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Do NOT impart new functions on any system, organ or cell
Only alter the PACE of ongoing activity
PRINCIPLE OF ACTION MODE EXAMPLE STIMULATION Selective Enhancement of level of activity of specialised cells - Excessive stimulation is often followed by depression of that function Adr stimulates Heart Pilocarpine stimulates salivary glands Picrotoxin – CNS stimulant convulsions coma death DEPRESSION Selective Diminution of activity of specialised cells Certain drugs – stimulate one cell type and depress others Barbiturates depress CNS Quinidine depresses Heart Ach – stimulates smooth muscle but depresses SA node IRRITATION Non-selective often noxious effect – applied to less specialised cells (epithelium, connective tissue) -stimulate associated function Bitters – salivary and gastric secretion Counterirritants increase blood flow to a site REPLACEMENT Use of natural metabolites, hormones or their congeners in deficiency states Levodopa in parkinsonism Iron in anaemia CYTOTOXIC ACTION Selective cytotoxic action for invading parasites or cancer cells – for attenuating them without affecting the host cells Penicillin, chloroquine
Proteins take part in transmembrane signaling and regulates ionic composition
Drugs also target these channels: mainly on 3 types
Ligand gated channels
G-protein operated channels
Direct action on channels
Examples: BZD opens ligand gated GABA A Cl- channel, Histamine binds GPCR and activates G-protein, local anesthetics – directly blocks channel
Many drugs modulate opening and closing of channels: Phenytoin, Ethosuximide, Nifedepine, Quinidine and Nicorandil etc.
+ + - - + + -- - - + + + + - - Na + + + + + - - - - Resting (Closed**) Open (brief) inactivated Very slow repolarization in presence of LA LA receptor LA have highest affinity for the inactivated form Refractory period LA acting on Na+ receptors
Substrates are translocated across membrane by binding to specific transporters (carriers) – Solute Carrier Proteins (SLC)
Pump the metabolites/ions in the direction of concentration gradient or against it.
Drugs can interact with these transport system
Examples: Probenecid (penicillin and uric acid), Furosmide (Na+K+2Cl- cotransport), Hemicholinium (choline uptake) and Vesamicol (active transport of Ach to vesicles), Thiazides block Na+Cl- symporter, Aphetamine (blocks Dopamine reuptake), Reserpine (blocks grannular reuptake of NA)
Drugs usually do not bind directly with enzymes, channels, transporters or structural proteins, but act through specific macromolecules – RECEPTORS
Definition: It is defined as a macromolecule or binding site located on cell surface or inside the effector cell that serves to recognize the signal molecule/drug and initiate the response to it, but itself has no other function, e.g. G-protein coupled receptor
Large number can be distinguished by their α -subunits
G protein Effectors pathway Substrates Gs Adenylyl cyclase Beta-receptors, H2, D1 Gi Adenylyl cyclase Muscarinic M2 D2, alpha-2 Gq Phospholipase C Alph-1, H1, M1, M3 Go Ca++ channel K+ channel in heart, sm
Activated receptors catalyze phosphorylation of tyrosine residues on different target signaling proteins, thereby allowing a single type of activated receptor to modulate a number of biochemical processes
Insulin - uptake of glucose and amino acids and regulate metabolism of glycogen and triglycerides
Trastuzumab , antagonist of a such type receptor – used in breast cancer
Lipid soluble biological signals cross the plasma membrane and act on intracellular receptors – NO acts by stimulating cGMP
Receptors for corticosteroids, mineralocorticoids, thyroid hormones, sex hormones and Vit. D etc. stimulate the transcription of genes in the nucleus by binding with specific DNA sequence – called - “Responsive elements”
Hormones produce their effects after a characteristic lag period of 30 minutes to several hours—the time required for the synthesis of new proteins – gene active hormonal drugs take time to be active (Bronchial asthma)
Beneficial or toxic effects persists even after withdrawal
In tonically active systems, prolonged deprivation of agonist (by denervation or antagonist) results in supersensitivity of the receptor as well as to effector system to the agonist. Sudden discontinuation of Propranolol, Clonidine etc.
Unmasking of receptors or proliferation or accentuation of signal amplification