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 ago-nists 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 parame-ters :
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.