Enzyme Induction and Inhibition Flashcards
Which factors can affect enzyme activity?
Enzyme activity can be altered by either changing substrate and/or enzyme concentration or changing the VMAX and/or Km.
Km is the Michaelis constant which is the concentration of substrate at which the velocity of the reaction is 1⁄2 the Vmax
What is the michaelis constant?
Michaelis constant is the concentration of substrate at which the velocity of the reaction is 1⁄2 the Vmax.
It is denoted at Km
What is the Michaelis menten equation?
V = Vmax [S] / (Km + [S])
How can drugs increase enzyme activity?
1. Direct positive allosteric modulation (increases Vmax or Km)
i.e. Insulin on Tyrosine Kinase
2. Indirect increase via intermediate messengers i.e. G-protein coupled receptors agonists coupled with adenylate cyclase i.e. H2, D1 & b- receptors.
3. Increase in the enzyme concentration (enzyme induction).
The CYP450 enzymes are responsible for the metabolism of many drugs and their chronic exposure to their drug substrate will result in increased concentrations and hence more effective clearing of that drug. Some isoforms metabolise many different drugs so each drug of that isoform will be affected as a result.
CYP1A2/CYP2 B6/C9/CYP2C19/CYP2E1/CYP3A4
Draw the table of the CYP enzyme inducers?
CYP1A2: OT (Omeprazole Tabbaco)
CYP2 B6/C9: Readily bite (Rifampicin, Barbituates)
CYP2C19: Picking red currents (Prednisolone, Rifampacin,Carbamazapine)
CYP2E1: is exciting (Isoniazid, Ethanol)
CYP3A4: Can’t really believe Paul’s goal (Carbamazapine, Rifampacin, Barbituates, Phenytoin, Glucocorticoids)
OT’s readily bite
Picking red currents is exciting
Can’t really believe Paul’s goal
Which muscle relaxant is effected by CYP enzymes?
Vecuronium. In the presence of rifmapacin and barbituates will have a reduced NMB blockade
How do drugs reduce enzyme activity?
- Direct inhibition of the enzyme via reduction in Km or Vmax.
- Indirect decrease in enzyme activity via intermediary messengers.
Enzyme inhibition can be classified as either reversible or irreversible.
Define competetive anatagonism?
The degree of enzyme inhibition depends upon plasma concentration of inhibitor compared to the natural agonist.
Competetive antagonism is an example of reversible enzyme inhibition.
List 4 competetive antagonists?
- Neostigmine – acetylcholinesterase inhibitor
- Ramipril – ACE inhibitor
- Milrinone – phosphodiesterase 3 inhibitor (pulmonary vasodilator used in heart failure)
- NSAIDs – COX inhibitor
Describe the function of acetylcholinesterase and the basic structure of its substrate binding sites?
Acetylcholinesterase is an enzyme which is responsible for breaking down acetylcholine into choline and acetic acid at the NMJ.
It contains a:
*Anionic site i.e. negatively charged attracting a positive quaternary ammonium ion
* Esteric site involved in ester hydrolysis to form choline and acetic acid.
3categories-4 (examples)
What are the different enzyme inhibitors for acetylcholinesterase?
-
Enzyme CARBAMYLATORS:
*Pyridostigmine, Neostigmine, Physostigmine
* These are substrates that bind to both sites of AChE. They carbamylated enzyme reacts more slowly reducing the rate of ACh breakdown allowing its build up in the cleft.
2. Anionic site competitive inhibitors:
* Edrophonium
* Binds only to the anionic site i.e. not a normal substrate. (It is a short acting competitive inhibitor used for diagnostic purposes)
3. Irreversible inhibitors
* Organophosphates
* Interact with the esteratic site to phosphorylate AChE. The drug-enzyme complex becomes ‘aged’ with time and inhibition becomes irreversible.
* The phosphorylated AChE reacts extremely slowly with water allowing ACh concentrations to rise in all sites centrally and peripherally. This is characterised by a cholinergic crisis involving salivation, abdominal pain, weakness and bradycardia.
Pralidoxime can be used in organophosphate poisoning, how does it work?
Can be used before ‘ageing’ occurs within 36-48 hours to reverse the complex more rapidly.
It does this by displacing phosphate from the esteratic site and remains bound for a time until the poison can be eliminated.
Oximes are then given to allow the enzyme to recover.
Without any treatment, recovery depends on the synthesis of new AChE.
How do phosphodiesterase inhibitors work?
Phosphodiesterases break the phosphodiestrase bond in the secondary messengers cAMP and cGMP rendering them inactive. Phosphodiesterase inhibitors prevent this from happening.
They therefore promote the activity of cGMP and cAMP.
cGMP activates PKG (protein Kinase G) resulting in: platelet aggregation and smooth muscle relaxation
cAMP activates PKA (protein Kinase A) glucose metabolism, lipid metabolism and Ca2+ release
Give examples of non selective phosphodiesterase inhibitors?
Theophylline and aminophylline.
Mainly promote bronchial smooth muscle relaxation but also can cause:
-vasodilation
-inhibition of platelet aggregation
-positive inotropy
Give examples of selective phosphodiesterase inhibitors?
Enoximone and milrinone selectively inhibit PDE-III and are structurally similar to cAMP. PDE-III is predominantly located in the heart producing a positive inotropic effect.
Dipyridamole and sildenafil both inhibit PDE-V which inhibits platelet aggregation and treats (pulmonary HTN and erectile dysfunction) respectively.
