DRUGS ACTING ON CNS,2016.pdf

DRUGS ACTING ON CENTERAL NERVOUS SYSTEM 9/1/2024 Alemseged.W 1 Learning Objectives Describe the common CNS neurotransmitters & receptors Explain the pathophysiology behind common CNS disorders List common medications used in the CNS Diseases Explain the mechan...

DRUGS ACTING ON CENTERAL NERVOUS SYSTEM 9/1/2024 Alemseged.W 1 Learning Objectives Describe the common CNS neurotransmitters & receptors Explain the pathophysiology behind common CNS disorders List common medications used in the CNS Diseases Explain the mechanism of action , adverse effects and choice of drugs for common CNS diseases 9/1/2024 2 Alemseged.W Outline  Central neurotransmitters (NTs)  Sedative hypnotics  Antiparkinsonian drugs  Antipsychotic drugs  Antidepressants  Drugs for manic and manic-depressive disorder  Antiseizure drugs  Local & general anesthetics  Analgesics: opoid analgesics 9/1/20243 Alemseged.W  SYNAPTIC POTENTIALS  In CNS receptors at synapses are coupled to ion channels ◦ Binding of NT to postsynaptic membrane results in rapid but transient opening of ion channels.  Change in ion composition across the membrane of the neuron ◦ Produce depolarization or hyperpolarization  EPSP & IPSP 9/1/2024 Alemseged.W 4 The synapse & synaptic potentials… The direction of the potential change may be either depolarizing or hyperpolarizing A depolarizing postsynaptic potential → excitatory postsynaptic potential (EPSP) Hyperpolarizing potential → Inhibitory postsynaptic potential (IPSP) 9/1/20245 Alemseged.W The synapse & synaptic potentials… A. Excitatory neurons: Opening of Na channels (influx of Na+ ) Depressed Cl- influx or K+ efflux or both  Influx of Na+ ion, inhibition of K+ ion conductance & Cl- ion channel opening causes ↑ed positively inside postsynaptic neuron ◦ Changes in internal metabolism of the postsynaptic neuron to excite cell activity or by increasing excitatory membrane receptors / ↓ inhibitory membrane receptors 9/1/2024 6 Alemseged.W The synapse & synaptic potentials… B. Inhibitory neurons: Opening of Cl- channels (Influx of Cl- ion ) ↑ conductance of K+ ions (efflux of K+)  Influx of Cl- ion & efflux of K+ ion causes hyperpolarization of postsynaptic neuron Activation of enzymes which inhibit cellular metabolic functions & ↑ inhibitory synaptic receptors or ↓ excitatory receptors 9/1/2024 7 Alemseged.W The synapse & synaptic potentials…  Excitatory neurones (EPSP): ↑ the probability of generating an AP  Inhibitory neurons (IPSP): ↓ the probability of generating an AP  There is always interaction b/n these neurons  The level of electrical activities determine the state of the pt ◦ E.g. seizure, anxiety, etc 9/1/20248 Alemseged.W CNS pathways A. Excitatory Pathways ◦ Stimulation of excitatory neuron causes movement of ions that result in a depolarization of the postsynaptic potentials (EPSP) by influx of Na+. B. Inhibitory Pathways ◦ Stimulation of inhibitory neurons cause movement of ions that results in hyper-polarization of synaptic membrane (IPSP) by influx of chloride (Cl-) & efflux of potassium(k+). 9/1/2024 Alemseged.W 9  Central Neuro-Transmitter (NT)  NT are endogenous chemical messengers that transmit signals from a neuron to a target cell across a synapse that enable neurotransmission.  They are unevenly distributed in the nervous system  Neuromodulators(NM) -are chemicals released by neurons have little or no direct effects on their own but can modify the effects of neurotransmitters.  NT and NM can be divided into two major categories:  small-molecule transmitters and  large-molecule transmitters. 9/1/2024 Alemseged.W 10  Cont….. Small-molecule transmitters: include ◦ Monoamines (eg, acetylcholine, serotonin, histamine), ◦ catecholamines (dopamine, NE, and epinephrine), and ◦ amino acids (eg, glutamate, GABA, glycine).  Large-molecule transmitters: include neuropeptides a large number of peptides (short chains of amino acids linked by peptide bonds) E.g substance P, enkephalin, vasopressin, In general, neuropeptides are colocalized with one of the small-molecule neurotransmitters. 9/1/2024 Alemseged.W 11 9/1/2024 Alemseged.W 12  Cont….. ◦ Neurotransmitters can be classified by chemical structure into various categories, including  amino acids ( glutamate, Aspartate, glycine & GABA)  acetylcholine (ACh), monoamines, neuropeptides, purines, lipids, and gases 1. Excitatory  Glutamate, Aspartate ( always excitatory)  Monoamines: DA, NE and 5-HT, Ach 2. Inhibitory  GABA, Glycine 9/1/2024 Alemseged.W 13 NT in CNS  Ach - the major transmitters & usually excitatory.  Noradrenaline, dopamine & serotonin (5- HT) excitatory transmitters to certain neurons & inhibitory to other.  Glycine & Gamma-Amino-Butric-Acid (GABA) inhibitory transmitters primarily in the spinal cord & in the brain respectively.  Aspartic & Glutmic Acid always excitatory transmitters 9/1/2024 Alemseged.W 14 a. GABA  Major inhibitory AA in the mammalian CNS  Reduced function/amount of GABA will cause excessive stimulation → Seizure  It acts by binding to and activating specific ionotropic or metabotropic receptors on both pre- and postsynaptic membranes.  Produced from localized interneurons ◦ Linked to chloride channel opening  Hyperpolarization 9/1/2024 15 Alemseged.W  GABA receptors: GABA … GABAA receptors GABAB receptors One subtype formerly known as the GABAC receptor is now classified as a type of GABAA receptor. Types of GABA receptors GABAA : Ion channel receptor (ionotropic) ↑ Cl- conductance (postsynaptic) Is serves as drug targets & site of action of many neuroactive drugs including benzodiazepines, Barbiturate, ethanol, anesthetic volatile anesthetics Blocked by bicuculine & picrotoxin causing generalized convulsions &16 facilitated Alemseged.W by BZDs 9/1/2024  9/1/2024 GABA … Types of GABA receptors… GABAB : G protein coupled receptor (metabotropic) Located pre-synaptically ↑ K+conductance (postsynaptic) ↓Ca 2+ influx (Presynaptic) GABAB receptors also inhibit adenylyl cyclase & ↓cAMP generation Selectively activated by antispastic drug Baclofen 17 Alemseged.W GABA …  Drugs that interact with GABA: ◦ BZD & Barabiturates: facilitate the action of GABA  CNS depressant ◦ Picrotoxin: convulsant (block anion channel)  GABA deficiency / defect causes excessive stimulation ◦ Seizure 9/1/2024 18 Alemseged.W b. Glycine  Inhibitory AA , Linked to Cl- ion channels  Glycine acts as a coagonist at NMDA receptors, such that both glutamate& glycine must be present for activation to occur.  Agonist for glycine receptor: Taurine and ẞ-alanine  Antagonist for glycine receptor: Strychnine(used as a rat poison)  Blockade of Glycine receptors cause seizure 9/1/2024 19 Alemseged.W  C. Glutamate and aspartate  are dicarboxylate a.a NT with excitatory actions in the CNS.  Both found in high concentrations in the brain and have powerful excitatory effects on neurons.  Glutamate is the most abundant & fast excitatory NT ◦ it acts though either ligand-gated ion channels (ionotropic) or metabotropic GPCRs receptors.  Types of ligand gated ion channels: ◦ NMDA receptors: permeable to Ca2+,to Na+ & K+, Bind with glycine ◦ AMPA receptors: permeable to Na+ & K+ ◦ KA receptors:permeable to Na+ & K+ 9/1/2024 Alemseged.W 20 d. Acetylcholine (Ach)  Widely distributed in CNS  The effects of ACh result from interaction with nicotinic receptors (ionotropic ligand-gated ion channels) and muscarinic receptors (metabotropic GPCRs).  Involved in different activities including in arousal, learning, short-term memory and movement coordination  Most CNS actions mediated by G protein coupled muscarinic receptor  Parkinsonism: relatively excessive Ach function  Benzatropine (Muscarnic Ach antagonist)  Alzheimer: profound cholinergic neuron loss  Revastigmine(cholinesterase inhibitor) 9/1/2024 21 Alemseged.W d. Monoamines  Include: Dopamine (DA), Norepinephrine (NE), serotonin/5-hydroxytryptamine (5-HT)  Present in very small amount in the CNS  These pathways are the site of action of many drugs ◦ Example, the CNS stimulants cocaine & amphetamine appear to act primarily at catecholamine synapses  Cocaine blocks the reuptake of DA & NE  Amphetamines cause presynaptic terminals to release these transmitters 9/1/2024 22 Alemseged.W i. Dopamine (DA)  DA is the precursor forNE and it is the predominant catecholamine in the CNS.  It play a role in motivation & reward (most drugs of abuse increase DA signaling), motor control, and the release of various hormones.  Common brain function disorders related with DA ◦ Parkinson's disease, psychosis/ schizophrenia, ◦ drug dependence, attention deficit disorder, ◦ certain endocrine disorders, depression  Drugs used clinically to treat these conditions work by influencing dopamine transmission 9/1/2024 23 Alemseged.W Dopamine (DA)… Dopaminergic pathways: 1. Mesolibic-mesocortical pathway-connects the ventral tegmental area to the limbic cortex Related to emotion & behavior Excess DA or altered DA receptors – causes psychosis 2. Nigrostriatal pathway Projection linking the substantia nigra to the neostriatum Involved in coordination of voluntary movement Deficient DA – causes Parkinsonism 9/1/2024 24 Alemseged.W  Dopamine (DA)… Dopaminergic pathways… 3. Tuberoinfundibular pathway (tuberohypophseal) Regulate prolactin secretion DA inhibits prolactin secretion 4. Medial periventricular pathway DA receptors located in the CTZ, GI, heart & splanchnic vessels DA acts in CTZ to induce N & V 9/1/2024 25 Alemseged.W 9/1/2024 26 Alemseged.W Dopamine (DA)…  Two types of DA receptors: all are metabotropic receptors ◦ D1 family (D1 & D5) activates adenylate cyclase ◦ D2 family (D2,D3 & D4) inhibits adenylate cyclase mediates most of DA functions  Bromocriptine (D2 agonist): to treat parkinsonism  Levodopa (DA precursor): to treat parkinsonism  Chlorpromazine (D2 antagonists): antipsychotic & antiemetics  Metoclopramide & domperidone (D2 antagonists in CTZ): antiemetics 9/1/2024 27 Alemseged.W ii. Norepinephrinre (NE)  Most noradrenergic neurons are located in the locus caeruleus or the lateral tegmental area of the reticular formation  All noradrenergic receptor are metabotropic  Alpha 2 inhibitory in locus caeruleus  Most other regions excitatory [alpha 1& beta ]  Important to remain awake ◦ ↑ed stimulation during awake phase  Also play role in attention, control of mood & feeding  Its reduction will contribute to occurrence of depression 9/1/2024 28 Alemseged.W iii. Serotonine ( 5-HT)  Most 5-HT pathways originate from neurons in the raphe or midline regions of the pons & upper brainstem  Can exert inhibitory or excitatory effects on individual neuron acting either pre or post-synapticaly  Mainreceptor subtypes in CNS: 5-HT1A,5-HT1B, 5-HT1D ,5-HT2 & 5-HT3 ◦ 5-HT3: Ionotropic receptor & exaitatory ◦ All other type of 5-HT receptor are metabotropic receptor 9/1/2024 29 Alemseged.W  Serotonine ( 5-HT)…  In most areas of the CNS, 5-HT has a strong inhibitory action  Involved in feeding behavior, behavioural responses, control of mood & emotion, sensory pathways, body T0 & vomiting  Sumatriptan(5-HT1D agonist): for migraine treatment  Fluoxetine (SSRI): antidepressant  Buspirone(5-HT1A agonist): to treat anxiety  Ondasartan(5-HT3 antagonist): antiemetic 9/1/2024 30 Alemseged.W 9/1/2024 Alemseged.W 31  I. DRUGS FOR NEURODEGENERATIVE DISEASES 9/1/2024 Alemseged.W 32 Introduction  Drugs acting on the CNS usually referred to as ‘Centrally acting drug’  The study of drugs affecting the CNS is known as Neuropharmacology. 9/1/2024 Alemseged.W 33 NEURODEGENERATIVE DISEASES  Includes: ◦ Alzheimer's disease (Ach neurones in nucleus basilis) ◦ Parkinson's disease (DA neurones in substantia nigra) ◦ Huntington's disease and ◦ Amyotrophic lateral sclerosis.  characterized by the progressive loss of selected neurons in discrete brain areas, resulting in characteristic disorders of movement, cognition, or both. 9/1/2024 Alemseged.W 34 OVERVIEW OF PARKINSON'S DISEASE  Parkinsonism: - is a progressive neurologic disorder of muscles movement characterized by ◦ tremors(hand ankles) ◦ muscular rigidity ◦ postural abnormalities (instability ◦ Brady kinesis(slowness in initiating & carrying out voluntary movements) 9/1/2024 Alemseged.W 35 Pathophysiology of PD  The basal ganglia are responsible for controlling automatic movements of the body by the action of dopamine (DA)  Degeneration of basal ganglia in the deeper grey matter of the brain (substantia nigra) causes PD.  DA level in the brain’s substantia nigra normally fall with ageing  The level has to fall to one-fifth of normal values for signs of PD to emerge  In PD, there is extensive destruction of dopaminergic neurons of SN. ◦ DA deficiency 9/1/2024 Alemseged.W 36  Etiology  It is correlated with destruction of dopaminergic neurons in the substantia nigra ◦ It is idiopathic disease but some causes may be: Genetic. Toxins (MPTP= methyl phenyl tetrahydropyridine). Head trauma, Cerebral anoxia, Oxidative stress Drug-induced Parkinson's disease e.g. antipsychotics like haloperidol Dopamine antagonists as metoclopramide (antiemetic) 9/1/2024 Alemseged.W 37 1. Substantia nigra ◦ Is the source of dopaminergic neurons that terminate in the striatum. ◦ Each DAnergic neuron synapse with neostriatum ◦ Modulates activity of large no. of cells. ◦ fire tonically, rather than in response to specific muscular movements or sensory inputs. 2. Neostriatum ◦ Connected to Substentia nigra by neurons that secret inhibitory NT GABA at their terni in substentia nigra ◦ In turn, cells of substentia nigra send neurons back to neostriatum, secreting the inhibitory transmitor Dopamin at their termini. 9/1/2024 Alemseged.W 38  Dopaminergic neurons originating in the substantia nigra normally inhibit the GABAergic output from the striatum, whereas cholinergic neurons exert an excitatory effect. In parkinsonism, there is a selective loss of dopaminergic neurons 9/1/2024 Alemseged.W 39 9/1/2024 Alemseged.W 40  Pathophysiology  The actions of dopamine are mediated by a family of dopamine-receptors  Two classes of dopamine receptor * The D1 and D5 - the class defined pharmacologically as D1 - they ↑cAMP * The D2, D3, and D4 - are of the D2 class - They ↓cAMP formation & modulate K+ and Ca2+ current 9/1/2024 Alemseged.W 41  Strategy of Treatment  Symptoms of Parkinson's reflect ◦ imbalance b/n the excitatory cholinergic neuron & the greatly diminished number of inhibitory dopaminergic neurons. Parkinson’s disease  Therapy Normal is aimed ◦ to restore the dopamine in the basal ganglia & antagonizing the excitatory effects of cholinergic neurons. ◦ Thus re-establishing the correct dopamine and -Ach balance. 9/1/2024 Alemseged.W 42 9/1/2024 Alemseged.W 43 Overview of Drug Therapy A.Therapeutic Goal—To improve ability for activities of daily life (only symptom relief) B.Treatment Strategy—Restore balance between DA and ACh by activating DA receptor or blocking ACh receptors C. Overview of Drugs Employed—Two major categories (dopaminergic drugs & anticholinergic drugs). 9/1/2024 Alemseged.W 44 9/1/2024 Alemseged.W 45 Classification of drugs 1. Drugs affecting brain dopaminergic system a. Dopamine precursors: levodopa b. Peripheral decarboxylase inhibitors: carbidopa & benserazide c. Dopaminergic agonists: bromocriptine, lisuride, pergolide, ropinirole, cabergoline & pramipexole d. MAO-B inhibitors : Selegiline e. COMT inhibitors: Entacapone, tolcapone f. Dopamine facilitator : Amantidine 9/1/2024 Alemseged.W 46 2. Drugs affecting brain cholinergic system a. Anticholinergics: Benzatropine, Trihexyphenidyl (benzhexol), Procyclidine, biperiden b. Antihistaminics: promethazine 3. Neural transplantation (on experimental phase)  Currently available drugs after temporary relief from the symptoms of the disorder, ◦ but do not arrest or reverse the neuronal degeneration caused by the disease. 9/1/2024 Alemseged.W 47 A. Levodopa (L-Dopa)  Dopamine does not cross the BBB and if given into the peripheral circulation has no therapeutic effect in parkinsonism.  Levodopa (L-DOPA) - ◦ (–)-3-(3,4-dihydroxyphenyl)-L-alanine  First-line treatment for PD  It is the immediate metabolic precursor of dopamine ◦ Prodrug for DA ◦ Levodopa can cross BBB while DA does not 9/1/2024 Alemseged.W 48 Pharmacokinetics  Levodopa is rapidly absorbed from the small intestine  Fooddelays absorption of the drug should be taken 30–60 minutes before meals  More than 95% of oral dose is decarbxylated in periphery tissue mainly in gut & liver ◦ DA formed peripherally is metabolized by MAO& COMT ◦ DA in periphery- acts on peripheral organs & may cause unwanted effects. It also acts on CTZ ◦ Less than 2% of each dose enters the brain  Therefore,peripheral dopa decarboxylase inhibitor (carbidopa or benserazide) reduce Levodopa metabolism in periphery 9/1/2024 Alemseged.W 49  Cont….  The most efficacious therapy- 1st line treatment.  The best results of levodopa are obtained in the first few years of treatment. - L-dopa ameliorates all signs of parkinsonism particularly bradykinesia & rigidity but does not cure the disease.  Should not be used in parkinsonism associated with antipsychotic drug therapy.  benztropine used for parkinsonism caused by antipsychotic drugs 9/1/2024 Alemseged.W 50  Pharmacodynamics  The benefits of levodopa treatment begin to diminish after about 3 or 4 years of therapy regardless of the initial therapeutic response.  Initial effective doses may fail to produce therapeutic benefit & responsiveness to levodopa may be lost completely. Possibly due to ◦ The disappearance of dopaminergic nigrostriatal nerve (disease progresses beyond ability of Ldopa to control it.) ◦ Some pathologic process - striatal DA receptors like tolerance. 9/1/2024 Alemseged.W 51  Pharmacodynamics  Two main adverse effects after prolonged therapy ◦ Dyskinesia (involuntary movements) ◦ On / off phenomenon  Psychological effects: schizophrenia-like syndrome ◦ C/I to psychotic patients ◦ Several atypical antipsychotic agents are now available and may be particularly helpful in counteracting the behavioral complications of levodopa.  Nausea & anorexia  Posturalhypotension, cardiac arrthymias & excerbation of angina 9/1/2024 Alemseged.W 52  Limitation of L-DOPA treatment:  Dyskinesia (involuntary movements occurs in 40 to 90% of patients) due to fluctuating plasma levels of levodopa. -The dyskinesia can be reduced by lowering the dosage; however, the symptoms of parkinsonism may then reappear.  Wearing-off effect (duration of “on” states becomes shorter)  - On-off phenomenon (On= improved mobility & Off=Akinesia or hypomobility)- b/c of short T1\2  Wearing off effect and on-off phenomena occur due to progression of the disease and the loss of striatal dopamine nerve terminals. 9/1/2024 Alemseged.W 53 On / off phenomenon Each dose of levodopa ◦ Effectively improves mobility for few hours with marked dyskinesia (on - period) ◦ Marked rigidity & akinesia return rapidly at the end of the dosing interval (off - period) - wearing off Most common on late stage of PD 'on-off' effect is not seen in untreated PD patients or with other anti-PD drugs Apomorphine may provide temporary benefit for pt with severe off-periods who are unresponsive to other measures 9/1/2024 Alemseged.W 54 On / off phenomenon  The possible reason for on/off effect ◦ As the disease advances The ability of neurons to store dopamine is lost The therapeutic benefit of levodopa depends on the continuous formation of extraneuronal dopamine Continuous supply of levodoapa is required otherwise the on/off phenomenon will occur  Strategies to manage: ◦ Infusion, sustained release, or multiple short interval doses of L-Dopa ◦ Add selegiline to prevent metabolism by MAO-B. ◦ Use receptor agonists 9/1/2024 Alemseged.W 55  Drug holidays  Discontinuance of the drug for 3–21 days ◦May temporarily improve responsiveness to levodopa ◦Alleviate some of the adverse effects  However drug holidays ◦Not alleviate the on/off phenomenon ◦B/c of the immobility accompanying severe parkinsonism  It Carries the risks of aspiration pneumonia, venous thrombosis, pulmonary embolism & depression  For these reasons & b/c of temporary nature of any benefit, drug holidays are no longer recommended 9/1/2024 Alemseged.W 56 Drug Interactions  High proteins meals.  Pyridoxine (Vitamin B6)- ↓ effect of L-dopa due to ↑ peripheral metabolism by Vit.B6, is cofactor for dopa decarboxylase(DDC)  Phenothiazines, butyrophenones & metoclopramide block DA receptors  Nonselective MAO inhibitors(phenelzine)- prevent degradation of peripherally synthesized DA & NA --- hypertensive crisis can occur ◦ Levodopa should not be given to patients taking MAO- A inhibitors or within 2 weeks of their discontinuance  Do not take MAOIs w\ any drug has catecholamine effects, * tyramine has similar effect of MAO inhibitors 9/1/2024 Alemseged.W 57  A. Levodopa (L-Dopa)  Adverse effect ◦ Are dose dependent  Nausea and vomiting – by stimulating the CTZ  dyskinesias – head bobbing, tics grimacing  Cardiovascular effects  Postural hypotension early in the treatment  Arrhythmias in patients with cardiac disease  Psychosis; clozapine can reduce psychotic symptoms with out intensifying symptoms of PD.  Other adverse effects.  May darken sweat and urine; patients should be forewarned of this harmless effect. 9/1/2024 Alemseged.W 58 9/1/2024 Alemseged.W 59  Levodopa plus carbidopa  More effective than levodopa alone  Carbidopa(don’t cross BBB) enhances effects of levodopa by inhibiting decraboxylases in GIT & periphery so levodopa available for CNS increases  Advantages of carbidopa - Combination superior in 3 ways ◦ Increases fraction of levodopa available for CNS ◦ Levodopa dose can be reduced by 75% ◦ Decreases cardiovascular response. 9/1/2024 Alemseged.W 60  B. Dopamine Agonists  Unlike levodopa ◦ They donot requier enzymatic conversion to an acitve metabolite ◦ Have no potentially toxic metabolites ◦ Do not compete with other substances for active transport in to blood and BBB. ◦ Some how selective to dopamine agonists ◦ May have limited Adverse Effect than L-dopa 9/1/2024 Alemseged.W 61 B. Dopamine Agonists  Four dopamine agonists are available ◦ ergot derivatives  Bromocriptine  Pergolide ◦ nonergot derivatives  Pramipexole,  Ropirinole  Cause fewer side effects than the ergot derivatives 9/1/2024 Alemseged.W 62  B. Dopamine Agonists  BROMOCRIPTINE ◦ D2 agonist, now rarely used as an antiparkinsonian ◦ Absorbed to a variable extent from GIT, Peak= 1-2 h ◦ Excreted in the bile and feces ◦ used to treat certain endocrinologic disorders, especially hyperprolactinemia ◦ Usual daily dose 7.5 – 30 mg depending on response and tolerance ( built up slowly 2-3 M) ◦ To minimize adverse effects, the dose is built up slowly over 2 or 3 months from a starting level of 1.25 mg twice daily after meals; ◦ the daily dose is then increased by 2.5 mg every 2 weeks depending on the response or the development of adverse reactions. 9/1/2024 Alemseged.W 63 Cont……  PERGOLIDE ◦ Ergot derivative ◦ Stimulates both D1 & D2 ◦ More effective than Bromocriptine in relieving the symptoms and signs of the disease, increasing "on-time" among response fluctuators, and permitting the levodopa dose to be reduced ◦ No longer avialable (Associated with valvular heart disease) 9/1/2024 Alemseged.W 64  B. Dopamine Agonists  PRAMIPEXOLE ◦ Not an erogt derivative, prefers D3 receptor ◦ Effective as a monotherapy for mild parkinsonism ◦ Permits the dose of L-dopa to be reduced and soothing out response flactuations. ◦ Started at low dose and slowly increased ◦ rapidly absorbed after oral administration, reaching peak plasma concentrations in approximately 2 hours, ◦ excreted largely unchanged in the urine. ◦ It is started at a dosage of 0.125 mg three times daily, doubled after 1 week, and again after another week. ◦ Most patients require between 0.5 and 1.5 mg TID. ◦ Renal insufficiency may necessitate dosage adjustment. 9/1/2024 Alemseged.W 65  Cont…..  ROPINIROLE ◦ Nonergoline derivative ◦ Relatively pure D2 receptor agonist, effective as monotherapy in patients with mild disease and as a means of smoothing the response to levodopa in patients with more advanced disease and response fluctuations. ◦ Started at 0.25 mg TID , and the total daily dose is then increased by 0.75 mg at weekly intervals until the fourth week and by 1.5 mg thereafter. ◦ In most instances, a dose of between 2 and 8 mg three times daily is necessary. ◦ Ropinirole is metabolized by CYP1A2 9/1/2024 Alemseged.W 66  Adverse Effects of Dopamine Agonists GI EFFECTS  Anorexia ,NV  minimized by taking the medication with meals.  Constipation, dyspepsia, and symptoms of reflux esophagitis may also occur.  CARDIOVASCULAR EFFECTS  Postural hypotension may occur, at the initiation of therapy.  Painless digital vasospasm is a dose-related complication of long-term treatment with the ergot derivatives (bromocriptine or pergolide).  When cardiac arrhythmias occurdiscontinue the medication.  Cardiac valvulopathy may occur with pergolide. 9/1/2024 Alemseged.W 67  Cont….. MENTAL DISTURBANCES  Confusion, hallucinations, delusions, and other psychiatric reactions are other complications of dopaminergic treatment and are more common and severe with dopamine receptor agonists than with levodopa.  They clear on withdrawal of the offending medication. Contraindications  Dopamine agonists are contraindicated in patients with a history of psychotic illness or recent myocardial infarction, or with active peptic ulceration.  The ergot-derived agonists are best avoided in patients with peripheral vascular disease. 9/1/2024 Alemseged.W 68 C. COMT inhibitors  Two COMT inhibitors are available Entacapone and Tolcapone.  Benefits of both derive from inhibiting metabolism of levodopa in the periphery  these drugs have no direct therapeutic effects of their own.  Levodopa clearance is decreased, and relative bioavailability of levodopa is thus increased 9/1/2024 Alemseged.W 69 Cont…..  These agents may be helpful in patients receiving levodopa who have developed response fluctuations— leading to a smoother response, more prolonged "on- time," and the option of reducing total daily levodopa dose.  Tolcapone and entacapone are both widely available, but entacapone is generally preferred because it has not been associated with hepatotoxicity. 9/1/2024 Alemseged.W 70  D. Monoamine Oxidase Inhibitors  Monoamine oxidase A metabolizes norepinephrine and serotonin;  monoamine oxidase B metabolizes dopamine. SELEGILINE, RASAGILINE  Actions and uses ◦ A selective inhibitor of type B monoamine oxidase, which is the enzyme that inactivates dopamine in striatum at normal doses (at higher doses it inhibits MAO-A as well), ◦ does not present risk of hypertensive crisis; ◦ used with levodopa and may delay progression of disease.  Pharmacokinetics – ◦ Rapidly absorbed, ◦ penetrates blood- brain barrier 9/1/2024 Alemseged.W 71  it retards the breakdown of dopamine; in consequence, it enhances and prolongs the antiparkinsonism effect of levodopa (thereby allowing the dose of levodopa to be reduced) and may reduce mild on-off or wearing-off phenomena.  It is therefore used as adjunctive therapy for patients with a declining or fluctuating response to levodopa 9/1/2024 Alemseged.W 72  D. Selegiline  Adverse effects – insomnia  Drug interactions ◦ Levodopa combined produces intensified adverse responses ◦ dangerous interaction with meperidine; tricyclic antidepressants ◦ should not be combined with fluoxetine( serotonin reuptake inhibitors) because of the risk of acute toxic interactions of the serotonin syndrome or as this could be fatal.  , 9/1/2024 Alemseged.W 73  E. Centrally acting Anticholinergics  Play an adjuvant role in parkinsonism therapy  Adverse effects: - similar to anti muscarinic agents xerostomia (dryness of mouth) interfere with GIT peristalsis sandy eye (dry eye). 9/1/2024 Alemseged.W 74  F. Amantadine  Is antiviral drug effective in the treatment of influenza A.  has anti-parkinsonism action. ◦ Its mode of action in parkinsonism is unclear, but it may potentiate dopaminergic function by influencing the synthesis, release, or reuptake of dopamine. ◦ It is given together with levo-dopa.  Peak plasma concentration 1-4 h after PO, t1/2 =2-4 h  Less efficacious than L-dopa  Adverse effects ◦ restlessness, depression, irritability, insominia, hallucination and confusion. 9/1/2024 Alemseged.W 75  2. DRUGS USED FOR EPILEPSY (ANTI-SEIZURE) 9/1/2024 Alemseged.W 76 Case Study  A 23-year-old woman presents to the office for consultation regarding her antiseizure medications. Seven years ago, this healthy young woman had a generalized tonicclonic seizure (GTCS) at home. She was rushed to the emergency department, at which time she was alert but complained of headache. A consulting neurologist placed her on levetiracetam, 500 mg bid. Four days later, EEG showed rare right temporal sharp waves. MRI was normal. One year after this episode, a repeat EEG was unchanged, 9/1/2024 and levetiracetam was Alemseged.W 77 Cont….  The patient had no significant adverse effects from this dosage. At age 21, she had a second GTCS while in college; further discussion with her roommate at that time revealed a history of two recent episodes of 1–2 minutes of altered consciousness with lip smacking (complex partial seizures). A repeat EEG showed occasional right temporal spikes. What is one possible strategy for controlling her present symptoms? 9/1/2024 Alemseged.W 78  Drugs used for Epilepsy (anti- seizure) OBJECTIVES At the end of the lectures, students should: 1-Describe types of epilepsy. 2-List the antiepileptic drugs. 3-Describe briefly the MOA & use of antiepileptic drugs. 4-Describe the adverse effects of each antiepileptic drug. 5-Describe treatment of status epilepticus. 9/1/2024 Alemseged.W 79  Introduction  Epilepsy is a syndrome characterized by ◦ sudden transient alterations in brain function (seizure), leading to motor, sensory, autonomic or psychic symptoms, often accompanied by unconsciousness with or with out convulsion.  chronic medical condition characterized by 2 or more unprovoked seizures(attacks) (within 6-12 months). 9/1/2024 Alemseged.W 80  Seizure Epilepsy disease syndrome provoked cause Unprovoked cause  cured controlled but not cured Each epilepsy accompany seizures but not all seizures are symptom of epilepsy Repetitive activation of electrical neurons in different brain areas>> attack Epilepsy episode last for (2sec-5min) while status epilepticus last for (30min). Etiology : Usually there is balance between excitatory and inhibitory NT, however when (glutamate, asparate) increase in their level and (GABA) decreases >> epilepsy occurs. 9/1/2024 Alemseged.W 81 Cont……  The causes of seizures are many including neurologic diseases—from infection to neoplasm and head injury.  In some, heredity has proved to be a predominant factor.  Seizures can be "non-epileptic" when evoked in a normal brain by treatments such as ◦ electroshock or chemical convulsants, or ◦ "epileptic" when occurring without evident provocation.  Seizures are thought to arise from the cerebral cortex, and not from other CNS structures such as the thalamus, brainstem, or cerebellum. 9/1/2024 Alemseged.W 82 Etiology 9/1/2024 Alemseged.W 83 Types of seizures  All types start with sudden (paroxysmal) discharge of neuron in the brain (focus) & this discharge may be confined in certain areas of the brain or distributed to other parts of the brain.  The behavioral manifestations of a seizure are determined by the functions normally served by the cortical site at which the seizure arises. For example, a seizure involving motor cortex is associated with clonic jerking of the body part controlled by this region of cortex. 9/1/2024 Alemseged.W 84 Cont….  There are two broad categories of seizures ◦ Partial (focal) seizures  Seizure activity begins focally in the cerebral cortex & usually undergoes limited spread only to adjacent cortical areas.  In one part ◦ Generalized seizures  Focal seizure activity is conducted widely through out both hemispheres.  In both hemisphere 9/1/2024 Alemseged.W 85 Cont….  Partial (focal) seizures ◦ Simple partial seizures ◦ Complex partial seizures ◦ Partial seizures secondarily generalized  Generalized seizures ◦ Generalized tonic-clonic (grand mal) seizures ◦ Absence (petit mal) seizures ◦ Tonic seizures ◦ Atonic seizures ◦ Clonic and myoclonic seizures ◦ Infantile spasms 9/1/2024 Alemseged.W 86  A. Partial (focal) seizures  involve only a portion of the brain, typically part of one lobe of one hemisphere.  Consciousness is usually preserved.  Partial seizures may progress, becoming generalized tonic- clonic seizures.  The symptoms of each seizure type depend on ◦ the site of neuronal discharge and ◦ the extent to which the electrical activity spreads to other neurons in the brain.  Simple partial  Complex partial 9/1/2024 Alemseged.W 87  i. Simple partial  Caused by a group of hyperactive neurons exhibiting abnormal electrical activity, which are confined to a single locus in the brain.  The electrical discharge does not spread, and the patient does not lose consciousness.  The patient often exhibits abnormal activity of a single limb or muscle group that is controlled by the region of the brain experiencing the disturbance.  The patient may also show sensory distortions.  Simple partial seizures may occur at any age. 9/1/2024 Alemseged.W 88  ii. Complex partial  These seizures exhibit complex sensory hallucinations, mental distortion, and loss of consciousness.  Motor dysfunction may involve chewing movements, diarrhea, and/or urination.  Consciousness is altered.  Simple partial seizure activity may spread and become complex and then spread to a secondarily generalized convulsion.  Partial seizures may occur at any age. 9/1/2024 Alemseged.W 89 B. Generalized Seizure  Producing abnormal electrical discharges throughout both hemispheres of the brain.  It may be convulsive or nonconvulsive, and the patient usually has an immediate loss of consciousness  Types:  Tonic-clonic  Absence  Myoclonic  Febrile seizures:  Status epilepticus 9/1/2024 Alemseged.W 90  B. Generalized Seizure …  Tonic-clonic (Grand mal): ◦ Seizures result in loss of consciousness, followed by tonic (generalized ↑ed muscle tone ,continuous contraction) and clonic (rapid contraction and relaxation) phases. ◦ The seizure may be followed by a period of confusion and exhaustion due to the depletion of glucose and energy stores. Drugs used: phenytoin, carbamazepin, phenobarbitone, primidone, valproic acid. 9/1/2024 Alemseged.W 91  Cont….  Absence (Petit mal): ◦ These seizures involve a brief, abrupt, and self- limiting loss of consciousness. ◦ The onset generally occurs in patients at 3 to 5 years of age and lasts until puberty or beyond. ◦ The patient stares and exhibits rapid eye- blinking, which lasts for 3 to 5 seconds. ◦ Drugs used = ethosuximide, valproic acid, clonazepam. 9/1/2024 Alemseged.W 92  Myoclonic: ◦ These seizures consist of short episodes of muscle contractions that may reoccur for several minutes. ◦ They generally occur after wakening and exhibit as brief jerks of the limbs. ◦ occur at any age but usually begin around puberty or early adulthood. ◦ Drug used = diazepam, valproic acid, clonazepame.  Febrile seizures: ◦ Young children may develop seizures with illness accompanied by high fever. ◦ The febrile seizures consist of generalized tonic-clonic convulsions of short duration and do not necessarily lead to a diagnosis of epilepsy. 9/1/2024 Alemseged.W 93  B. Generalized Seizure …  Status epilepticus: Neurological emergency characterized by series of convulsions, rapidly repeated without intervals of consciousness, if untreated may lead to coma & death In status epilepticus, two or more seizures recur without recovery of full consciousness between them. ◦ Status epilepticus is life-threatening and requires emergency treatment  Drugs used = diazepam, clonazepam 9/1/2024 Alemseged.W 94 9/1/2024 Alemseged.W 95 9/1/2024 Alemseged.W 96 A) partial seizure, B)primary generalized seizure C) partial seizure with generalized seizure 9/1/2024 Alemseged.W 97 Mechanism of Action of Antiepileptic Drugs  Drugs that are effective in seizure reduction accomplish this by a variety of mechanisms, including: ◦ Blockade of voltage-gated channels (Na+ or Ca2+), ◦ Potentiation of inhibitory GABAergic impulses, or ◦ interference with excitatory glutamate transmission. ◦ Increase outward positive current - (K+ ) 9/1/2024 Alemseged.W 98 Mechanism of Action of Antiepileptic Drugs A. Suppression of sodium influx (Na-channel blockers) ◦ Reversibly bind to sodium channels while they are in the inactivated state, and thereby prolong channel inactivation. ◦ By delaying return to the activated state, these drugs decrease the ability of neurons to fire at high frequency. B. Suppression of calcium influx (Ca- channel blockers) ◦ Valproic acid and ethosuximide, which are used for absence seizures, act by inhibiting influx of calcium ions through a special class of calcium channels. Known as T-type calcium channels 9/1/2024 Alemseged.W 99 Mechanism of Action of Antiepileptic Drugs C. Potentiation of GABA  By augmenting the inhibitory influence of GABA several drugs decrease neuronal excitability and thereby suppress seizure activity.  Drugs increase the influence of GABA by several mechanisms.  Benzodiazepines and barbiturates enhance effects of GABA by mechanisms that involve direct binding to GABA receptors.  Gabapentin promotes GABA release, and  Vigabatrin inhibits enzyme that degrades GABA  Tiagabine inhibits GABA reuptake. 9/1/2024 Alemseged.W 100  Classification of Antiepleptic Drugs 1. Barbiturate with aromatic rings 101 4. Succinimides ◦ Phenobarbital ◦ Mephobarbital ◦ Ethosuximide ◦ Metobarbital ◦ Phensuximide ◦ Primidone ◦ Methsuximide 2. Hydantoins 5. Benzodiazepines ◦ Phenytoin (diphenyl hydantoin) ◦ Diazepame ◦ Mephentoin ◦ phenylethyl hydantoin ◦ Clonazepame 3. Oxazolidinediones 6. Others ◦ Trimethadiones ◦ Valproic acid ◦ paramethadione ◦ Carbamazepine 9/1/2024 Alemseged.W  Cont…. Most frequently used drugs are 1st generation: Phenytoin, Phenobarbital, Carbamazepine, Ethosuximide and Valproic acid 2nd generation: Lamotrigine Topiramate Notes: Second generation is not used alone except in rare state and its advantage does not affect liver enzymes 9/1/2024 Alemseged.W 102 Treatment DESIRED OUTCOME  The ultimate goal of treatment for epilepsy is complete elimination of seizures and no side effects with an optimal quality of life.  The best quality of life is associated with a seizure-free state Non-drug treatment  Advice on a healthy lifestyle with good sleep habits and the avoidance of excessive alcohol and caffeine.  It includes diet, surgery, and vagus nerve stimulation (VNS). 9/1/2024 Alemseged.W 103  Cont….  Therapy is symptomatic in that available drugs inhibit seizures, but neither effective prophylaxis nor cure is available.  Compliance with medication is a major problem because of the need for long-term therapy together with unwanted effects of many drugs.  The patient should know the name and the dose of his medication and should be warned of the consequences of poor compliance. 9/1/2024 Alemseged.W 104 Cont…  If a decision is made to start AED therapy, monotherapy is preferred,  Drugs can be combined in an attempt to help the patient become seizure-free.  Combining AEDs with different mechanisms of action can be advantageous, 9/1/2024 Alemseged.W 105 Cont.……  If a patient fails to respond to the first AEDs, trials with other AEDs should be attempted as appropriate.  Completion of the evaluation often requires a reassessment of the patient and development of a new care plan taking into account patient compliance, efficacy, and safety of the initial treatment.  Medication noncompliance can be the most common reason for treatment failure.  The rate of noncompliance is increased by the complexity of the drug regimen and by doses taken three and four times a day. 9/1/2024 Alemseged.W 106  Cont…. N.B.  Epileptics are not allowed to drive a vehicle unless the patient has had a two-year attack-free period.  They should not swim.  Refer all adult onset epilepsy, complicated or atypical epilepsy, and if there is a progressive increase in uncontrollable attacks.  Pregnancy is better avoided in patients with difficult to control epilepsy. 9/1/2024 Alemseged.W 107 Cont….  Optimal management of epilepsy, therefore, requires that AED treatment be individualized. Specifically, different patient groups (e.g., children, women of child-bearing potential, and the elderly)  The first drug choice depend on the type of epilepsy, as well as on the interface between drug-specific adverse effects and patient preferences.  Ultimately, AED effectiveness is the result of the interaction of each of these factors. 9/1/2024 Alemseged.W 108 A. Phenobarbitone  It suppresses high-frequency repetitive firing in neurons in through an action on Na+ conductance, but only at high concentrations.  Barbiturates block some Ca2+ currents (L-type and N-type).  Both the enhancement of GABA-mediated inhibition and the reduction of glutamate-mediated excitation are seen with therapeutically relevant concentrations of phenobarbital.  It is well absorbed after oral administration & widely distributed.  Renal excretion is enhanced by acidification of the urine.  well absorbed orally penetrate the brain freely. It is about 75% metabolized in liver. 9/1/2024 Alemseged.W 109 Cont…..  It is potent inducer of the CYP-450 system.  Accelerates the metabolism of many drugs like oral contraceptives and warfarin. Clinical Use ◦ Generalized tonic-clonic epilepsy, Simple partial seizures. ◦ It is a first choice for recurrent seizure in children.  There is little evidence for its effectiveness in absence, atonic attacks, and infantile spasms  The most important unwanted effect is sedation. 9/1/2024 Alemseged.W 110 Cont….  Adverse effects ◦ drowsiness or sedation, ◦ respiratory depression, hangover effects, ◦ CNS depression, confusion, vertigo, dizziness.  Drug interactions ◦ with valproic acid( Enzyme inhibiter) = Increased serum levels and therapeutic and toxic effects of Phenobarbital ◦ Increased CNS depression with alcohol ◦ Increased risk of neuromuscular excitation and hypotension with barbiturate anesthetics ◦ Decreased effects of the following drugs:  Theophyllines, oral anticoagulants, beta-blockers, doxycycline, corticosteroids, hormonal contraceptives and estrogens, metronidazole, phenylbutazones, quinidine, felodipine 9/1/2024 Alemseged.W 111 B. Primidone (deoxybarbiturate)  Effective against partial and tonic clonic seizures.  Less potent antiseizure effect.  Partially metabolized to Phenobarbital.  Adverse effects ◦ Sedation, vertigo, dizziness, nausea, vomiting. 9/1/2024 Alemseged.W 112  General rules for treatment of epilepsy  Epilepsy is usually controlled but not cured with medication.  Upto 80% of pts can expect partial or complete control of seizures with appropriate treatment.  Antiepileptic drugs are indicated when there is two or more seizures occurred in short interval (6 m -1y).  An initial therapeutic aim is to use only one drug (monotherapy).If it’s complicated >> use politherapy  Drugs are usually administered orally  Monitoring plasma drug level is useful (not essential)  Triggering factors can affect seizure control by drugs.  Sudden withdrawal of drugs should be avoided causing status epilepticus 9/1/2024 Alemseged.W 113 9/1/2024 Alemseged.W 114 9/1/2024 Alemseged.W 115 9/1/2024 Alemseged.W 116 9/1/2024 Alemseged.W 117 9/1/2024 Alemseged.W 118 9/1/2024 Alemseged.W 119 9/1/2024 Alemseged.W 120  Drugs used for treatment of Status Epilepticus  Most seizures last from few seconds to few minutes. When seizures follow one another without recovery of consciousness, it is called “status epilepticus”.  It has a high mortality rate. Death is from cardiorespiratory failure. Intravenous injection of :  Lorazepam is the drug of choice  Phenytoin, Fosphenytoin.  Diazepam, Phenobarbital. 9/1/2024 Alemseged.W 121 9/1/2024 Alemseged.W 122  Pregnancy & antiepileptics  Seizure is very harmful for pregnant woman.  Most antiepileptic drug is not safe in pregnancy.  Monotherapy usually better than drug combination.  use of lamotrigine or levetiracetam is not associated with an increased risk of fetal loss, prenatal growth restriction, or preterm birth.  Patient has to continue therapy.  Use the lowest effective doses. 9/1/2024 Alemseged.W 123  Cont…..  use of phenobarbital, topiramate, and zonisamide during pregnancy is associated with an increased risk of intrauterine growth retardation (small for gestational age  taking carbamazepine in early pregnancy can increase the chance of some birth defects, including neural tube defects  Valproate & phenytoin are contraindicated during pregnancy.  Immediate treatment(emergency case) is with magnesium sulfate 4 g intravenous bolus  Administer high-flow oxygen to all seizing pregnant patient to prevent fetal hypoxia. Twenty-five percent of eclamptic seizures occur in the postpartum period. 9/1/2024 Alemseged.W 124  Common antiepileptic medication choices for seizures in children Seizure Type Prescribed Antiepileptic Medications absence seizures ethosuximide, lamotrigine, sodium valproate myoclonic, tonic and clobazam, clonazepam, lamotrigine, levetiracetam, atonic seizures sodium valproate, topiramate 9/1/2024 Alemseged.W 125 9/1/2024 Alemseged.W 126