic anemia
hemolysis
SLE
Type III/
retarded,
Arthus
reaction:
Rashes, serum
sickness,
polyateritis
nodosa, SJS
Type IV/ Delayed
hypersensitivity
reactions:
Contact
dermatitis, rashes,
fever,
photosensitisation

38. TREATMENT OF ALLERGY
Anaphylactic shock/ laryngeal angioedema:
 Immediate stoppage of
 Patient in reclining position, O2 admn
offending drug
at high flow rate, CPR
 Mild rxns: self subsiding
 Inj. Adrenaline 0.5mg (0.5 ml of 1 in
 Antihistamines: type I rxns & 100 solution) im
skin rashes
 chlorpheniramine 10-20 mg i.m/ slow
i.v
 i.v. hydrocortisone sodium succinate
100-200 mg- severe/ recurrent cases

39. DRUGS CAUSING ALLERGY
FREQUENTLY
 Penicillins
 Salicylates
 Cephalosporins
 Carbamazepine
 Sulfonamides
 Allopurinol
 Tetracyclines
 ACE inhibitors
 Quinolones
 Methyldopa
 AntiTB drugs
 Hydralazine
 Phenothiazines
 Local anesthetics

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

47. COMPETITIVE
ANTAGONISM
 Partial agonist: competes with full agonist- submaximal response

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

49. NONCOMPETITIVE
ANTAGONISM
 ACh & papaverine: smooth muscle
 Ach & decamethonium : NMJ
 Reversible/ irreversible effect

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

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

80. 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

81. THANK YOU!!!!