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Transcript
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.