# Presentation: 329185

## Jo Ellen Dyer, PharmD

**Associate Clinical Professor of Pharmacy**
**University of California at San Francisco**
**California Poison Control System - San Francisco**

**Gamma Hydroxybutyrate**

## Gamma Hydroxybutyrate: California Exposures 

**California Poison Control Statewide 32-34 million**

**San Francisco Poison Control**
**Bay Area 7-8 million**

## GHB Safety Issues

**•  ****GHB produces profound coma**
**Experimental studies as anesthetic**
**Numerous occurrences of coma in abusers**

## Adverse Events in IV Anesthetic Studies

**Blumenfeld ****	****1962 ****	****n=26 ****	****Dose 650mg-8gm**
**Shulman****	****1967****	****n=42****	****Dose 4-10Gm**
**Soloway****	****1965****	****n=348****	****Dose 50-60mg/kg**
**Cole ****	****1970****	****n=121****	****Dose 60-70mg/kg**
**Brown ****	****1970 ****	****n=200 peds.****	****Dose 50-100mg/kg**
**Profound unconsciousness, coma, as intended**
**Cheyne-stokes, aspiration, one case pulmonary edema-unexplained**
**	****many cases intubated, airway attended not left to chance**
**Bradycardia, elevated arterial pressure, HTN 30-60mmHg**
**Muscle movements, EPS-like, twitching, myoclonus**
**Emergence delirium ****	**
**Jaw relaxation, easy intubation, abolished pharyngeal reflexes**
**Salivation,  vomiting, incontinence, diaphoresis**

## Widespread Public Experience: Adverse Effects

**CDC 1990**
**Dyer 1991 **
**Adornato and Tse 1992**
**Chin, Kreutzer et al 1992 **
**Einspruch and Clark 1992 **
**Ross 1995**
**Steele and Watson 1995 **
**James 1996 **
**Louagie, Verstraete et al. 1997 **
**Ryan and Stell 1997 **
**Sanguineti, Angelo et al. 1997**
**Suner, Szlatenyi et al. 1997 **
**Thomas, Bonner et al. 1997**
**Chin, Sporer et al. 1998**
**Li, Stokes et al. 1998**
**Ingels, Rangan et al. 2000**** **

**Profound Coma **
**Respiratory Acidosis**
**Bradycardia**
**Myoclonus**
**Emergence delirium**
**Aspiration**
**Vomiting**
**Salivation**
**Incontinence**

## 88 GHB Overdoses over 3 years @ SFGH

**Male: 69%****	****Age: 18 - 51    *****33% no co-ingestion ***
**Co-ingestion 67% *****(*****patient report or toxicology)**
**Multiple co-ingestion 13% ****	**

**Ethanol ****	****34****	****MDMA  12   Heroin 2    Sedative****	****2 **
**Amphetamine ****	****15 ****	****Cocaine 4   MJ ****	****2    LSD ****	****1**

- Chin. AEM 1998; 31:716-722

**GCS 3: 28%   GCS 4-8: 33%  Coma 15min-6hr**
**Common symptoms ~1/3 cases**
**• ****Bradycardia,HR <55 BPM   ****	****• Hypothermia, T < 35°C **
**• ****Respiratory acidosis, PCO2 >45, pH 7.24-7.34     • Vomiting**
**Hypotension 11%, most co-ingested ethanol**
**Emergence - myoclonus, confusion & combative**

## 15 GHB Overdoses Over 6 Months @ SFGH

**Age 20-39****	****male 73%**
**Study inclusion GCS<8,  ****	****73% had GCS-3**
**Serum GHB range highest level 45 to 300mg/l**
**Urine GHB range 432 to 2407mg/l**
**Complications:  aspiration 7%, intubation 13%, pulse oximetry<90 20%, bradycardia 30%, hypothermia 40%**** **
**5 cases negative ethanol and urine toxicology**
**GCS-3 80%, GCS-6 20%**
**Serum GHB highest 220-85mg/l, Urine 1021- 434mg/l**
**Time to awakening 70-190 minutes**
**GHB levels upon awakening 76-133mg/l**

## Coma

**Coma is life-threatening**
**Accident, injury, and respiratory compromise**
** ****aspiration, apnea, positional asphyxia, pulmonary edema**

## 20 GHB-Related Fatalities

**Age: 15 - 46 years****	****Sex: Male 75%  Female 25%**
**Toxicology :  ****20% no co-ingestion**
**Co-ingestants 80%**
**	****60% Ethanol  [0.01-0.17%]****	**
**	****10% THC, MDMA, Cocaine, Caffeine **
**	****5% Methamphetamine, Butalbital, Venlafaxine, APAP****	****	****	****	****	****	**
**	****	****	**

**GHB Levels:**
**Blood 140 - 2900 mg/l**
**Urine 305 - 27,000 mg/l**

**Physical Findings:**** **
**Pulmonary edema   ****	****80%****	**
**Cardiomegaly LVH****	****35%****	**
**Aspiration ****	****	****	****20%**

- Dyer and Haller submitted

**Cause: positional asphyxia, hot tub drowning, nose bleed**

## Societal Costs of GHB Abuse

**DUI’s****:  numerous cases plus vehicular manslaughter **
**	****2000 Alcohol 30mg/dl, GHB 92mg/l**
**	****1996 Alcohol 90mg/dl, GHB 94mg/l**
**Assault****: Victim under the influence of GHB**
**CA 1999 ****42 year old F lost consciousness, assaulted **
**Blood alcohol 10mg/dl,****	****Urine GHB 400mg/l**
**CA 1994-1996 ****10  victims unconscious and assaulted**
**Convictions: rape by drug, rape of unconsciousness person**
**IL 1998 ****24 year old M admitted using GHB to assault twice **
**Freshman assaulted twice and has no memory of the assault.**** **
**MI 1999 ****Two 15 year old females unconscious at a party **
**One hospitalized, one died.   GHB detected****	**

## GHB Addiction: 8 Withdrawal Cases

**Age: 22-38****	****  Sex: M 75%, ****	****  F 25%**
**Reason: bodybuilding 63%  •  Employed or student: 88%**
**Dose: 43-144gm/day, q1-3h A.T.C., 2mo-3yr**
**Onset 1-6 hours after last dose **
**Insomnia, tremor, anxiety, diaphoresis**
**Progression over 1-3 days**
**Agitation, dysphoria, delirium, hallucinations **
**Tachycardia, hypertension**
**Duration 5-15 days - episodic symptoms**
**Miotto *****in Press *****GHB, GBL Withdrawal: 5 Case Studies**

- Dyer et al. 2001 AEM

## Minimize the Risk?

**Difficulty minimizing risk**
**Abrupt onset CNS depression**
**Variation in drug levels with same dose**
**Variation in patient response to same level**
**GHB  adverse events with therapeutic GHB**
**Gallamberti 2000 n = 196 over 10 years for addiction**
**14.9% problematic GHB use**
**Dose escalation**
**GHB intoxication 1-10 times/year**
**GHB dependence**

## GHB Oral Pharmacokinetic Studies

**Individual variation in GHB kinetics**
_**Author**__**	**__**	**__**	**__**n**_**	****	****	****	****	****	****	**_**Oral Dose **__**	**__**	**__**	**__**Cmax**__**mg/l   mean(sdev)**_
**Ferrara 1992****	****10 alcoholics****	****	**** ****	****	****25, 50 ****mg/kg**** ****	****	****	****	**** 54(19), 90(34)****	**
**Palatini 1993****	****  8 volunteers****	****12.5,25, 50 ****mg/kg****	****  23(9), 46(22), 80(28)**
**Scharf 1998****	****  6 narcoleptic ****	****3gm (26-54mg/kg) ****	****	****	****	****	****63(27)**
**Coefficient of variation (standard of deviation/mean)**
**oral clearance 50%****	****	****	****	**** - Cmax 35-48%****	**
**Capacity-limited absorption and elimination**
**The source and consequences of individual differences in GHB kinetics is unknown**

## Current Level of GHB Abuse Unknown

**Project from survey experience?**
**Miotto *****in press. ***** Survey 42 GHB users**
**LOC 69%, amnesia 13-45%, OD 28%- only 9% ED**
**Arrests, one of many   Dose = 2gm**
**Marin CA. ****	****Butanediol 207L = 103,500 doses**
**Problem surveying and policing abuse**
**No systematic method in place for data collection**
**Rapid metabolism - tox only able to detect in blood 6h, urine 12h**
**Poor assays - no hospital or field assays**
**Human background levels will prevent low level detection**
**Current documentation grossly underestimates abuse**