18.May.2012-Expires: 7 days - Do not archive

Charge (BZP)

Charge (BZP)
18.May.2012-Expires: 7 days - Do not archive

DESCRIPTION

SUBSTANCE NAME

Benzylpiperazine (BZP)
 

SUBSTANCE CLASS

Psychoactive Central Stimulant

Piperazine-Based Hallucinogenic Stimulant
 

USES

While piperazine-based hallucinogenics or stimulants are not currently used therapeutically, they are misused. It is believed to have a similar action as the hallucinogenic-amphetamines, explaining the reason for its abuse. It is less potent than methamphetamine or MDMA, but is being sold in continuously increasing doses, making the effects more consistent with these more potent drugs.[1]
 

PRODUCT INFORMATION

This substance may be available in a stated dosage, however, this should be treated with some caution particularly if obtained illicitly, due to variables such as uncontrolled manufacturing process, inappropriate packaging, and product bulking.
 
Some names for piperazine-based designer drugs are actually street names that refer to the imprint on the tablet, rather than a brand name. These pills are sometimes sold to a consumer as MDMA (Ecstasy) but may contain anywhere between zero to 500 mg of benzylpiperazine (BZP) plus trifluoromethylphenylpiperazine (TFMPP).

Generally, tablets and capsules contain Benzylpiperazine (BZP). These capsules can range from 70 to 1000 mg BZP. Some products contain BZP in combination with Trifluoromethylphenylpiperazine (TFMPP), generally in a ratio of 2:1 (e.g. 200 mg BZP plus 100 mg TFMPP).
 
Some products may contain flipiperazine (PFPP), m-chlorophenylpiperazine (MCPP), p-methoxyphenylpiperazine (MEOPP) or methylenedioxybenzylpiperazine (MDBP).
 
Some products come with separate "recovery" capsules containing 5-hydroxytryptophan (5-HTP), which is a serotonin precursor and causes serotonergic symptoms. These capsules generally contain between 50 and 500 mg of 5-HTP.
 
Some capsules claim to contain an "anti-seizing" agent, which is actually therapeutically inactive.
 

FORM

Caplet
 

ACTIVE INGREDIENT

Charge Capsule:
105mg() Benzylpiperazine  (equivalent to mg )()
 
Recommended dose is 1 to 2 capsules, then another 1 to 2 after 2 hours. Maximum dose 3 capsules. Available in packets of 6 or 18.
 
Warning: Note: tablets claim to contain "500 mg". However, this refers to total mg of all ingredients, not active ingredients, and is effectively a meaningless statement.
 

PHYSICOCHEMICAL PROPERTIES

DESCRIPTION
 
Pale yellow viscous liquid, sensitive to light, air and moisture. No odor
 
PHYSICAL PROPERTIES
 
Molecular Weight
176.26
Melting Point
0 degrees C
Flash Point
> 112 degrees C
Specific Gravity
1.0140 g/cu cm

INTERVENTION CRITERIA

Intervention Level

Child

Observation is recommended:

For any exposure to a piperazine based hallucinogenic stimulant

(Note: the interval for useful decontamination is very limited.)

Adult

Observation is recommended:
> 400 mg of a piperazine-based hallucinogenic stimulant is ingested
Symptomatic patients (other than mild)
Exposures with intent to self-harm
 
(Note: the interval for useful decontamination is very limited.)
 

Observation Period

Observation at Home

In the case of standard release formulations, if the patient does not require medical observation they can be monitored at home for 4 hours in the care of a reliable observer.
 
Medical attention should be sought if ANY symptoms occur, including:
Euphoria
Confusion/agitation
Anxiety
Increased heart rate
Palpitations
Chest pain
Gastrointestinal upset
Fever
Tremor
 

Medical Observation

If medical observation is required the patient must be monitored for 4 hours following exposure for onset or worsening of symptoms.
 
Once the patient remains asymptomatic for 4 hours and any necessary decontamination or investigations have been carried out:
Discharge into the care of a reliable observer, or
Refer for psychological assessment (if the overdose was intentional)
 

Investigations

Serum levels do not aid management.
 
Heart rate
Blood pressure
Body temperature
12 lead ECG
Blood glucose
Serum sodium

Admission Criteria

Admission to a hospital facility is required for those suffering significant signs of toxicity including:
Agitation - sufficient to impair ability to function alone
Paranoia
Vomiting
Abdominal pain
Palpitations
Chest pain
Hyperthermia
Seizure
Cardiac dysrhythmia, including supraventricular tachycardias
Evidence of hepatotoxicity
 
Admission into an intensive care facility is required for those suffering severe overdose or complications.
 

TREATMENT

TREATMENT SUMMARY

Piperazine based hallucinogenic stimulants are considered to possess an hallucinogenic-amphetamine-like effect.
 
The majority of hallucinogenic-amphetamine presentations will recover with a period of observation, calming environment and, if required, benzodiazepine. Gastrointestinal decontamination is unlikely to be beneficial. Stimulant abuse may be via intravenous injection of ground tablets. Pulmonary granuloma formation in chronic abusers predisposes to reduced pulmonary function,[2] vascular obliteration, pulmonary hypertension, and cor pulmonale.[3][4]
 
Patients may become dehydrated and require significant volume replacement – however, it is imperative to recognize those suffering hyponatremia as administration of fluids may prove fatal. Serum sodium must be measured, and CT brain scan undertaken to exclude cerebral edema in those with CNS signs.
 
The severely toxic may suffer seizure or cardiovascular abnormality. Chest pain may indicate an acute coronary syndrome (arteriospasm) which will likely settle if the patient is calmed with a benzodiazpeine, nitrate, or in severe cases a vasodilator such as phentolamine. Hyperthermia should be immediately and actively managed, and the patient carefully monitored for further complications including rhabdomyolysis, DIC, and renal failure. Hepatotoxicity is well recognized, and while recovery is usual, fulminant hepatic failure requiring liver transplant may manifest. Serotonin syndrome should be considered, especially in those using other serotonergic compounds either therapeutically or recreationally.
 
Emergency Stabilization
Ensure adequate cardiorespiratory function
Emergency monitoring
Decontamination
Ingestion
Single dose activated charcoal
Antidote(s)
None recommended
Enhanced Elimination
Supportive Care
Monitoring
Neurologic
Seizure
Intracranial hemorrhage
Serotonin toxicity
Delirium
Fluid and electrolytes
Dehydration
Hyperkalemia
Cardiovascular
Tachycardia
Hypertension
Acute coronary syndrome
Cardiac dysrhythmia
Metabolic
Hyperthermia
Metabolic acidosis
Musculoskeletal
Rhabdomyolysis
Respiratory
Non-cardiogenic pulmonary edema
Renal
Acute renal failure
Hepatic
Hepatotoxicity
Other
Movement disorder
Ocular
Corrosive eye injury
Dermatologic
Skin burn
 

EMERGENCY STABILIZATION

A range of acute cardiovascular emergencies may occur due to vasospasm or vascular rupture. Such events include hemorrhagic or ischemic stroke, cardiac dysrhythmia/arrest, dissection of large vessels including the aorta.
 
Hyponatremia may occur and initially present as seizure. Should respiratory arrest develop likelihood of recovery is remote.[5]
 

Ensure Adequate Cardiopulmonary Function

Ensure the airway is protected if compromised (intubation may be necessary).
 

Cardiovascular

Immediately establish secure intravenous access.
 

Cardiac Arrest

Prolonged cardiac resuscitation following standard ACLS protocols is warranted as recovery with a good neurological outcome is occasionally reported in poisoned patients receiving CPR for periods of 3 to 5 hours.[6]
 

Seizure

Most toxic seizures are short-lived and often do not require intervention.
 
Administer a benzodiazepine as first-line treatment to patients with seizure activity.
 
Blood glucose concentration should be promptly determined. If the result indicates hypoglycemia, or is unobtainable, 50% dextrose should be administered IV (preceded by thiamine in adults).
 

Emergency Monitoring

Respiratory rate
Heart rate
Blood pressure
State of hydration
12 lead ECG
Serum electrolytes - especially sodium
Blood glucose
Neurological status
 

DECONTAMINATION

Efficacy of gastrointestinal decontamination is questionable as amphetamines and amphetamine-like compounds are rapidly absorbed; and the patient likely a late presenter and less than co-operative.
 

Ingestion

Single Dose Activated Charcoal

Administration of activated charcoal may be considered if a patient has ingested a potentially toxic amount up to 1 hour previously.[7]
 
Single dose activated charcoal[8]
CHILD
1 to 2 g/kg orally
ADULT
50 to 100 g orally
 

Nasogastric Intubation

Nasogastric instillation of activated charcoal is not recommended unless the ingestion is considered potentially severely toxic and oral administration is not successful. Accurate placement of the nasogastric tube and protection of the airway must be ensured.
 

Whole Bowel Irrigation

Whole bowel irrigation is not recommended for this drug unless a potentially severely toxic dose of an enteric coated or modified release (e.g. sustained release) formulation has been ingested,[9] or the quantity of compound is too great for activated charcoal alone to be an effective decontaminant (ratio of charcoal to compound is less than ten to one). Due to the risk of pulmonary aspiration ensure that the airway is fully protected if whole bowel irrigation is used.
 
The only irrigant recommended is an iso-osmotic polyethylene glycol electrolyte solution administered at the following rates until the rectal effluent is clear.[10]
 
CHILD
9 months to 6 years:
20 mL/kg/h orally or via NG tube
6 to 12 years:
20 mL/kg/h orally or via NG tube
ADOLESCENT or ADULT
1,500 to 2,000 mL/h orally or via NG tube
 

ANTIDOTE(S)

There Are No Antidotes For This Substance

ENHANCED ELIMINATION

Enhanced Elimination Not Recommended

Hemodialysis:
Not considered effective
Hemoperfusion:
Not considered effective
Hemofiltration:
Not considered effective
Multiple dose activated charcoal:
Not considered effective

SUPPORTIVE CARE

Monitoring

ECG
Blood pressure
Heart rate
Body temperature
Blood glucose
Fluids and electrolytes
Arterial blood gases
Respirations
Chest auscultations
Oxygen saturations
Neurological status
Serum urea
Serum creatinine
Liver function tests
Serum creatine phosphokinase
 

Neurologic

Seizures

Seizures secondary to sympathomimetic toxicity occur uncommonly and should be managed with a benzodiazepine, or if still refractory a barbiturate.[11] If persistent or prolonged, seizure activity may cause hyperthermia which can in turn lead to metabolic acidosis, rhabdomyolysis, and renal failure.[11]
 
Observe the patient closely for onset of seizure activity.
 

Intracranial Hemorrhage

Intracerebral hemorrhage is well recognized following sympathomimetic overdose and is likely due to acute hypertension associated with arterial spasm and vascular rupture.[12] Patients suffering severe headache should be fully investigated. Patients with arteriovenous malformations,[13] or with drug induced cerebral vasculitis, may be more susceptible.[14]
 
Closely monitor mental status

Manage intracranial hemorrhage using standard treatment protocols.

Serotonin Toxicity (Syndrome)

Some abusers of sympathomimetic compounds suffer onset of serotonin syndrome; particularly at risk are those taking other serotonergic drugs either therapeutically or recreationally. If severe, complications may include hypotension, metabolic acidosis, rhabdomyolysis, cardiovascular collapse, renal failure, disseminated intravascular coagulation, and death.[15][16]
 
Development of serotonin toxicity may be detected by applying the Hunter Serotonin Toxicity Criteria – Decision Rules:[17]
 
In the presence of a serotonergic agent:
  1. IF (spontaneous clonus = yes) THEN serotonin toxicity = YES
  2. ELSE IF (inducible clonus = yes) AND [(agitation = yes) OR (diaphoresis = yes)] THEN serotonin toxicity = YES
  3. ELSE IF (ocular clonus = yes) AND [(agitation = yes) or (diaphoresis = yes)] THEN serotonin toxicity = YES
  4. ELSE IF (tremor = yes) AND (hyperreflexia = yes) THEN serotonin toxicity = YES
  5. ELSE IF (hypertonia = yes) AND (temperature > 38ºC) AND [(ocular clonus = yes) or (inducible clonus = yes)] then serotonin toxicity = YES
  6. ELSE serotonin toxicity = NO
 
NOTE: Other etiologies such as infection, metabolic changes, substance abuse or withdrawal need to be ruled out. Neuroleptic syndrome should be considered if the patient has been started on neuroleptic agents or had an increase in dosage.
 

Delirium

Psychosis and severe agitation may be prominent following sympathomimetic overdose. Agitation and increased muscular activity risks hyperthermia and rhabdomyolysis.

Monitor for signs of delirium
 
A calming, non-stimulating environment and benzodiazepines are recommended as first-line management.[11] Titration of a benzodiazepine is recommended, and high cumulative doses can be required (100 mg of diazepam or its equivalent).[18] High potency antipsychotic agents such as droperidol or haloperidol may be considered; however, they interfere with thermoregulation and may precipitate dystonia, cardiac dysrhythmia, or hypotension.[19][20][21][22]
 

Fluid and Electrolytes

Hyponatremia

Hyponatremia may result from profuse sweating and excessive rehydration and/or SIADH (syndrome of inappropriate secretion of antidiuretic hormone).[23] Further fluid ingestion may have severe consequences. While the majority should settle with fluid restriction and observation, cerebral edema, seizures, life-threatening encephalopathy, and tentorial herniation may occur.
 
Monitor serum sodium

Management is controversial. Rapid correction of hyponatremia with hypertonic fluid is not considered necessary: Fluid restriction to < 1 L/day, and close observation may be all that is required in the majority of cases. Central venous pressure may need to be determined to measure extra-cellular fluid depletion.[24] If there are CNS signs, perform a CT brain scan to identify cerebral edema. If there is evidence of cerebral edema than IV mannitol or loop diuretics may be necessary.[5]
 

Dehydration

Profuse sweating, increased activity, tachypnea, and hyperthermia not uncommonly leads to significant body-fluid depletion. Before managing patients for dehydration it is important to exclude the possibility of hyponatremia as fluid administration may potentially be fatal in such cases.

Monitor for signs of hypovolemia:
Blood pressure
Measure serum electrolytes including sodium
 
Serum sodium must be measured prior to rehydration to exclude the possibility of hyponatremia. Aggressive intra-venous rehydration with Swan-Ganz monitoring may be required.[25]
 

Hyperkalemia

Development of hyperkalemia is a poor prognostic indicator.[25] Management with hemodialysis should be considered if rhabdomyolysis or renal failure are present.
 
Observe for:
Abdominal pain/diarrhea
Weakness
Ascending paralysis
Respiratory failure
Monitor:
ECG changes suggestive of hyperkalemia include
Peaked T waves (tenting)
Flattened P waves
Prolonged PR interval (first-degree heart block)
Widened QRS complex
Deepened S waves and merging S and T waves
Idioventricular rhythm
Sine-wave formation
VF and cardiac arrest
Arterial blood gases
Serum potassium
 

Cardiovascular

Tachycardia

Tachycardia is a common finding following sympathomimetic overdose. Initial management is provision of a non-stimulating environment and a benzodiazepine. Further intervention is only required if hemodynamic compromise occurs.

Monitor:
Heart rate
Blood pressure
ECG
 
Tachycardia from sympathomimetic overdose can respond to a benzodiazepine, though doses that depress level of consciousness or interfere with respiration should not be employed. If a hemodynamically significant tachycardia develops, very cautious use of propranolol may be considered.[6] Titrate dose to reduce heart rate to less than 100 bpm while maintaining an adequate blood pressure.[25]
 

Hypertension

Hypertension is very common and is secondary to alpha-1 adrenoreceptor stimulation causing vasoconstriction.
 
Monitor:
Heart rate/rhythm
Blood pressure
ECG
 
As sympathomimetic-induced hypertensive emergencies are usually of short duration aggressive management may result in hypotension. The following regimen is recommended:[6]
Benzodiazepine, and calming environment should be provided
Nitroprusside should be considered as second-line therapy if blood pressure does not settle
Labetalol, in carefully titrated doses, has been recommended as a third-line agent for sympathomimetic overdoses. (Beware of potential increases in blood pressure due to unopposed alpha-adrenergic receptor agonism).
 

Acute Coronary Syndrome

Myocardial ischemia may occur following sympathomimetic overdose due to coronary artery vasoconstriction, thrombus formation and platelet aggregation.[26][27] Myocardial ischemia can progress to infarction. Use of beta-adrenergic receptor blockers is contra-indicated as they may worsen hypertension.[28][6]
 
Monitor:

Heart rate

Blood pressure

ECG

Recommended management of this condition includes:
Benzodiazpeine, and a calming environment
Nitroglycerin in either sublingual, oral, topical or IV form may be used and titrated to effect, with sublingual route preferred[29][30]
Phentolamine may be used as a second-line agent in those refractory to vigorous nitrate and benzodiazepine therapy[31][32]
If there is still not adequate improvement, intra-coronary (rather than peripheral) administration of thrombolytics or coronary vasodilators should be considered[6]
 

Cardiac Dysrhythmia

Dysrhythmias may occur as a consequence of direct catecholamine effects, myocardial ischemia, hypoxia, or possibly electrolyte abnormality.
 
Monitor:
Heart rate/rhythm
Blood pressure
12 lead ECG
 
Inotropic and chronotropic cardiac effects should be treated with a calcium channel blocker such as diltiazem or verapamil.[33] A beta-blocker is often necessary, but should be administered with caution, preferably combined with a vasorelaxant. There is a theoretical risk that beta-blockers may precipitate alpha-adrenergic activity and hypertension.[33] Although propranolol has been used safely,[34][35] labetalol is preferred, since it has both alpha and beta-adrenergic antagonist activity.[36]
 
For patients suffering hemodynamically stable ventricular tachycardia, both sodium bicarbonate and lidocaine (lignocaine) are recommended.[6][32]
 

Metabolic

Hyperthermia

Severe hyperthermia may develop as a result of hypothalamic dysfunction, metabolic and muscle hyperactivity, or prolonged seizures.[25][37] Hyperthermia is a poor prognostic indicator and aggressive cooling is required.[38][25]
 
Closely monitor core body temperature

Metabolic Acidosis

Patients suffering metabolic acidosis have poor outcome.[25] This complication should be aggressively managed.
 
Monitor:
Arterial blood gases (pH, bicarbonate, pCO2, pO2)
Plasma lactate
Base excess
 
Follow standard protocols for the management of metabolic acidosis.
 

Musculoskeletal

Rhabdomyolysis

Those suffering severe agitation, excessive muscular activity, or hyperthermia are at risk of developing rhabdomyolysis.[39][40]
 
Examine patient for dermal bullae indicative of prolonged immobilization. Also consider:
Serum creatine kinase (CK)
Urinalysis:
Myoglobin
pH
 

Respiratory

Non-Cardiogenic Pulmonary Edema

Sympathomimetic compounds have been associated with the development of severe non-cardiogenic pulmonary edema.[41]
 
Non-cardiogenic pulmonary edema may manifest with desaturation and pulmonary rales. On occasion frothy, pink sputum may be apparent. Monitoring for this condition should include:
Chest auscultation
Oxygen saturations
Arterial blood gases
Chest X-ray
 
Follow standard protocols for the management of non-cardiogenic pulmonary edema.
 

Renal

Acute Renal Failure

Sympathomimetic-induced acute renal failure is considered to occur due to circulatory collapse rather than direct toxicity;[25] or as a result of rhabdomyolysis. Hyperkalemia may result, requiring urgent management with hemodialysis.
 
Patients should be monitored for the onset of renal failure:
Urine output
Creatinine
Blood urea nitrogen (urea)
Proteinuria
Hematuria
Loin pain may occur
 
Manage following standard treatment protocols for acute renal failure.
 

Hepatic

Hepatotoxicity

Hepatotoxicity is well recognized with certain hallucinogenic amphetamines. Commonly it is a mild (viral-like) hepatitis with jaundice, hepatomegaly, increased bleeding tendency and liver enzymes, and an acute hepatitis evident on biopsy. Spontaneous recovery usually occurs over a period of weeks or months, though attacks may be repeated in chronic users.[42][43] This picture may however progress to fulminant hepatic failure – fatal unless liver transplant can be arranged. An intermediate stage is reported where recovery may spontaneously occur, after a prolonged course, but permanent liver fibrosis may develop.[44]
 
Hepatic monitoring should include:
Alanine aminotransferase (ALT)
Aspartate aminotransferase (AST)
International normalized ratio (INR)
Serum bilirubin
Plasma glucose
 
Follow standard protocols for the management of acute hepatotoxicity.
 

Other

Movement Disorder

Choreoathetoid movements are uncommon, but are associated with both acute and chronic abuse of sympathomimetic compounds.[45][46] They can be managed with a benzodiazepine, or if still refractory, cautious use of haloperidol.[47] It must be remembered that haloperidol lowers seizure threshold, interferes with thermoregulation and may precipitate dystonia or cardiac dysrhythmia.
 

Infection

Drug abuse may be via intravenous injection of ground tablets. Bacterial endocarditis is a recognized complication,[3] and there is potential for viral hepatitis/HIV infection.
 

Ocular

Ensure thorough and adequate decontamination using water or saline. Irrigation should be continued until a normal pH (of 7) is achieved and maintained for 2 hours.[48]
 
Examine for:
Conjunctivitis
Lacrimation
Photophobia
Pupil abnormality
Visual acuity
Corneal defect with fluorescein staining
 

Dermatologic

Skin Burn

Examine patient for skin burns:
Tenderness
Erythema
Blistering
 
Manage chemical skin burns following standard treatment protocols for thermal skin burns.
 

DISCHARGE CRITERIA

Patients may be discharged from hospital care when clearly asymptomatic and fully recovered from any complications. Appropriate psychiatric intervention may be necessary depending on the circumstances of the exposure.
 

FOLLOW UP

If exposure arose from intentional self use or dependency, patients should be referred if possible to an appropriate substance abuse program.

SIGNS AND SYMPTOMS

Piperazines have a stimulant effects, as a result of increased monoamine (dopamine, serotonin, noradrenaline) availability.[49]
 
Piperazine toxicity commonly causes tachycardia, hypertension, palpitations, gastrointestinal upset (nausea, abdominal pain, vomiting, diarrhea), dehydration, headache, anxiety, fever and agitation.[50][51][52] Mydriasis, blurred vision, sweating, tremor, ataxia and confusion are relatively common. Nystagmus, trismus and paresthesia may uncommonly occur.[50][53] Hallucinations, hyperventilation, shortness of breath and flushed skin are rare.
 
In more severe cases, seizures, collapse, myoclonic jerking and extrapyramidal features (choreoathetoid movements, dystonic reactions) may occur.[50] Serotonin syndrome has also been reported.[54] Hypertension can be severe.[50] If prolonged or severe, fever and excessive motor activity may lead to hyperthermia, metabolic acidosis, disseminated intravascular coagulation and renal failure. Renal failure has been reported on one occasion,[55] as has psychosis.[56] Given piperazine's mechanism of action, theoretical concerns are cardiac dysrhythmia, acute hepatitis/liver failure, and death.[57]
 
Hypersensitivity reactions, such as bronchospasm, Stevens-Johnson syndrome, acute hepatitis, thrombocytopenia, hemolytic anemia and angioedema have occurred in individuals taking piperazine therapeutically.[53]
 
The correct identification of the substance is important. If the symptoms are inconsistent with those described, or the history is considered unreliable, other substances may need to be considered.
 

Onset/Duration of Symptoms

Onset of affect is usually delayed about 2 hours post-ingestion.[1][58] Effects generally persist for about 12 to 24 hours, but may occur for up to 72 hours following use.[50] There may be a role for monoamine depletion/withdrawal in prolonged toxicity.

Routes of Exposure

Benzylpiperazine (BZP) liquid and dust is known to be corrosive. This may cause burns to the gastrointestinal tract if swallowed or to the eye or skin if these areas are contaminated. Piperazine based hallucinogenic stimulants are also smoked by some individuals and there is also the potential for effects similar to inhalation of a corrosive (or acid) gas to manifest.
 
Tablets are often dissolved and directly injected. Due to the bulk of these tablets being composed of non-water soluble agents such as talc there is a high rate of complications following granuloma formation and vascular obliteration.[4][3] While the lung is a particular target with resultant pulmonary hypertension/cor pulmonale, other organs can be affected. Infection following such abuse is also a concern.[2]
 

Severity of Poisoning

Mild Hallucinogenic Amphetamine ToxicityModerate Hallucinogenic Amphetamine ToxicitySevere Hallucinogenic Amphetamine Toxicity
Euphoria
Increased alertness
Mydriasis
Bruxism (grinding of teeth)
Altered mental status
Muscle aches
Tachycardia
Hypertension
Agitation
Paranoia
Hallucinations
Diaphoresis
Vomiting
Abdominal pain
Palpitations
Chest pain
Hyperthermia
Hyponatremia
Metabolic acidosis
Rhabdomyolysis
DIC (disseminated intravascular coagulation)
Acute renal failure
Coma
 

ACUTE EFFECTS (ROUTE OF EXPOSURE)

Ingestion

Ingestion of liquid free-base BZP is corrosive and may cause burns to the mouth, throat, esophagus and stomach. Ingestion of tablets or capsules is not likely to cause any local effects.

Skin

BZP liquid may cause burns if left on the skin for a prolonged period of time.

Eye

BZP liquid or dust may cause corrosive injury to the eye. The exact nature of injury has not yet been determined.

Injection

Intravenous Abuse

Tablets are often dissolved and directly injected. As the bulk of these tablets are composed of non-water soluble agents such as talc there is a high rate of complications following granuloma formation and vascular obliteration.[4][3] While the lung is a particular target with resultant pulmonary hypertension/cor pulmonale, other organs can be affected. Vasculitis and infection following such abuse is also a concern;[2] and inadvertent arterial injection or tissue extravasation may cause granuloma formation, vasospasm, ischemia[59] and necrosis.[60]
 
Inadvertent arterial injection or tissue extravasated drug may cause vasospasm, ischemia and necrosis.[60] Both intravenous and oral amphetamine may cause vasculitis.[61][62]
 
Vasculitis
Infection
Foreign body reaction
Bacterial endocarditis
Pulmonary granuloma
Pulmonary hypertension
Cor pulmonale
 

Inhalation

BZP is sometimes dried in air or salted out with hydrochloric acid to form a solid which is then smoked in a manner similar to crack cocaine. This may cause effects similar to inhalation of a corrosive (or acid) gas, as the liquid and dust forms of BZP are known to be corrosive. These effects may include respiratory irritation, chest pain, cough and bronchospasm. This may progress to pneumonia or pulmonary edema.

ACUTE EFFECTS (ORGAN SYSTEM)

Neurologic

Initial stimulation and excitation may be followed by depressive effects and psychosis. A variety of tremors, tics, choreoathetoid movements, and dyskinesias can develop in both adults and children.[47][63][64] Ischemic stroke is recognized,[65] as is cerebral hemorrhage in patients suffering arteriovenous malformation or drug-induced vasculitis.[61][62]
 
Agitation[25][19]
Fatigue[66]
Irritability[67]
Confusion[19]
Anxiety[68]
Delirium[19]
Insomnia[69]
Hallucinations[19]
Hyperactivity[25]
Aggression[68]
Restlessness[70]
Paranoid psychosis[71][72]
Headache[66]
Depression (with suicidal thoughts)[73]
Seizure[66]
Ischemic stroke[65]
Coma[66]
Cerebral vasculitis[74][75]
Cerebral hemorrhage[61][62]
Cerebral edema[76]
 
Subarachnoid
Bruxism (teeth grinding)[77][78]
 
Intraventricular
Choreoathetoid movements[79]
 
Intracerebral
Hyperreflexia[74]
 

Cardiovascular

Tachycardia and hypertension are common, and a range of dysrhythmias may occur. Myocardial ischemia/infarction is recognized due to direct cardiac toxicity, vasospasm or thrombus formation.[80] Vasculitis may arise with subsequent dissection/rupture of vessels. Hypotension is a poor prognostic indicator.[25]
 
Tachycardia[25][68]
Hypertension[68][81][82]
Palpitations[19]
Chest pain[19]
Dysrhythmias[68][83][84][85]
Ectopic ventricular beats
Supraventricular tachydysrhythmias
Ventricular tachydysrhythmias
Ventricular fibrillation
Heart block[86]
Myocardial ischemia/infarction[68][87][88]
Cardiomyopathy[89][90][91][92]
Cardiomegaly[87]
Aortic dissection[82][93]
Bradycardia[83][88]
Hypotension[25]
 

Gastrointestinal

Anorexia[94]
Nausea[95]
Diarrhea[96][97]
Vomiting[97]
 

Respiratory

Sympathomimetic compounds have been associated with the development of severe non-cardiogenic pulmonary edema.[41]
 
Protracted vomiting has caused a case of pneumomediastinum and pneumoretroperitoneum.[98]
 
Hyperventilation[99][97]
Non-cardiogenic pulmonary edema[100][101][41]
Pulmonary aspiration
 

Renal

Urinary retention can result from increased bladder tone, and acute renal failure an outcome of dehydration, hyperthermia, and rhabdomyolysis.[25][39][102][103]
 
Dysuria
Hesitancy
Acute urinary retention[103][104]
Hematuria[74][104]
Myoglobinuria[39][105]
Acute renal failure[25][39]
 

Hepatic

Hepatic injury is well recognized, often presenting as a mild (viral-like) hepatitis. In some cases this may progress to fulminant hepatic failure.[97][106][42]
 
Elevated transaminases[97][106][42][107]
Liver tenderness[97]
Hepatomegaly[97]
Coagulopathy[97][107]
 

Metabolic

Severe hyperthermia may develop as a result of hypothalamic dysfunction, metabolic and muscle hyperactivity, or prolonged seizures. It is an indicator of poor prognosis.[25][21][37][109][97]
 
Metabolic acidosis[110][111][112][113][114]
 

Fluid and Electrolytes

Dehydration[115]
 

Musculoskeletal

Bruxism (tooth grinding)[77]
Trismus (tonic spasms of jaw muscles)[116][117]
Rhabdomyolysis[99][97][100]
Muscular activity (particularly the lower limbs)[95]
Muscular ache[118]
 

Dermatologic

Diaphoresis[97][99]
Pallor[119]
Piloerection[120]
 

Ocular

Mydriasis (dilated pupils)[97][121]
Nystagmus[101]
 
Symptoms in those who are awake for long periods include:[122]
Eye pain
Blurred vision
Corneal epithelial erosions
 

Hematologic

Serious exposures may cause:[99][109][97]
Disseminated intravascular coagulation[97]
Thrombocytopenia[123]
Aplastic anemia[124]
 

Other

Serotonin Toxicity (Syndrome)

Some abusers of amphetamine and amphetamine-like compounds suffer onset of serotonin syndrome. There is significantly increased risk if an hallucinogenic amphetamine is used by those taking other serotonergic drugs, either therapeutically or recreationally (e.g. SSRI’s, MAOI’s).[125][16] Onset is usually within 2 hours of the first dose/overdose of the precipitating agent, and generally resolves within 6 to 24 hours of removal of the offending compound(s). Severe cases may persist for more than 48 hours[126] (potentially longer than 96 hours if there are complications, or a drug with prolonged duration of action is involved).[127] If severe, complications may include hypotension, metabolic acidosis, rhabdomyolysis, cardiovascular collapse, renal failure, disseminated intravascular coagulation, and death.[15][16]
 
Suggested diagnostic criteria for serotonin syndrome are the presence of three or more of the following clinical features:[128]
 
Mental status changes (e.g. confusion, hypomania)
Agitation
Myoclonus
Hyperreflexia
Diaphoresis
Shivering
Tremor
Diarrhea
Incoordination
Fever
 

CHRONIC EFFECTS

Hypersensitivity reactions, such as bronchospasm, Stevens-Johnson syndrome, acute hepatitis, thrombocytopenia, hemolytic anemia and angioedema have occurred in individuals taking piperazine therapeutically.[53]
 
Given their mechanism of action, theoretical concerns following chronic us/abuse of piperazines would be similar to hallucinogenic amphetamines.
 

Respiratory

Injection of ground tablets is a common form of abuse of this drug. As the bulk of the tablet is composed of non-water soluble agents such as talc, chronic abuse can lead to foreign body granuloma formation and vascular obliteration.[3] The lung is the particular target and a range of abnormalities in pulmonary function have been noted;[2] pulmonary hypertension/cor pulmonale may also result and can be fatal.
 
Tachypnea
Dyspnea
Pleuritic chest pain
Pulmonary function testing abnormalities[2]
Obstructive pattern
Restrictive pattern
Hypoxia when breathing room air
Diffusing capacity less than 60%
Pulmonary granuloma
Pulmonary hypertension
Cor pulmonale
 

Neurologic

If large amounts of amphetamine or amphetamine-like compounds are consumed over a long period of time, amphetamine psychosis can develop, which is similar to paranoid schizophrenia. The psychosis is manifested by hallucinations, delusions and paranoia. Symptoms usually disappear within a few weeks after drug use stops.
 
A range of sequelae have been noted following chronic human abuse including:
Choreoathetoid movements[129]
Hallucinations
Visual
Tactile
Olfactory
Auditory (less common)
 
A lasting paranoid psychotic reaction may develop,[130] and behavior can become destructive and violent. While the majority of patients recover within 10 days, effects persist for more than 6 months in 10% of cases.[131][132][133] Single re-exposures may produce acute exacerbations even after long periods of abstinence.
 

Cardiovascular

Chronic oral amphetamine abuse has been associated with:
Cardiomyopathy
Vascular spasm
Aortic dissection[93]
 
Chronic intravenous abuse with:[134]
Widespread necrotising angiitis
Aneurysm
Sacculations
Segmental stenosis
Thrombosis
Hypertension
Vascular rupture
Pulmonary edema
Renal failure
 
Accidental intra-arterial injection can cause a more localized but severe arterial vasospasm.[135][60] Pulmonary hypertension has occurred after chronic inhalation of an amphetamine.[136]
 
Injection of crushed and dissolved tablets also risks bacteremia and bacterial endocarditis;[3] vasculitis[137] and intracranial hemorrhage; pulmonary granuloma and pulmonary hypertension with cor pulmonale.[3][4]
 

Gastrointestinal

Anorexia and weight loss
Ischemic colitis

Other

Diffuse hair loss has been associated with long-term amphetamine use.[138][139]
 
Amphetamine and amphetamine-like compounds have rarely produced aplastic anemia and a fatal pancytopenia after prolonged use.[140]
 
Infections such as hepatitis B and C and HIV are possible complications of intravenous use of amphetamine and amphetamine-like compounds.[140]
 

Tolerance

Tolerance can develop to the anorectic and various autonomic effects including body temperature, blood pressure, heart rate and respirations.[141]
 

Withdrawal Syndrome

Acute withdrawal may precipitate severe depression and suicidal thoughts. Symptoms usually peak after 2 to 3 days and are seldom directly life-threatening.
 
Physical symptoms associated with withdrawal are:[142]
Abdominal cramps
Anxiety
Craving
Diaphoresis
Dyspnea
Exhaustion
Gastroenteritis
Headache
Increased appetite
Irritability
Lethargy
Mental confusion
Moderate to severe depression
Psychotic reaction
Restlessness
Insomnia
 

TOXICITY

TOXIC MECHANISM

Piperazines act to increase monoamine availability. Different piperazines have varying effects on the different monoamines, but in overdose this selectivity is generally lost.
 
Benzylpiperazine (BZP) has direct serotonin[143]and dopamine agonist activity,[49]and also inhibits uptake of serotonin, dopamine and noradrenaline.[143][144][145] Trifluoromethylphenylpiperazine (TFMPP) has direct serotonin agonist activity[146][49] but lacks the dopaminergic and noradrenergic action of BZP.[147][148] When administered together, BZP and TFMPP mimic the release of both dopamine and serotonin following methylenedioxymethamphetamine (MDMA),[49][149]to a greater degree than when BZP or TFMPP are given alone.[145] Other piperazines are less well studied. Methoxyphenylpiperazine (MeOPP) is a serotonin (5HT-1) agonist,[144] methylenedioxybenzylpiperazine (MDBP) inhibits serotonin uptake[145]and m-chlorophenylpiperazine (mCPP) acts similarly to MDMA,[150]probably via its action on monoamines.[151]Methylbenzylpiperazine (MBZP), and p-fluorophenylpiperazine (pFPP) remain unstudied.
 

HUMAN

The correct identification of the substance is important. If the symptoms are inconsistent with those described, or the history is considered unreliable, other substances may need to be considered.
 
Clinical observation is more relevant than an estimate of the actual dose.

Acute

There is no human or animal toxicity data for piperazine-based designer drugs.
 
An ingestion of 50 to 100 mg of BZP in an adult is unlikely to cause serious toxicity. It is likely to produce mild effects, such as wakefulness and alertness and very mild increases in heart rate and blood pressure.[1]
 
It is predicated that doses over a total of 250 mg of a piperazine-based designer drug would be likely to cause moderate toxicity, such as anxiety, agitation, hypertension, tachycardia, palpitations, gastrointestinal upset and headache. This may be uncommonly accompanied by seizure, tremor, hallucinations, fever, chest pain, jaw clenching, fever and hallucinations.
 
An increase in dose to 500 mg may cause these toxic effects to be prolonged. Symptoms appear to last approximately 24 to 48 hours, but anecdotally, have been reported to last up to 3 days.
 

Chronic

There is no conclusive evidence of the effects of chronic use of piperazine-based designer drugs in humans.
 
In one study, former amphetamine addicts were given separate single doses of 100 mg BZP and 7.5 mg dexamphetamine. Subjects rated both drugs as equally pleasurable, and both doctor and patient subjective ratings of stimulant effects were similar for both drugs.[58]
 
There are no studies to show the effects of multiple doses, or long term effects of this drug.
 

BIOLOGICAL LEVELS - TOXIC

Blood levels may be used to confirm ingestion but are not a reliable guide to patient management.
 

REPRODUCTION

PREGNANCY

The effects of exposure to this substance during pregnancy are unknown.
 
It is recommended that this substance should not be used during pregnancy.

Piperazine itself does cross the placenta and may affect the infant. Taking piperazine during pregnancy is generally not considered acceptable, particularly in the first trimester, unless immediately essential.
 
Piperazine is reported as teratogenic in rabbits. There have been two isolated cases of human fetal malformation, but a causal link was not established.[152][153]
 
Given the mechanism of action, chronic use/abuse of piperazines may pose the same risks of dependence and withdrawal in the fetus and neonate.
 
Maternal abuse of injectable substances carries a high risk of exposure to infections such as HIV or hepatitis through exchange of needles and lack of sterile equipment/procedure. During pregnancy, many of these infections, if developed, can be passed directly on the infant.
 
There is limited data concerning the effect of amphetamine usage on the fetus in humans.
 
Possible effects of use experienced by the infant after exposure:[154]
During Pregnancy
- Intrauterine growth retardation
- Decreased head circumference
- Preterm delivery with fetal distress
- Anemia
- Placental abruption
- Amphetamine withdrawal
- Reduced birth weight
Post delivery
- Hypoglycemia
- Sweating
- Poor feeding
- Poor visual tracking
- Seizures
- Amphetamine withdrawal
 
Effects on the pregnant women exposed to amphetamines.
Increased risk of serious obstetric complications
- Intracranial hemorrhage
- Seizures
- Amniotic fluid embolism
 
Experiments in rats show no effects other than subtle behavioral alterations on the neonate.[155][156]
 

Withdrawal Syndrome

Some maternal withdrawal syndromes can be as detrimental to the fetus as the original substance itself; alternate periods of drug abuse and withdrawal can be even more so. In some cases, the best approach may be to displace the addiction with a course of a similar, but less fetotoxic, drug. As soon as pregnancy is suspected in a female drug addict, a drug withdrawal specialist should be consulted for advice.
 

Child

Amphetamine withdrawal pattern in infants:[154]

- Abnormal sleep patterns

- Tremors

- Hypertonia

- High-pitched cry

- Poor feeding

- Vomiting

- Sneezing

- Frantic sucking

- Tachycardia

Australian Classification:
X
 
FDA Classification:
X
 
For full details of the FDA and Australian ADC pregnancy classifications, Click here.
 

LACTATION

It is unknown whether this compound is excreted in human breast milk.
 
It is recommended that this substance should not be used while breast feeding.

Piperazine itself is excreted into breastmilk and may affect the infant. Piperazine is cautiously administered to nursing mothers, provided that there is no breastfeeding for 8 hours post ingestion, and any milk is expressed and discarded during this time.[153][152]
 

THERAPEUTIC DRUG INFORMATION

PHARMACOLOGICAL ACTION

Piperazines act to increase monoamine availability. Different piperazines have varying effects on the different monoamines, but in overdose this selectivity is generally lost.
 
Benzylpiperazine (BZP) has direct serotonin[143]and dopamine agonist activity,[49]and also inhibits uptake of serotonin, dopamine and noradrenaline.[143][144][145] Trifluoromethylphenylpiperazine (TFMPP) has direct serotonin agonist activity[146][49] but lacks the dopaminergic and noradrenergic action of BZP.[147][148] When administered together, BZP and TFMPP mimic the release of both dopamine and serotonin following methylenedioxymethamphetamine (MDMA),[49][149]to a greater degree than when BZP or TFMPP are given alone.[145] Other piperazines are less well studied. Methoxyphenylpiperazine (MeOPP) is a serotonin (5HT-1) agonist,[144] methylenedioxybenzylpiperazine (MDBP) inhibits serotonin uptake[145]and m-chlorophenylpiperazine (mCPP) acts similarly to MDMA,[150]probably via its action on monoamines.[151]Methylbenzylpiperazine (MBZP), and p-fluorophenylpiperazine (pFPP) remain unstudied.
 

BIOLOGICAL LEVELS - THERAPEUTIC

Blood levels may be used to confirm ingestion but are not a reliable guide to patient management.
 

KINETICS

ABSORPTION

Oral Absorption
Yes, rapidly absorbed[157]
Onset of Action
Onset usually delayed about 2 hours post-ingestion.[1][58]
Duration of Action
Effects may persist for about 12 to 24 hours or longer.[50]
Time to Peak Plasma Levels
60 to 75 minutes[157][158]
 

DISTRIBUTION

Distribution
  1. Distributed throughout the body
 

METABOLISM

Metabolism
  1. Extensively metabolized[159]
Metabolites
  1. 3-hydroxy-BZP
  2. 4-hydroxy-BZP
  3. 4-hydroxy-3-methoxy-BZP
  4. Piperazine
  5. Benzylamine
  6. N-benzylethylenediamine[160]
Major Metabolic Pathways
Parent:
  1. Hydroxylation
  2. Methylation
  3. Dealkylation[160]
 

ELIMINATION

Excretion
Urine
  1. 12.5 to 13.3% of BZP and its metabolites recovered in urine after 24 hours[157][158]
Half-life
Overdose
  1. 4.3[158] to 5.5[157] hours
Time to Completion
  1. Approximately 44 hours[157]
 

IDENTIFICATION

OTHER NAME(S)

Chemical Name

BZP:
1-Benzyl-1,4-diazacyclohexane dihydrochloride
 

Common Names

1-benzylpiperazine
A2
Benzylpiperazine
 

“Street” Names

  1. A2
  2. Amp
  3. Black pepper extract
  4. Blizzard
  5. Chanel
  6. Cosmic bliss
  7. Crystal
  8. ESP
  9. Exodus - the journey
  10. Good stuff
  11. Groove
  12. Herbal E
  13. Herbal speed
  14. Ice Diamonds
  15. Jet
  16. Kandi
  17. Legal E
  18. Move
  19. Mr Grin
  20. Pulse
  21. Purple hooters
  22. Purple tart
  23. Rapture gold
  24. Shotgun
  25. Sweet tarts
  26. The good stuff
  27. Triple crown
  28. Up
  29. Wannabe
  30. X
  31. Zoom
  1. Altitude
  2. Aquarius
  3. Blast
  4. Bolts
  5. Charge
  6. Cosmic jet
  7. Divine
  8. Euphoria
  9. Extra sensory pill
  10. Green fly
  11. Grunter
  12. Herbal ecstasy
  13. Herbal X
  14. Jax
  15. Jet pills
  16. Kandis
  17. Legal X
  18. MPH
  19. Nemesis
  20. Purple dome
  21. Purple passion
  22. Question mark
  23. Red Hearts
  24. Smiley
  25. Synthetic black pepper extract
  26. The grunter
  27. Triple stacked crown
  28. Viper
  29. White butterfly
  30. X Extreme
  1. Altitude Ultra Premium
  2. Big Grin
  3. Bliss
  4. C4
  5. Charge herbal
  6. Crown
  7. Double T
  8. Exodus
  9. Frenzy
  10. Grin
  11. Guerrilla mini
  12. Herbal high
  13. Hummer
  14. Jaxx
  15. Jump
  16. Kiniside
  17. Mashed
  18. MPH 750
  19. Nemi
  20. Purple frenzy
  21. Purple pills
  22. Rapture
  23. Scarfies
  24. Smurfs
  25. The big grin
  26. Torque
  27. Twisted
  28. Voyager
  29. Whizzers
  30. Xtreme
 

CODES

CAS NUMBER

1-Benzylpiperazine:
2759-28-6
 

MOLECULAR FORMULA

Benzylpiperazine:
C11H16N2
 

REFERENCES

 
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