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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.