f.dinamik1&2.blok 12&13.2012
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PHARMACODYNAMICS
Sutomo Tanzil
Dept.of Pharmacology, Faculty of
Medicine, Sriwijaya University.
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Targets for drug action
A drug is a chemical that affects a physiologicalfunction in a specific way
target proteins: -enzymes, -carriers, -ionchannels, -receptors.
Specificity is reciprocal : individual classes of drugbind only to certain targets, and individual targetsrecognise only certain classes of drug.
No drugs are completely specific in their actions.
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Drug-receptor interaction
affinity
efficacy (intrinsic activity)
agonist / full agonist (e.g.adrenalin)
antagonist (e.g. propranolol)
partial agonist (e.g.acebutolol)
spare receptors Inverse agonists (eg.famotidine,
losartan, metoprolol, risperidone)
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Agonists, antagonists and efficacy
Drugs acting on receptors may be ago-nists or antagonists
Agonists initiate changes in cell function,producing effects of various types;
Antagonists bind to receptors withoutinitiating such changes.
Agonist potency depends on two parame-ters : affinity (i.e.tendency to bind to
receptors) and efficacy (i.e.ability toinitiate changes that lead to effects. For antagonists, efficacy is zero
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Drug antagonism
chemical antagonism
pharmacokinetic antagonism
competitive antagonism
non-competitive antagonism
physiological antagonism
Examples ?
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Effectors controlled by G-proteins
1) the adenylate cyclase/cAMP system
2) the phospholipase C/inositol phosphate system
3) phospholipase A :the formation of AA &eicosanoids
4) ion channels: e.g. K+ and Ca++ channels, thusaffecting membrane excitability, transmitterrelease, contractility, etc.
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Adenylate cyclase(AC) /cAMP system
AC catalyses the formation of theintracellular messenger cAMP
cAMP activates various protein kina-ses, which control cell function inmany different ways by causingphosphorylation of various
enzymes, carriers & other proteins.
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Phospholipase C/ inositoltriphosphate
(IP3)/diacylglycerol (DAG) system
Catalyses the formation of two intracellularmessengers, IP3 and DAG, from membranephospholipid
IP3 acts to increase free cytosolic Ca++ by
releasing Ca++ from intracellular compartments Increased free Ca++ initiates many events,
including contraction, secretion, enzymeactivation and membrane hyperpolarisation
DAG activates protein kinase C, which controls
many cellular functions by phosphorylating avariety of proteins.
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Types of ADRs
Type A (augmented) ADRs : are ADRsthat are related to the main pharmaco-logical action of the drug.
postural hypotension (prazosin) bleeding (warfarin)
sedation (diazepam)
cardiac dysrhytmia (digoxin).
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Types of ADRs
Type B (bizarre) ADRs, unrelated to themain pharmacological action of the drug
liver damage(paracetamol poisoning) tinnitus(aspirin) ototoxicity (streptomycin) teratogenicity( thallidomide ) agranulocytosis (carbimazole) anaphylactic shock (penicilline) aplastic anaemia (chloramphenicol)
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General mechanisms of cell damage
and cell death
Drug-induced cell damage/death isusually caused by reactive metabolites ofthe drug, involving non-covalent and/orcovalent interactions w/ target molecules.Cell death is often caused by apoptosisrather than acute necrosis.
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Non-covalent interactions
Lipid peroxidation that produces freeradicals.
Generation of cytotoxic oxygen radicals
Reactions causing depletion ofglutathione, resulting in oxidative stress
Modification of sulfhydryl groups on keyenzymes (eg. Ca++-ATPases, glutathionedisulfide reductase) and structuralproteins
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Covalent interactions
Adduct formation between themetabolite of paracetamol (NAPBQI: N-acetyl-p-benzoquinone imine)and cellular macromolecules.
Covalent binding to protein canproduce an immunogen;binding to
DNA can cause carcinogenesis andteratogenesis.
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Apoptosis (1)
programmed cell death, essential inembryogenesis and tissue homeostasis
brought about principally by a cascade ofproteases the caspases.
2 main pathways to activation:the death receptorpathway and the mitochondrial pathway.
The death receptor pathway involve stimulation ofmembers of the TNF receptor family; and themain initiator caspases is caspase 8.
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Apoptosis (2)
The mitochondrial pathway:activated byDNA damage, which results intranscription of gene p53. The p53
protein activates a subpathway thatresults in release of cytochrome c frommitochondrion, which complexes w/protein Apaf-1(apoptotic-activating
protease factor-1) and together theyactivate initiator caspase 9.
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Apoptosis (3)
In undamaged cells, survival factors (cytokines,hormones, cell-to-cell contact factors)continuously activate anti-apoptotic mechanisms.Withdrawal of survival factor stimulation causes
cell death through the mitochondrial pathway. The effector caspases (eg. Caspase 3) start a
pathway that results in cleavage of cellconstituents: DNA, cytoskeletal components,enzymes, etc. This reduces the cell to a cluster ofmembrane-bound entities that are eventuallyphagocytosed by macrophages.
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Hepatotoxicity
Hepatocytes are exposed to reactive metabolitesof drugs as these are formed by P450 enzymes.
Liver damage can be produced by generalmechanisms of cell injury (eg. Liver damage by
paracetamol) Some drugs (eg. Chlorpromazine, androgens) can
cause reversible cholestatic jaundice
Cirrhosis hepatis (long-term low-dosemethotrexate)
Immunological mechanisms (eg. Halothane)
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Nephrotoxicity
In heart or liver diseases,NSAIDs reduce renal perfusion
In patients w/ bilateral renalartery stenosis: acute renalfailure occurs on starting anACEI drug.
NSAIDs can also cause anallergic interstitial nephritis.
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Nephrotoxicity
Analgesic nephropathy is a renaldamage that is associated withprolonged and massive overuse of
analgesics(eg.NSAIDs, paracetamol) Higer doses of captopril,can cause
proteinuria. This is the result ofglomerular injury, which is also
caused by other drugs that containa sulfhydryl group(eg.penicillamine)
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References and Further Reading
Brunton,L.L.; et al.(2006). Goodman &Gilmans The Pharmacological Basis ofTherapeutics, 11th Ed.,McGraw-HillMedical Publishing Division, USA.
Katzung,B.G.(2007).Basic&ClinicalPharmacology,10th Ed., McGraw-Hill,USA.
Rang & Dale (2003). Pharmacology, 5thEd.,Churchill Livingstone, London, UK.
Staf Pengajar Dep.Farmakologi FK Unsri(2008). Kumpulan Kuliah Farmakologi,Edisi 2, EGC,Jakarta.