Basic Mechanisms of Drug Actions (Examples of Drug Effects on Receptors, Ion channels, Enzymes, Carrier Systems and Effects mediated by Physicochemical Interactions) Flashcards
Receptors
Definitions
Types of Interactions
Proteins which specifically bind molecules of endogenous or exogenous substances; no known function other than detecting presence of ligands.
Classical R theory: Rs are functionally silent if not occupied by agonist
BUT: special circumstances: agonist indep R activity can be detected
Agonist
Reversibly binds to R and evokes response
Antagonist
Binds (typ reversibly) to site where agonists bind
Unable to evoke response
Can prevent binding and effect of agonist
Allosteric Modulator
Binds to another site on R and alters binding and or
action of agonist
Positive: enhances agonist binding and or action
Ex: Benzos at GABA A
Negative: decreases agonist binding and or action
Ex: Picrotoxin at GABA A
Inverse Agonist
Binds to agonist binding site; evokes opposite response
Ion Channels
Ion channels: pore forming membrane proteins; allow passage of ions across membrane.
Ligand gated = ionotropic Rs ergo belong to prev. category.
Voltage gates: open in resp to change in membrane potential; mostly to depolarisation
Effects of Drugs on Ion Channels
Channel Blockade
Drug physically blocks channel-> prevents flux of ions
Voltage dep. Na channels: local anaesthetics
Voltage dep. Ca channels: divalent cations
Channel Modulations
Drug binds to specific sites and facilitates or inhibits
channel opening
Voltage dep Na channels: veratridine (+ modulation)
Voltage dep. Ca channels: DHP (- modulation)
ATP sensitive K channels: Minoxidil (- modulation)
Channel opening not typical for drugs; only increased capability.
Example: channel already opens at -60 instead of -50
–> decrease threshold
Effects of Drugs on Enzymes
Reversible (competitive or non-comp inhibition)
Acetylcholinesterase: Physostigmine, neostigmine
ACE: captopril, ramipril
Irreversible Inhibition (usually via covalent binding)
Acetylcholinesterase: organophosphates
COX: Aspirin
Formation of new enzyme molecules can overcome this
Drugs have long duration of action as takes time
False substrate
Drug is so similar to natural substrate that the enzyme
accepts it-> conversion into false product+ formation of
natural product is decreased due to decreased
capability.
DOPA decarboxylase: a methyldopa–> a methyNA
Enzyme Stimulation
Guanylyl Cyclase: Nitroglycerine
Transporters
Specialised membrane spanning proteins
Aid movement of ion peptides, small molecules, lipids,
macromolecules across lipid bilayer
Can move substances either actively or passively
Effects of Drugs on Transporters
Reversible Transport Block
Drug reversibly blocks carrier; don’t use it
Uptake-1: cocaine, TCAs
Na-K ATPases: Cardiac Glycosides
Irreversible Transporter Block: long duration of action
VMAT: reserpine
H-K ATPase: H pump inhibitor
False Substrate
Drug uses carrier; transported+ transport for natural
ligand becomes less available
Uptake-1: Indirectly acting sympathomimetics
Ex: Amphetamine
VMAT: Indirectly acting sympathomimetics
Effects of Drugs on Other Drugs
Structural Proteins: colchicines on tubulin
Immuniphilins: Cyclosporin, tacrolimus
Effects of Drugs on DNA
Alkylating anticancer drugs
Ex: Cyclophosphamide
Mechanisms of Drug Actions other than binding Proteins or DNA
Neutralisation via Salt or Complex Formation
Osmotic Activity
Interaction with Lipids of Neuronal Cell Membrane
Neutralisation via Salt or Complex Formation
Antacids-> HCl
Protamine-> Heparin
Drug specific AB-> Drug
Osmotic Activity
Osmotic Diuretics ex Mannitol, Urea
Osmotic Laxatives ex Lactulose, Glauber Salt
Interactions with Lipids of Neuronal Cell Membrane
General Aesthetics
Ethanol
Can accumulate in membrane lipids-> disturbance of normal membrane functions
