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basic types of drug action classified are stimulation depression irritation replacement cytotoxic action
Stimulation -refers to selective enhancement of the level of activity of specialised cells. eg adr.on heart ,pilocarpine on salivary glands excessive stimulation depression Eg. High dose of picrotoxin Resp. depression
Depression- Selectivediminution of activity of specialised cells eg.barbiturates depress CNS quinidine depress heartsome drugs stimulate one type of cells and depress the other typeEg.acetyl choline stimulates smooth muscle and depress the SA node
Irritation-- Non-selective often noxious effect – applied to less specialised cells (epithelium, connective tissue) eg. Bitters increase salivary and gastric secretion Counter irritants increaseblood flow. Strong irritantscause crrosion ,necrosis Replacement-- Use of natural metabolites, hormones or their congeners in deficiency states Levodopa in parkinsonism, Iron in anaemia,insulin in diabetes.
Cytotoxic action-for invading bacteria parasite, cancer cells,without effecting the host cells Used for cure /palliation of infections and neoplasms Eg Pencillins, chloroquin, zidovudine, cyclophosphamide.
Drugs act by their physical or chemical property Bulk laxatives –physical mass Dimethicon – physical form opacity PABA-absorption of UV rays Activated charcoal adsorptive property Mannitol,Mg.So4 –osmotic activity KMNO4 –oxidising property Antaacids –nuetralisation of gastric activity
MECHANISM OF DRUG ACTION MAJORITY OF DRUGS INTERACT WITH TARGET BIOMOLECULES: Usually a Protein ENZYMES ION CHANNELS TRANSPORTERS RECEPTORS
Enzyme Inhibition - Examples Equilibrium: Physostigmine Vs Acetylcholine (cholinesterase) Sulfonamides Vs PABA (folate synthetase) Moclobemide Vs Catecholamines (MAO-A) Captopril Vs Angiotensin 1 (ACE) Nonequilibrium: Orgnophosphorous compounds/Nerve gases (cholinesterase) Non-competitive: Acetazolamide (carbonic anhydrase), Omeprazole (HKATPase) , Aspirin (cyclooxygenase)
Transporters Substrates are translocated across membrane by binding to specific transporters (carriers) – Solute Carrier Proteins (SLC),ATP binding cassettes(ABC). Pump the metabolites/ions In the direction of concentration gradient or against it Drugs 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 9/26/2010 ThepowerpointTemplates.com 11
Receptors 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 9/26/2010
Some Definitions Agonist: An agent which activates a receptor to produce an effect similar to a that of the physiological signal molecule, e.g. Muscarine and Nicotine) response Ra Ri RaA Ri
Ion Channnels Proteins take part in transmembrane signaling and regulates ionic composition Drugs also target these channels: Ligand gated channels G-protein operated channels Direct action on channels Examples: Local anaethetics and Class I anti arrythmics act/depress Na+ channels
Antagonist: an agent which prevents the action of an agonist on a receptor or the subsequent response, but does not have an effect of its own, e.g. atropine and muscarine no response 9/26/2010 ThepowerpointTemplates.com 14 Ra Ri RaB RiB
: Partial agonist: An agent which activates a receptor to produce submaximal effect but antagonizes the action of a full agonist, e.g. pentazocine Partial response 9/26/2010 ThepowerpointTemplates.com 15 RaC+Ra Ri+RiC
Enzymes – drug targets -All Biological reactions are carried out under catalytic influence of enzymes – major drug target Drugs – increases/decreases enzyme mediated reactions - In physiological system enzyme activities are optimally set -Enzyme stimulation- is less common by drugs – common by endogenous substrateseg.Pyridoxine (cofactor in decarboxylase activity) Adrenaline stimulates hepatic glycogen phosphorylase (hyperglycaemia) throughß receptors and cyclic AMPStimulation of enzyme increases the affinity for the substrate so that rate constant km of that reaction loweredApparent increase in enzyme activity can occur through enzyme induction
Enzyme inhibition – common mode of drug action Enzyme Inhibition – Ex. Equilibrium: Physostigmine Vs Acetylcholine (cholinesterase) Sulfonamides Vs PABA (folate synthetase) Moclobemide Vs Catecholamines (MAO-A) Captopril Vs Angiotensin 1 (ACE) Nonequilibrium: Orgnophosphorous compounds/Nerve gases (cholinesterase) Non-competitive: Acetazolamide (carbonic anhydrase), Omeprazole (HKATPase) , Aspirin (cyclooxygenase)
FUNCTIONS OF RECEPTORS : FUNCTIONS OF RECEPTORS To propogate signals from outside to inside To amplify the signal To integrate various extracellular and intracellular regulatory signals To adapt to long term changes in maintaining homeostasis
Slide 16: Inverse agonist: an agent which activates receptors to produce an effect in the opposite direction to that of the agonist, e.g. DMCM on bzp receptors opposite response 9/26/2010 ThepowerpointTemplates.com 16 Ra Ri+RiD Slide 17:
Non-receptor Mechanisms : Non-receptor Mechanisms Actions on Enzymes Enzymes = Biological catalysts Speed chemical reactions Are not changed themselves Drugs altering enzyme activity alter processes catalyzed by the enzymes Examples Cholinesterase inhibitors Monoamine oxidase inhibitors
Ligand: any molecule which attaches selectively to particular receptors or sites (only binding or affinity) Affinity: Ability of a substrate to bind with receptor Intrinsic activity (IA): Capacity to induce functional change in the receptor If explained Agonist: Affinity+ IA Antagonist: Affinity+ IA (0) Partial agonist: Affinity + IA (0-1) Inverse agonist: Affinity + IA (0 to -1) Drug Mechanisms :
Ion channels : Ion channels Slide 25: Ligand gated ion chanels Fastest intracellular responce, ms Binding of ligand - opening of chanel - ion (K+, Na+) in or out of cell - responce Ligands Fast neurotransmittors ex. Acetylcholine (nicotinic reseptors) Nobel prize chemistry 2003, Roderick MacKinnon “for structural and mechanistic studies of ion channels”. http://nobelprize.org/chemistry/laureates/2003/press.html G-Protein coupled receptor : G-Protein coupled receptor Membrane bound receptors which are bound to effector system through G-proteins. These are hetero trimeric molecules having 3 subunits α,β and ϒ. Based on α-sub unit they are further classified into 3 main varieties Gs, Gi and Gq 9/26/2010 ThepowerpointTemplates.com 26 Slide 27: G-Protein coupled receptors G-protein: Guanine nucleotide binding protein Slide 28: Subtypes of G-proteins - Targets (Second messenger systems) Ion chanels: G12 Na+ / H+ exchange Enzyms: Gi Inhib. Adenylyl cyclase Gs Stimul. Adenylyl cyclase Gq Stimul. Phospholipase C One ligand can bind to more than one type of G-prot. coupled receptors second messenger pathways Slide 29: Subtypes of G-proteins - Targets (Second messenger systems) Ion chanels: G12 Na+ / H+ exchange Enzyms: Gi Inhib. Adenylyl cyclase Gs Stimul. Adenylyl cyclase Gq Stimul. Phospholipase C second messenger pathways ENZYME LINKED RECEPTORS : ENZYME LINKED RECEPTORS a. Intrinsic enzyme receptors intracellular domain is either protein kinase or guanyl cyclase Ex:Insulin,EGF,NGF b.JAK-STAT-Kinase binding receptors no intrinsic catalytic domain but agonist induced dimerization affinity for cytosolic tyrosine kinase protein Ex:cytokines,growth hormone,IF 9/26/2010 ThepowerpointTemplates.com 30 Slide 31: Enzyme coupled receptors - Catalytic receptors STAT: Signal transducers and activators of transcription Ligands: Peptide hormones TRANSCRIPTION RECEPTORS : TRANSCRIPTION RECEPTORS Receptors regulating gene expression Intracellular- cytoplasmic or nuclear Ex:All steroid hormones,thyroxine, Vit A 9/26/2010 ThepowerpointTemplates.com 32 Slide 33: Cytoplasmic receptors (not bound to cell membranes) (HSP-90: Heat shock protein) Slide 34: Receptor subtypes Most receptor classes - several sub-types Each subtypes - differend A(nta)gonists Sub types cholinerge reseptors Nicotinerge receptors Muscarinerge receptors Acetylcholine M1: G-Protein coupled receptors Stimulate phopholipase A M2: G-Protein coupled receptors Inhib. adenylyl cyclase Nmuscle: Ligand gated ion chanels Incr. Na+/Ca2+ Nneuro: Ligand gated ion chanels Incr. Na+/Ca2+ Slide 35: Spare receptors - Partial agonist Slide 36: Desensitizing Sensitizing
Non-receptor Mechanisms : Non-receptor Mechanisms Combining With Other Chemicals Antacids Antiseptic effects of alcohol, phenol Chelation of heavy metals
Non-receptor Mechanisms : Non-receptor Mechanisms Anti- metabolites Enter biochemical reactions in place of normal substrate “competitors” Result in biologically inactive product Examples Some anti-neoplastics Some anti-infectives