Transcript UPMC PowerPoint - Pitt Pharmacy Portfolio

Treatment of Alcohol Withdrawal
Pam Lyons
PharmD Candidate 2014
Pharmacotherapy Scholars Program
University of Pittsburgh School of Pharmacy
Objectives
• Explain the pathophysiology of alcohol
withdrawal
• Design a treatment algorithm for a patient in
alcohol withdrawal
• Describe the role of alcohol in the treatment of
alcohol withdrawal
•
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The Impact of Alcohol Abuse
Prevalence: 7% of the US population
24% of all emergency room visits
80,000 alcohol-related deaths each year
500,000 episodes of alcohol withdrawal requiring treatment
per year
Estimated cost per year: 223.5 billion dollars
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Stehman CR. Am J Emerg Med. 2013;31:734-42 .
Mayo-Smith MF. Arch Intern Med. 2004;164:1405-11.
Walker B. J Trauma Acute Care Surg. 2013;74(3):926-31.
Criteria for Alcohol Withdrawal – DSM V
A. Cessation of (reduction in) alcohol use that has been heavy
and prolonged
B. Two or more of the following that develop w/in several hours
of cessation of use:
–
–
–
–
–
–
–
–
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Autonomic hyperactivity
Increased hand tremor
Insomnia
N/V
Transient visual , tactile, or auditory hallucinations
Psychomotor agitation
Anxiety
Generalized tonic-clonic seizures
American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders,
Fifth Edition. Arlington, VA, American Psychiatric Association, 2013. Web. [access date: 1
June 2013]. dsm.psychiatryonline.org
Criteria for Alcohol Withdrawal – DSM V (continued)
C. Symptoms cause distress or impairment
D. Signs and symptoms are not attributable to another medical
condition and are not better explained by another mental
disorder, including intoxication or withdrawal form another
substance.
5
American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders,
Fifth Edition. Arlington, VA, American Psychiatric Association, 2013. Web. [access date: 1
June 2013]. dsm.psychiatryonline.org
Pathophysiology of Alcohol
Withdrawal
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Normal Physiology
NMDA
receptor
Ca+2
Vs.
Ca+2
Inhibitory
7 Stehman CR. Am J Emerg Med. 2013;31:734-42
Walker B. J Trauma Acute Care Surg. 2013;74(3):926-3
Excitatory
Physiology in the Presence of Alcohol – Acute Setting
NMDA
receptor
Ca+2
Vs.
Ca+2
Inhibitory
8
Excitatory
Stehman CR. Am J Emerg Med. 2013;31:734-42
Walker B. J Trauma Acute Care Surg. 2013;74(3):926-3
Physiology in the Presence of Alcohol – Chronic Setting
9
Inhibitory
• Decrease in
number of GABA
receptors
Excitatory
• Increase in
number of NMDA
receptors
•Decrease in
sensitivity of GABA
receptors to GABA
and EtOH
•Increase in NMDA
sensitivity to
glutamate
Stehman CR. Am J Emerg Med. 2013;31:734-42
Walker B. J Trauma Acute Care Surg. 2013;74(3):926-3
Pathophysiology – Alcohol Withdrawal
Removal of Alcohol
Glutamate activates highly
sensitive NMDA receptors
Little GABA present to act on
small number of GABA receptors
Agitation
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Stehman CR. Am J Emerg Med. 2013;31:734-42
Sign and Symptoms of Withdrawal
Time from last drink:
2-6 hours
7-48 hours
Abnormal vital
signs, N/V,
tremulousness,
diaphoresis
Hallucinations,
seizures
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Stehman CR. Am J Emerg Med. 2013;31:734-42
Walker B. J Trauma Acute Care Surg. 2013;74(3):926-3
48-72 hours
Delirium
tremens
Delirium Tremens
• Confusion, delirium, psychosis
• Hallucinations
• Seizures
• Usually lasts ~5 days
• May be fatal
• Risk factors for development:
– Previous Delirium Tremens
– Others - unknown
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Stehman CR. Am J Emerg Med. 2013;31:734-42
Walker B. J Trauma Acute Care Surg. 2013;74(3):926-3
Treatment of Alcohol Withdrawal
13
Mainstay of Therapy: Benzodiazepines
•
•
•
•
Reduce the severity and duration of symptoms
Reduce mortality
Ease of administration
MOA in EtOH withdrawal:
– Enhance GABA activity  increase inhibition
• No clear benefit of one particular agent
– Usually choose IV options:
• Diazepam
• Midazolam
• Lorazepam
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Stehman CR. Am J Emerg Med. 2013;31:734-42
Mayo-Smith MF. Arch Intern Med. 2004;164:1405-11.
Walker B. J Trauma Acute Care Surg. 2013;74(3):926-3
Choosing a Benzodiazepam: Pros and Cons
Diazepam
Midazolam
Lorazepam
1-5 min
2-5 min
5-20 min
30-60 hours
(30-100 hours metabolite)
2-6 hours
9-21 hours
Active
Metabolite?
Yes
Yes
no
Metabolism
Hepatic
Hepatic
Hepatic
Renal
Renal
Renal/fecal
Hepatic/renal impairment
Clcr<10
Renal
impairment
Erratic IM absorption,
propylene glycol toxicity at
very large doses
Longer sedation
in obese pts and
those with low
albumin
Risks of lactic
acidosis and
ATN
Onset of action
Half life
Excretion
Dose
adjustments
Special
considerations:
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Stehman CR. Am J Emerg Med. 2013;31:734-42
Mayo-Smith MF. Arch Intern Med. 2004;164:1405-11.
Initial Treatment
1) Load Benzodiazepine:
–
–
Diazepam:
• 5-20 mg q 5-10 minutes
Lorazepam:
• 1-4 mg q 10-15 minutes
2) Benzodiazepine doses PRN
3) Determine the need for further treatment
May require large doses because of decreased
sensitivity of the GABA receptor
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Stehman CR. Am J Emerg Med. 2013;31:734-42
Mayo-Smith MF. Arch Intern Med. 2004;164:1405-11.
Benzodiazepam Resistance
• Kindling Phenomenon
–
–
–
–
Episodes of EtOH withdrawal become harder to treat
Benzodiazepam resistance
Due to permanent alterations in neurotransmitters/receptors
Consider diagnosis after:
• >40 mg lorazepam
• 200 mg diazepam
• Consider other treatment options
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Stehman CR. Am J Emerg Med. 2013;31:734-42
Propylene glycol toxicity
• Propylene Glycol (PG)
–
–
–
–
–
–
–
–
Solvent
T1/2 = 1.4-3.3 hrs
Metabolized by liver  lactate, acetate, pyruvate
Excreted in urine
• 12-45% unchanged
• Clearance decreases as dose increases = saturation
No established acceptable level of IV PG
• PO level max = 25mg/kg/day
Toxicity profile:
• Serum hyperosmolality, lactic acidosis, kidney failure, SIRS
Diagnosis: osmolar gap at 48hrs
• Poor indicators: anion gap and lactic acidosis
Treatment: Hemodialysis
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Zar T. Seminars in Dialysis. 2007;20(7):217-9.
How much Propylene glycol is too much?
Drug
Amount of PG (mg/ml)
Drug dose = 69g/day PG
Lorazepam 2 mg/ml
828
166 mg/day
Phenobarbital 130 mg/ml
702
12.8 g/day
Diazepam 5 mg/ml
414.4
832 mg/day
Pentobarbital 50 mg /ml
414.4
8.3 g/day
Phenytoin 50 mg/ml
414.4
8.3 g/day
Bactrim 16:80 mg/ml
414.4
2.7:13.3 g/day
Etomidate 2 mg/ml
362.6
381 mg/day
Risk Factors for PG accumulation:
•Long term EtOH abuse
•Children
•Pregnant women
•Hepatic disease
•CKD
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Zar T. Seminars in Dialysis. 2007;20(7):217-9.
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Non-Benzodiazepine Options
• Barbituates
– MOA: Directly open Chloride channel in GABA, enhance
GABA binding, increase duration of opening
– Promotes benzodiazepine binding to GABA
– ADE: respiratory depression, cardiac depression
– Phenobarbital:
• 65-260 mg q 15-30 minutes until symptom control
• Time to onset: 5-30 minutes
• Hepatic metabolism/Renally eliminated
• Max: 600mg/24hrs
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Stehman CR. Am J Emerg Med. 2013;31:734-42
Phenobarbital sodium powder for IV injection package insert.
Hospira, Lake Forest, IL, 2008.
Non-Benzodiazepine Options
• Propofol
– MOA in EtOH withdrawal: Slowing closure of Chloride channel in
GABA receptor, NMDA antagonist
– Requires mechanical ventillation
– Time to onset= 1-2 minutes
– Dose:
• 0-5mg/kg/hr PRN continuous infusion
• 0.25-2 mg/kg intermittent
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Stehman CR. Am J Emerg Med. 2013;31:734-42
Mayo-Smith MF. Arch Intern Med. 2004;164:1405-11.
Non-Benzodiazepine Options
• Ketamine
– MOA: NMDA receptor antagonist
– May be useful in the treatment of EtOH withdrawal
• “Ethanol-like effects”
• Does not cause EtOH cravings
– ADE: HTN, tachycardia, pulmonary secretions, respiratory
depression, out of body experience
– Initial doses = 0.2-0.5mg/min
– Current Phase 2 clinical trial for the use of Ketamine in the treatment
of depression and alcohol dependence
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Krystal JH. Arch Gen Psychiatry. 1998;55:354-60
Krystal JH. Ann of NY Acad Sci. 2003;1003:176-184.
Dickerson D. J Psychopharm. 2010; 24(2):203-11
Harrison YE. Behavor Pharm. 1998;9:31-40.
Ketamine for Depression and Alcohol Dependence. Clinical trials.gov
Ketamine Package insert. Bioniche Pharma USA LLC, Lake Forest, IL, 2008.
Adjunct Treatment Options
• Carbamazepine
– Limited data
– No IV formulation – for mild AWS only
• Antipsychotics
– Haloperidol – only use when patient is already adequately treated
• May be beneficial for hallucinations
• Cardiac Medications
– Alpha agonists (Dexmedetomidine, clonidine), BB
• Only mask s/s AWS
• Use only as adjunct therapy
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Stehman CR. Am J Emerg Med. 2013;31:734-42
Mayo-Smith MF. Arch Intern Med. 2004;164:1405-11.
Walker B. J Trauma Acute Care Surg. 2013;74(3):926-3
Supportive Care
• Hydration
– IV dextrose for hypoglycemia
• Nutritional Supplementation
– Thiamine 100 mg x 3 days
– Magnesium
• NMDA antagonist
– Folic Acid
• Elevate head of bed to prevent
aspiration
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Stehman CR. Am J Emerg Med. 2013;31:734-42
Mayo-Smith MF. Arch Intern Med. 2004;164:1405-11.
Walker B. J Trauma Acute Care Surg. 2013;74(3):926-3
http://blog.hqperformance.com/2013/04/14/going
-bananas-who-knew/
Why is Thiamine so important?
• Role in the body:
– Coenzyme for sugar and protein metabolism
– Needed for production of GABA and acetylcholine
• Give thiamine before glucose
• Lack of thiamine can cause:
– Wernicke’s encephalopathy
• confusion, loss of motor control, abnormal vision
– Korsakoff syndrome
• Memory loss, hallucination, confabulation
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Brust JCM. In: Goldman L, Ausiello D, eds. Cecil Medicine. 23rd ed. Saunders Elsevier; 2007:chap 443.
Walker B. J Trauma Acute Care Surg. 2013;74(3):926-31.
Controversial use of EtOH
• Ethanol is not recommended for treatment of withdrawal:
– Variable metabolism – difficult to predict kinetics
– Compared to benzodiazepines:
• Shorter duration
• Narrow therapeutic window
• Lowers the seizure threshold
– Irritates stomach
– Damages the liver
– Toxic for neutrophils and macrophages
– Acetaldehyde accumulation  respiratory failure
– Prescribing EtOH condones alcoholism
• Is the patient going to drink on discharge?
• Lack of controlled studies
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Mayo-Smith MF. Arch Intern Med. 2004;164:1405-11.
Monitoring - CIWA
• Clinical Institute Withdrawal Assessment Scale for alcohol
– Scale 0-7
– 10 areas of observation:
• N/V
• Tremor
• Paroxysmal Sweats
• Anxiety, Agitation
• Tactile, Auditory, Visual disturbances
• HA
• Orientation/sensorium
– Interpreting the score:
• <9 = Minimal/absent withdrawal
• 10-19 = Mild – moderate
• >20 = Severe
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UPMC Protocol
• Withdrawal Assessment Scale (WAS)
– Similar to CIWA
• Addition of vital signs, flight of ideas, quality of contact
• Only on a scale from 1-6
• Not useful for intubated patients
– Initiate: Lorazepam 2 mg PO q2hr per WAS
– Protocol attaches directions to scores
• WAS <10 – no action needed, repeat WAS in 4 hrs
• Was 10-14 – PRN benzo, repeat WAS in 4 hrs
• WAS >14 – PRN benzo + call treating MD for reassessment,
repeat WAS in 2hrs
– Scheduled benzos
• Symptoms have been stabilized with WAS PRN for >24 hrs OR
• Pt requires >6 mg lorazepam in 12 hrs of treatment
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Patient Case: TW
• 41 yo male
• PMH:
–
–
–
–
–
–
EtOH withdrawal-related seizures
Seizures not related to EtOH
Tourette syndrome
Anxiety/depression
Tremors
EtOH abuse
• Social Hx: Drink 3-4 beer x ~3nights/wk, marijuana use
3x/month
• HPI: Three intoxicated falls. Last fall was off a curb.
Presented to OSH on 10/12/13 @22:53
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Patient Case - TW
• Home Medications:
–
–
–
–
–
–
Zonisamide (Zonegran®) 100 mg BID
Lamotrigine (Lamictal®) 200 mg daily
Paroxetine (Paxil®) 10 mg daily
Quetiapine (Seroquel®) 300 mg HS
Trazodone (Desyrel®) 100 mg HS PRN
Folic acid 100 mg BID
• Claims compliance with medications
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Patient Case - TW
• Diagnosed with Tibia/fibula fractures and transported
• Labs:
– Blood alcohol: 277
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What steps should we take to adequately treat
this patient and prevent withdrawal?
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Patient Case - TW
• D1 – patient does not receive home medications
– Starting to become fairly agitated
– Recieves 8 mg Lorazepam per WAS
• D2 – Agitation uncontrollable
– Escalating doses of IV diazepam
• 1125 mg diazepam total
– Phenobarbitol 500 mg IV
– Soft tissue infection suspected – start IV vancomycin
• D4 – restart home lamictal at slow titration
– Vanco level came back low
– Infection progressing  added Zosyn D5
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Patient Case - TW
• D5 – AKI
• Repeat K @ 9:37 = 3.4
• Repeat Scr @9:37 = 3.2
• Vancomycin level = 56
– Repeat random level = 53.7
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10/14 10/15 10/16
10/17
10/18
10/19
10/20 10/21 10/22
Valium dose
(mg)
1125
800
400
50
20
60
280
160
40
Phenobarb
(mg)
500
500
Propylene
95.7
glycol (gram)
69
33.2
4.1
1.7
4.9
23.2
38.2
3.3
Scr
0.7
0.7
0.7
3
5.2
6.7
7.5
9.9
10.8
Vancomycin
levels
Start
5.8
56
53.7
51.7
UO
850
Increased
Vanco dose to
1.5 q 8hr, added
Zosyn
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44.6
700
755
What are the possible causes for his AKI?
37
What other treatment options for alcohol
withdrawal do we have?
38