Antiepileptic Agents Past Paper PDF 2022-2023

Antiepileptic agents Epilepsy control agents Medications to treat seizure onset Carbamazepine Diazepam Valproic acid Midazolam Lamotrigine Lorazepam Gabapentin Ph...

Antiepileptic agents Epilepsy control agents Medications to treat seizure onset Carbamazepine Diazepam Valproic acid Midazolam Lamotrigine Lorazepam Gabapentin Phenobarbital Ethosuximide Valproic acid Phenobarbital Levetiracetam Levetiracetam Topiramate RSU Farmakoloģijas katedra 1 2022/2023  Antiepileptics Epilepsy is a brain disorder characterized by persistent propensity to cause epileptic seizures and neurobiological, cognitive, psychological and social consequences. Diagnosis of the disease requires at least one presence of occurred epileptic seizures. An epileptic seizure is an event of short-term, transient clinical signs and / or symptoms. It has a clearly defined onset of beginng and onset of end, starts rapidly (suddenly) and usually ends rapidly, resulting from abnormal excessive or synchronous brainneuronal activity. Seizures can be very variable such as sensor, motor, vegetative symptoms, disturbances in consciousness, emotion, memory, thinking and behavior Status seizure (status epilepticus) is repeated or continuous epileptic seizures lasting at least 30 minutes and the patient does not regain consciousness in between Strautmanis J. Ieskats epilepsijā, Doctus 2008 RSU Farmakoloģijas katedra 2 2022/2023  Antiepileptics The following types of epilepsy are distinguished: focal forms, generalized forms, combined forms and forms of unknown origin. Focal seizures begin in the localized (focal) area of ​the brain and its clinical manifestations are associated with a specific functional importance of the brain region involved. One of the most severe forms of generalized epilepsy is tonic-clonic form (belonging to motor forms). Another form of generalized epilepsy is absence (belongs to non-motor forms). Absence - a sudden, brief shutdown for a few seconds, during which the patient loses contact with the surrounding world (impaired consciousness). Often seizures go unnoticed because consciousness is maintained. In clinical practice, the concepts grand mal and petit mal still persist. These terms have been preserved from medieval France and are usually understood as grand mal generalized tonic-clonic seizure, but with petit mal - absance Strautmanis J. Ieskats epilepsijā, Doctus 2008 RSU Farmakoloģijas katedra 3 2022/2023  Antiepileptics Classification of Partial Seizures. Epilepsy, Oster, Joel M., Netter's Neurology, 14, 175-190 RSU Farmakoloģijas katedra 4 2022/2023  Antiepileptics Classification of motor seizures: tonic seizure - increase in muscle tone, clonic seizure - muscle twitching. A combination of both motor seizures is possible. Sensor seizures manifest themselves in a variety of sensory phenomena - paraesthesia, visual disturbances (light flashes, simple hallucinations), changes in the perception of the world around (macropsies, micropsies), sound phenomena (drumming), sense of smell, taste and balance. Vegetative seizures are characterized by peculiar epigastric sensations (like on a carousel), sweating, flushing, goose bumps, and et.c. Attacks with psychic symptoms - sudden fear, anger, feelings of unreality, deja vu (former) and jamais vu (as opposed to deja vu - not recognized familiar situation) phenomena, inappropriate behavior. Such attacks are difficult to differentiate clinically from different psychiatric conditions Strautmanis J. Ieskats epilepsijā, Doctus 2008 RSU Farmakoloģijas katedra 5 2022/2023  Antiepileptics Generalized Tonic–Clonic Seizures. Epilepsy, Oster, Joel M., Netter's Neurology, 14, 175-190 RSU Farmakoloģijas katedra 6 2022/2023  Antiepileptics Main mechanisms of action of antiepileptic drugs All mechanisms ensure the reduction of excessive neuronal activity 1. Reduction of excitatory neurotransmitter release a) reduction of axonal conductivity by delaying Na + influx through fast Na + channels b) * Inhibition of Ca2 + influx through presynaptic channels in thalamic neurons c) effect on the operation of SV2A 2. Enhancement of inhibitory system activity by facilitating GABA-mediated hyperpolarization to reduce excessive neuronal activity 3. Inhibition of glutamate activating effects (AMPA receptor blockade or NMDA receptor blockade) with the aim of reducing excessive neuronal activity * antiepileptic drugs block N-type, T-type and P / Q- type Ca2 + channels RSU Farmakoloģijas katedra 7 2022/2023  Antiepileptics Mechanisms of action of antiepileptic drugs AMPA/ + Ca2+ channel GABA A GABA Generalised Na Kainite Status blockers receptor trans- Focal epilepsy channel SV2A receptor epilep- allosteric aminase epilepsy blockers antagonist ticus modulators inhibitors *LVA **HVA s TC A Epilepsy control agents Ethosuximide +++ + Phenobarbital +++ + + + Gabapentin ++ + Carbamazepine +++ + + Lamotrigine +++ ++ + + + Levetiracetam +++ + + + Topiramate ++ ++ ++ ++ + + Valproic acid ++ ++ ++ + + + + TC- tonic-clonic form A-Absence *Low-voltage-activated (LVA) channel (T-type) SV2A - Synaptic vesicle protein 2A **High-voltage-activated (HVA) channels (N; P/Q-type) Status epilepticus - epileptic condition RSU Farmakoloģijas katedra 8 2022/2023  Antiepileptics Mechanisms of action of antiepileptic drugs AMPA/ Status Na+ Ca2+ channel GABA A GABA Kainite Focal Generalised epilep- blockers receptor trans- epilepsy epilepsy channel SV2A receptor ticus allosteric aminase blocker antagonist modulators inhibitors s *LVA **HVA TC A Medications to treat seizure onset Diazepam +++ + Phenobarbital +++ + + + Levetiracetam +++ + + + Lorazepam +++ + Midazolam +++ + Valproic acid ++ ++ ++ + + + + RSU Farmakoloģijas katedra 9 2022  Antiepileptics Valproic acid Blockade of voltage-dependent Na + and Ca2 + channels in neurons, inhibits GABA transaminase (prolongs GABA activity). anticonvulsant effect (control of epilepsy), mood stabilization Generalized (TC, A) and focal epilepsy Status epilepticus Bipolar disorder SE: Teratogenic activity NB! Take special care with women of childbearing potential Ethosuximide anticonvulsant effect (control of epilepsy) Blockade of Ca2 + channels in neurons Generalized epilepsy (A) RSU Farmakoloģijas katedra 10 2022/2023  Antiepileptics Lamotrigine Blockade of voltage-dependent Na + and Ca2 + channels in neurons, anticonvulsant activity (control of epilepsy), mood stabilization Generalized (TC, A) and focal epilepsy Bipolar disorder RSU Farmakoloģijas katedra 11 2022/2023  Antiepileptics Carbamazepine Blockage of voltage-dependent Na + channels in neurons, anticonvulsant activity (control of epilepsy), mood stabilization, co-analgic effect Generalized (TC) and focal epilepsy Bipolar disorder Neuropathic pain (trigeminal neuralgia) Gabapentin Structural analogue of GABA Inhibition of voltage-sensitive Ca2 + channels, anticonvulsant effect (control of epilepsy), coanalgesic effect Focal epilepsy Neuropathic pain (diabetic neuropathy, postherpetic neuralgia) Chronic pain syndrome RSU Farmakoloģijas katedra 12 2022/2023  Antiepileptics Glutamatergic synapse Levetiracetam binds to the synaptic vesicle protein 2A (SV2A), affects the neurotransmitter exocytosis * SV2A is considered to be involved vesicle fusion and Generalized (TC) and focal epilepsy neurotransmitters, especially glutamate, Status epilepticus excretion processes RSU Farmakoloģijas katedra 13 2022/2023  Antiepileptics Topiramate GABA-ergIc synapse 1) Blocks * Kainate/ AMPA (amino hydroxymethylisoxazole- propionic acid) receptors 2) blocks voltage dependent Na + channels 3) blocks Ca2 + channels 4) GABA-A receptor allosteric modulation Glutamate receptor * subtypes Generalized (TC) and focal epilepsy RSU Farmakoloģijas katedra 14 2022/2023  Antiepileptics SE of antiepileptic drugs Effects on CYP450 Interaction with hormonal contraceptives - carbamazepine, phenobarbital, lamotrigine, topiramate It is necessary to choose an alternative Valproic acid Example of pharmacovigilance monitoring For 1962 invented medicine the issue of serious teratogenic risks has been brought to the attention Valproate Pregnancy Prevention Program Objective: To provide information on the risk of teratogenicity According to the program, the patient should sign an informed consent document - annual risk awareness information during treatment with valproate RSU Farmakoloģijas katedra 15 2022/2023  Antiparkinsonian agents Dopamine precursors and dopamine receptor agonists Levodopa / Benserazide or Carbidopa Pramipexole COMT inhibitors MAO inhibitors Entacapone Selegiline Tolcapone Centrally acting cholinoblocker Trihexifenidil NMDA receptor antagonists Amantadine RSU Farmakoloģijas katedra 16 2022/2023  Antiparkinsonian agents Parkinson's disease (PD) - a chronic, slowly progressive neurodegenerative disease caused by selective loss of dopaminergic neurons in pars compacta region of the brain substantia nigra (SN) nigrostriatal tract as well changes in other neuro-anatomical structures and neurotransmitters (e.g., serotonergic, cholinergic, etc.) systems. Disorders of the dopaminergic system of the basal ganglia, clinically causes a combination of characteristic symptoms - tremor, bradykinesia, rigidity and postural instability A disturbed balance between dopamine inhibitory and ACh activating effects on GABA-ergic neurons RSU Farmakoloģijas katedra 17 2022/2023  http://tmedweb.tulane.edu/pharmwiki/doku.php/treating_parkinson_s_disease Antiparkinsonian agents Schematic of the neurologic pathways affected in Parkinson Disease (PD), and the major sites of action of medications used for treatment of its motor symptoms. Dopaminergic afferents from the substantia nigra, glutaminergic afferents from the cerebral cortex & thalamus, and cholinergic striatal interneurons all converge to exert effects on the activity of GABAergic neurons, which are the main efferent neurons of the striatum. Dopaminergic neurons exert inhibitory effects on GABAergic neurons, whereas cholinergic and glutaminergic neurons produce excitatory effects. The loss of dopaminergic neurons in Parkinson Disease results in abnormally high output by GABAergic efferents. Increased inhibitory output causes increased inhibition of the thalamus, as well as reduced excitatory input to the motor cortex. Clinically this is expressed as bradykinesia and other parkinsonian signs & symptoms. Drugs that produce symptomatic relief in PD act by either elevating regional dopamine levels (levodopa, MAOBIs, COMT inhibitors), stimulating dopamine receptors (DA agonists), inhibiting the effect of cholinergic afferents (anticholinergics), or inhibiting glutaminergic NMDA receptors (amantadine). RSU Farmakoloģijas katedra 18 2022/2023  http://tmedweb.tulane.edu/pharmwiki/doku.php/treating_parkinson_s_disease Antiparkinsonian agents Treatment strategies for dopaminergic therapy of Parkinson Disease. Carbidopa (which itself does not cross the blood brain barrier) inhibits the peripheral metabolism of L-DOPA to dopamine, so that a 3-10 fold higher amount of L-DOPA is available for transport across the blood brain barrier into the CNS (as illustrated in the right two panels). Antagonizing the peripheral breakdown of L-DOPA to dopamine also reduces the incidence of dopamine-induced side effects including nausea & vomiting,1) as well as dopamine effects on the cardiovascular system. COMT inhibitors reduce metabolism of both L-DOPA and dopamine in either the periphery, and/or centrally. Inhibitors of MAO-B (the form of MAO expressed in the CNS) prevents the breakdown of dopamine to inactive metabolites in the CNS. Synthetic dopamine agonists can directly stimulate dopamine receptors in the CNS. RSU Farmakoloģijas katedra 19 2022  Antiparkinsonian agents Dopaminergic agents Dopamine Prodrugs * L-DOPA + Decarboxylase Inhibitors (DCI) CNS ~ 10% By converting L-dopa to dopamine in the nigrostriatal tract, restores neurotransmission in Corpus striatum reduces EPS Carbidopa, benserazide DCI - peripheral levodopa inhibitors of metabolism (DCI does not cross the blood-brain barrier) Reduces dopamine-induced gastrointestinal side effects - nausea, vomiting and cardiovascular side effects - arrhythmias and hypotension NB! Discontinue L. gradually due to the risk of Neuroleptic Malignant Syndrome! * amino acid L-dihydroxyphenylalanine RSU Farmakoloģijas katedra 20 2022/2023  Antiparkinsonian agents Dopaminergic agents(L-DOPA continue) SE: After about 5 y. therapies motor complications can develop (conditionally called L. tolerance) Initially the phenomenon of Wearing Off develops and consequently episodic exacerbations of the disease (shortening of duration of action of L. causes acute exacerbation of symptoms) b) Later on-off phenomena develops, manifesting as acute cycles of exacerbation of symptoms throughout the day PD – Parkinsona slimība Levodopa-induced dyskinesia (LID) or involuntary movement during on-time, and bradykinesia during off-time Parkinson's disease Parkinsonism (except one caused by antipsychotics) RSU Farmakoloģijas katedra 21 2019  Antiparkinsonian agents Dopaminergic agents Non-selective agonists of striatal dopamine D2 receptors Pramipexole MAO-B inhibitors Selegiline COMT inhibitors Entacapone (does not cross BBB) Tolcapone (Crosses BBB) Parkinson's disease * Hyperprolactinemia (bromocriptine only) RSU Farmakoloģijas katedra 22 2022/2023  Antiparkinsonian agents Cholinolytic agents Dopamine acts as an ACh antagonist in certain regions of the CNS. In the event of dopamine deficiency in the nigrostriatal tract, ACh is one of the neurotransmitters that mediate EPS Trihexyphenidyl As a central actiong M1 choline blocker blocks Ach-induced EPS Parkinsonism Correction of EPT induced by antipsychotic agents RSU Farmakoloģijas katedra 23 2022  Antiparkinsonian agents NMDA receptor antagonists Amantadine NMDA receptor blockade suppresses glutamatergic activity,promotes dopamine synthesis and secretion, inhibits dopamine presynaptic reuptake Parkinsons disease RSU Farmakoloģijas katedra 24 2022/2023  Anti-dementia agents NMDA receptor antagonists Anticholineserases Memantine Donepezil RSU Farmakoloģijas katedra 25 2022/2023  Anti-dementia drugs Dementia is a brain disorder that causes persistent and versatile cognitive impairment (memory, language, visual-spatial sense, different skills, understanding of causation, reasoning). The most common form of dementia is Alzheimer's dementia or Alzheimer's disease It is a chronic neurodegenerative disease of the brain, which is clinically manifested as advancing cognitive psychiatric and behavioral disorders Other Common Dementias: vascular dementia and dementia in Parkinson's disease RSU Farmakoloģijas katedra 26 2022/2023  Anti-dementia drugs Acetylcholinesterase inhibitors Donepezil * Rivastigmine (also inhibition of * butyrylcholinesterase) reduces symptoms of neurodegeneration, slows cognitive decline SE: cholinergic hyperactivation IA: Medicines with anticholinergic properties (1st generation histamine receptor blockers, tricyclic antidepressants) Alzheimer's dementia Vascular dementia Parkinson's dementia (additional indication for rivastigmine) Glutamate NMDA receptor channel blocker (uncompetitive NMDA receptor antagonist) Memantine Alzheimer's dementia RSU Farmakoloģijas katedra 27 2022/2023