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!!!!