Pharmacology of Ion Channels & Ionotropic Receptors PDF

L41. Ion Channels & Ionotropic Receptors- Use in Seizure Disorders & Beyond Disorders of the nervous system cover a wide gamut ranging from conceptually straightforward disorders such as for example paralysis of the extremities or seizures to complex, difficult to conceptualize disorders involving d...

L41. Ion Channels & Ionotropic Receptors- Use in Seizure Disorders & Beyond Disorders of the nervous system cover a wide gamut ranging from conceptually straightforward disorders such as for example paralysis of the extremities or seizures to complex, difficult to conceptualize disorders involving disturbances of though, mood or emotion. Yet, surprisingly, the mechanistic substrates of these disorders may be less varied than we may be tempted to expect. For example, a symptomatic compassion of the motor sequelae of a stroke, Parkinson’s disease and insomnia would yield very little in common, yet the underlying pathology in all cases involves neuronal cell death, and the differences are accounted by the location of the lesion. In this context, we can conceptualize pathologies as distinct as epilepsy, neuropathic pain and bipolar disorder as disorders of aberrant excitability that are treated, not surprisingly, with overlapping pharmacological approaches. We will begin this class by considering the pharmacotherapy of epilepsy and later expand to examine how these approaches to controlling aberrant excitability have found uses in the treatment of other, on the surface apparently unrelated, disorders. A brief primer on the classification and pathophysiology of epilepsy Epilepsy is chronic disorder characterized by recurrent seizures (abnormal electrical activity in the CNS and its clinical manifestations). It affects ~1% population worldwide has epilepsy and it is the most common neurological disorder after stroke. Epilepsy is quite heterogeneous and can have a genetic basis or result secondary to an insult (e.g. trauma, stroke, tumors or neurodegenerative diseases). Epileptic seizures are generally classified into two main types, focal seizures (sometimes referred to as partial seizures) and primary generalized seizures. Each of these can be further subdivided into more restricted clinical entities.  Figure 1. Classification of epileptic seizures Focal seizures are localized to a patch of cortex (seizure focus) and its specific symptomatology depends on the area of cortex affected. Focal seizures can progress into generalized tonic-clonic seizures (see Fig. 1 for description). This progression involves recruitment of the thalamus, which is very strongly interconnected with all areas of cortex and is thought to play a key role in the generalization of the seizure. In contrast to focal seizures, which originate in cortex, absence generalized are thought to originate in the thalamus. These differences shape how we treat these seizures. Figure 2, Basic classification of epileptic seizures Pharmacotherapy of epileptic seizures The origins of pharmacotherapy for epilepsy can be traced to the initial discovery of the antiseizure activity of potassium bromide in the late 19th century, and of the barbiturates at the beginning of the 20th century. Subsequent efforts involving synthetic efforts and screening identified many compounds with robust antiseizure activity, some of which are still in use today (see below). More recent work has focused on specific molecular targets and has resulted in the discovery of additional drugs. Yet, even with this robust pharmacological armamentarium, standard drug therapies control seizures for only ~2/3 of patients (somewhat better for new- onset epilepsy in adults), still leaving hundreds of thousands in the US with poor seizure control. And although the newer drugs may have lesser side effects, they have not yet changed the prevalence of drug-resistant seizures. Finally, it is important to emphasize that available drugs are antiseizure, not antiepileptic (i.e., clinical evidence for prevention or reversal of pathological processes is not strong). Figure 3 provides a quick overview of the most prescribed anti-seizure drugs (for the year 2019). ll prescrip ons Figure 3. Most prescribed antiseizure drugs These drugs suppress epileptic seizures by reducing network excitability through four broad classes of mechanisms. However, since a large fraction of antiseizure drugs (ASDs) were identified through animal screenings rather than target driven design, multiple sites of action is a common occurrence among them. echanism of ac on of an sei ure ru s. o ula on of ca on channels a , , a. his can inclu e prolon a on of the inac ate state of olta e ate a channels, posi e mo ula on of channels, an inhi i on of a channels.. nhancement of neurotransmission throu h ac ons on receptors, mo ula on of meta olism, an inhi i on of reuptake into the synap c terminal.. o ula on of synap c release throu h ac ons on the synap c esicle protein or a channels containin the su unit.. iminishin synap c excita on me iate y ionotropic lutamate receptors e.., P receptors. From oo man an ilman, he Pharmacolo ical asis of herapeu cs Modulation of Sodium channel inactivation. Action potentials are mediated by voltage dependent sodium channels. They open in response to suprathreshold depolarizations which allows sodium influx into the cell leading to the upstroke of the action potential. After a brief period of time they inactivate, a process that contributes to the decay of the action potential, and the cell/axon enters a refractory period. Several ASDs including carbamazepine, phenytoin, lamotrigine, oxcarbazepine and zonisamide are thought to act primarily by facilitating sodium channel inactivation. This results in the selectively suppression of the high frequency spiking that constitute the seizure while sparing ongoing neuronal activity, which presumably involves lower frequencies of action potential firing. Figure 4. Some antiseizure drugs act by facilitating sodium channel inactivation (from Rogawski, M., Löscher, W. The neurobiology of antiepileptic drugs. Nat Rev Neurosci 5, 553–564 (2004). T -Type calcium channel inhibition. Low threshold (T Type) calcium channels play a key role in the firing of the thalamus. Ethosuximide is highly effective in the treatment of generalized absence seizures but no other seizure types. This likely reflects blockade of T-type calcium channels but other mechanisms may also contribute. Potassium channels form a molecularly diverse group of channels that dampen neuronal excitability. Thus, in principle, they could provide important targets for the development of ASDs. Surprisingly, there are currently no potassium-targeting drugs in common use for the treatment of epilepsy. Retigabine (ezogabine in the US) facilitates the activity of Kv7 channels (KCNQ), a potassium channel that is well expressed in cortex where it contributes to the resting membrane potential and regulates membrane excitability. This drug was approved for use as an ASD in 2011 but was subsequently removed from distribution due to retinal toxicity. Facilitation of inhibitory GABAergic synaptic transmission. Inhibitory GABAergic transmission is a key mechanism controlling runaway excitation in the brain. GABA acts on ionotropic GABAA receptors and on metabotropic GABAB receptors to implement feedforward/feedback inhibition and presynaptic inhibition respectively. Barbiturates such as pentobarbital, an effective but now rarely used ASD, and benzodiazepines such as clonazepam, lorazepam, and diazepam facilitate GABA-induced chloride fluxes through GABAA receptors, In other words, these drugs are positive allosteric modulators of GABAA channels. Consequently, they facilitate inhibitory GABAergic synaptic transmission.  Figure 5. Site of action for benzodiazepine ASDs. GABAA receptors are heteropentamers composed of α, β an γ or δ su units an the su unit composition provides some degree of selectivity to these drugs. Specifically, benzodiazepines act on only a subset of the GABAA receptors efine y the inclusion of γ as well as specific α su units. Figure 6. Mechanism of action of Benzodiazepines and barbiturates (from Rogawski, M., Löscher, W. The neurobiology o awski, ofneuro., scher,. he antiepileptic iolo y of andrugs. epilep cNat ru Rev s. Neurosci 5, 553–564 (2004).. An alternative approach to facilitating GABA inhibition would be to increase extracellular GABA. After release, GABA is recaptured by GABA transporters on neurons and astrocytes. Tiagabine inhibits this reuptake thus causing a rise in ambient GABA leading to the activation of extrasynaptic GABAA channels. Tiagabine has been approved by the FDA as an adjunct therapy for epilepsy. In contrast, Vigabtrin blocks GABA metabolism. This causes a rise in cytoplasmic GABA and its efflux from terminals through a reverse of the GABA transporter. This again leads to a rise in ambient GABA and the activation of extrasynaptic GABAA receptors. Vigabtrin has been approved by the FDA for refractory partial seizures, but its use is limited by potentially irreversible vision loss. Inhibition of synaptic transmission. Efforts to generate a brain blood barrier permeable GABAergic agonist led to the synthesis of the GABA analogs GABApentin and pregabalin. Both drugs proved to be effective ASDs but surprisingly both were also found to be inactive at GABAA receptors. Subsequent work showe that these ru s exhi ite hi h affinity for the α δ-1 subunit of the calcium channel and that this action was essential for their antiseizure activity. More recent work has emphasized a potential role for α δ proteins in synaptic function eyon calcium channels. Howe er exactly how pentin and pregabalin exert its antiseizure activity is not yet clear. e e racetam, ri aracetam a apen n, Pre a alin Figure 7. Site of action of Gabapentin and Levetiracetam The ASD drug Levetiracetam was originally identified through a screening and subsequently was found to target the synaptic vesicle protein SV2A. Subsequent work has supported the idea that SV2 is the primary target through which Levetiracetam and its analog brivaracetam exerts their antiseizure activity. However, the exact function of SV2A in the dynamics of vesicle cycling remain unclear so exactly how levetiracetam inhibits seizures is not currently known. Figure 8, Synaptic vesicle cycle Blockade of excitatory postsynaptic receptors. As we saw earlier, glutamate is the principal excitatory neurotransmitter in the brain and spinal cord and thus represents a clear target for the development of ASDs. Perampanel is a noncompetitive antagonist of GluA (AMPA) receptors that reduces synaptic transmission. As could be expected for a blocker of GluA receptor this drug has a narrow therapeutic window and at therapeutic doses is thought to block a small fraction of GluA receptors, enough to suppress the development of seizures while sparing most physiological synaptic transmission. Valproic acid and Topiramate Valproic acid and Topiramate are widely used and effective ASDs whose mechanism of action remains poorly understood. Valproic acid (Depakene) Accidental discovery (1962) Efficacious against focal seizures, generalized tonic- clonic and combination seizures. Also used to treat bipolar disorder and migraine, Broad spectrum presumably related to multiple targets Sodium channels inactivation GABA levels in brain T type Ca channels Histone deacetylase inhibition, etc, etc  Topiramate (Topamax): Discovered using phenotypic assessment (1979) Efficacious against focal and generalized tonic-clonic seizures. Also used to treat migraines. Likely multiple targets Sodium channel inactivation GABAA receptors GluA receptors Disease specific ASDs. Many epilepsies emerge from specific genetic mutations which result in a characteristic presentation leading to their recognition as discrete clinical entities. For example, mutations in NaV1.1 lead to Dravet syndrome while mutations in TSC1 lead to tuberous sclerosis (TSC). In a few cases the defined pathophysiology of these epilepsies offers unique opportunities for treatment. For example, the loss of TSC1 or TSC2 lead to the constitutive activation of mTOR, which is though to be the proximal cause of the cortical malformations and seizures. Everolimus is a mTOR inhibitor approved for the treatment of focal epilepsies associated with TSC. More frequently, insightful clinical observations have led to the identification of effective for the treatment of specific epilepsies, although the exact mechanism for these effect is not understood. For example, fenfluramine (a serotonin releaser) and cannabidiol are both effective for the treatment of Dravet and Lennox-Gastaut syndromes although we still lack a mechanistic explanation for their therapeutic effects. Adverse effects ASDs display adverse effect that are extensions of their therapeutic actions including CNS depression (e.g. sedation, drowsiness, fatigue, impaired cognition, etc). They also have drug specific adverse effect which can be serious. For example fatal liver toxicity is a rare adverse effect of valproate. Side effects for selected ASDs are listed in Table 1. Antiepileptic Drug Adverse Effects Benzodiazepines Sedation, tolerance, dependence Carbamazepine Diplopia, cognitive dysfunction, drowsiness, ataxia; rare occurrence of severe blood dyscrasias and Stevens Johnson syndrome; induces hepatic drug metabolism; teratogenic potential Ethosuximide Gastrointestinal distress, lethargy, headache, behavioral changes Gabapentin Dizziness, sedation, ataxia, nystagmus; does not affect drug metabolism (pregab alin is similar) Lamotrigine Dizziness, ataxia, nausea, rash, rare Stevens Johnson syndrome  Levetiracetam Dizziness, sedation, weakness, irritability, hallucinations, psychosis Oxcarbazepine Similar to carbamazepine, but hyponatremia is more common; unlike carbamaze pine, does not induce drug metabolism Perampanel Dizziness, somnolence, headache; behavioral hostility, anger. Drug interactions with CYP inducers (carbamazepine, oxcarbazepine, phenytoin) Phenobarbital Sedation, cognitive dysfunction, tolerance, dependence, induction of hepatic drug metabolism; primidone is similar Phenytoin Nystagmus, diplopia, sedation, gingival hyperplasia, hirsutism, anemias, peripher al neuropathy, osteoporosis, induction of hepatic drug metabolism Retigabine Dizziness, somnolence, confusion, dysarthria, pigment discoloration of retina (ezogabine) and skin Tiagabine Abdominal pain, nausea, dizziness, tremor, asthenia; drug metabolism is not induced Topiramate Drowsiness, dizziness, ataxia, psychomotor slowing and memory impairment; pa resthesias, weight loss, acute myopia Valproate Drowsiness, nausea, tremor, hair loss, weight gain, hepatotoxicity (infants), inhibition of hepatic drug metabolism Vigabatrin Sedation, dizziness, weight gain; visual field defects with long- term use, which may not be reversible Zonisamide Dizziness, confusion, agitation, diarrhea, weight loss, rash, Stevens- Johnson syndrome Table 1. Adverse effects and complications of ASDs (extracted from Katzung & T ’ Pharmacology: Examination and Board Review). Use of ASDs beyond epilepsy ASDs are widely used in the treatment of multiple conditions, especially neuropathic pain and psychiatric disorders. Gabapentin and pregabalin are effective in the treatment of postherpetic neuralgia, diabetic neuropathy and fibromyalgia. Valproic acid and topiramate for the prevention of migraine (not first line anymore).  s in the treatment of neuropathic pain a apen n an pre a alin are e ec e in the treatment of postherpe c neural ia, ia e c neuropathy an romyal ia alproic aci an topiramate for the pre en on of mi raine not rst line anymore. Carbamazepine, lamotrigine and Valproate are first line pharmacological treatments for bipolar disorder and benzodiazepines are prototypical anxiolytics. Pregabalin has been shown to be effective in the treatment of generalized anxiety disorder and topiramate and gabapentin (both off label) for the treatment of alcohol withdrawal syndrome. Valproic acid and topiramate for the prevention of migraine (not first line anymore). From aufman, pilepsy eha ior ,