Pharmacodynamics Yousaf khanIPMS- KMU

Pharmacodynamics Gr. Pharmacon : drug; dynamis : power

Cover all the aspect relating to what the drug does the to body

Mechanism of action, pharmacological action and adverse effect

Types of drug action Stimulation: act like increasing the activity of specialized cell e,g

adrenaline – heart – increase heart rate and force of contraction.

Depression: act like decreasing the activity of specialized cell e.g alcohol, general anaesthtics depress CNS

Irritation: certain agents on topical application can cause irritation of the skin and adjacent tissue e.g methyl salicylate useful in joint pain

Replacement: deficiency of endogenous substances can be replace by drug e.g insulin in diabetes mellitus

Cytotoxic: Drug are selective toxic for the infecting organism/cancel cell e.g antibiotics, anticancer

Mechanism of Drug actionReceptor mediated Non-Receptor mediated

Non-receptor mediated mechanism of action of drugs

1. By physical action:

a. Osmosis: act as exerting an osmotic effect e.g 20% mannitol in cerebral oedema

b. Adsorption: activated charcoal adsorbs toxin hence it is used in the treatment of drug poisoning.

c. Demulcent: Cough syrup produce a soothing effect in pharyngitis by coating the inflamed mucosa

d. Radioactivity: Radioactive isotopes emit rays and destroy the tissue

Non-receptor mediated mechanism of action of drugs2. By chemical action:

a. Antacids are weak bases – neutralise gastric acid – useful in peptic ulcer e.g antacid, ENO, Trisil etc

b. Metal like iron, copper, mercury etc are eliminated from the body with the help of chelating agent. Trap metal – water soluble complex – excreted e.g dimercaprol in arsenic poisoning

Non-receptor mediated mechanism of action of drugs3. Through Enzyme: drug act by inhibiting the enzyme activity e.g ACE inhibitor such captopril, enalapril

4. Through ion channels: drug directly bind to ion channels and alter the flow of ion e.g local anaesthetic block sodium channels in neuronal membrane to produce local anaesthesia.

5. Through antibody production: vaccine produce their effect by stimulating the formation of antibodies e.g vaccine against tuberculosis

6. Transporters: Some drugs produce their effect by binding to transporters e.g SSRIs – bind to 5-HT transporter – block 5-HT reuptake into neuron – antidepressant effect

7. Others: Anticancer drugs e.g cyclophosphamide – binding to nucleic acids

Receptor- Mediated Mechanisms Receptor: Macromolecules present on the cell surface,

cytoplasm or in the nucleus – drug bind and interacts to produce cellular changes e.g adrenergic receptor ( alpha and beta) etc

Affinity: ability of the drug to get bound to the receptor

Intrinsic Activity: ability of the drug to produce pharmacological action after combing with the receptor

Agonist: drug that have capable of producing pharmacological action after binding to receptor

Agonist has high affinity + high intrinsic activity e.g morhine etc

Receptor- Mediated Mechanisms Antagonist: drug that prevents binding of agonist to

its receptor or block its effect its does not produce any effect itself.

Competitive antagonist: : drug has high affinity with out intrinsic activity

Partial agonist: a drug that bind to the receptor but produce an effect less than that of an agonist, it block effect of agonist

Inverse agonist: it has full affinity towards the receptor but produce effect opposite to that of an agonist

Receptor FamiliesLigand-gated ion channels (inotropic

receptors)

G-Protein coupled receptors (Metabotropic receptor)

Enzymatic receptors

Receptor regulating gene expression or the nuclear receptor

Ligand-gated ion channels (inotropic receptors) Location: membrane Effector: ion channels Coupling: direct Time required for response: milliseconds Example: nicotonic, GABA receptor

Binding of agonist to iontropic receptor – open the ion channels ( Na, K, Ca, Cl) – Flow of ions through channels – hyperpolarization/ depolarization – tissue response.

G-Protein coupled receptors (Metabotropic receptor)

Location: membrane Effector: channels or enzyme Coupling: G proteins ( Gs, Gi, Gq, etc) Time required for response: Second

G protein membrane protein and have three subunits (α, β and γ)

G protein coupled receptor control cell function via adenylyl cyclase, phospholipase C and Ion channels

Binding of agonist to receptors – coupling of G protein to the receptor – GDP bound to α subunit exchange with GTP -- Subunit of Gs protein dissociates and activates adenylyl cyclase -- When hormone is no longer present, the receptor reverts to its resting state. GTP on the subunit is hydrolyzed to GDP, and adenylyl cyclase is deactivated.

Enzymatic receptor Location: membrane Effector: enzyme Coupling: direct Time required for response: hours Example: insulin, growth factor, cytokine recptore

Binding of agonist to extracellular domain of enzyme linked receptor – dimerization of the receptor – stimulates intrinsic/ cytosolic kinase activity – activate intracellular signaling pathways – gene transcription – tissue response

Nuclear receptor Location: intracellular Effector: Gene Transcription Coupling: Via DNA Time required for response: Hours Example: Steroid, thyroid hormone receptor

Regulation of receptors Regulate by various mechanism resulting in either

their up regulation or down regulation

Receptor down regulation: Prolonged use of agonist – ↓↓ receptor number and

sensitivity -- ↓↓ drug effect

Receptor up regulation: Prolong use of antagonist -- ↑↑ receptor number and

sensitivity on sudden stoppage of antagonist -- ↑↑ response to agonist

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