PHTH1011 011 Anti Parkinson and Anti Epileptic Drugs - Sandiford.pdf

Antiepileptic and Antiparkinson’s Drugs Dr. Simone Sandiford [email protected] Antiepileptic drugs Antiepileptic drugs are used to treat epilepsy as well as non-epileptic disorders With optimal drug therapy, epilepsy is controlled completely in about 66% of patients ~10% of patients co...

Antiepileptic and Antiparkinson’s Drugs Dr. Simone Sandiford [email protected] Antiepileptic drugs Antiepileptic drugs are used to treat epilepsy as well as non-epileptic disorders With optimal drug therapy, epilepsy is controlled completely in about 66% of patients ~10% of patients continue to have seizures at intervals of 1 month or less Patients usually need to take drugs continuously for many years Nature of epilepsy Epilepsy refers to a disorder of brain function characterised by the periodic and unpredictable occurrence of seizures Seizure refers to a transient alteration of behaviour due to disordered firing of populations of brain neurons Epilepsy affects ~ 1% of the population About one-third of the cases are familial and involve genetic mutations; most genes involved encode neuronal ion channels Seizure is caused by an asynchronous high frequency discharge of a group of neurons Classification of epileptic seizures Goodman et al. The Pharmacological basis of therapeutics 13th edition Pathophysiology of epilepsy Neurochemical basis of the abnormal discharge is not well understood Involves neuronal ion channels closely involved in controlling action potential generation May be associated with Enhanced excitatory amino acid transmission Impaired inhibitory transmission Abnormal electrical properties of affected cells Treatment of epilepsy Goals: Prevent the occurrence of seizures Drugs do not correct the underlying cause Choice of medication: depends on type of seizures Monotherapy is preferred Especially in patients not severely affected Multiple drugs used simultaneously in hard to control seizures Patients who do not achieve control with two or more drugs are termed “pharmacoresistant” Mechanism of action of antiepileptic drugs Antiepileptic drugs aim to inhibit the abnormal neuronal discharge Main mechanisms of action of antiepileptic drugs Modulation of voltage gated sodium and calcium channels Enhancement of fast GABA mediated synaptic inhibition Diminish fast glutamate mediated excitation Modification of synaptic release processes Inhibition of sodium channel function Many antiepileptic drugs affect membrane excitability by an action on voltage-dependent sodium channels Their blocking action is usedependence They block preferentially the excitation of cells that are firing repetitively Higher frequency of firing, the greater the block produced Phenytoin (Dilantin) and Carbamazepine Phenytoin Used to treat all types of seizures Drug most commonly used worldwide except absence seizures due to its low cost Use dependent block of sodium Metabolism: Hepatic channels Excretion: Renal Side effects include gingival hyperplasia (20% of patients) with long term use, nystagmus, vertigo, ataxia, marked confusion, anaemia, hirsutism www.wikipedia.com Gabapentin (Neurontin) Used in the treatment of focal seizures May aggravate absence and myoclonic seizures Various nonepilepsy indications Neuropathic pain (first line treatment) Restless legs syndrome Anxiety disorders MOA of Gabapentin Despite close structural resemblance to GABA does NOT act on GABA receptors Bind to a2d protein Auxiliary subunit of voltage gated P/Q type calcium channels Precise way binding protects against seizures is unknown May relate to decrease glutamate release at excitatory synapses Arnold et al Nature Clinical Practice Neurology 2007 Gabapentin Adverse effects Metabolism and excretion Generally well tolerated. Somnolence, dizziness, ataxia, headache and tremor, weight gain and peripheral oedema Not metabolised Excreted unchanged in the urine Antiepileptic drug selection Attempt should be made to determine the cause of the epilepsy Choice of medication depends on the type of seizure or patient’s syndromic classification Cost/benefit ratio of the efficacy and adverse effects Use of a single drug is preferred especially in patients not severely affected Therapies are typically continued for at least 2 years https://www.youtube.com/watch?v=frhzr8_spNo https://www.youtube.com/watch?si=CLTtM6 kmnqTDIfJw&v=S33TFgAFd1M&feature=yout u.be Parkinson’s disease Progressive neurological disorder of muscle movement Symptoms usually start appearing between the ages of 50 and 60 ~ One million people in the US live with Parkinson’s disease Higher incidence reported among males Male to female ratio 2:1 Symptoms of Parkinson’s disease Muscle rigidity Bradykinesia Tremor at rest Postural instability and gait Cognitive decline as the disease advances Causes of Parkinson’s disease No obvious underlying cause May be the result of: Cerebral ischaemia Viral encephalitis Types of pathological damage Drug induced (haloperidol or chlorpromazine) Rare instances of familial early onset Parkinson’s Environmental toxins Pathophysiology of Parkinson’s disease – neurochemical changes Nigrostriatal pathway accounts for 75% of dopamine in the brain Dopamine content in the substantia nigra is less than 10% of normal in PD patients Loss of dopamine occurs over several years Symptoms appear only when striatal dopamine has fallen to 20-40% of normal Rang and Dale’s Pharmacology 8th edition Figure 39.3 Pathogenesis of Parkinson’s disease Destruction of dopaminergic neurons in the substantia nigra Normal inhibitory influence of dopamine on cholinergic neurons is diminished Reduced inhibition of cholinergic neurons results in overactivity of cholinergic neurons that then increases inhibitory output from basal ganglia to striatum Goal of treatment Primary goal: Restore dopamine receptor function Secondary goal: Inhibition of muscarinic receptor function Treatment of Parkinson’s disease Available drugs cause temporary relief of symptoms but do not arrest or reverse the neuronal degeneration Levodopa Dopamine agonists Monoamine oxidase B inhibitors Catechol-O-methyltransferase inhibitors Muscarinic receptor antagonist Levodopa Metabolic precursor of dopamine that crosses blood brain barrier First line treatment for Parkinson’s disease Enhances the synthesis of dopamine in surviving neurons of the substantia nigra Combined with peripherally acting dopa decarboxylase inhibitor; carbidopa Levodopa/carbidopa (Sinemet) Levodopa Therapeutic Effectiveness Best results obtained in first few years of treatment 80% of patients show marked initial improvement (primarily in terms of resolution of muscle rigidity & bradykinesia) 20% show virtually normal motor function Over time, levodopa therapy becomes less effective Levodopa Side effects– related to increased peripheral concentrations of dopamine Nausea Anorexia Postural hypotension Confusion Insomnia Nightmares Delusions & hallucinations due to enhanced CNS concentrations of dopamine Levodopa Dyskinesias – occur in 80% of patients on long-term levodopa therapy “On-off” Effect – fluctuations in clinical response to levodopa “Off” = marked akinesia “On” = improved mobility but marked dyskinesia Thought to be related to fluctuations in levodopa plasma concentrations Trihexyphenidyl (Artane) Selective CNS M1 muscarinic receptor antagonist Decreases excitatory actions of cholinergic neurons on cells in the striatum Less efficacious than levodopa and plays a role only in adjunctive therapy Improves tremor and rigidity of parkinsonism but has little effect on bradykinesia Trihexyphenidyl Adverse effects Metabolism and excretion dry mouth, inability to sweat, blurred vision, urinary retention, constipation, drowsiness, confusion Metabolism: not well defined Excretion: urine https://www.youtube.com/watch?v=j86omOwx0Hk Learning objectives Understand the importance of antiepileptic and antiparkinson’s drugs and how they work Give examples of antiepileptic and antiparkinson’s drugs and their adverse effects and mechanisms of action