Good afternoon….
PHARMACOLOGY
DEEPTHI P.R.
1st YEAR MDS
DEPT.OF CONSERVATIVE DENTISTRY
ENDODONTICS
MECHANISM OF DRUG ACTION
CONTENTS
• Principles of drug action
• Action via discrete
functional proteins:
 Enzymes
 Ion channels
 Transporters
 ...
INTRODUCTION
• Mechanism of drug actionpharmacodynamics
• Study of drug effects
• Modification of one drug’s action by ano...
PRINCIPLES OF DRUG
ACTION
• Alter the pace of ongoing activity
not impart new function
• Types of drug action:
1. Stimulat...
PRINCIPLES OF
DRUG ACTION
Stimulation:
• Selective enhancement of the level
of activity of specialized cells
Eg: Adrenalin...
PRINCIPLES OF
DRUG ACTION
Depression:
• Selective diminution of activity
of specialized cells
Eg: Barbiturates- CNS, Quini...
PRINCIPLES OF DRUG ACTION
Morphine
vagus
oculomotor nuclei
CTZ

respiratory &
cough centres
PRINCIPLES OF DRUG ACTION
Irritation:
• Non selective, noxious effect: less specialized
cells
• Mild: stimulate function
E...
PRINCIPLES OF DRUG ACTION
Cellular changes produced by irritation:
• Astringent effect:
• If dissolution of precipitated p...
PRINCIPLES OF DRUG ACTION
• Irritant applied locally to the skin to relieve
deep seated pain: counterirritant
Stimulation ...
PRINCIPLES OF DRUG ACTION
Sensory impulses from skin
Interfere with pain impulses from viscera &
partial/complete exclusio...
PRINCIPLES OF DRUG ACTION
Replacement:
• Use of natural metabolites, hormones or
congeners in their deficiency
Eg: Levodop...
PRINCIPLES OF DRUG ACTION
Antimicrobial action:
• Prevention, arrest & eradication of infections
• Act specifically on cau...
MECHANISM OF DRUG ACTION
Majority : interaction with discrete target
molecules- Proteins
 Enzymes
 Ion channels
 Transp...
ENZYMES
• Important target : all biological reactions
under enzyme action
• Enzyme stimulation/ enzyme inhibition
ENZYMES
•
•
•
•
•

STIMULATION
Unusual with foreign substances
Occurs with endogenous ones
Adrenaline  adenyl cyclase; py...
ENZYME INHIBITION
•
•
•
•
•
•

NON SPECIFIC
Denaturing proteins:
altering tertiary
structure
Heavy metal salts
Strong acid...
SPECIFIC ENZYME INHIBITION
COMPETITIVE(equilibrium type)
• Drug- similar structure to the normal substrate
• Competes for ...
COMPETITIVE INHIBITION
SPECIFIC ENZYME INHIBITION
ENZYME

SUBSTRATE

DRUG

Cholinesterase

Acetyl choline

Physostigmine
Neostigmine

Bacterial f...
SPECIFIC ENZYME INHIBITION
Non equilibrium type:
• Drugs which react with the same catalytic site:
strong covalent/ high a...
SPECIFIC ENZYME INHIBITION
Non competitive inhibitor

Enzyme

Acetazolamide

Carbonic anhydrase

Aspirin, Indomethacin

Cy...
ION CHANNELS
• Ion selective channels: transmembrane
signaling & regulate intracellular ionic
composition
Drugs
Specific r...
ION CHANNELS
ION CHANNELS
Quinidine

Blocks

Myocardial Na+ channels

Dofetilide
Amiodarone

Block

Myocardial delayed rectifier
K+ cha...
TRANSPORTERS
• Substrates translocated across membranes by
binding to specific transporters
• Facilitate diffusion: concen...
TRANSPORTERS
TRANSPORTERS
METABOLITE/ ION

TRANSPORTER

DRUG

Noradrenaline

Norepinephrine transporterneurons

Desipramine
Cocaine

Se...
RECEPTORS

DEFINITION:
‘A macromolecule or binding site located on the
surface or inside the effector cell that serves to
...
RECEPTORS
• The largest no. of drugs act through themcontrol effectors
• Cell membrane/ cytosol
• Endogenous substances & ...
RECEPTORS
• Recognition molecule: for specific ligands
• Transmits the signal: ligand to proteins in cell
membrane & withi...
RECEPTORS
• Selectivity: binding of drugs to receptorsdepends on physico-chemical structure
• Affinity: strength of bindin...
RECEPTORS
Agonist:
• Drug which initiates pharmacological action after
binding to the receptor
• Similar to natural hormon...
RECEPTORS
Inverse agonist:
• An agent which activates a receptor to
produce an effect in the opposite direction to
that of...
RECEPTORS
Antagonist:
• An agent which prevents the action of an agonist
on a receptor or the subsequent response, but
doe...
RECEPTORS
RECEPTORS
Partial agonists:
• An agent which activates the receptor to
produce submaximal effect but antagonizes
the actio...
RECEPTORS
• Opioid drugs: agonists/partial agonists on
some receptors, antagonists on other
• Pentazocine & nalbuphine ago...
RECEPTORS
Ligands:
• Any molecule which attaches selectively to
particular receptors or sites
• Affinity/ binding without ...
RECEPTORS
RECEPTOR REGULATION
Density & efficacy: regulated by• Level of ongoing activity
• Feedback from own signal output
• Other ...
RECEPTOR REGULATION
Down regulation
• Continued exposure to a drug/ agonist:
blunted response: desensitisation/
refractori...
RECEPTOR REGULATION
Up regulation
• Depletion of noradrenaline/ treatment with
adrenergic antagonists: supersensitivity of...
NATURE OF RECEPTORS
• Regulatory macromolecules: proteins/ nucleic
acids
• Each receptor family: common structural
motif &...
NATURE OF RECEPTORS
• Physiological: transmitters, autacoids,
hormones. Eg: Cholinergic, adrenergic,
histaminergic, leukot...
NATURE OF RECEPTORS
• Types & subtypes

Muscarinic: M1, M2, M3,
M4, M5
Atropine

• ACh

Nicotinic: NM, NN
Curare

• Adrene...
CLASSIFICATION OF RECEPTORS
I. Pharmacological criteria:
• Relative potencies of agonists & antagonists
• Classical & olde...
CLASSIFICATION OF RECEPTORS
III. Ligand binding:
• Measurement of specific binding of high
affinity radiolabelled ligand t...
Serotonin
receptors
CLASSIFICATION OF RECEPTORS
IV. Transducer pathway:
• Mechanism through which activation is linked
to the response
• NM – ...
CLASSIFICATION OF RECEPTORS
V. Molecular cloning:
• Receptor protein cloned: amino acid & 3D
structure worked out
• Subtyp...
CLASSIFICATION OF RECEPTORS
Silent receptors:
• Sites bind specific receptors: but no
pharmacological response
• Drug acce...
RECEPTORS
Drug action: The initial
combination
of the drug with its receptor 
conformational change (agonists)
or its pre...
TRANSDUCER MECHANISMS
• Highly complex multistep process :
amplification & integration of intra- and
extracellular signals...
G- PROTEIN COUPLED RECEPTORS
• GTP-activated proteins/ G-proteins/ Guanine
nucleotide binding proteins
• Coupled to certai...
G- PROTEIN
COUPLED
RECEPTORS
• 7 membrane spanning
helical segments of
hydrophobic amino acids
• Intervening segments: 3
l...
G- PROTEIN COUPLED RECEPTORS
Ligand + GPCR
G-protein to GTP

Enzymes: Adenyl cyclase
Phospholipase

Active G-protein
Ion c...
G- PROTEIN COUPLED RECEPTORS
2nd messengers:
• Intracytoplasmic calcium ion concentration
• cAMP
Phospholipid
• Inositol 1...
G- PROTEIN COUPLED RECEPTORS
G- PROTEIN COUPLED RECEPTORS
Classic Egs. :β1 & dopamine receptors
• Opiates , peptides, acetyl choline, biogenic
amines :...
RECEPTORS WITH INTRINSIC ION
CHANNEL
• Cell membrane spanning proteins:
Agents bind with them
open transmembrane channel
I...
RECEPTORS WITH INTRINSIC ION
CHANNEL
RECEPTORS WITH INTRINSIC ION
CHANNEL
• Nicotinic Ach receptors: Na+
• GABA receptor: Cl• Tubocurarine & BZDs: modify funct...
KINASE LINKED RECEPTORS
2 types:
Intrinsic enzymatic activity
Tyrosine kinases + hormone
self activation by autophosphoryl...
Intrinsic tyrosine protein kinase
receptor
JAK-STAT-Kinase binding receptors
Agonist

Affinity for
Activated
JAK

Phosphorylation
of tyrosine
residues

Dimerisation
...
RECEPTORS REGULATING GENE
EXPRESSION
• Intracellular soluble proteins: lipid soluble
chemicals
• Nuclear/ cytoplasmic
Rece...
RECEPTORS REGULATING GENE
EXPRESSION
• All steroidal hormones :
glucocorticoids,
mineralocorticoids,
androgens, estrogens,...
MECHANISM OF DRUG ACTION
Others: action by means of other properties
 Chemically reactive agents
 Physically active agen...
CHEMICALLY REACTIVE AGENTS
• Interact with molecules/ ions or attack proteins/
macromolecules
• Lack specificity: except c...
CHEMICALLY
REACTIVE AGENTS
Neutralisation:
• Gastric antacids &
metallic ion chelators +
inorganic substances
• Anticoagul...
CHEMICALLY REACTIVE AGENTS
Chelation:
• Dimercaprol: coordination complexes with
mercury & heavy metals
• EDTA: Ca2+
• Cal...
CHEMICALLY REACTIVE AGENTS
Oxidation:
• Potassium permanganate
Ion exchangers:
• Anion exchange resin: cholestyramine
exch...
PHYSICALLY ACTIVE AGENTS
Colour:
• Psychological effect: pleasant colour.
Eg: tincture of cardamom
Physical mass:
• Water ...
PHYSICALLY ACTIVE AGENTS
Smell:
• Volatile oils: peppermint oil, mask the unpleasant
smell of mixtures
Taste:
• Compounds ...
PHYSICALLY ACTIVE AGENTS
Adsorption:
• Kaolin & activated charcoal: antidiarrhoeal
• Methylpolysiloxane & simethicone:
ant...
PHYSICALLY ACTIVE AGENTS
Soothing demulcent:
• Coat inflamed mucous membrane: soothing
effect
• Pectin: antidiarrhoeal pre...
PHYSICALLY ACTIVE AGENTS
Reduction in surface tension:
• Cationic surfactants: cetrimide
Electrical charge:
• Strongly aci...
PHYSICALLY ACTIVE AGENTS
Radio-opacity
• BaSO4: barium meal
• Organic iodine compounds: urinary & biliary
tracts
Absorptio...
PHYSICALLY ACTIVE AGENTS
Physical form:
• Dimethicone – antifoaming agent
• petroleum jelly
Astringents:
• Precipitate & d...
PHYSICALLY ACTIVE AGENTS
Saturation in the biophase:
• Cellular sites/ biophase of CNS: saturated by
general anesthetics
•...
COUNTERFEIT / FALSE
INCORPORATION MECHANISMS
• Artificial analogues of natural substrates
• No effect on enzymes: but inco...
PROTOPLASMIC POISONS
• Germicides & antiseptics: phenol , HCHO
• Death of bacteria
FORMATION OF ANTIBODIES
• Vaccines: induce antibody formation &
stimulate defense mechanisms
• Active immunity: against sm...
PLACEBO ACTION
• Pharmacodynamically inert & harmless: dosage
form resembling actual medication
• Physician: good patient ...
TARGETING SPECIFIC GENETIC
CHANGES
• Inhibitors of ras- modifying- enzyme farnesyl
transferase: reverses malignant
transfo...
CLASSIFICATION OF MECHANISM
I. On the cell membrane
• Specific receptors - agonists & antagonists on
adrenoceptors, histam...
CLASSIFICATION OF MECHANISM
II. Metabolic processes within the cell
• Enzyme inhibition: COX by aspirin,
cholinesterase by...
CLASSIFICATION OF MECHANISM
• Incorporation into larger molecules: 5-FU into
mRNA in place of uracil
• Altering metabolic ...
BIBLIOGRAPHY
• Pharmacology & PharmacotherapeuticsSatoskar, Bhandarkar, Rege: 9th edition
• Essentials of Medical Pharmaco...
Thank you!!!!
Upcoming SlideShare
Loading in...5
×

Mechanism of drug action

15,531

Published on

Briefly on the pharmacodynamic aspects of drugs in general.

Published in: Health & Medicine, Technology
0 Comments
18 Likes
Statistics
Notes
  • Be the first to comment

No Downloads
Views
Total Views
15,531
On Slideshare
0
From Embeds
0
Number of Embeds
0
Actions
Shares
0
Downloads
546
Comments
0
Likes
18
Embeds 0
No embeds

No notes for slide
  • Natural Standard Monograph (www.naturalstandard.com)
  • Mechanism of drug action

    1. 1. Good afternoon….
    2. 2. PHARMACOLOGY DEEPTHI P.R. 1st YEAR MDS DEPT.OF CONSERVATIVE DENTISTRY ENDODONTICS
    3. 3. MECHANISM OF DRUG ACTION
    4. 4. CONTENTS • Principles of drug action • Action via discrete functional proteins:  Enzymes  Ion channels  Transporters  Receptors • Chemically reactive agents • Physically reactive agents  Counterfeit biochemical constituentsCounterfeit biochemical constituents  Protoplasmic poisons  Formation of antibodies  Placebo action  Targeting specific genetic changes
    5. 5. INTRODUCTION • Mechanism of drug actionpharmacodynamics • Study of drug effects • Modification of one drug’s action by another
    6. 6. PRINCIPLES OF DRUG ACTION • Alter the pace of ongoing activity not impart new function • Types of drug action: 1. Stimulation 2. Depression 3. Irritation 4. Replacement 5. Cytotoxic action 6. Antimicrobial action 7. Modification of immune status
    7. 7. PRINCIPLES OF DRUG ACTION Stimulation: • Selective enhancement of the level of activity of specialized cells Eg: Adrenaline – heart, Pilocarpine- salivary glands • Excessive stimulation: followed by depression Eg: Picrotoxin : convulsions  coma & respiratory depression
    8. 8. PRINCIPLES OF DRUG ACTION Depression: • Selective diminution of activity of specialized cells Eg: Barbiturates- CNS, Quinidine- heart • Certain drugs stimulate one type of cells & depress the other. Eg: Acetyl choline intestinal smooth SA node muscle in the heart
    9. 9. PRINCIPLES OF DRUG ACTION Morphine vagus oculomotor nuclei CTZ respiratory & cough centres
    10. 10. PRINCIPLES OF DRUG ACTION Irritation: • Non selective, noxious effect: less specialized cells • Mild: stimulate function Eg: Bitters increasing salivary & gastric secretion, • Strong: inflammation
    11. 11. PRINCIPLES OF DRUG ACTION Cellular changes produced by irritation: • Astringent effect: • If dissolution of precipitated proteins deeper penetration of irritants- corrosive effect • Dehydration • Action on cellular enzymes- usually inhibition • Cytotoxic action
    12. 12. PRINCIPLES OF DRUG ACTION • Irritant applied locally to the skin to relieve deep seated pain: counterirritant Stimulation of sensory nerve endings –skin Afferent impulses relayed in cerebrospinal axis – efferent vasomotor fibers to internal organ Increased circulation in skin- deep structures
    13. 13. PRINCIPLES OF DRUG ACTION Sensory impulses from skin Interfere with pain impulses from viscera & partial/complete exclusion • Vasodilation and blockade of pain impulses: relief of deep seated pain
    14. 14. PRINCIPLES OF DRUG ACTION Replacement: • Use of natural metabolites, hormones or congeners in their deficiency Eg: Levodopa- parkinsonism, Insulin- diabetes mellitus, Iron- anemia Cytotoxic: • Selective cytotoxic action for invading parasites or cancer cells Eg: Antibiotics, antivirals, anticancer drugs
    15. 15. PRINCIPLES OF DRUG ACTION Antimicrobial action: • Prevention, arrest & eradication of infections • Act specifically on causative organisms Eg: antibiotics Modification of immune status: • Enhancing or depressing the immune status Eg: Vaccines, sera, levamisole, corticosteroids
    16. 16. MECHANISM OF DRUG ACTION Majority : interaction with discrete target molecules- Proteins  Enzymes  Ion channels  Transporters  Receptors
    17. 17. ENZYMES • Important target : all biological reactions under enzyme action • Enzyme stimulation/ enzyme inhibition
    18. 18. ENZYMES • • • • • STIMULATION Unusual with foreign substances Occurs with endogenous ones Adrenaline  adenyl cyclase; pyridoxine as cofactor decarboxylase Stimulation affinity for substrate Enzyme induction: synthesis of more enzyme protein activity
    19. 19. ENZYME INHIBITION • • • • • • NON SPECIFIC Denaturing proteins: altering tertiary structure Heavy metal salts Strong acids Phenol Alkalies Too damaging for systemic use SPECIFIC I. Competitive/ equilibrium type non- equilibrium type II. Non competitive A. Reversible B. Irreversible
    20. 20. SPECIFIC ENZYME INHIBITION COMPETITIVE(equilibrium type) • Drug- similar structure to the normal substrate • Competes for the catalytic binding site Product not formed Non functional product • Increased substrate concentration: inhibitor is displaced
    21. 21. COMPETITIVE INHIBITION
    22. 22. SPECIFIC ENZYME INHIBITION ENZYME SUBSTRATE DRUG Cholinesterase Acetyl choline Physostigmine Neostigmine Bacterial folate synthase PABA Sulfonamides Mono amino oxidase Catecholamines Moclobemide Angiotensin converting enzyme Angiotensin I Captopril 5α reductase Testosterone Finasteride Aromatase Androstenedione Testosterone Letrozole Xanthine oxidase Hypoxanthine Allopurinol alloxanthine Dopa decarboxylase Alcohol dehydrogenase levodopa Methanol Carbidopa, methyldopa Ethanol These are examples of reversible inhibition of enzyme activity
    23. 23. SPECIFIC ENZYME INHIBITION Non equilibrium type: • Drugs which react with the same catalytic site: strong covalent/ high affinity • Normal substrate: not able to displace it • Organophosphates: covalent bond with cholinesterase • Methotrexate with 5000x affinity than DHFA for dihydrofolate reductase Non equilibrium type & COX inhibition in platelets by Aspirin : Egs. of irreversible inhibition
    24. 24. SPECIFIC ENZYME INHIBITION Non competitive inhibitor Enzyme Acetazolamide Carbonic anhydrase Aspirin, Indomethacin Cyclooxygenase Disulfiram Aldehyde dehydrogenase Omeprazole H+ K+ ATPase Digoxin Na+ K+ ATPase Theophylline Phosphodiesterase Propylthiouracil Peroxidase in thyroid Lovastatin HMG-CoA reductase Slidenafil Phosphodiesterase-5
    25. 25. ION CHANNELS • Ion selective channels: transmembrane signaling & regulate intracellular ionic composition Drugs Specific receptors: ligand gated ion channels/ G-protein coupled receptors Direct binding to ion channel Modulating opening and closing of the channels
    26. 26. ION CHANNELS
    27. 27. ION CHANNELS Quinidine Blocks Myocardial Na+ channels Dofetilide Amiodarone Block Myocardial delayed rectifier K+ channel Nifedipine Blocks L-type voltage sensitive Ca2+ channel Nicorandil Opens ATP sensitive K+ channels Sulfonylureas Inhibit Pancreatic ATP sensitive K+ channels Amiloride Inhibits Renal epithelial Na+ channel Phenytoin Modulates voltage sensitive Na+ channel Ethosuximide Inhibits T-type Ca2+ channels in thalamic neurones
    28. 28. TRANSPORTERS • Substrates translocated across membranes by binding to specific transporters • Facilitate diffusion: concentration gradient • Pump against the concentration gradient using metabolic energy • Drugs: direct interaction with the solute carrier(SLC) class of transporter proteins: inhibition
    29. 29. TRANSPORTERS
    30. 30. TRANSPORTERS METABOLITE/ ION TRANSPORTER DRUG Noradrenaline Norepinephrine transporterneurons Desipramine Cocaine Serotonin Serotonin transporterneurons Selective Serotonin Reuptake Inhibitors Dopamine Dopamine transporterneurons Amphetamines Noradrenaline Serotonin Vesicular amine transporter Reserpine Acetyl choline Choline uptake- neurons Hemicholinium GABA GABA transporter GAT1 Tigabine Organic acids: uric acid, penicillin Organic anion transporterrenal tubules Probenecid Furosemide inhibits: Na+K+ 2Cl- cotransporter in ascending limb of LOH Hydrochlorothiazide inhibits Na+Cl- symporter in early distal tubule
    31. 31. RECEPTORS DEFINITION: ‘A macromolecule or binding site located on the surface or inside the effector cell that serves to recognize the signal molecule/drug and initiate the response to it, but itself has no other function’
    32. 32. RECEPTORS • The largest no. of drugs act through themcontrol effectors • Cell membrane/ cytosol • Endogenous substances & drugs Regulate cell function by altering:  Enzyme activity  Permeability to ions  Conformational features  Genetic material
    33. 33. RECEPTORS • Recognition molecule: for specific ligands • Transmits the signal: ligand to proteins in cell membrane & within the cell- amplify the original signal: cascade effect ligand Active receptor Inactive receptor POST RECEPTOR EVENTS
    34. 34. RECEPTORS • Selectivity: binding of drugs to receptorsdepends on physico-chemical structure • Affinity: strength of binding between the drug & receptor • Efficacy/ Intrinsic activity: ability of a drug to elicit a pharmacological response after its interaction with the receptor
    35. 35. RECEPTORS Agonist: • Drug which initiates pharmacological action after binding to the receptor • Similar to natural hormone/ transmitter • High affinity & intrinsic activity • Value rests on greater capacity to resist degradation & act for longer than endogenous ligands • Bronchodilation : salbutamol >> adrenaline
    36. 36. RECEPTORS Inverse agonist: • An agent which activates a receptor to produce an effect in the opposite direction to that of the agonist • β-carbolines : BZD receptors in CNSstimulation, anxiety, increased muscle tone, convulsions
    37. 37. RECEPTORS Antagonist: • An agent which prevents the action of an agonist on a receptor or the subsequent response, but does not have any effect of its own • Same affinity for the receptor & similar to agonist; poor intrinsic activity • Receptor with low efficacy agonist: inaccessible to a subsequent dose of high efficacy agonistopioids
    38. 38. RECEPTORS
    39. 39. RECEPTORS Partial agonists: • An agent which activates the receptor to produce submaximal effect but antagonizes the action of a full agonist • Affinity equal to or less than agonists; less intrinsic activity • Agonist-antagonists
    40. 40. RECEPTORS • Opioid drugs: agonists/partial agonists on some receptors, antagonists on other • Pentazocine & nalbuphine agonists on κreceptors; antagonist on μ • β- blockers: pindolol& oxprenolol: partial agonist; propanolol: pure antagonist • Exercise tachycardia maybe abolished by both types, but resting heart rate is lower with propanolol
    41. 41. RECEPTORS Ligands: • Any molecule which attaches selectively to particular receptors or sites • Affinity/ binding without regard to functional change • Agonists & competitive antagonists: ligands • Multiple receptor types & subtypes: dopamine-2, histamine-3, acetyl choline & adrenaline-5
    42. 42. RECEPTORS
    43. 43. RECEPTOR REGULATION Density & efficacy: regulated by• Level of ongoing activity • Feedback from own signal output • Other physiopathological influences
    44. 44. RECEPTOR REGULATION Down regulation • Continued exposure to a drug/ agonist: blunted response: desensitisation/ refractoriness/ tolerance • affinity to drug & no. of receptors • Repeated admn. – adrenergic agonists in asthma down regulate β-receptors
    45. 45. RECEPTOR REGULATION Up regulation • Depletion of noradrenaline/ treatment with adrenergic antagonists: supersensitivity of tissues to noradrenaline & in receptor no. • C/C admn. Of β-blocker: in adrenergic receptors • Sudden withdrawal of β-blockers in ischemic heart disease : susceptible to effects of circulating noadrenaline- arrhythmias
    46. 46. NATURE OF RECEPTORS • Regulatory macromolecules: proteins/ nucleic acids • Each receptor family: common structural motif & individual receptor differs in amino acid sequencing, length of loops etc
    47. 47. NATURE OF RECEPTORS • Physiological: transmitters, autacoids, hormones. Eg: Cholinergic, adrenergic, histaminergic, leukotriene, steroid, insulin • Drug : no known physiological ligands. Eg: BZD, sulfonyl urea, cannabinoid receptors
    48. 48. NATURE OF RECEPTORS • Types & subtypes Muscarinic: M1, M2, M3, M4, M5 Atropine • ACh Nicotinic: NM, NN Curare • Adrenergic α1, α2 β1, β2
    49. 49. CLASSIFICATION OF RECEPTORS I. Pharmacological criteria: • Relative potencies of agonists & antagonists • Classical & oldest: direct clinical bearing • Cholinergic, adrenergic & histaminergic receptors II. Tissue distribution: • Subtypes • Cardiac β-receptor:β1 & bronchial: β2
    50. 50. CLASSIFICATION OF RECEPTORS III. Ligand binding: • Measurement of specific binding of high affinity radiolabelled ligand to cellular fragments in vitro & displacement by selective agonists/ antagonists • 5-HT receptors distinguished
    51. 51. Serotonin receptors
    52. 52. CLASSIFICATION OF RECEPTORS IV. Transducer pathway: • Mechanism through which activation is linked to the response • NM – G proteins; NN – Na+ influx • β adrenergic cAMP • α adrenergic IP3- DAG pathway & cAMP • GABAA : ligand gated Cl- channel • GABAB : K+ conductance through G- protein
    53. 53. CLASSIFICATION OF RECEPTORS V. Molecular cloning: • Receptor protein cloned: amino acid & 3D structure worked out • Subtypes: sequence homology • Doubtful functional significance
    54. 54. CLASSIFICATION OF RECEPTORS Silent receptors: • Sites bind specific receptors: but no pharmacological response • Drug acceptors/ Sites of loss • Receptor: applied to sites capable of generating response
    55. 55. RECEPTORS Drug action: The initial combination of the drug with its receptor  conformational change (agonists) or its prevention (antagonists) Drug effect: The ultimate change in biological function: as consequence of drug action, through a series of intermediate steps
    56. 56. TRANSDUCER MECHANISMS • Highly complex multistep process : amplification & integration of intra- and extracellular signals • 4 categories: G- protein coupled receptor: GPCR Receptors with intrinsic ion channel Kinase linked receptor Receptor regulating gene expression/ Transcription factors
    57. 57. G- PROTEIN COUPLED RECEPTORS • GTP-activated proteins/ G-proteins/ Guanine nucleotide binding proteins • Coupled to certain receptors & regulate secondary messengers • Gs/ Gi
    58. 58. G- PROTEIN COUPLED RECEPTORS • 7 membrane spanning helical segments of hydrophobic amino acids • Intervening segments: 3 loops on either side • Amino terminus on extracellular side • Carboxy terminus on cytosolic side • Agonist binds: between helices on extracellular face • Recognition site by cytosolic segments: Gprotein binding
    59. 59. G- PROTEIN COUPLED RECEPTORS Ligand + GPCR G-protein to GTP Enzymes: Adenyl cyclase Phospholipase Active G-protein Ion channels: Ca2+ & K+
    60. 60. G- PROTEIN COUPLED RECEPTORS 2nd messengers: • Intracytoplasmic calcium ion concentration • cAMP Phospholipid • Inositol 1,3,5- triphosphate (IP3 ) & in cell membrane Diacylglycerol (DAG)
    61. 61. G- PROTEIN COUPLED RECEPTORS
    62. 62. G- PROTEIN COUPLED RECEPTORS Classic Egs. :β1 & dopamine receptors • Opiates , peptides, acetyl choline, biogenic amines : GPCR • neuromodulators in brain- GPCR • 65% prescription drugs: against GPCRs • Onset of response: seconds
    63. 63. RECEPTORS WITH INTRINSIC ION CHANNEL • Cell membrane spanning proteins: Agents bind with them open transmembrane channel Ion movement across membrane phospholipid bilayer • Ion flow & voltage change: type of channel
    64. 64. RECEPTORS WITH INTRINSIC ION CHANNEL
    65. 65. RECEPTORS WITH INTRINSIC ION CHANNEL • Nicotinic Ach receptors: Na+ • GABA receptor: Cl• Tubocurarine & BZDs: modify function of receptor channels • Onset & offest of response: fastest- in milliseconds
    66. 66. KINASE LINKED RECEPTORS 2 types: Intrinsic enzymatic activity Tyrosine kinases + hormone self activation by autophosphorylation Phosphorylates intracellular proteins on tyrosine residues Eg: Insulin, epidermal growth factor receptors Guanyl cyclase : Atrial natriuretic peptide
    67. 67. Intrinsic tyrosine protein kinase receptor
    68. 68. JAK-STAT-Kinase binding receptors Agonist Affinity for Activated JAK Phosphorylation of tyrosine residues Dimerisation of STAT Tyrosine protein kinase JANUS KINASE Binds signal transducer & activator of transcription STAT phosphorylated by JAK Translocation to nucleus – gene transcription regulation Eg:Cytokines, growth hormone, interferons Onset of response: few minutes to hours
    69. 69. RECEPTORS REGULATING GENE EXPRESSION • Intracellular soluble proteins: lipid soluble chemicals • Nuclear/ cytoplasmic Receptor protein Specific genes hormone proteins mRNA
    70. 70. RECEPTORS REGULATING GENE EXPRESSION • All steroidal hormones : glucocorticoids, mineralocorticoids, androgens, estrogens, progesterone, thyroxine, Vit.D, Vit. A • Onset of action: slowest- hours
    71. 71. MECHANISM OF DRUG ACTION Others: action by means of other properties  Chemically reactive agents  Physically active agents  Counterfeit biochemical constituents  Protoplasmic poisons  Formation of antibodies  Placebo action  Targeting specific genetic changes
    72. 72. CHEMICALLY REACTIVE AGENTS • Interact with molecules/ ions or attack proteins/ macromolecules • Lack specificity: except chelating agents • Not affected by minor structural variations • Covalent bonding/ strong ionic attachments  Sodium hypochlorite  HOCl  chemical disruption of biologic matter  Germicides & antineoplastic alkylating agents+ macromolecules
    73. 73. CHEMICALLY REACTIVE AGENTS Neutralisation: • Gastric antacids & metallic ion chelators + inorganic substances • Anticoagulant action of heparin: neutralises the basic groups of clotting factors: prevents thrombin action
    74. 74. CHEMICALLY REACTIVE AGENTS Chelation: • Dimercaprol: coordination complexes with mercury & heavy metals • EDTA: Ca2+ • Calcium sodium edetate : Pb2+ • Penicillamine: Cu2+ • Desferrioxamine : Iron
    75. 75. CHEMICALLY REACTIVE AGENTS Oxidation: • Potassium permanganate Ion exchangers: • Anion exchange resin: cholestyramine exchanges chloride ions from bile saltscholesterol lowering • Cation exchange resin: reduce sodium absorption from intestine
    76. 76. PHYSICALLY ACTIVE AGENTS Colour: • Psychological effect: pleasant colour. Eg: tincture of cardamom Physical mass: • Water absorption & size: peristalsis & laxative effect Eg: agar, ispaghula, psyllium seeds
    77. 77. PHYSICALLY ACTIVE AGENTS Smell: • Volatile oils: peppermint oil, mask the unpleasant smell of mixtures Taste: • Compounds with bitter taste HCl flow: improve appetite Osmolality: • Diuretic: mannitol • Purgative: MgSO4
    78. 78. PHYSICALLY ACTIVE AGENTS Adsorption: • Kaolin & activated charcoal: antidiarrhoeal • Methylpolysiloxane & simethicone: antiflatulent Protective: • Various dusting powders
    79. 79. PHYSICALLY ACTIVE AGENTS Soothing demulcent: • Coat inflamed mucous membrane: soothing effect • Pectin: antidiarrhoeal preparations • Menthol, syrup vasaka: Pharyngeal demulcents in cough • Calamine lotion: eczema
    80. 80. PHYSICALLY ACTIVE AGENTS Reduction in surface tension: • Cationic surfactants: cetrimide Electrical charge: • Strongly acidic heparin- exerts action due to negative charge Radioactivity: • I131 : hyperthyroidism
    81. 81. PHYSICALLY ACTIVE AGENTS Radio-opacity • BaSO4: barium meal • Organic iodine compounds: urinary & biliary tracts Absorption of UV rays • Paraamino benzoic acid: topical use in sunscreen preparations* *Natural Standard Monograph (www.naturalstandard.com)
    82. 82. PHYSICALLY ACTIVE AGENTS Physical form: • Dimethicone – antifoaming agent • petroleum jelly Astringents: • Precipitate & denature mucosal proteins: protects mucosa – firms up the surface • Tannic acid- gum paints
    83. 83. PHYSICALLY ACTIVE AGENTS Saturation in the biophase: • Cellular sites/ biophase of CNS: saturated by general anesthetics • Packed between membrane lipids- hinder metabolic functions/ disrupt membrane organisation
    84. 84. COUNTERFEIT / FALSE INCORPORATION MECHANISMS • Artificial analogues of natural substrates • No effect on enzymes: but incorporated into specific macromolecules by the cell • Cell: altered biologic activity/ susceptibility to destruction • 5-bromouracil: mutation rate & chromosomal disturbances- antineoplastic • Sulfa drugs : non functional folic acidbacteriostatic
    85. 85. PROTOPLASMIC POISONS • Germicides & antiseptics: phenol , HCHO • Death of bacteria
    86. 86. FORMATION OF ANTIBODIES • Vaccines: induce antibody formation & stimulate defense mechanisms • Active immunity: against small pox & cholera • Passive immunity: antisera against tetanus & diphtheria
    87. 87. PLACEBO ACTION • Pharmacodynamically inert & harmless: dosage form resembling actual medication • Physician: good patient confidence- dramatic relief to subjective symptoms: psychological • Starch/ lactose: solid dosage forms • Double blind clinical trials
    88. 88. TARGETING SPECIFIC GENETIC CHANGES • Inhibitors of ras- modifying- enzyme farnesyl transferase: reverses malignant transformation of cancer cells with ras oncogene • Inhibitors of specific tyrosine kinase – block the activity of oncogenic kinases Promising approaches: Delivering genes to cancer cells: more sensitive to drugs Delivering genes to healthy cells : protect from chemotherapy Tag cancer cells with genes that make them immunogenic
    89. 89. CLASSIFICATION OF MECHANISM I. On the cell membrane • Specific receptors - agonists & antagonists on adrenoceptors, histamine receptors etc • Interference with selective passage of ions across membranes - calcium channel blockers • Inhibition of membrane bound enzymes & pumps – membrane bound ATPase by cardiac glycoside, TCAs blocking pumps of amine transport
    90. 90. CLASSIFICATION OF MECHANISM II. Metabolic processes within the cell • Enzyme inhibition: COX by aspirin, cholinesterase by pyridostigmine, xanthine oxidase by allopurinol • Inhibition of transport processes: blockade of anion transport in renal tubule cell by probenecid- delays penicillin excretion & enhances urate elimination
    91. 91. CLASSIFICATION OF MECHANISM • Incorporation into larger molecules: 5-FU into mRNA in place of uracil • Altering metabolic processes unique to microorganisms: Interference with cell formation by penicillin III. Outside the cell • Direct chemical interaction: chelating agents, antacids • Osmosis: purgatives, diuretics like mannitol
    92. 92. BIBLIOGRAPHY • Pharmacology & PharmacotherapeuticsSatoskar, Bhandarkar, Rege: 9th edition • Essentials of Medical Pharmacology- Tripathi, 6th edition • Clinical Pharmacology- Bennett, Brown- 9th edition • Textbook of Dental Pharmacology- Sharma, Sharma, Gupta
    93. 93. Thank you!!!!
    1. A particular slide catching your eye?

      Clipping is a handy way to collect important slides you want to go back to later.

    ×