Pathways

Levetiracetam is an oral anticonvulsant agent used as an adjunct medication to manage partial onset, myoclonic, and generalized tonic-clonic seizures in patients with epilepsy. The exact mechanism through which levetiracetam exerts its anti-epileptic effects is unclear, but is thought to be unique amongst other anti-epileptic medications. Current knowledge suggests that levetiracetam’s binding to synaptic vesicle protein 2A (SV2A) is a key driver of its action. SV2A is a membrane-bound protein that is found on synaptic vesicles and is ubiquitous throughout the CNS - it appears to play a role in vesicle exocytosis and in the modulation of synaptic transmission by increasing the available number of secretory vesicles available for neurotransmission. Stimulation of pre-synaptic SV2A by levetiracetam may inhibit neurotransmitter release, but this action does not appear to affect normal neurotransmission. This has led to the suggestion that levetiracetam exclusively modulates the function of SV2A only under pathophysiological conditions. Levetiracetam can also inhibit the N-type voltage gated calcium channel in the presynaptic membrane. This prevents the influx of calcium ions into the presynaptic neurons. Calcium is also responsible for triggering the release of glutamate via exocytosis. Lower levels of calcium in the presynaptic neuron, decreases neurotransmitter release. By inhibiting the release of excitatory neurotransmitters like glutamate, the activation of excitatory receptors such a AMPA and NMDA glutamate receptors are reduced. These receptors allow the influx of cations like sodium and calcium ions into the post-synaptic cell when activated. Cation influx would ultimately lead to depolarization and excitation of the post synaptic neuron. If there is less glutamate released into the synapse, less AMPA and NMDA receptors are activated and the post synaptic neurons are less likely to become depolarized. Levetiracetam has also been shown to indirectly affect GABAergic neurotransmission (despite having no direct effect on GABAergic or glutamatergic receptors). The most common side effects of levetiracetam are neurobehavioral, like somnolence, fatigue, mood swings, headache, agitation, irritability, aggression, depression, memory loss, confusion, paresthesia, the decline in cognition and increased suicide risk. Most of the time, side effects are mild. About 1% of patients experience serious side effects like psychosis, hallucinations, and suicidal thoughts. These side effects are more common in the first month of treatment but can develop during treatment and improve once the drug is discontinued. Dose reduction is associated with improvement in behavioral problems.

Metabolites of Levetiracetam are predicted with biotransformer.

Levobunolol (also known as Betagan) is an ophthalmic beta blocker (non-selective) that can produce cardiovascular effects and systemic pulmonary effects. Levobunolol bind to beta1-adrenergic and beta2-adrenergic receptors in heart and vascular smooth muscle to block the binding of other adrenergic neurotransmitters such as norepinephrine, which lead to decreased blood pressure, heart rate and cardiac output.

Levobunolol is a ophthalmic beta-blocker, equally effective at both β(1)- and β(2)-receptor sites. It can be administered orally, where it passes through hepatic portal circulation, and enters the bloodstream and travels to act on cardiomyocytes. In bronchial and vascular smooth muscle, levobunolol can compete with epinephrine for beta-2 adrenergic receptors. By competing with catecholamines for adrenergic receptors, it inhibits sympathetic stimulation of the heart. The reduction of neurotransmitters binding to beta receptor proteins in the heart inhibits adenylate cyclase type 1. Because adenylate cyclase type 1 typically activates cAMP synthesis, which in turn activates PKA production, which then activates SRC and nitric oxide synthase, its inhibition causes the inhibition of cAMP, PKA, SRC and nitric oxide synthase signaling. Following this chain of reactions, we see that the inhibition of nitric oxide synthase reduces nitric oxide production outside the cell which results in vasoconstriction. On a different end of this reaction chain, the inhibition of SRC in essence causes the activation of Caspase 3 and Caspase 9. This Caspase cascade leads to cell apoptosis. The net result of all these reactions is a decreased sympathetic effect on cardiac cells, causing the heart rate to slow and arterial blood pressure to lower; thus, levobunolol administration and binding reduces resting heart rate, cardiac output, afterload, blood pressure and orthostatic hypotension. By prolonging diastolic time, it can prevent re-infarction. One potentially less than desirable effect of non-selective beta blockers like levobunolol is the bronchoconstrictive effect exerted by antagonizing beta-2 adrenergic receptors in the lungs. Clinically, it is used to increase atrioventricular block to treat supraventricular dysrhythmias. Levobunolol also reduce sympathetic activity and is used to treat hypertension, angina, migraine headaches, and hypertrophic subaortic stenosis.

Metabolites of Levobunolol are predicted with biotransformer.

Levobupivacaine is an anaesthetic most commonly used for nerve block, it belonds to the pipecoloxylidide family. It is an enantiomer of bupivacaine, capable of less vasodilation and longer duration of action. Adverse effects only are anticipated if levobupivacaine is administered incorrectly, which leads to systemic exposure and toxicity due to overexposure. Levobupivacaine acts as an anaesthetic through blocking nerve impulse generation and conduction, by reducing the rate of action potential through binding of the intracellular portion of sodium channels and blocks the sodium influx into nerve cells. Levobupivacaine is metabolized by CYP3A4 and CYP1A2 into desbutyl levobupivacaine and 3-hydroxy levobupivacaine. 3-hydroxy levobupivacaine is capable of being further metabolized to glucuronide and sulfate conjugates.