PCOL 2 Prelim Notes PDF

5. Dopamine PCOL 2 Present in some secretomotor and interneurons in the ENS Prelim Notes Appea...

5. Dopamine PCOL 2 Present in some secretomotor and interneurons in the ENS Prelim Notes Appear to inhibit ACh release and thereby inhibit peristalsis May stimulate secretion Autonomic Nervous System (Katzung) 6. Enkephalin and related opioid peptides Nervous System Present in secretomotor neurons Central Nervous System (CNS) may play a role in appetite-satiety mechanisms Peripheral Nervous System (PNS) 7. Galanin GABA (y-aminobutyric acid) May have presynaptic effects on excitatory ENS nerve Central Nervous System (CNS) terminals Brain – receives and processes sensory information, Has some relaxant effect on the gut initiates responses, stores memories, generates thoughts Probably not a major transmitter in the ENS. and emotions 8. Gastrin-releasing peptide (GRP) Spinal Cord – conducts signals to and from the brain, Extremely potent excitatory transmitter to gastrin cells controls reflex activities a.k.a. mammalian bombesin Peripheral Nervous System (CNS) 9. Neuropeptide Y (NPY) *mnemonics: SAME! Found in many noradrenergic neurons Sensory Neurons – “Afferent”; sensory organs to CNS Present in some secretomotor neurons in the ENS and may Motor Neurons – “Efferent” CNS to muscles and glands inhibit secretion of water and electrolytes by the gut o Somatic Nervous System – voluntary movements causes long-lasting vasoconstriction o Autonomic Nervous System – involuntary responses is also a cotransmitter in some parasympathetic a. Sympathetic Division – “Fight or Flight” postganglionic neurons b. Parasympathetic Division – “Rest or Digest” 10. Nitric oxide (NO) Transmitter Types: A cotransmitter at inhibitory ENS and other neuromuscular Some of the transmitter substances found in autonomic nervous junctions system, enteric nervous system, and non-adrenergic, non-cholinergic may be especially important at sphincters neurons. Cholinergic nerves innervating blood vessels appear to activate the synthesis of NO by vascular endothelium 1. Acetylcholine (ACh) NO is not stored, it is synthesized on demand by nitric oxide the primary transmitter at ANS ganglia, at the somatic synthase, NOS neuromuscular junction, and at parasympathetic postganglionic nerve endings 11. Norepinephrine (NE) A primary excitatory transmitter to smooth muscle and The primary transmitter at most sympathetic postganglionic secretory cells in the ENS nerve endings Probably also the major neuron-to-neuron ("ganglionic") transmitter in the ENS 12. Serotonin (5-HT) An important transmitter or cotransmitter at excitatory 2. Adenosine triphosphate (ATP) neuron-to-neuron junctions in the ENS Acts as a transmitter or cotransmitter at many ANS-effector Substance P, related tachykinins synapses 13. Substance P 3. Calcitonin gene-related peptide (CGRP) is an important sensory neurotransmitter in the ENS and Found with substance P in cardiovascular sensory nerve elsewhere fibers Tachykinins appear to be excitatory cotransmitters with ACh Present in some secretomotor ENS neurons and at ENS neuromuscular junctions. Found with CGRP in interneurons cardiovascular sensory neurons cardiac stimulant is a vasodilator (probably via release of nitric oxide) 4. Cholecystokinin (CCK) 14. Vasoactive intestinal peptide (VIP) May act as a cotransmitter in some excitatory Excitatory secretomotor transmitter in the ENS neuromuscular ENS neurons may also be an inhibitory ENS neuromuscular cotransmitter A modulatory transmitter in some ganglia and the ENS A probable cotransmitter in many cholinergic neurons Possibly a postganglionic sympathetic transmitter in renal A vasodilator (found in many perivascular neurons) and blood vessels cardiac stimulant SYnergistic  Adrenergic Transmission *mnemonics: True Love Does Not Exist! Tyrosine → L-Dopa → Dopamine → NE → Epinephrine Enzymes: 1. Tyrosine Hydroxylase (most important) 2. Dopa-Decarboxylase Fate of NE: 3. Dopamine-b-dehydroxylase 1. Bind to receptor 4. Phenylethanolamine-N-methyltransferase 2. Metabolism: a. Monoamine Oxidase (MAO) Biosynthesis: b. Catechol-O-methyltransferase (COMT) 1. Uptake of Tyrosine Tyrosine – most important AA End Product: Inhibited by: Metyrosine Vanillyl Mandelic Acid (3-methoxy-4-hydroxy-mandelic acid) o Normal Urinary Levels: 4mg-8mg/day 2. Tyrosine to Dopamine o ↑ levels of VMA = tumor in the suprarenal Adrenal rate-limiting step Medulla (Pheochromocytoma) slowest, most important step 3. Reuptake 3. Formation of 1st Catecholamine primary termination of effects L-Dopa to Dopamine done by Norepinephrine Transported (NET) Inhibited by: TCAs and Cocaine 4. Vesicular Storage/Uptake Transported by: Vesicular Monoamine Transporter (VMAT) Inhibited by the alkaloid, Reserpine (Rauwolfia serpentina) 5. Dopamine to NE occurs in the adrenal medulla 6. Release of NE exocytosis needs Ca+ Inhibited by: Bretylium, Guanethidine, Guanadrel SYnergistic  Adrenergic Transmission Effects on Adrenoceptor Activation ADRENERGIC DRUGS Adrenergic Agonists & Sympathomimetic Drugs Adrenoceptor Antagonist Drugs Endogenous Catecholamines (Non-selective) Adrenergic Agonists & Sympathomimetic Drugs 1. Epinephrine “5 in 1” affects all adrenoceptors used for resuscitation from cardiac arrest local vasoconstrictor used in combination with local anesthetics (prolongs action of local anesthetics due to vc) DOC for anaphylactic shock: EpiPen, Auvi-Q 2. Norepinephrine DOC for septic shock (↓ blood volume) Dopamine – for shock with renal involvement DIRECT-ACTINGSYMPATHOMIMETICS Alpha-1 Selective (Uses: nasal and eye decongestants, vasoconstrictors) Direct agonists – directly interact with and activate 1. Midodrine adrenoceptors for chronic orthostatic hypotension Indirect agonists – enhance the actions of endogenous catecholamines by: 2. Phenylephrine a. inducing the release of catecholamines mydriatic agent, decongestant b. decreasing the clearance of catecholamines, or c. preventing the enzymatic metabolism of 3. Tetrahydrozoline, Oxymetazoline norepinephrine for conjunctival itching and congestion SYnergistic  Alpha-2 Selective Beta-2 Selective (Long-acting) (Uses for no.1-3: HTN) (Uses: controller for asthma & COPD) used with inhaled corticosteroids (i.e. Fluticasone) 1. Clonidine can decrease craving for narcotics and alcohol 1. Salmeterol, Formoterol, Bambuterol used to diminish menopausal hot flushes 2. Indacaterol for rebound HTN due to abrupt withdrawal 3. Olodaterol treated by: 4. Vilanterol o reconstituting clonidine new ultra-long acting o Labetalol (b-blocker) once a day use 2. Methyldopa, Guanfacine, and Guanabenz Beta-3 Selective Methyldopa 1. Mirabegron o A/E: sedation treatment of symptoms of overactive bladder o (+) Coombs Test = hemolytic anemia o for pregnant with HTN Dopamine Selective 1. Levodopa *mnemonics: Mother Hates Labor Now! Parkinson’s Disease ▪ M – Methyldopa ▪ H – Hydralazine 2. Bromocriptine ▪ L – Labetalol D2-agonist ▪ N – Nifedipine Parkinson’s Disease Prolactinemia (↓milk production) 3. Moxonidine, Rilmenidine 3. Fenoldopam 4. Dexmedetomidine D1-agonist prominent sedative effects and used in anesthesia for hypertensive emergency o main drug: Na+ Nitroprusside (if oxidized, will produce 5. Tizanidine cyanide which is toxic) central muscle relaxant an adjunct drug for HTN 6. Apraclonidine and brimonidine for glaucoma INDIRECT-ACTING SYMPATHOMIMETICS Beta Nonselective Releasers (Amphetamine-Like) 1. Isoproterenol (↑ NE, ↑BP, used as a stimulant) for atrioventricular (AV) block B1, B2 – bronchodilator effect 1. Amphetamine administered as a metered-dose inhaler (MDI) anorexiant (suppress appetite) for asthma ADHD A/E: Tachyphylaxis – rapid tolerance 2. Methamphetamine Beta-1 Selective anorexiant 1. Dobutamine used as a pharmacologic cardiac stress test 3. Methylphenidate for cardiogenic shock ADHD cold flu patients 4. Modafinil Beta-2 Selective (Short-Acting) for narcolepsy [Uses: acute treatment of asthma (reliever)] 1. Albuterol 5. Tyramine 2. Salbutamol present in food 3. Metaproterenol are metabolites 4. Terbutaline, Ritodrine e.g., beer, aged cheese, etc. tocolytic action (prevents premature labor) SYnergistic  TOXICITY Catecholamines – excessive vasoconstriction, cardiac arrhythmias, myocardial infarction, hemorrhagic stroke, and pulmonary edema or hemorrhage Α1 agonists – hypertension β1 agonists – sinus tachycardia and serious arrhythmias Beta 2 agonists – skeletal muscle tremor Cocaine – cardiac arrhythmias or infarction and convulsions Adrenergic Antagonists & Sympatholytic Drugs Reuptake Inhibitors (no. 1-4 uses: antidepressants) 1. Atomoxetine ADHD 2. Reboxetine for major depression 3. Sibutramine appetite suppressant ALPHA BLOCKERS 4. Duloxetine Alpha Nonselective antidepressant (Uses: Pheochromocytoma) 5. Milnacipran 1. Phenoxybenzamine (Irreversible)- for Raynaud’s phenomenon treatment of pain in fibromyalgia 2. Phentolamine (Reversible)- for erectile dysfunction 6. Cocaine Alpha-1 Selective vasoconstrictor, local anesthetic (uses: HTN and BPH) 1st prototype local anesthetic Erythroxylum coca 1. Prazosin prototype MIXED-ACTING SYMPATHOMIMETICS no longer indicated for BPH 1. Ephedrine First-dose hypotension (Synocope) for chronic orthostatic hypotension (old) o 30-90mins. after 1st dose o Prevention: 2. Pseudoephedrine ▪ small dose at bedtime ▪ gradually ↑ dose 3. Droxidopa a synthetic (L-threo-dihydrophenylserine, L-DOPS) molecule 2. Doxazosin that has been approved by the FDA to treat neurogenic longest duration of action (22H) orthostatic hypotension 3. Terazosin is a prodrug that is converted to norepinephrine by the aromatic L-amino acid decarboxylase (dopadecarboxylase) 4. Alfuzosin may increase risk of QT prolongation (occurs when the heart muscle takes longer to contract and relax than usual) SYnergistic  Beta-2 Selective 5. Tamsulosin 1. Butoxamine most common drug for BPH for research purposes ↑ affinity for α1A and α1D (responsible for smooth muscle promotes bronchoconstriction contraction on prostatic tissue) 6. Silodosin Partial Beta Agonist 7. Indoramin (Uses: effective for HTN and angina) for HTN 1. Pindolol, Acebutolol 8. Urapidil 2. Penbutolol, Carteolol 3. Celiprolol – promotes bronchodilation Alpha-2 Selective 4. Bopindolol 5. Oxprenolol 1. Yohimbine for orthostatic hypotension Mixed Alpha & Beta Blocker previously used for erectile dysfunction 1. Labetalol – for Pheochromocytoma must be injected 2. Carvedilol – for chronic heart failure 2. Rauwolscine 3. Medraxolol HTN 4. Bucindolol ALPHA-BLOCKERS TOXICITY Membrane Stabilizing Activity Orthostatic Hypotension (First-Dose Phenomenon) 1. Propranolol 30-90mins. after 1st dose 2. Metoprolol VD = ↓BP Prevention: BETA BLOCKERS USES a. small dose at bedtime 1. Hypertension b. gradually ↑ dose 2. Ischemic Heart Disease (Timolol, Propranolol, Metoprolol) Reflex Tachycardia for nonselective 3. Cardiac Arrhythmias (Esmolol, Sotalol) 4. Heart Failure (Metoprolol, Bisoprolol, Carvedilol) BETA BLOCKERS 5. Galucoma (Timolol, Betaxolol, Carteolol, Levobunolol, (CI: asthmatics) Metipranolol) Beta Nonselective 6. Hyperthyroidism, Migraine Headache, Performance Anxiety 1. Propranolol (Propranolol) prototype most common for prophylaxis of migraine BETA BLOCKERS TOXICITY Lipophilic – hepatic metabolism (Multiple Daily Dosing) 1. Bradycardia ↑ CNS penetration 2. CNS effects local anesthetic 3. Worsening of asthma (for nonselective) for hyperthyroidism 4. Severe hypotension, bradycardia (if combined with CCB) 2. Timolol – doc for open angle glaucoma (↓ IOP; ↓ aq. humor sec) 5. May mask episodes of hypoglycemia 3. Nadolol – very long duration of action 6. Life-threatening cardiac effects (relieved by Glucagon) 4. Levobunolol 5. Carteolol CHOLINERGIC DRUGS Beta-1 Selective *mnemonics: BEAMCN! Cholinoceptor-Activating & Cholinesterase Inhibiting Drugs 1. Betaxolol doc for open angle glaucoma (along with Timolol) 2. Esmolol ultra-short acting 3. Atenolol hydrophilic once daily dosing 4. Metoprolol 5. Celiprolol promotes bronchodilation 6. Nebivolol most highly selective B1-selective antagonist SYnergistic  DIRECT ACTING-CHOLINOMIMETICS (parasympa-like effects) Alkaloids 1. Muscarine chiefly muscarinic 2. Pilocarpine glaucoma local eye drops for glaucoma source: Pilocarpus jaborandi Sjorgen’s Syndrome – dry mouth 3. Nicotine chiefly nicotinic smoking cessation available in transdermal patches 4. Lobeline smoking cessation 5. Varenicline smoking cessation Choline Esters 1. Acetylcholine 2. Methacholine 3. Cevimeline synthetic Sjorgen’s Syndrome Xerostomia 4. Carbachol resistant to hydrolysis by AChE used as local eye drops for glaucoma 5. Bethanechol similar w/ neostigmine long duration of action (2-3hrs) used to reverse post-operative urine retention and paralytic ileus urinary retention *Toxicity of cholinergic drugs = DOC: Atropine SYnergistic Effects of Direct-Acting Cholinomimetics INDIRECT-ACTING Cholinesterase Inhibitors (Alcohol) (MOA: inhibition of AChE enzyme) Short-Acting 1. Edrophonium very short duration (5-15mins) Tensilon test (small doses of Edrophonium) o ↑ muscle strength (untreated pt) o worsen muscle weakness (excessive dose of AChE inh.) INDIRECT ACTING (Mechanism of Action) Intermediate-Acting Cholinesterase Inh. (Carbamates) 1. Neostigmine DOC: Atropine poisoning Natural plant alkaloid 4 ° amine ↓ Lipophilic uterine retention and paralytic ileus CI: Obstruction Atropine + Neostigmine = block unwanted muscarinic effects caused by excessive AChE Myasthenia gravis (Tensilon test; skeletal muscle weakness) 2. Pyridostigmine more preferred in chronic myasthenia gravis than neostigmine more selective on NMJ ↑ duration 3. Physostigmine 3° amine 3-4 hours ↑ Lipophilic local eye drops for glaucoma 4. Ambenonium 5. Carbaryl SYnergistic  Uses & Durations of Action CNS Effects/Centrally Acting (Alzheimer’s Disease) 1. Tacrine first drug for AD 2. Donepezil Long-acting Cholinesterase Inhibitors (Organophosphates) given once daily (uses: biological warfare; insecticides) no hepatotoxic effect Organophosphate Toxicity = doc: Atropine 3. Rivastigmine 1. Ecothiophate similar effects with donepezil ONLY clinically significant drug ↑ ACh levels in CNS ONLY non-absorbable ↑ memory and cognitive deficit miotoc eye drops for glaucoma 100 hours 4. Galantamine 2. Malathion malaoxon (metabolites) TOXICITY D – Diarrhea 3. Parathion U – Urination paraoxon (metabolites) M – Miosis B – Bronchoconstriction 4. Nerve gases B – Bradycardia Tabun E – Excitation of skeletal muscles (Emesis) Sarin L – Lacrimation Soman S – Salivation S – Sweating ANTI-CHOLINERGIC DRUGS (CHOLINOCEPTOR-BLOCKING DRUGS & CHOLINESTERASE REGENERATORS) (sympa-like effects) (main drug: Atropine) SYnergistic ANTIMUSCARINIC CNS (PD & MOTION SICKNESS DRUGS) Respiratory (Bronchodilators) OPHTHALMOLOGY (available for nebulizing) RESPIRATORY GASTROINTESTINAL DISORDERS 1. Ipratropium URINARY Ipratropium bromide + salbutamol CHOLINERGIC POISONING asthma and COPD Parkinson’s Disease 2. Tiotropium 1. Biperiden quaternary amine for use in asthma 2. Benztropine ↑ duration than ipratropium 3. Trihexyphenidyl 3. Aclidinium CNS (Motion Sickness Drugs) 4. Umeclidinium 1. Scopolamine available in transdermal patches Gastrointestinal Disorders 1. Dicyclomine irritable bowel syndrome peptic disease & hypermotility 2. Hyoscyamine anti-spasmodic Hyoscine butylbromide (Buscopan®) 3. Atropine with Diphenoxylate atropine is used to prevent abuse of the drug, diphenoxylate, which has stimulating effects 4. Pirenzipine Ophthalmology (Mydriatic-Cycloplegic) M1 selective blocker 1. Atropine ↓ HCl secretion 5-6 days peptic ulcer 2mg IV bolus rarely used (+) Diphenoxylate = treatment of Diarrhea (Lomotil®) o ↓ hypermotility 5. Telenzipine o ↓ secretions M1 selective blocker Iridocyclitis – inflammation of the vascular layer of the eye, peptic ulcer which includes the iris and ciliary body 2. Homatropine Urinary Incontinence (Bladder Disorder/Hyperactivity) 1. Oxybutinin 3. Cyclopentolate acute cystitis funduscopic examination ↓ bladder spasm and urinary urgency 4. Tropicamide 2. Darifenacin, Solifenacin funduscopic examination once-daily dosing 3. Tolterodine, Fesoterodine urine incontinence in adults ↑ selectivity for M3 Long duration 4. Trospium 5. Propiverine SYnergistic CHOLINERGIC POISONING Drugs: Antimuscarinic Therapy: Atropine 1. Tetraethylammonium (TEA) 2. Hexamethonium (“C6”) Cholinesterase Regenerator: Pralidoxime, Diacetylmonoxime, first drug effective for management of hypertension Obidoxime 3. Mecamylamine Pralidoxime rarely used reactivates (dephosphorylates) AChE enzymes at NMJ only used in emergencies available as: ready-to-use autoinjector adjunct with transdermal nicotine patch to reduce nicotine PAM; 2mg IV over 20-30mins. craving in patients attempting to quit smoking ADVERSE EFFECTS of ANTIMUSCARINIC DRUGS 4. Trimethaphan (Dry and Hot Effects) rarely used Dry mouth only used in emergencies Mydriasis Tachycardia Hot and flushed skin ANTINICOTINIC (NEUROMUSCULAR BLOCKERS) Agitation Delirium Depolarizing Elevated body temperature 2 phases of blocking (initial contraction → paralysis) Atropine Fever (infants or children) 1. Succinylcholine CONTRAINDICATIONS only depolarizing NMB Acute Angle closure glaucoma duration (few mins. only) Prostatic hyperplasia (used with caution or avoided) preferred for short procedures (e.g., endotracheal Acid-peptic disease (Esp. for nonselective drugs) – cause of intubation) slow gastric emptying; acid will rise Non-depolarizing (direct blocker; 1 phase; automatic paralysis) ANTINICOTINIC (GANGLION BLOCKERS) Effects: A. Isoquinoline derivative 1. Tubocurarine prototype drug rarely used from the South American arrowhead/arrow poison 2. Atracurium spontaneous plasma hydrolysis 20-30mins. may cause seizures due to its breakdown product, Laudanosine -cis isomer is better 3. Cisatracurium -cis isomer of atracurium 4. Mivacurium 10-20mins. 5. Gantacurium B. Steroidal derivative 1. Pancuronium 2. Rocuronium TOXICITY is limited to autonomic effects SYnergistic  Levodopa and Carbidopa (dopa decarboxylase inhibitor) = SINEMET DRUGS FOR NEURODEGENERATIVE DISEASES Diminishes the metabolism of levodopa in the Gl tract and peripheral tissues NEURODEGENERATIVE DISEASE Effective for the 1st few years but declines response during a disease in which the nervous system progressively and 3rd to 5th year of therapy irreversibly deteriorates and eventually may cause death of neurons Adverse Effects of Levodopa a. Anorexia b. Nausea NEUROTRANSMITTERS c. Tachycardia Excitatory pathways – causes a movement of ions that d. Hypotension results in the depolarization of the postsynaptic membrane e. Psychiatric problems NT: Glutamate, Acetylcholine o inhibitory pathways o causes movement of ions that results in a hyperpolarization of the postsynaptic membrane NT: y-aminobutyric acid (GABA), Glycine PARKINSON'S DISEASE A progressive neurological disorder of muscle movement, characterized by tremors, muscular rigidity, bradykinesia (slowness in initiating and carrying out voluntary movements), and postural and gait abnormalities happens mostly to people aged 65 and above Incidence: 1 in 100 individuals Etiology Cause: Mostly unknown Loss or destruction of dopaminergic neurons in the substantia nigra Genetics do not play a dominant role in the etiology of PD instead, an as-yet-unidentified environmental factor may play a role in the loss of dopaminergic neurons Symptoms Slow movement (bradykinesia) – slowness in voluntary movement such as standing up, walking, and sitting down. In severe cases, can cause "freezing episodes" once walking has begun Resting tremors – in the extremities, mouth and chin. Happens when the limbs are at rest Rigidity "stiff muscles" – produces muscle pain that is increased 2. Monoamine Oxidase Inhibitors during movement (Selegiline, Rasagiline Selegiline) MOA: At low to moderate doses: Postural instability – loss of reflexes that help posture, which can selectively inhibits MAO type B (metabolizes dopamine) lead to falls but does not inhibit MAO type A (metabolizes NE and SE) Drugs Used in Parkinson’s Disease At high doses, loses its selectivity 1. Levodopa Enhances the synthesis of dopamine in the surviving neurons of Enhances actions of levodopa when these drugs are the substantia nigra administered together; reduces the required dose of levodopa Relief is only symptomatic Metabolized to methamphetamine and amphetamine SYnergistic  Monoamine Oxidase Inhibitors – Rasagiline MOA: Irreversibly and selectively inhibits brain MAO type B; Ergot derivative drugs has 5x potency of selegiline a. Bromocriptine Not metabolized to an amphetamine-like substance Non-ergot drugs 3. Catechol-O-methyltransferase Inhibitors a. Ropinirole (Entacapone, Tolcapone) b. Pramipexole MOA: Selectively and reversibly inhibit COMT c. Rotigotine ↑ central uptake of Levodopa ↓ wearing-off phenomena in patients on levodopa-carbidopa durations of action longer than that of levodopa and, thus, have been effective in patients exhibiting fluctuations in their response to levodopa Effective in patients complicated by motor fluctuations and dyskinesias Apomorphine – an injectable dopamine agonist, used in severe and advanced stages 5. Amantadine An antiviral drug that has an antiparkinsonism effect MOA: ↑ release of dopamine, blocks cholinergic receptors and inhibits N-methyl-D-aspartate (NMDA) type of glutamate receptors 6. Antimuscarinic Agents (Benztropine, Trihexyphenidyl, Procyclidine, and Biperiden) much ↓ less efficacious than levodopa and play only an adjuvant role in anti-parkinsonism therapy Induce mood changes and produce xerostomia (dryness of the mouth, constipation) and visual problems typical of muscarinic blockers 4. Dopamine-Receptor Agonists ADRs a. Sedation b. Hallucinations c. Confusion d. Nausea e. Hypotension SYnergistic ALZHEIMER’S DISEASE MULTIPLE SCLEROSIS Characterized by the loss of cholinergic neurons in the nucleus is an autoimmune inflammatory demyelinating disease of the Basalis of Maynert CNS most common form of dementia a chronic, relapsing, or progressive disease that may span 10 to 20 years is diagnosed in people over 65 years of age, although the less- prevalent early-onset Alzheimer's can occur much earlier. In Corticosteroids (dexamethasone and prednisone) – have been 2006, there are 26.6 million sufferers worldwide. Alzheimer's is used to treat acute exacerbations of the disease predicted to affect 1 in 85 people globally by 2050 Chemotherapeutic agents, such as cyclophosphamide and Three distinguishing features: azathioprine, have also been used a. accumulation of senile plaques (β-amyloid accumulations) b. formation of numerous neurofibrillary tangles Drugs Used in Multiple Sclerosis c. loss of cortical neurons, particularly cholinergic neurons 1. Disease-Modifying Therapies Pharmacologic intervention for Alzheimer's disease is only (Interferon ẞ1a and interferon ẞ1b, Glatiramer, Fingolimod, palliative and provides modest short-term benefit Teriflunomide, Dimethyl fumarate, Natalizumab, Mitoxantrone) None of the available therapeutic agents alter the MOA: Modify the immune response through inhibition of white underlying neurodegenerative process blood cell- mediated inflammatory processes that eventually lead to myelin sheath damage and decreased or inappropriate axonal communication between cells Drugs Used in Alzheimer’s Disease 1. Acetylcholinesterase Inhibitors 2. Symptomatic Treatment Dalfampridine (Rivastigmine, Tacrine Galantamine, Donepezil) an oral potassium channel blocker MOA: Inhibition of acetylcholinesterase (AChE) within the CNS improves walking speeds in patients with MS improves cholinergic transmission, at least at those neurons that is the first drug approved for this use are still functioning Drugs Used in Amyotrophic Lateral Sclerosis Galantamine may also augment the action of acetylcholine at nicotinic Amyotrophic Lateral Sclerosis receptors in the CNS is characterized by progressive degeneration of motor neurons, resulting in the inability to initiate or control Rivastigmine muscle movement is the only agent approved for the management of dementia associated with Parkinson's disease Treatment only AChE inhibitor available as a transdermal formulation 1. Riluzole an NMDA receptor antagonist, is currently the only drug Adverse Effects of AChE Inhibitors: indicated for the management of ALS a. Diarrhea b. Anorexia MOA: Inhibits glutamate release and blocks sodium c. Myalgia channels d. Tremors e. Bradycardia It may improve survival time and delay the need for ventilator support in patients suffering from ALS f. Nausea 2. NMDA-Receptor Antagonist NMDA receptor (NMDAR), a glutamate receptor, the predominant molecular device for controlling synaptic plasticity and memory function Memantine MOA: acts by blocking the NMDA receptor and limiting Ca2+ influx into the neuron, only a fraction of these channels are actually blocked SYnergistic