PHARMACODYNAMICS

Sutomo Tanzil Dept.of Pharmacology, Faculty of Medicine, Sriwijaya University.

Targets for drug action

A drug is a chemical that affects a physiological function in a specific way target proteins: -enzymes, -carriers, -ion channels, -receptors. Specificity is reciprocal : individual classes of drug bind only to certain targets, and individual targets recognise only certain classes of drug. No drugs are completely specific in their actions.

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)

Agonists, antagonists and efficacy

Drugs acting on receptors may be agonists or antagonists Agonists initiate changes in cell function, producing effects of various types; Antagonists bind to receptors without initiating such changes. Agonist potency depends on two parameters : affinity (i.e.tendency to bind to receptors) and efficacy (i.e.ability to initiate changes that lead to effects. For antagonists, efficacy is zero

Drug antagonism

chemical antagonism pharmacokinetic antagonism competitive antagonism non-competitive antagonism physiological antagonism Examples ?

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, thus affecting membrane excitability, transmitter release, contractility, etc.

Adenylate cyclase(AC) /cAMP system

AC catalyses the formation of the intracellular messenger cAMP cAMP activates various protein kinases, which control cell function in many different ways by causing phosphorylation of various enzymes, carriers & other proteins.

Phospholipase C/ inositoltriphosphate (IP3)/diacylglycerol (DAG) system

Catalyses the formation of two intracellular messengers, IP3 and DAG, from membrane phospholipid IP3 acts to increase free cytosolic Ca++ by releasing Ca++ from intracellular compartments Increased free Ca++ initiates many events, including contraction, secretion, enzyme activation and membrane hyperpolarisation DAG activates protein kinase C, which controls many cellular functions by phosphorylating a variety of proteins.

Types of ADRs

Type A (augmented) ADRs : are ADRs that are related to the main pharmacological action of the drug. postural hypotension (prazosin) bleeding (warfarin) sedation (diazepam) cardiac dysrhytmia (digoxin).

Types of ADRs

Type B (bizarre) ADRs, unrelated to the main pharmacological action of the drug liver damage(paracetamol poisoning) tinnitus(aspirin) ototoxicity (streptomycin) teratogenicity( thallidomide ) agranulocytosis (carbimazole) anaphylactic shock (penicilline) aplastic anaemia (chloramphenicol)

General mechanisms of cell damage and cell death

Drug-induced cell damage/death is usually caused by reactive metabolites of the drug, involving non-covalent and/or covalent interactions w/ target molecules. Cell death is often caused by apoptosis rather than acute necrosis.

Non-covalent interactions

Lipid peroxidation that produces free radicals. Generation of cytotoxic oxygen radicals Reactions causing depletion of glutathione, resulting in oxidative stress Modification of sulfhydryl groups on key enzymes (eg. Ca++-ATPases, glutathione disulfide reductase) and structural proteins

Covalent interactions

Adduct formation between the metabolite of paracetamol (NAPBQI : N-acetyl-p-benzoquinone imine) and cellular macromolecules. Covalent binding to protein can produce an immunogen;binding to DNA can cause carcinogenesis and teratogenesis.

Apoptosis (1)

programmed cell death, essential in embryogenesis and tissue homeostasis brought about principally by a cascade of proteases the caspases. 2 main pathways to activation:the death receptor pathway and the mitochondrial pathway. The death receptor pathway involve stimulation of members of the TNF receptor family; and the main initiator caspases is caspase 8.

Apoptosis (2)

The mitochondrial pathway:activated by DNA damage, which results in transcription of gene p53. The p53 protein activates a subpathway that results in release of cytochrome c from mitochondrion, which complexes w/ protein Apaf-1(apoptotic-activating protease factor-1) and together they activate initiator caspase 9.

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 cell constituents: DNA, cytoskeletal components, enzymes, etc. This reduces the cell to a cluster of membrane-bound entities that are eventually phagocytosed by macrophages.

Hepatotoxicity

Hepatocytes are exposed to reactive metabolites of drugs as these are formed by P450 enzymes. Liver damage can be produced by general mechanisms of cell injury (eg. Liver damage by paracetamol) Some drugs (eg. Chlorpromazine, androgens) can cause reversible cholestatic jaundice Cirrhosis hepatis (long-term low-dose methotrexate) Immunological mechanisms (eg. Halothane)

Nephrotoxicity
In heart or liver diseases, NSAIDs reduce renal perfusion In patients w/ bilateral renal artery stenosis: acute renal failure occurs on starting an ACEI drug. NSAIDs can also cause an allergic interstitial nephritis.

Nephrotoxicity

Analgesic nephropathy is a renal damage that is associated with prolonged and massive overuse of analgesics(eg.NSAIDs, paracetamol) Higer doses of captopril,can cause proteinuria. This is the result of glomerular injury, which is also caused by other drugs that contain a sulfhydryl group (eg.penicillamine)

References and Further Reading

Brunton,L.L.; et al.(2006). Goodman & Gilmans The Pharmacological Basis of Therapeutics, 11th Ed.,McGraw-Hill Medical Publishing Division, USA. Katzung,B.G.(2007).Basic&Clinical Pharmacology,10th Ed., McGraw-Hill,USA. Rang & Dale (2003). Pharmacology, 5th Ed.,Churchill Livingstone, London, UK. Staf Pengajar Dep.Farmakologi FK Unsri (2008). Kumpulan Kuliah Farmakologi, Edisi 2, EGC,Jakarta.