Pharmacology – Block 3 Exam 2
 Define the different pharmacologies used for neuropathic pain
o Neuropathic Pain
 Neuropa...
o Rectal – for patients with difficulty swallowing
o Transmucosal – absorbed by oral mucosa, increased bioavailabilty, Fen...
o Early tx may be protective; improves symptoms only
 *Rivastigmine
o Inhibits acetyl & butrylcholinesterase
o Pseudoirre...
 Ginkgo Bilboa
 Curcumin
o Tx of Non-Cognitive Behavioral Abnormalities in AD
 Non-Cognitive Problems in AD – Depressio...
 Describe the etiology and pharmacology for Parkinson’s disease. Also, describe a
treatment paradigm for Parkinson’s begi...
Epileptic Disorders
 Describe the different types of ion channels affected by antiepileptics
o Seizure homeostasis disrup...
o Some progress along anatomic lines - Jacksonian march
(the progression of the location of the seizure in the
brain leads...
 Describe the etiology, pathology, and treatment for Neuroleptic Malignant
Syndrome and Tardive Dyskinesia
o Neuroleptic ...
 Know which SSRI’s selectively affect serotonin vs. norepinephrine
o Norepi – tricyclic antidepressents (choice of TCA is...
o TCAs & heterocyclic antidepressants inhibit NE & 5-HT transporter → increased
levels of NE & 5-HT in synaptic cleft
o SS...
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Pharmacology – Block 3 Exam 2 Define the different pharmacologies ...

  1. 1. Pharmacology – Block 3 Exam 2  Define the different pharmacologies used for neuropathic pain o Neuropathic Pain  Neuropathic pain results from nerve injury  Look for diabetics, MS, amputations, spinal cord injuries  Causes structural & functional alterations in neurons & CNS, reorganization in dorsal horn.  Induced by  Inflammatory mediators (cytokines), Lack of trophic support  Inappropriate regeneration, altered expression of Na+ channels  Does NOT respond to opioid analgesics  Tx of Neuropathic Pain  Gabapentin: anti-sz drug; reduces neuronal excitability by increasing GABA (major inhibitory nt); also effective in diabetic neuropathy & trigeminal neuralgia  Cabamazepine & Lamotrigine: anti-sz drugs; block Na channels  Tricyclic Antidepressants: amitriptyline, nortriptyline, imipramine; increase NE & serotonin @ synapse & block Na+ channels → inhibit ascending pain pathways o SSRI’s also have some use here.  Narcotic Analgesics Drugs o Morphine – severe pain, trauma o Remifentanil – IV only, rapidly acting, drug of choice for short, painful procedures, does not last long o Codeine & hydrocodone – high bioavailabity, combined w/ aspirin/acetaminophen, good antitussive (anti-cough)  Know which opioids do NOT induce histamine release o Fentanyl (sublimaze) o Possibly Alfentanil, Sufentanil, Remifentanil  Treatment of opioid overdoes – Naloxone  Delivery mechanisms for opioids (transthecal, transdermal, etc) and how they are used o Patient Controlled Analgesia (PCA) – patient controls dosing from infusion pump (IV, epidural) o Intrathecal or Epidural infusion – direct access to spinal cord and dorsal horn, lower doses, easy chronic administration
  2. 2. o Rectal – for patients with difficulty swallowing o Transmucosal – absorbed by oral mucosa, increased bioavailabilty, Fentanil for breakthrough cancer pain o Transdermal – good for sustained pain, heating affects absorption, Fentanil patch o Peripheral delivery – direct injection to site  Describe the different treatments for AD and how they work o Alzeimer’s disease  Symptoms – short term memory impairment (initially, leads to irreversible progressive total memory loss), dementia  Path – loss of cholinergic neurons, followed by glutamatergic and serotonergic; cortex and hippocampus are affected  Lesions o Neurofibrillary tangles – tangles of microtuble-associated protein Tau o Amyloid plaques – polymers of amyloid b protein + dead neurons + inflammatory cells  *Case Study Drugs  Donepezil – acetylcholinesterase inhibitor  Memantine – “use dependent” inhibitor of NMDA-type glutamate receptors, which blunts excitotoxicity  Vitamin E – antioxidant, neuroprotective  Omega 3 fatty acids – cannot be converted to inflammatory mediators so they will blunt inflammation, may inhibit  Alternative drugs o Rivastigmine, galantamine – cholinesterase inhibitors o Cholinergic Hypothesis for AD  Symptoms of Alzheimer’s are due to loss of cholinergic neurotransmission  True, but this is only at one stage of dz  Later stages show glutamatergic, serotonergic, & other sys. also affected  Cholinesterase inhibitors currently used to tx mild-moderate levels dz  Tacrine o Noncompetitive, reversible inhibitor of butyrylcholinesterase and acetylcholinesterase o No longer widely Rx due to associated liver damage  *Donepezil (Aricept) o Reversible & noncompetitive AChE inhibitor o Approved forall stagesofAD
  3. 3. o Early tx may be protective; improves symptoms only  *Rivastigmine o Inhibits acetyl & butrylcholinesterase o Pseudoirreversible o 2x daily dosing, high discontinuance rate (GI side-effects) o Few drug interactions; metabolism non-hepatic  *Galantamine o Reversible, competitive, AChE inhibitor  Derived from the daffodil  Most selective  More selective for AChE over BChE o Positive allosteric modulator of ACh @ nicotinic R’s  Make ACh bind to nicotininc R’s better o NMDA Receptor Antagonists  Excitotoxicity is factor in Aβ neuronal death  By blocking NMDA R (glutamate R; involved in Ca2+ influx & increase in enzyme activity and therefore Tau protein hyperphosphorylzation), possibly can slow Alzheimer’s  Drugs  *Memantine (Namenda) o 1st tx for more advanced AD o Non-competitive antagonist @ NMDA-R  Blocks Ca2+ by blocking channel  Use dependent; decreases excitotoxicity o Voltage sensitive; low affinity (so only blocks if low, sustained conc. of glutamate present) o Doesn’t affect learning & memory (which involve high conc. of glutamate; memantine blockade relieved) o Also found to be beneficial in vascular dementia o Contraindicated w/ other NMDA-R antagonists o Anti-inflammatory agents  Inflmm. is a component of AD that induces neuronal demise  Antioxidants  Selegiline o MAO-B inhibitor w/ antioxidant properties  *Vitamin E  *Omega-3 FA – Improved cognition  Estrogen – may alter course of dz; studies underway  *Statins – block protein isoprenylation  Alzhemed – decreases beta-sheet formation
  4. 4.  Ginkgo Bilboa  Curcumin o Tx of Non-Cognitive Behavioral Abnormalities in AD  Non-Cognitive Problems in AD – Depression & Psychoses  Must tx w/ caution  For psychoses - chlorpromazine, haloperidol, benzodiazepines  For depression - SSRI antidepressants, imipramine  Antipsychotics in AD  Increased mortality over long term; e.g. sudden cardiac death  OTHER Neurodegenerative disorders (NOT on Dr. Z’s study guide or case studies) o Huntington’s  Symptoms – fidgeting, choreiform movements  Path – neuronal loss in caudate/putamen  Decrease in striatal GABA  Drugs  Depression – Fluoxetine, Carbamazepine  Psychosis, paranoia – antipsychotics, clozapine, or carbamazepine  Stress – benzodiazepines o Amyotropic Lateral Sclerosis  Symptoms – rapid progressive weakness, muscle atrophy, fascifulations, dysarthria, dysphagic, and respiratory compromise  Sensory, cognitive, and autonomic functioning is spared  Path – disorder of neurons of ventral horn of spinal cord and afferent cortical output  Drugs  Treatment for spasticity o Baclofen – GABA agonist o Tizanidine o Benzodiazepines  Riluzole – inhibits glutamate release, blocks post-synaptic NMDA R’s
  5. 5.  Describe the etiology and pharmacology for Parkinson’s disease. Also, describe a treatment paradigm for Parkinson’s beginning with mild disease and progressing to more severe  Parkinson’s Dz o Path – loss of dopaminergic neurons in the striatal area o Symptoms – resting tremor, loss of facial expression, slowness in initiation in movement o Drugs  Levodopa – metabolite of dopamine  Used for initial diagnosis  Side effects – production of free radicals and increased oxidative stress…leads to progression of the disease  On/off phenomenon  Ropinarole – dopamine receptor agonist  Use for initial treatment due to fewer side effects  Bromocriptine (w/ Levodopa) – older D1/D2 agonist, SE: hypertension, insomnia, no used anymore  Pramipexole (w/ Levodopa) – D2/D3 agonist, reduces “on/off”, reduced free radicals  Amantadine (w/ Levodopa) – blocks dopamine reuptake and stimulates D2/D3 receptors, improves dyskinesias, neuroprotective  Promising treatments  Coenzyme Q – improves mitochondria functioning  Deep brain stimulation  Antiinflammatory drugs  Describe a treatment for Multiple Sclerosis  Multiple Sclerosis o Path – destruction of myelin sheath o Symptoms – more frequent exacerbations, increased lesion formation of MRI o Drugs  Glatiramir – start for treatment in MS (follow up with Interferons as disease progresses)  Interferons – reduced cytokine activity and inflammatory T cell activity, 1b may also enhance T suppressor activity  Statins – reduces MS relapses by a mechanism related to lowering cholesterol  Oxybutinin – treats bladder spasticity (urinary incontinence)  Gabapentin – treat foot (neuropathic) pain  Amatidine – used to combat fatigue
  6. 6. Epileptic Disorders  Describe the different types of ion channels affected by antiepileptics o Seizure homeostasis disruption  Increased sodium, calcium, and/or glutamate  Decreased GABA o Na+ - some antiseizure drugs prolong the inactivation of the sodium channels, thereby reduicing the ability of neurons to fire at high frequencies  Drugs – carbamaepine, phenytoin, topiramate, Iamotrigine, valproate, zonisamide o Ca+2 – drugs for absence (Ethosuximide) and some generalized seizures block T- type voltage-gated calcium channels o Drugs affecting BOTH channels  Valproic acid  Zonisamide  Felbamate  Select an antiepileptic based on seizure type  Absent seizure drug o Ethosuximide – drug of choice for absent seizures, affects T type calcium channels in the hypothalamus  Tiagabine – contraindicated!  Generalized seizure drugs o Carbamazepine – prolongs the refractoriness of voltage gated Na+ channels, making them less likely to fire, decreases efficacy of birth control pills and is a teratogen, MOA – Na+ channels, adenosine receptors, blocks NE reuptake o Phenytoin – can undergo zero order elimination, Na+ channels o Barbs and benzos (e.g. Clonazepam, Clorazepate, Diazepam) – increase GABA current  Seizure o ID of seizure type important for pharm tx o 2 broad types  Partial (focal)  Involves only 1 cerebral hemisphere  May spread to cause secondary generalized seizure  Simple or focal o Short lasting, no loss or alteration in consciousness o Aura may occur  Complex or psychomotor o Change, rather than loss, in consciousness o Hallucinations; déjà vu o Repetitive behavior (automatisms) o Often originate in temporal lobe
  7. 7. o Some progress along anatomic lines - Jacksonian march (the progression of the location of the seizure in the brain leads to a “march” of the motor presentation of symptoms)  3 steps o Initiation o Synchronization o Spread  Generalized  Involves both cerebral hemispheres  Spreads through brain; pt. doesn’t remember having sz  Types o Secondarily Generalized Sz  Partial sz that becomes generalized to both cerebral hemispheres via corpus callosum o Tonic (continuous contraction) - Clonic (rapid contraction & relaxation)  Rigidity, jerking of body  Terminates w/ drowsiness, confusion o Absence Sz  Non-convulsive  Abrupt LOC & muscle tone  Stare off into space; last 5 - 30 sec. o Myoclonic – twitching, involves motor cortex o Atonic – loss of muscle tone, person falls down o Status epilepticus  Freq. long, lasting szs; recurrent episodes of tonic- clonic  Remain unconscious btn. attacks  Describe treatment for Status Epilepticus o Status epilepticus  Neuro emergency  Tx goal: rapid termination of behavioral & electrical sz activity  Longer status epilepticus continues, greater the neuro damage  Attention to hypoventilation & hypotension  IV drug admin  Diazepam or lorazepam slow IV, fosphenytoin @ same time  If failure, give Phenobarbital  Last resort = general anesthesia
  8. 8.  Describe the etiology, pathology, and treatment for Neuroleptic Malignant Syndrome and Tardive Dyskinesia o Neuroleptic Malignant Syndrome  Etiology – a life-threatening reaction to neuroleptic or antipsychotic drugs; presents with fever, muscle rigidity, and cognitive changes, resembles Parkinsonism  FEVER (F-fever, E-encephalopathy, V-vitals unstable, E-elevated enzymes (CPK), R-rigidity of muscles)  Path  Drugs – dantrolene may be antidotal o Tardive Dyskinesia  Etiology – pharmacotherapy  Path – supersensitivity to dopamine to develop leading to tremors, rigidity, abnormal face gestures (e.g. lip smacking, spasms of jaw muscles, increased blinking, and difficulty w/ speech)  Irreversible  Treatment  Decreaseddosage until symptoms reappear  Change drug  Psychosis and Mania: Antipsychotics o Drugs  Chlorpromazine – low potency neuroleptic, D2 receptor antagonist with some activity at serotonin receptors  Rispiradone – atypical antipsychotic (will NOT induce tardive dyskinesia)  Olanzapine – worsens diabetes  Haloperidol – neuroleptic that induces tardive dyskinesia  Drugs for affective disorders o Panic disorder – spontaneous panic attacks + anticipatory anxiety + phobic avoidance and functional impairment  Treatment – SSRI o Obsessive-Compulsive disorder – SSRI, especially Fluvoxamine o Post-Traumatic Stress disorder – SSRIs o Enuresis SSRI – tricyclics, Imipramine o Mood disorders – SSRIs in severe cases, pediatric studies fail to show superiority of drug to placebo o Bulimia – fluoxetine o Attention Deficit Disorder – imipramine, desipramine o Social phobia – SSRIs o Childhood Anxiety Disorder – psychotherapy + antidepressant is the most effective therapy (i.e. cognitive behavioral therapy + sertaline (Zoloft) o Stroke – Escitalopran enhances cognitive recovery following a stroke
  9. 9.  Know which SSRI’s selectively affect serotonin vs. norepinephrine o Norepi – tricyclic antidepressents (choice of TCA is based on adverse effects and response of the patient)  Explain the difference between an SSRI and SNRI o SSRI – inhibit the reuptake of Serotonin  no effects on muscarinic, histaminergic, or adrenergic receptors  Greatly reduced side effects (compared to tricyclics/heterocyclics)  Safe (even in overdose)  Effects on glia  Increased suicide risk in children and adults  Fluoxetine – impair blood glucose regulation in diabetics, may induce hyponatremia and elevated urine osmolarity o SNRI – inhibit the reuptake in BOTH serotonin and norepinephrine  Discuss treatment paradigms for depression and anxiety o Depression  Major Depression  Acute o SSRI o TCA if major depression alone – Imipramine, amytryptline o MOAIB for depression w/ atypical symptoms o Switch out of class if treatment fails o Wait 2-3 weeks!  Continuation o Lithium, tricyclic, MAOI, burpropion, SSRI o Watch for drug interactions  Maintenance o Lower dose o Switch to treating comorbid condition o May add another agent (i.e. bupropion + SSRI)  Life event or medication induced depression  SSRI’s and SNRI’s are drug of choice  Fluoxetine o Anxiety  Symptoms – excessive, unrealistic worry extended 6 months or longer  Treatment  Paroxetine – SSRI  Venlafaxine – SNRI  Imipramine – the only tricycle to show any effects  Action of Antidepressants o @ NE & 5-HT o MAOIs inhibit MAO  Increases cytosolic monoamines → increased release of nt during exocytosis
  10. 10. o TCAs & heterocyclic antidepressants inhibit NE & 5-HT transporter → increased levels of NE & 5-HT in synaptic cleft o SSRIs inhibit 5-HTT-mediated reuptake of 5-HT o TCAs, heterocyclics, & SSRIs increase duration of nt action in synaptic cleft → increased downstream signaling o Resperine blocks VMAT-mediated uptake of monoamines into synaptic vesicles → destroys vesicles

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