AWABS - Enzymes and Nuclear receptors Flashcards
Methods by which drugs work
Physico-chemical properties
Receptor interaction
Enzyme interaction
Examples of medications which work via physico-chemical properties
Mannitol
Chelators - eg sugammadex
Examples of receptor types which can be targeted by medications
Ionic channels
Metabotropic receptors eg cyclic amp G protein coupled
Enzyme definition
Biological catalyst which speeds up reaction but not consumed within the reaction itself
Carbonic anhydrase enzyme catalyses which reaction
CO2 + H2O -> H2CO3 -> H+ + HCO3-
Location of carbonic anhydrase
Widespread inc:
RBCs
Eye
Stomach
Pancreas
Kidney
Role of carbonic anhydrase
Allows respiratory and metabolic / renal systems to compensate for acid-base imbalance
Example of carbonic anhydrase inhibitor
Acetazolamide
Examples of reversible enzyme inhibitors
ACEi
Neostigmine
Allopurinol
Carbidopa
Examples of irreversible enzyme inhibitors
Aspirin (COX-2)
Organophosphates
MAO inhibitors
PPI
Commonly used drugs which enhance enzyme activity
None common
Common enzymes which are increased in NUMBER (not activity) by drugs
Cytochrome P450 class
Novichok mechanism of action
Group of agents which irreversibly inhibit acetylcholinesterase
Short acting acetylcholinesterase inhibitors
Eg Edrophonium
Used to diagnose myasthenia gravis and differentiate from “myasthenic” and “cholinergic crisis” (Tensilon test)
Binds weakly to serine site of acetylcholinesterase and causes allosteric change
Duration of 10-30 mins
Medium acting acetylcholinesterase inhibitors
Eg Neostigmine
Duration of action 2-3 hours – well matched to exceed half life of NDMR
Routine reversal of neuromuscular blockade and treatment of MG
Binds esteratic site of Acetylcholinesterase
Long-acting acetylcholinesterase inhibitors
Eg Ecothiopate – only clinical application
Novichok is another example, along with other organophosphates
Seen in pesticides and chemical warfare
Stable and irreversible covalent integration to enzyme acetylcholinesterase
Neostigmine structure
Has quaternary nitrogen and therefore polar
Does not cross blood brain barrier
Physostigmine structure
Has a tertiary nitrogen and less polar
Has CNS effects
Muscarinic symptoms
(SLUDGE M)
Seen with organophosphate / long acting acetylcholinesterase inhibition:
* Salivation
* Lacrimation
* Urination
* Diarrhoea
* GI upset
* Emesis
* Miosis
Cholinergic symptoms
Severe weakness
Inc respiratory muscle weakness - SOB
Michaelis-Menten equation
V= rate of reaction
V max = max possible rate of reaction
[S] = substrate concentration
Km is a constant
Michaelis-Menten equation use
Predicts rate of a biological reaction according to the concentration of substrate and the characteristics of the enzyme involved
Interpretation of Michaelis-Menten equation at low substrate concentrations
At low substrate concentrations the “+ [S]” aspect becomes negligible and equation becomes Vmax/Km (which is a constant) x [S].
Therefore V is proportional to substrate concentration – This is First order reaction (rate is proportional to substrate concentration)
Interpretation of Michaelis-Menten equation at high substrate concentrations
The Km constant becomes almost insignificant.
Therefore increasing substrate concentration will no longer increase rate of reaction.
This is Zero order reaction.
Tendency for substrate accumulation in these reactions
Examples of Zero order reactions
Phenytoin
Alcohol
Warfarin
Amiodarone
Michaelis-Menten graph
Zero order reaction graph
Example of drug / hormone which acts at nucleus receptor
Thyroid hormones and glucocorticoids
T4 main storage form, T3 active form which transports across lipid bilayer
Alters protein, carbohydrate and fat metabolism
Controls basal metabolic rate
Features that drugs / hormones acting at nuclear receptors require in order to pass through cell membrane
Non-polar / non-charged
Small and lipid soluble
