Enzyme Inhibitors

• The degree of enzyme inhibition is dependent on the concentration of the competitive antagonist vs. the concentration of the natural agonist
• There are a multitude of examples:
• Neostigmine - AChE inhibitor
• Milrinone - PDE inhibitor
• Ramipril - ACE inhibitor
• NSAIDs - COX inhibitor

• Drugs have a long duration of action as they require re-synthesis of the enzyme before normal activity can be resumed
• Examples include:
• Aspirin acetylation of COX
• Phenelzine and tranylcypromine, which are non-selective MAO inhibitors

• Action of intermediary messengers to reduce enzyme activity
• Drugs that demonstrate indirect enzyme inhibition may be:
• Agonists at G-protein coupled receptors linked to G_i alpha subunits, which reduces intracellular cAMP e.g. clonidine, opioids (MOP)
• Antagonists at G-protein receptors linked to G_s alpha subunits, which inhibits increases in intracellular cAMP e.g. β-blockers

Adapted from Physics, Pharmacology and Physiology for Anaesthetists

• E.g. edrophonium
• Short-acting inhibitors that are used for diagnostic purposes

• E.g. neostigmine, physostigmine, pyridostigmine
• Bind to both esteratic and anionic sites
• Carbamylate the enzyme, which reacts with water more slowly
• This reduces the rate of ACh breakdown, increasing concentrations in the synaptic cleft
• As such they increase ACh concentration to reverse the effect of the competitive, non-depolarising nAChR antagonists
• Patients with myasthenia gravis take pyridostigmine

• E.g. organophosphates, certain biochemical agents
• Interact with the esteratic site to phosphorylate the enzyme
• The enzyme becomes 'aged' with time
• The phosphorylated enzyme reacts with water even more slowly, causing ACh concentrations to rise centrally and peripherally, leading to cholinergic crisis
• Pralidoxime (if used before 36-48hrs post-exposure) displaces the phosphate from the esteratic site and remains bound, allowing clearance of the poison
• Without treatment, recovery is dependent on new AChE synthesis

• PDE is responsible for degrading the phosphodiester bond in the second messengers cAMP and cGMP, inactivating them

• E.g. aminophylline, theophylline
• Inhibit PDE in many tissues:
• Bronchial smooth muscle → bronchodilation
• Vasculature → vasodilation
• Cardiac → positive inotropy
• Inhibit platelet aggregation

• PDE-III inhibitors e.g. milrinone, enoximone
• Both drugs are structurally similar to cAMP
• Inhibit cardiac PDE causing positive inotropy


• PDE-IV inibitors e.g. dipyridamole, sildenafil
• Inibit platelet aggregation
• Reduce pulmonary pressures
• Treat erectile dysfunction

• Warfarin is a racemic mixture of R- and S-warfarin and is a vitamin K epoxide reductase (VKOR) inhibitor
• VKOR is responsible for the recycling of vitamin K into its reduced, active form
• VKOR itself is subject to genetic polymorphisms
• Vitamin K is required for clotting factor 2, 7, 9 and 10 activation
• The S-enantiomer is a more potent VKOR inhibitor, though is metabolised by CYP2C9 which is subject to genetic variation

• Fibrinolytics e.g. streptokinase, alteplase, urokinase
• Hyaluronidase in ophthalmic regional blocks to help LA diffusion
• Inhaled DNAse (dornase) for cystic fibrosis

• Enzyme inhibitors will increase the concentration of available drug
• Specific examples of relevant clinical interactions include:
• Verapamil and diltiazem will increase the concentration of beta-blockers, leading to dangerous bradycardia, AV nodal block (CYP3A4)
• Amiodarone will increase warfarin concentrations (CYP2C9)
• Grapefruit juice will increase ciclosporin concentrations and may cause toxicity (CYP3A4)
• Paroxetine increases risk of bleeding with NSAIDs (CYP2D6)
• Ketoconazole increases plasma levels of buprenorphine (CYP2D6)
• Clarithromycin given with terfenadine can cause Torsades de Pointes