PHARMACODYNAMICS
• In Greek

Pharmacon = Drug
Dynamics = Action/Power
It covers all the aspects relating to
“What a drug does to the body”
...
• Action: How and Where the
effect is produced is called as
Action.
• Effect: The type of response
producing by drug.
Site of Drug Action
• Where:

1. Extra cellular
2. Cellular
3. Intracellular
Types of Drug Action
EFFECT (Type of responses):-

1.Stimulation
2.Inhibition/Depression
3.Replacement
4.Irritation
5.Cyto...
Mechanism of Action of Drugs
• Drug act either by receptor or by non
receptor or by targeting specific genetic
changes.
Ma...
Receptor Mediated action
• Drug produce their effect through interacting
with some chemical compartment of living
organism...
Ligand binding
domain

Transduction of
signal into response

Receptor Functions : Two essential functions
• 1. Recognizati...
Drug(D) +Receptor®

Drug receptor complex

Response

Drug receptor interaction:1. Selectivity:- Degree of complimentary co...
Drug classification
(on the basis of affinity & efficacy)
Response

No response
• Partial agonist :These drug have full affinity to
receptor but with low intrinsic activity (IA=0 to 1).
• These are only...
• Inverse agonist: These have full affinity
towards the receptor but intrinsic activity is
zero to -1 i.e., produces effec...
Receptor families
Four types of receptors families
1. Ligand-gated ion channels (inotropic
receptors)
2.G-protien coupled ...
Characteristics of receptor families
Ligand
gated

G-protein
coupled

Enzymatic Nuclear

Location

Membrane

Membrane

Mem...
Signal transduction mechanism
• Ion gated receptors:- Localized on cell
membrane and coupled directly to an ion
Io
channel...
• Ex: Nicotinic cholinergic receptor
G-protein coupled receptors
• Membrane bound, which are coupled to
effector system through GTP binding
proteins called as ...
Varieties of G-protein
G-protein

Gs

Receptor for

Gi1,2,3

ß adrenegic,
H,5HT,Glucagon
α2 adrenergic, Ach,

Gq

Ach

Go
...
G-protein effector systems
• 1.Adenylase cyclase : cAMP system
• 2.Phospholipase –C: Inositol phosphate system
• 3. Ion ch...
cAMP system
Phospholipase-C system
Ion channel regulation
• G-protein coupled receptors can control
the functioning of ion channel by don't
involving any sec...
Enzymatic receptors
• These receptor are directly linked tyrosine
kinase.
• Receptor binding domain present in extra
cellu...
Enzymatic receptors
Extra cellular receptor
binding domain

Intra cellular
changes
Receptor regulating gene expression

(transcription factors)
Increase RNA
polymerase activity

Unfolds the receptor and
ex...
Receptor regulation theory

• Receptors are in dynamic state.

• The affinity of the response to drugs is not fixed.
It al...
• Receptor up regulation:
Prolonged use of antagonist
Receptor number and sensitivity
Drug effect
• Ex:- propranolol is st...
Agonist: Both the high affinity as well as
intrinsic activity (IA=1)
These drug trigger the maximal biological response or...
Types of agonism
• Summation :- Two drugs eliciting same
response, but with different mechanism and their
combined effect ...
Types of agonism
• Additive: combined effect of two drugs acting by
same mechanism
Aspirin
PG

PG

Analgesic+

Analgesic+
...
• Synergism (Supra additive):-

(1+1=3)

The combined effect of two drug effect is
higher than either individual effect.
E...
Types of antagonism
Antagonism: Effect of two drugs is less than sum
of the effects of the individual drugs.

1. Chemical ...
Pharmacokinetic antagonism
• One drug affects the absorption,
metabolism or excretion of other drug and
reduce their effec...
Pharmacological antagonism
• Pharmacodynamic antagonism between two
drugs acting at same receptors.
• Two important mechan...
Reversible antagonism
(Competitive antagonism)
• These inhibition is commonly observed
with antagonists that bind reversib...
Irreversible Antagonism
• It occurs when the antagonist dissociates
very slow or not at all from the receptors
result that...
Non receptor mediated action
• All drugs action are not mediated by receptors.
Some of drugs may act through chemical acti...
Dose
• It is the required amount of drug in
weight, volumes, moles or IU to provide a
desired effect.
• In clinical it is ...
Single dose:
1.Piperazine (4-5g) is sufficient to eradicate round
worm.
2.Single IM dose of 250mg of ceftriaxone to treat
...
• Total dose: It is the maximum quantity of the
drug that is needed the complete course of the
therapy.
Ex:- procaine peni...
Maintenance dose:- Loading dose normally
followed by maintenance dose.
• Needed to maintain the steady state
plasma concen...
Therapeutic index:
• Margin of safety
• Depend upon factor of dose producing
desirable effect  dose eliciting toxic
effec...
Therapeutic window:
Optimal therapeutic range of plasma
concentrations at which most o the patients
experience the desired...
•
•
•
•
•
•

Cyclosporine – 100-400ng/ml
Carbamazapine- 4-10µg/ml
Digoxin- 0.8-2ng/ml
Lithium- 0.8-1.4 mEq/L
Phenotoin – 1...
• Tolerance: Increased amount of drug
required to produce initial pharmacological
response.
• Usually seen with alcohol, m...
Types of tolerances
• Innate tolerance: Genetically lack of
sensitivity to a drug.
Ex:
• Rabbits tolerate to atropine larg...
• Acquired tolerances:
• Occurs due to repeated use of drug
– Pharmacokinetic tolerances
– Pharmacodynamic tolerance
– Acu...
• Pharmacodynamic tolerance
• Down regulation of receptors

• Impairment in signal transduction
• Ex: Morphine, caffeine, ...
• Ex: Monday disease.
• Nitroglycerine – Monday , Tuesday
workers get headache, after they get
tolerances.
• After holiday...
FACTORS MODIFYING THE
EFFECTS OF DRUGS


Individuals differ both in the degree and the
character of the response that a drug may elicit



Variation in respons...


Differences among individuals are responsible for

the variations in drug response:


Individuals differ in pharmacoki...


These factors modify drug action either:
a)

Quantitatively


The plasma concentration and / or the drug action is
inc...

1.

The various factors are:
Body weight/size:


It influences the concentration of drug attained at the
site of action...
•

For exceptionally obese or lean individuals and for children
dose may be calculated on body weight basis

Individual do...
2.

Age:

Infants and Children:


The dose of drug for children often calculated from the adult
dose

Age
Child dose
x ad...


However, infants and children are have important
physiological differences



Higher proportion of water



Lower pla...
Elders:


In elderly, renal function progressively declines (intact

nephron loss) and drug doses have to be reduced


C...
3.

Sex:



Females have smaller body size, and so require
doses of drugs on the lower side of the dose
range



They sh...
4.

Pregnancy:



Profound physiological changes which may affect
drug responses:


GI motility reduced –delayed absorpt...
5.

Food:



Delays gastric emptying, delays absorption (ampicillin)



Calcium in milk –interferes with absorption of
t...
6.

Species and race:



Rabbits resistant to atropine



Rat & mice are resistant to digitalis



In humans: blacks re...
7.

Route of drug administration:



I.V route dose smaller than oral route



Magnesium sulfate:


Orally –purgative

...
8.

Biorhythm: (Chronopharmacolgy)



Hypnotics –taken at night



Corticosteroid –taken at a single morning dose

9.

P...
10.

Presence of diseases/pathological states:



Drug may aggravate underlying pathology



Hepatic disease may slow dr...
11.

Cumulation:



Any drug will cumulate in the body if rate of

administration is more than the rate of elimination

...
12.

Genetic factors:



Lack of specific enzymes



Lower metabolic rate


Acetylation



Plasma cholinesterase (Atyp...
13.

Tolerance:



It means requirement of a higher dose of the drug
to produce an effect, which is ordinarily produced

...
14.


Other drugs:

By interactions in many ways
Drug classification

(on the basis of affinity & efficacy)

Agonist: Both the high affinity as well as
intrinsic activity ...
• Antagonist:- Which have only the affinity
no intrinsic activity (IA=0). IA=0 so no
pharmacological activity.
• Rather th...
cAMP system
Some drugs, hormones or neurotransmitters
produce their effect by increasing or
decreasing the activity of ade...
Stimulation
• Some of drug act by increasing the activity
of specialized cells.
Ex: Catecholamines stimulate the heart and...
Inhibition
• Some drug act by decreasing the activity of
specialized cells.
Ex: Alcohol, Barbiturates, General anesthetic
...
Replacement
• When there is a deficiency of endogenous
substances, they can replaced by drugs.
Ex: Insulin in Diabetes mel...
Irritation
• Certain drugs on topical application cause
irritation of the skin and adjacent tissues.
• These drugs are usi...
Cytotoxic
• Treatment of infectious disease/cancer
with drugs that are selectively toxic for
infecting organism/cancer cel...
Phospholipase-C system
Activation

Hydrolysis

Agonist
Gq

PIP2

PLC

Hydrolysis

DAG

Water soluble
release

PKC

IP3
ATP...
Extra cellular site of action
1.Antacids neutralizing gastric acidity.
2.Chelating agents forming complexes
with heavy met...
Cellular Site of Action
1.Ach on Nicotinic receptors of motor end
plate, leading to contraction of skeletal
muscle.
2.Effe...
Intracellular site of action
-Folic acid synthesis inhibitors.
Folic acid which is intracellular component
essential for s...
Gs/Gi
G protein

Effector

or

AC

+

cAMP

ATP
Phosphorylation

Ca+2 release

Protein kinase Active

FC of heart muscle

...
Physical action
• Absorption: Kaolin absorbs bacterilal toxin
and thus acts as antidiarrhoeal agent.
• Protectives:- Vario...
• Antagonist:- Which have only the affinity
no intrinsic activity (IA=0). IA=0 so no
pharmacological activity.
• Rather th...
Physical Action
• Osmosis:- MgSo4 acts as a purgative by
exerting osmatic effect within lumen of the
intestine.
• Astringe...
False incorporation
• Bacteria synthesis folic acid from PABA
(Para Amino Benzoic Acid), for growth
sand development.

• S...
Protoplasmic poison
• Germicides and antiseptics like phenol
and formaldehyde act as non specifically
as protoplasmic pois...
Through formation of antibodies
• Vaccines produce their effect by inducing
the formation of antibodies and thus
stimulate...
Targeting specific genetic changes.
• Anti cancer drugs that specifically target
genetic changes.
• Inhibitors of specific...
Physiological antagonism
• Two antagonists, acting at different sites,
counter balance each other by producing
opp. effect...
Chemical action
1.Ion Exchanges:-Anticoagulant effect of
heparin(-ve charge) antagonized by
protamine (+ve charged) protei...
Pharmacodynamics
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Pharmacodynamics

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  • Rabbit  liver contain atropinase enzyme , which destroys fasterChinese cook their food in castor oil
  • Pharmacodynamics

    1. 1. PHARMACODYNAMICS
    2. 2. • In Greek Pharmacon = Drug Dynamics = Action/Power It covers all the aspects relating to “What a drug does to the body” Mechanism of action
    3. 3. • Action: How and Where the effect is produced is called as Action. • Effect: The type of response producing by drug.
    4. 4. Site of Drug Action • Where: 1. Extra cellular 2. Cellular 3. Intracellular
    5. 5. Types of Drug Action EFFECT (Type of responses):- 1.Stimulation 2.Inhibition/Depression 3.Replacement 4.Irritation 5.Cytotoxic
    6. 6. Mechanism of Action of Drugs • Drug act either by receptor or by non receptor or by targeting specific genetic changes. Majority of drugs acts by (HOW) Receptor mediated Non receptor mediated
    7. 7. Receptor Mediated action • Drug produce their effect through interacting with some chemical compartment of living organism c/s Receptor. • Receptors are macromolecules • Most are proteins • Present either on the cell surface, cytoplasm or in the nucleus
    8. 8. Ligand binding domain Transduction of signal into response Receptor Functions : Two essential functions • 1. Recognization of specific ligand molecule (Ligand binding domain) • 2. Transduction of signal into response (Effector domain)
    9. 9. Drug(D) +Receptor® Drug receptor complex Response Drug receptor interaction:1. Selectivity:- Degree of complimentary co relation between drug and receptor. Ex:- Adrenaline Selectivity for α, ß Receptor 2. Affinity:- Ability of drug to get bound to the receptor. 3. Intrinsic activity (IA) or Efficacy:- Ability of drug to produce a pharmacological response after making the drug receptor complex.
    10. 10. Drug classification (on the basis of affinity & efficacy)
    11. 11. Response No response
    12. 12. • Partial agonist :These drug have full affinity to receptor but with low intrinsic activity (IA=0 to 1). • These are only partly as effective as agonist (Affinity is lesser when comparison to agonist) Ex: Pindolol, Pentazocine
    13. 13. • Inverse agonist: These have full affinity towards the receptor but intrinsic activity is zero to -1 i.e., produces effect is just opposite to that of agonist. Ex:- ß-Carboline is inverse agonist for Benzodiazepines receptors.
    14. 14. Receptor families Four types of receptors families 1. Ligand-gated ion channels (inotropic receptors) 2.G-protien coupled receptor (Metabotropic receptors) 3. Enzymatic receptors (tyrosinekinase) 4.Receptor regulating gene expression (transcription factors/ Steroid )
    15. 15. Characteristics of receptor families Ligand gated G-protein coupled Enzymatic Nuclear Location Membrane Membrane Membrane Intracellular Effector Ion channel Ion Channel or enzyme Enzyme Gene coupling Direct G-protein Direct Via DNA Example Nicotinic Muscarinic Insulin Steroid , hormone
    16. 16. Signal transduction mechanism • Ion gated receptors:- Localized on cell membrane and coupled directly to an ion Io channel. n Blocker Agonist Receptor Receptor Na+2 Hyper polarization or depolarization Permeation of ion is blocked No cellular effect Cellular effect
    17. 17. • Ex: Nicotinic cholinergic receptor
    18. 18. G-protein coupled receptors • Membrane bound, which are coupled to effector system through GTP binding proteins called as G-proteins Bound to inner face of plasma membrane (2nd messenger)
    19. 19. Varieties of G-protein G-protein Gs Receptor for Gi1,2,3 ß adrenegic, H,5HT,Glucagon α2 adrenergic, Ach, Gq Ach Go Neurotransmitters in brain Signaling pathway/ Effector AC— cAMP AC— cAMP, Open K+ Phospholipase-C, IP3’cytoplasmic Ca+2 Not yet clear
    20. 20. G-protein effector systems • 1.Adenylase cyclase : cAMP system • 2.Phospholipase –C: Inositol phosphate system • 3. Ion channels
    21. 21. cAMP system
    22. 22. Phospholipase-C system
    23. 23. Ion channel regulation • G-protein coupled receptors can control the functioning of ion channel by don't involving any second messenger • Ex:- In cardiac muscle
    24. 24. Enzymatic receptors • These receptor are directly linked tyrosine kinase. • Receptor binding domain present in extra cellular site. • Produce conformational changes in intra cellular Ex:- Insulin receptors
    25. 25. Enzymatic receptors Extra cellular receptor binding domain Intra cellular changes
    26. 26. Receptor regulating gene expression (transcription factors) Increase RNA polymerase activity Unfolds the receptor and expose normally masked DNA binding site
    27. 27. Receptor regulation theory • Receptors are in dynamic state. • The affinity of the response to drugs is not fixed. It alters according to situation. • Receptor down regulation: Prolonged use of agonist Receptor number and sensitivity Drug effect Ex: Chronic use of salbutamol down regulates ß2 adrenergic receptors.
    28. 28. • Receptor up regulation: Prolonged use of antagonist Receptor number and sensitivity Drug effect • Ex:- propranolol is stopped after prolong use, produce withdrawal symptoms. Rise BP, induce of angina.
    29. 29. Agonist: Both the high affinity as well as intrinsic activity (IA=1) These drug trigger the maximal biological response or mimic effect of the endogenous substance. Ex:- Methacholine is a cholinomimetic drug which mimics the effect of Ach on cholinergic receptors.
    30. 30. Types of agonism • Summation :- Two drugs eliciting same response, but with different mechanism and their combined effect is equal to their summation. (1+1=2) Aspirin Codiene PG Opiods receptor Analgesic+ Analgesic+ ++
    31. 31. Types of agonism • Additive: combined effect of two drugs acting by same mechanism Aspirin PG PG Analgesic+ Analgesic+ ++
    32. 32. • Synergism (Supra additive):- (1+1=3) The combined effect of two drug effect is higher than either individual effect. Ex:1.Sulfamethaxazole+ Trimethoprim 2. Levodopa + Carbidopa.
    33. 33. Types of antagonism Antagonism: Effect of two drugs is less than sum of the effects of the individual drugs. 1. Chemical antagonism Ex: -heparin(-ve) protamine +ve, Chelating agents 1. Physiological /Functional antagonism 2. Pharmacokinetic antagonism 3. Pharmacological antagonism I. Competitive ( Reversible) II. Non competitive (Irreversible)
    34. 34. Pharmacokinetic antagonism • One drug affects the absorption, metabolism or excretion of other drug and reduce their effect. Ex:-Warfarin in presence of phenobarbitone, warfarin metabolism is increased, it effect is reduced.
    35. 35. Pharmacological antagonism • Pharmacodynamic antagonism between two drugs acting at same receptors. • Two important mechanism according to which these antagonists »1.Reversible(Competitive) »2.Irreversible(Non)
    36. 36. Reversible antagonism (Competitive antagonism) • These inhibition is commonly observed with antagonists that bind reversibly to the same receptor site as that of an agonist. • These type inhibition can be overcome increasing the concentration of agonist • Ex:- Atropine is a competitive antagonist of Ach.
    37. 37. Irreversible Antagonism • It occurs when the antagonist dissociates very slow or not at all from the receptors result that no change when the agonist applied. • Antagonist effect cannot be overcome even after increasing the concentration of agonist
    38. 38. Non receptor mediated action • All drugs action are not mediated by receptors. Some of drugs may act through chemical action or physical action or other modes. »Chemical action »Physical action (Astringents, sucralfate) »False incorporation (PABA) »Being protoplasmic action (antiseptics) »Formation of antibody (Vaccines) »Targeting specific genetic changes.
    39. 39. Dose • It is the required amount of drug in weight, volumes, moles or IU to provide a desired effect. • In clinical it is called as Therapeutic dose • In experimental purpose it is called as effective dose. • The therapeutic dose varies from person to person
    40. 40. Single dose: 1.Piperazine (4-5g) is sufficient to eradicate round worm. 2.Single IM dose of 250mg of ceftriaxone to treat gonorrhoea. Daily dose: It is the quantity of a drug to be administered in 24hr, all at once or equally divided dose. 1.10mg of cetrizine (all at once) is sufficient to relive allergic reactions. 2.Erythromycin is 1g per day to be given in 4 equally divided dose (i.e., 250mg every 6 hr)
    41. 41. • Total dose: It is the maximum quantity of the drug that is needed the complete course of the therapy. Ex:- procaine penicillin early syphilis is 6 million unit  given as 0.6 million units per day for 10days. Loading dose:- It is the large dose of drug to be given initially to provide the effective plasma concentration rapidly. The drugs having high Vd of distribution. Chloroquine in Malaria – 600 mg Stat 300mg after 8 hours 300 mg after 2 days.
    42. 42. Maintenance dose:- Loading dose normally followed by maintenance dose. • Needed to maintain the steady state plasma concentration attained after giving the loading dose.
    43. 43. Therapeutic index: • Margin of safety • Depend upon factor of dose producing desirable effect  dose eliciting toxic effect. Therapeutic index LD 50 ED 50 • TI should be more than one
    44. 44. Therapeutic window: Optimal therapeutic range of plasma concentrations at which most o the patients experience the desired effect. Therapeutic range Therapeutic window Sub optimal optimal Toxic
    45. 45. • • • • • • Cyclosporine – 100-400ng/ml Carbamazapine- 4-10µg/ml Digoxin- 0.8-2ng/ml Lithium- 0.8-1.4 mEq/L Phenotoin – 10-20µg/ml Qunindine- 2-6µg/ml
    46. 46. • Tolerance: Increased amount of drug required to produce initial pharmacological response. • Usually seen with alcohol, morphine, barbiturates, CNS active drugs • Reverse tolerance:- Same amount drug produces inc pharmacological response. • Cocaine, amphetamine  rats- inc. motor activity
    47. 47. Types of tolerances • Innate tolerance: Genetically lack of sensitivity to a drug. Ex: • Rabbits tolerate to atropine large doses • Chinese Castor oil • Negros  Mydriatic action of sympathomimetics • Eskimos high fatty diets
    48. 48. • Acquired tolerances: • Occurs due to repeated use of drug – Pharmacokinetic tolerances – Pharmacodynamic tolerance – Acute tolerance Pharmacokinetic tolerances:- Repetitive administration causes decrease their absorption or inc. its own metabolism Ex: Alcohol  dec. absorption Barbiturates Inc. own metabolism
    49. 49. • Pharmacodynamic tolerance • Down regulation of receptors • Impairment in signal transduction • Ex: Morphine, caffeine, nicotine. • Acute tolerance: Tachyphylaxis Acute development of tolerance after a rapid and repeated administration of a drug in shorter intervals • Ex; Ephedrine, tyramine
    50. 50. • Ex: Monday disease. • Nitroglycerine – Monday , Tuesday workers get headache, after they get tolerances. • After holiday (Sunday) they get again headache . • Cross tolerances: Cross tolerance among drugs belonging to same category. • MORPHINHEROIN NARCOTIC
    51. 51. FACTORS MODIFYING THE EFFECTS OF DRUGS
    52. 52.  Individuals differ both in the degree and the character of the response that a drug may elicit  Variation in response to the same dose of a drug between different patients and even in the same patient on different occasions.
    53. 53.  Differences among individuals are responsible for the variations in drug response:  Individuals differ in pharmacokinetic handling of drugs  Variation in number or state of receptors, coupling proteins or other components of response  Variation in neurogenic/ hormonal tone or concentrations of specific constituents
    54. 54.  These factors modify drug action either: a) Quantitatively  The plasma concentration and / or the drug action is increased or decreased b) Qualitatively  The type of response is altered, eg: drug allergy and idiosyncrasy
    55. 55.  1. The various factors are: Body weight/size:  It influences the concentration of drug attained at the site of action  The average adult dose refers to individuals of medium built
    56. 56. • For exceptionally obese or lean individuals and for children dose may be calculated on body weight basis Individual dose Individual dose  BW (kg) x Average adult dose 70 BSA (m2) x Average adult dose 1.7 BSA=BW(Kg)0.425 x Height(cm)0.725 x 0.007184
    57. 57. 2. Age: Infants and Children:  The dose of drug for children often calculated from the adult dose Age Child dose x adult dose .........( Young' s formula) Age 12 Child dose Age x adult dose...... ...(Dilling' s formula) 20
    58. 58.  However, infants and children are have important physiological differences  Higher proportion of water  Lower plasma protein levels   More available drug Immature liver/kidneys  Liver often metabolizes more slowly  Kidneys may excrete more slowly
    59. 59. Elders:  In elderly, renal function progressively declines (intact nephron loss) and drug doses have to be reduced  Chronic disease states  Decreased plasma protein binding  Slower metabolism  Slower excretion  Dietary deficiencies  Use of multiple medications  Lack of compliance
    60. 60. 3. Sex:  Females have smaller body size, and so require doses of drugs on the lower side of the dose range  They should not be given uterine stimulants during menstruation, quinine during pregnancy and sedatives during lactation
    61. 61. 4. Pregnancy:  Profound physiological changes which may affect drug responses:  GI motility reduced –delayed absorption of orally administered drugs  Plasma and ECF volume expands  Albumin level falls  Renal blood flow increases markedly  Hepatic microsomal enzyme induction
    62. 62. 5. Food:  Delays gastric emptying, delays absorption (ampicillin)  Calcium in milk –interferes with absorption of tetracyclines and iron by chelation  Protein malnutrition  Loss of BW  Reduced hepatic metabolizing capacity  Hypoproteinemia
    63. 63. 6. Species and race:  Rabbits resistant to atropine  Rat & mice are resistant to digitalis  In humans: blacks require higher Mongols require lower concentrations of atropine and ephedrine to dilate their pupil
    64. 64. 7. Route of drug administration:  I.V route dose smaller than oral route  Magnesium sulfate:  Orally –purgative  Parenterally –sedative  Locally –reduces inflammation
    65. 65. 8. Biorhythm: (Chronopharmacolgy)  Hypnotics –taken at night  Corticosteroid –taken at a single morning dose 9. Psychological state:  Efficacy of drugs can be effected by patients beliefs, attitudes and expectations  Particularly applicable to centrally acting drugs  In some patients inert drugs (placebo) may produce beneficial effects equivalent to the drug, and may induce sleep in insomnia
    66. 66. 10. Presence of diseases/pathological states:  Drug may aggravate underlying pathology  Hepatic disease may slow drug metabolism  Renal disease may slow drug elimination  Acid/base abnormalities may change drug absorption or elimination  Severe shock with vasoconstriction delays absorption of drugs from s.c. or i.m  Drug metabolism in:  Hyperthyroidism –enhanced  Hypothyroidism -diminished
    67. 67. 11. Cumulation:  Any drug will cumulate in the body if rate of administration is more than the rate of elimination  Eg: digitalis, heavy metals etc.
    68. 68. 12. Genetic factors:  Lack of specific enzymes  Lower metabolic rate  Acetylation  Plasma cholinesterase (Atypical pseudo cholinesterase)  G-6PD  Glucuronide conjugation
    69. 69. 13. Tolerance:  It means requirement of a higher dose of the drug to produce an effect, which is ordinarily produced by normal therapeutic dose of the drug  Drug tolerance may be:  Natural  Acquired  Cross tolerance  Tachyphylaxis (ephedrine, tyramine, nicotine)  Drug resistance
    70. 70. 14.  Other drugs: By interactions in many ways
    71. 71. Drug classification (on the basis of affinity & efficacy) Agonist: Both the high affinity as well as intrinsic activity (IA=1) These drug trigger the maximal biological response or mimic effect of the endogenous substance. Ex:- Methacholine is a cholinomimetic drug which mimics the effect of Ach on cholinergic receptors.
    72. 72. • Antagonist:- Which have only the affinity no intrinsic activity (IA=0). IA=0 so no pharmacological activity. • Rather these drug bind to the receptor and produce receptor blockade. • Atropine blocks the effects of Ach on the cholinergic muscarinic receptors.
    73. 73. cAMP system Some drugs, hormones or neurotransmitters produce their effect by increasing or decreasing the activity of adenylate cyclase and thus raising or lower cAMP with in the cell.
    74. 74. Stimulation • Some of drug act by increasing the activity of specialized cells. Ex: Catecholamines stimulate the heart and Heart rate, Force of contraction
    75. 75. Inhibition • Some drug act by decreasing the activity of specialized cells. Ex: Alcohol, Barbiturates, General anesthetic these drug depress the CNS system. Atropine inhibits Ach action.
    76. 76. Replacement • When there is a deficiency of endogenous substances, they can replaced by drugs. Ex: Insulin in Diabetes mellitus Throxine in cretinism and myxedema
    77. 77. Irritation • Certain drugs on topical application cause irritation of the skin and adjacent tissues. • These drugs are using for counter irritant. Ex: Eucalyptus oil, methyl salicylates (Used in sprains, joint pain, myalgia.
    78. 78. Cytotoxic • Treatment of infectious disease/cancer with drugs that are selectively toxic for infecting organism/cancer cells Ex: Anticancer drugs All Antibiotics
    79. 79. Phospholipase-C system Activation Hydrolysis Agonist Gq PIP2 PLC Hydrolysis DAG Water soluble release PKC IP3 ATP S Cam E ADP Product Ca+2 Cam E* Response PLC= Phospholipase-C PIP2 =Phosphotiydl inositol 4,5 di phosphate IP3 =Inositol tri phosphate DAG = Diacylglycerol E= Ezyme PKC = Phosphokinase -C
    80. 80. Extra cellular site of action 1.Antacids neutralizing gastric acidity. 2.Chelating agents forming complexes with heavy metals. 3.MgSo4 acting as purgative by retaining the fluid inside the lumen of intestine.
    81. 81. Cellular Site of Action 1.Ach on Nicotinic receptors of motor end plate, leading to contraction of skeletal muscle. 2.Effect of sympathomimetics on muscle and blood vessels. heart
    82. 82. Intracellular site of action -Folic acid synthesis inhibitors. Folic acid which is intracellular component essential for synthesis of proteins. Trimethoprim and sulfa drug interfere with synthesis.
    83. 83. Gs/Gi G protein Effector or AC + cAMP ATP Phosphorylation Ca+2 release Protein kinase Active FC of heart muscle Lipolysis Glycogen synthesis Glycogen breakdown to glucose
    84. 84. Physical action • Absorption: Kaolin absorbs bacterilal toxin and thus acts as antidiarrhoeal agent. • Protectives:- Various dusting powders.
    85. 85. • Antagonist:- Which have only the affinity no intrinsic activity (IA=0). IA=0 so no pharmacological activity. • Rather these drug bind to the receptor and produce receptor blockade. • Atropine blocks the effects of Ach on the cholinergic muscarinic receptors.
    86. 86. Physical Action • Osmosis:- MgSo4 acts as a purgative by exerting osmatic effect within lumen of the intestine. • Astringents:- They precipitate the surface proteins and protect the mucosa Ex: tannic acid in gum patients • Demulcent:- These drugs coat the inflamed mucus membrane and provide soothing effect. Ex: Menthol
    87. 87. False incorporation • Bacteria synthesis folic acid from PABA (Para Amino Benzoic Acid), for growth sand development. • Sulfa drugs resemble PABA, therefore falsely enter into the synthesis process of PABA, cause nonfunctional production and no utility for bacterial growth.
    88. 88. Protoplasmic poison • Germicides and antiseptics like phenol and formaldehyde act as non specifically as protoplasmic poison causing the death of bacteria
    89. 89. Through formation of antibodies • Vaccines produce their effect by inducing the formation of antibodies and thus stimulate the defense mechanism of the body • Ex:- Vaccines against small pox and cholera
    90. 90. Targeting specific genetic changes. • Anti cancer drugs that specifically target genetic changes. • Inhibitors of specific tyrosine kinase that that block the activity of oncogenic kinases.
    91. 91. Physiological antagonism • Two antagonists, acting at different sites, counter balance each other by producing opp. effect on same physiological system. • Histamine –Vasodilatation • Nor epinephrine – Vasoconstriction
    92. 92. Chemical action 1.Ion Exchanges:-Anticoagulant effect of heparin(-ve charge) antagonized by protamine (+ve charged) protein. 2.Neutralization:- Excessive gastric acid is neutralized by antacids. 3. Chelation:-These are trap the heavy metals. Ex:-EDTA, BAL.
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