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PM&R and Drugs Osmotic Therapy • • Decrease ICP • Increase osmolality of blood • Draw fluid into vascular space from interstitial space 1. Mannitol 2. Hypertonic Saline (3%) • 6 mL/kg bolus 3%NS increases Na 5 mosm/L • Monitor • Serum osmolality • Fluid balance • Renal function • Electrolytes Other Therapies • Raise head of bed • Hyperventilate patient • Therapeutic spinal tap • Drill bore holes Insomnia • • • Benzodiazepines • Decrease sleep latency and awakenings • Improve amount and quality of sleep • Use short acting, long acting metabolites accumulate Non Benzo GABA Agonist • Zolpidem (Ambien) • 1.5-2.5 hr duration: use for sleep onset • Zaleplon (Sonata) • 1.5-2.5 hr duration: use for sleep onset • Eszopiclone (Lunesta) • 5-7 hr duration: use for sleep onset and maintenance Ramelteon (Rozerem) • Melatonin agonist- binds at suprachiasmatic nucleus • Improves sleep latency • Not associated with hypnotic side effects, withdrawal, or rebound insomnia Insomnia • • Anti-Depressants • Central anti-cholinergic and anti-histamine effects • Useful for concominant depression and insomnia • Amitriptyline (Elavil) • TCA • Doxepin (Silenor) • TCA • Use for sleep maintenance • Trazadone (Oleptro) • Blocks Seratonin Reuptake • Very sedating • Special Side Effect: Priapism Anti-Histamines • Diphenhydramine (Benadryl) • Doxylamine (Aldex) • • • Use • Anxiolytic • Centrally Acting Muscle Relaxation • Sedation • Anticonvulsant • Lorazepam (Ativan) for status epilepticus • Alcohol Withdrawal Mechanism • Binds Benzodiazepine site on GABA-A receptors • Increases frequency of channel opening • vs. barbituates increase duration of channel opening Side Effects • Dose dependent respiratory and CV depression • Less dangerous vs. barbituates • Additive and dangerous effects with alcohol • Rebound Insomnia • Accumulation (depends on metabolites, hepatic function) • Induction of Cyt-P450 • Addiction and Withdrawal Benzodiazepines Benzodiazepines • • • Potency • Affinity for GABA-A Receptors • Lorazepam (Ativan)- most potent • Midazolam (Versed) and Diazepam (Valium) progressively less Rapidity of Action • Rate crosses BBB (lipophilicity) • Diazepam (immediate) • Midazolam (2-5 min) • Lorazepam (5-20 min) Duration of Effect • Redistribution from CNS (lipophilicity) • Accumulation in adipose • Active metabolites • Diazepam- Short (30-60 min) • 2 Active metabolites • Midazolam- Short (2-4 hr) • 1 Active metabolite • Lorazepam- moderate (4-8 hr) • No active metabolite (good for longer use) Sedation • • Severe Head Injury • Elevated ICP • Reduces metabolic demand • Control ventilator asynchrony • Decrease sympathetic responses (HTN and Tachycardia) Barbituate Coma • Pentobarbital • Improved ICP control • No decrease in mortality • Thiopental • More effective in ICP control • High dose barbituates • Increase risk of hypotension • May require pressors • Load 5-20 mg/kg bolus • Infuse 1-4 mg/kg/hr • Monitor EEG • Titrate to produce burst-suppression pattern Sedation • • Propofol • Shorter duration of action • Allows intermittent neuro assessment • ICP Reduction and Neuroprotection • TBI patients at risk for PRIS • Infuse max: 4 mg/kg/hr • Monitor: EEG, lactic acid, CPK, myoglobin Other Sedatives • Midazolam, Morphine, Fentanyl Propofol • • • Use • General Anesthesia • ICU Sedation for mechanically ventilated • Refractory status epilepticus (off label) Mechanism • Short acting, lipophilic IV anesthetic • Global CNS depression • GABA-A agonist • Possible NMDA blockade Side Effects • CNS, respiratory, CV depression • Injection site burning and pain • Hypertriglyceridemia (due to formulation) • Propofol Related Infusion Syndrome (PRIS) • Potentially fatal • Dysarrhythmia, heart failure, rhabdomyolysis, renal failure • Tolerance and withdrawal • Taper after long term use • Antiepileptic Drugs Na Channel Blockade • Phenytoin (Dilantin) hypertrophy, hirsutism, rash, (AED) • Gingival lymphadenopathy • Fetal Hydantoin Syndrome • Carbamazepine (Tegretol) • Steven-Johnson Syndrome (SJS), SIADH, agranulocytosis • Cyt-P450 Induction • Oxcarbazine (Trileptal) • Very similar to Carbamazepine • Lamotrigine (Lamictal) • SJS • Ca Channel Blockade • Gabapentin (Neurontin) • Pain associated with peripheral neuropathy • No significant drug interactions • Ethosuximide (Zarontin) • T-type Ca Channels • Drug of choice for absence seizures Antiepileptic Drugs (AED) • • • GABA Effects • Barbituates (Phenobarbital) • Benzodiazepines (Lorazepam, Diazepam) Multiple Mechanisms of Action • Valproate (Depakote) • Na block, T-type Ca block, increase levels of GABA • N/V/D, Hepatoxicity • Weight gain, metabolic syndrome • Topiramate (Topamax) • Na block, GABA agonist, NMDA block • Weight loss, cognitive slowing, metabolic acidosis Other/ Unknown mechanism • Levetiracetam (Keppra) • Rapid onset of action • Few interactions, does not induce CYP-P450 • Well tolerated Antiepileptic Drugs (AED) • • • • • Early post traumatic seizures • First 2 weeks following head injury • Up to 30% with severe TBI Use of AEDs reduces incidence of early seizures and avoids potential sequelae • Status epilepticus (potentially fatal) • Systemic illness • Increased ICP • Increased metabolic demands • Secondary brain injury Not shown to reduce long term risk of seizure Glucocorticoids • use shown to increase mortality at 2 weeks and 6 month following TBI Erythropoiten • Potentially neuroprotective Chronic Headache • Migraine • Limit use of acute headache medication to prevent overuse headahces • NSAID • Triptans (5-HT-1B and 5-HT-D agonist) -selective vasoconstriction of cerebral vasculature • Prophylactic Therapy • TCA, Antiepileptics, CCB, Beta Blockers, Riboflavin • Tension • Abortive: NSAID • Prophylaxis: TCA • Cluster • Abortive: 100% Oxygen • Prophylaxis: Verapamil (CCB), Li, Topiramate, Methysergide • Chronic Paroxysmal Hemicrania • Abortive: Indomethacin NSAID • • • Use • Analgesia • Antiinflammatory • Antipyretic • CV protection (Aspirin) Inhibit Cyclooxygenase (COX) • →Inhibits formation of Prostaglandins, Prostacyclin, Thromboxane • COX-1 • Constitutive (Blood vessels, GI, kidney) • COX-2 • States of inflammation • Glucocorticoids also inhibit Kinetics • Fully absorbed, no first pass metabolism • Bound tightly to albumin, very low volume of distribution NSAID • Major Side Effects • Pre-renal failure (high BUN/Cr, low FeNa) • PGE1 dilates afferent • Avoid in dehydrated, compromised renal function (elderly) • GI Toxicity • PGE1 promotes protective mucus formation • Can alleviate with Misoprostol (PGE1) • Allergic Reactions • Interactions: • Due to altered renal perfusion • ACE Inhibitors • Diuretics (decrease efficacy) • Li (increase levels) • Combined GI toxicity • Glucocorticoids • Combined hemorrhagic potential • Warfarin NSAID • Drugs • Aspirin (acetylsalicylic acid) • 81mg and 325mg • Special use: Kawasaki (high dose), anti-platelet therapy • Special Concern: Reye Syndrome (post influenza or VZV) • Ibuprofen (Advil, Motrin) • Naproxen (Aleve, Naprosyn, Midol) • Indomethacin (Indocin) • Special use: closure of patent ductus arteriosus (PDA) • Ketorolac (Toradol) • Available IM and IV • Selective COX-2 • Celecoxib (Celebrex) • Sulfa allergies • May have higher CV risk associated Glucocorticoids • • Use • Antiinflammatory • Arthritis • Asthma • Immunomodulatory • Allergic reactions • Autoimmune disease • Chemotherapy • Replace adrenal insufficiency • Addison’s or CAH • Glucogenic • Supports vasculature (expression of alpha-1 receptors) Mechanism • Steroid: works by altering gene expression • Up regulates and Down regulates transcription factors • Inhibits action of Nuclear Factor Kappa B • Major activator for inflammatory proteins and cytokines • Alters cell membrane proteins/ interactions at high doses Glucocorticoids • Down Stream Effects • Suppresses migration of PMN • Decrease capillary permeability • Inhibits COX-2 • Decreases activity and volume of lymphatic system • Induces cell death of immature lymphocytes • Inhibits glucose transport/ maintains glucose concentrations • Augments expression of alpha-1 receptors in vasculature • Administration • Parenteral (Septic shock, severe asthma) • Oral (Chronic therapy) • Nonsystemic (minimizes side effects) • Inhalation- asthma • Intraarticular injection- arthritis • Topical- rashes Glucocorticoids • Drugs • Hydrocortisone, Prednisone, Prenisolone, Methylprednisolone, Dexamethasone, Betamethasone, Triamcinolone, Beclometasone, Fludrocortisone, Deoxycorticosterone • Major Side Effects • Short term steroid use has limited side effects • Chronic steroid use • Adrenal Suppression (negative feedback to hypothalamus and pituitary) • Must taper when discontinuing • Immunosuppression • Delayed Healing • Iatrogenic Cushing’s Disease, Diabetes, Obesity • Osteoporosis, Avascular necrosis • Growth Arrest • Cataracts, Glaucoma • Skin fragility, easy bruisability Spasticity • Disruption of descending inhibition of alpha motor neurons • Excitability → increased tone and spasms • Pain, decreased mobility, contractures, spasms, interfere with sleep and ADL • Oral • Limited efficacy • Side efects are dose limiting • Slow dose elevation 1. Baclofen 2. Tinazidine • Centrally acting alpha-2 agonist 3. Diazepam or Clonazepam • Benzo, GABA-A agonist • Can use with Baclofen or Tinazidine • Useful for nighttime spasm 4. Dantrolene • Peripherally acting • Inhibits Ca release from SER • Produces more weakness than any other med • Hepatotoxicity: monitor LFTs 5. Other • Clonidine, Gabapentin, Cannabinoids, Cyproheptadine • Intrathecal • Baclofen • Centrally acting • Poor at crossing BBB • 4X CNS delivery with 1% of oral dose • Surgically impanted computer programmer infusion pump with catheter into intrathecal space • Trial intrathecal injection before pump placement • Decreased systemic side effects • Increased complications • Spinal fluid leaks • Hemorrhage • Infection • Catheter Dislodgement • Pump Failure Injections • Chemodennervation • Avoids systemic side effects • Muscle weakness and injection site reactions • 1. Botulinum-A Toxin • 2. Phenol • 3. Alcohol Spasticity • Baclofen • • • • Use • Spasticity • Cerebral Palsy • Meningomyelocele (Spina bifida) • Spinal Cord Injury • Not shown to develop tolerance with long term use Administration • Oral • Intra-thecal • Decreases systemic side effects • Complications with pump Mechanism • GABA analog • Binds GABA-B enhancing membrane polarization Side Effects • CNS, respiratory, CV depression • Severe withdrawal with abrupt discontinuation • Resembles alcohol withdrawal • May be fatal Botulinum-A Toxin • • • • Use • Dystonia • Local Spasticity and Contractures • Ideal for targeting isolated muscle groups • Less use for generalized spasticity • Hyperhydrosis • Migraine prophylaxis Mechanism • Irreversibly inhibits ACh release from presynaptic nerve terminals • Effective dennervates muscle until new fibrils grow from nerve Duration • Approx. 3 months Side Effects • Limited systemic side effects due to local action • If systemic absorption occurs: respiratory difficulty, dysphagia, muscle weakness, ptosis, bowel and bladder difficulty DVT Prophylaxis- IV/ SC • • • • Heparins Action indirect via anti-thrombin III Measure efficacy with Partial Thromboplastin Time (PTT) Risk: Heparin Induced Thrombocytopenia (HIT) • Unfractioned Heparin (UFH) • 5000U q8hr • Hepatic elimination • Protamine for reversal • Low Molecular Weight Heparin • Enoxaparin (Lovenox) • Renal elimination • Longer duration of action • No reversal • Significantly lower risk of DVT compared to UFH • No difference in overall mortality • Fondaparinux DVT Prophylaxis- Oral • • • Aspirin (ASA) • COX-1 inhibition → Decrease TXA2→ Decrease Platelet Aggregation • Only beneficial in reducing arterial events (Stroke, MI) • No benefit for preventing venous thrombosis (DVT, PE) Clopidogrel (Plavix) • ADP Receptor Inhibition → Decrease Platelet Aggregation • Similar spectrum of use as aspirin Warfarin (Coumadin) • Inhibits Epoxide Reductase in liver • Prevents recycling of Vit. K • Prevents gamma glutamination of factors III, VII, IX, X, C, S • Factors C and S are anticoagulatory, have shortest half life • Effect depends on natural half life of coagulation factors • Bridge with heparin until procoagulation factors are appropriately reduced, otherwise temporary hypercoaguable state • Reverse with Vit K or Fresh Frozen Plasma • Measure efficacy with Prothrombin Time (PT) DVT Prophylaxis- other • Direct Thrombin Inhibitors • Use if develop HIT • Lepirudin • Bivalirudin • Dabigatran (Oral) • GP IIb/IIIa Inhibition • Abciximab References • Bonnet, MH, Arand, DL. Treatment of Insomnia. In: UpToDate, Sanders, MH, Basner, RC, Benca, R(Ed), UpToDate, Waltham, MA, 2012. • Tietze, K., Fuchs, B. Sedative-analgesic medications in critically ill patients: Properties, dosage regimens and adverse effects. In: UpToDate, Parsons, P(Ed), UpToDate, Waltham, MA, 2012. • Lexicomp. Propofol: Drug information. In: UpToDate, UpToDate, Waltham, MA, 2012. • Lexicomp. Baclofen: Drug information. In: UpToDate, UpToDate, Waltham, MA, 2012. • Lexicomp. Botulinum toxin type A (onabotulinumtoxinA, Botox®): Drug information. In: UpToDate, UpToDate, Waltham, MA, 2012. • Schachter, SC. Pharmacology of antiepileptic drugs. In: UpToDate, Pedley, TA(Ed), UpToDate, Waltham, MA, 2012. • Nieman, L. Pharmacologic use of glucocorticoids. In: UpToDate, Lacroix, A(Ed), UpToDate, Waltham, MA, 2012.
