Details About Overdose or Poisoning Generic Salt :: Benzodiazepines Diazepam, Lorazepam, And Midazolam
Benzodiazepines [Diazepam, Lorazepam, and Midazolam]
Drug Pharmacology ::
I. Pharmacology./b>
Benzodiazepinespotentiate inhibitory GABA neuronal activity in the CNS. Pharmacologiceffects include reduction of anxiety, suppression of seizure activity,CNS depression (possible respiratory arrest when given rapidlyintravenously), and inhibition of spinal afferent pathways to produceskeletal muscle relaxation.
Inaddition, diazepam has been reported to antagonize the cardiotoxiceffect of chloroquine (the mechanism is unknown, but diazepam maycompete with chloroquine for fixation sites on cardiac cells).
Benzodiazepinesgenerally have little effect on the autonomic nervous system orcardiovascular system. However, enhancement of GABA neurotransmissionmay blunt sympathetic discharge (and lower blood pressure associatedwith sympathomimetic intoxications), and diazepam may have an effect oncholine transport and acetylcholine turnover in the CNS this may bepart of the basis for its beneficial effect for nerve agent poisoning(eg, Sarin, VX).
Pharmacokinetics. Allthese agents are well absorbed orally, but diazepam is not wellabsorbed intramuscularly. The drugs are eliminated by hepaticmetabolism, with serum elimination half-lives of 1–50 hours. Theduration of CNS effects is determined by the rate of drugredistribution from the brain to peripheral tissues. Active metabolitesfurther extend the duration of effect of diazepam.
1. Diazepam.Onset of action is fast after intravenous injection but slow tointermediate after oral or rectal administration. The half-life isgreater than 24 hours, although anticonvulsant effects and sedation areoften shorter as a result of redistribution from the CNS.
2. Lorazepam.Onset is intermediate after intramuscular dosing. The eliminationhalf-life is 10–20 hours, and anticonvulsant effects are generallylonger than those for diazepam.
3. Midazolam.Onset is rapid after intramuscular or intravenous injection andintermediate after nasal application or ingestion. The half-life is1.5–3 hours, and the duration of effects is very short owing to rapidredistribution from the brain. However, sedation may persist for 10hours or longer after prolonged infusions as a result of saturation ofperipheral sites and slowed redistribution.
Drug Indications ::
Indications
Anxiety and agitation. Benzodiazepinesoften are used for the treatment of anxiety or agitation (eg, caused bysympathomimetic or hallucinogenic drug intoxication).
Convulsions. Allthree drugs can be used for the treatment of acute seizure activity orstatus epilepticus resulting from idiopathic epilepsy or convulsantdrug overdose. Midazolam and lorazepam have the advantage of rapidabsorption after intramuscular injection. Lorazepam also has a longerduration of anticonvulsant action than do the other two agents.
Hypertension. These drugs can be used for the initial treatment of sympathomimetic-induced hypertension.
Muscle relaxant. Thesedrugs can be used for relaxation of excessive muscle rigidity andcontractions (eg, caused by strychnine poisoning or black widow spiderenvenomation or rigidity syndromes with hyperthermia or dyskinesias ortetanus).
E. Chloroquine poisoning. Diazepam may antagonize cardiotoxicity.
F. Alcohol or sedative-hypnotic withdrawal. Diazepamand lorazepam are used to abate symptoms and signs of alcohol andhypnosedative withdrawal (eg, anxiety, tremor, and seizures).
G. Conscious sedation. Midazolamis used to induce sedation and amnesia during brief procedures and inconjunction with neuromuscular paralysis for endotracheal intubation.
H. Nerve agents. Thesedrugs can be used for the treatment of agitation, musclefasciculations, and seizures associated with nerve agent poisoning (seeWarfare Agents—Chemical). They may have an additive or synergisticeffect with other nerve agent antidotes (2-PAM, atropine).
Drug Contra-Indications ::
III. Contraindications. Do not use in patients with a known sensitivity to benzodiazepines.
Drug Adverse Effects ::
IV. Adverse effects
Centralnervous system–depressant effects may interfere with evaluation ofneurologic function. They also may cause a paradoxic reaction(restlessness, agitation) in less than 1% of patients (adults andchildren). Flumazenil (see Flumazenil) has been used successfully tomanage this effect.
Excessive or rapid intravenous administration may cause respiratory arrest.
The drug may precipitate or worsen hepatic encephalopathy.
Rapidor large-volume IV administration may cause cardiotoxicity similar tothat seen with phenytoin (see Phenytoin) because of the diluentpropylene glycol. Continuous infusions with this vehicle may alsoresult in a hyperlactatemia, increased osmolar gap, and renaldysfunction. Several products also contain up to 2% benzyl alcohol as apreservative.
E. Use in pregnancy. FDAcategory D. All these drugs readily cross the placenta. However, thisdoes not preclude their acute, short-term use for a seriouslysymptomatic patient (see Table III–1).
Drug Lab Interactions ::
Drug or laboratory interactions
Benzodiazepineswill potentiate the CNS–depressant effects of opioids, ethanol, andother sedative-hypnotic and depressant drugs.
Flumazenil(see Flumazenil) will reverse the effects of benzodiazepines and maytrigger an acute abstinence syndrome in patients who use the drugschronically. Patients who have received flumazenil will have anunpredictable but reduced or absent response to benzodiazepines.
Diazepam may produce a false-positive glucose reaction with Clinistix and Diastix test strips.
Drug Dose Management ::
Dosage and method of administration
Anxiety or agitation; muscle spasm or hyperactivity; hypertension
1. Diazepam.Give 0.1–0.2 mg/kg (usual doses: children > 5 years and adults 2–10mg; children > 30 days to 5 years 1–2 mg) IV initially (no fasterthan 5 mg/min in adults; administer over 3 minutes in children),depending on severity (tetanus requires higher doses); may repeat every1–4 hours as needed. The oral dose is 0.1–0.3 mg/kg (adults 2–10 mg;lower doses for geriatric patients not to exceed 2.5 mg and lessfrequent intervals; children > 6 months 1–2.5 mg). Doses should beadjusted to tolerance and response. Caution: Do notgive intramuscularly because of erratic absorption and pain oninjection. Use lorazepam or midazolam if IM administration is necessary.
2. Lorazepam.Give 1–2 mg (children: 0.04 mg/kg IV) not to exceed 2 mg/min or 0.05mg/kg IM (maximum 4 mg). The usual adult oral dose is 2–6 mg daily.
3. Midazolam.Give 0.05 mg/kg (up to 0.35 mg/kg for anesthesia induction) IV over20–30 seconds (usual adult doses vary from 1 mg to a maximum of 5 mggiven in increments of 2.5 mg every 2 minutes; lower dose in geriatricpatients with maximum at 3.5 mg) or 0.07–0.1 mg/kg IM. Repeat after10–20 minutes if needed. Continuous infusions have also been used tomaintain effect with initial rates of 0.02–0.1 mg/kg/h (usual adultdose 1–7 mg/h; children 1–2 mcg/kg/min) and then titrated to effect. Caution:There have been several reports of respiratory arrest and hypotensionafter rapid intravenous injection, especially when midazolam is givenin combination with opioids. Prolonged continuous infusion may lead topersistent sedation after the drug is discontinued because midazolamaccumulates in tissues.
Convulsions. Note:If convulsions persist after initial doses of benzodiazepines, consideralternative anticonvulsant drugs such as phenobarbital (seePhenobarbital), phenytoin (Phenytoin and Fosphenytoin), pentobarbital(Pentobarbital),and propofol (Propofol). Also, see treatment ofseizures (Seizures).
1. Diazepam. Give 0.1–0.2 mg/kg IV, not to exceed 5 mg/min, every 5–10 minutes (usual initial doses: adult, 5–10 mg; children 
5 years, 1–2 mg; children 
5 years, 0.2–0.5 mg), to a maximum total of 30 mg (adults) or 5 mg (young children) or 10 mg (older children).
2. Lorazepam.Give 1–2 mg (neonates, 0.05–0.1 mg/kg; older children, 0.04 mg/kg) IV,not to exceed 2 mg/min; repeat if needed after 5–10 minutes. Usual dosefor status epilepticus is up to 4 mg slow IV push over 2 minutes(dilute with an equal volume of saline). The drug can also be given IM(0.05 mg/kg, maximum 4 mg), with onset of effects after 6–10 minutes.
3. Midazolam.Give 0.05 mg/kg (up to 0.2 mg/kg for refractory status epilepticus) IVover 20–30 seconds or 0.1–0.2 mg/kg IM; this may be repeated if neededafter 5–10 minutes or maintained with a continuous infusion (see noteabove). The drug is absorbed rapidly after IM injection and can be usedwhen IV access is not readily available.
Chloroquine and hydroxychloroquine intoxication. There is reported improvement of cardiotoxicity with high-dose administration of diazepam at 1–2 mg/kg IV (infuse over 30 minutes) followed by an infusion of 2 mg/kg/24 hours. Caution: This probably will cause apnea; the patient must be intubated, and ventilation must be controlled.
Alcohol withdrawal syndrome
1. Diazepam.Administer 5–10 mg IV initially, then 5 mg every 10 minutes until thepatient is calm. Large doses may be required to sedate patients withsevere withdrawal. The oral dose is 10–20 mg initially, repeated every1–2 hours until calm.
2. Lorazepam. Administer1–2 mg IV initially, then 1 mg every 10 minutes until the patient iscalm. Large doses may be required to sedate patients in severewithdrawal. (Note: Multidose vials may contain diluentsand preservatives such as propylene glycol and benzyl alcohol, whichcan be toxic in high doses.) The usual oral dose is 2–4 mg, repeatedevery 1–2 hours until calm.
Drug Chemical Formulations ::
Formulations
Parenteral
1. Diazepam(Valium, others): 5-mg/mL solution, 2-mL prefilled syringes. 10 mg IMautoinjector (ComboPen) for nerve agent poisoning; note caution above.
2. Lorazepam (Ativan, others): 2- and 4-mg/mL solutions; 1 mL in 2-mL syringe for dilution and 10 mL multidose vials.
3. Midazolam (Versed): 1- and 5-mg/mL solutions; 1-, 2-, 5-, and 10-mL vials.
Oral
1. Diazepam (Valium, others): 2-, 5-, and 10-mg tablets.
2. Lorazepam (Ativan, others): 0.5-, 1-, and 2-mg tablets; 2 mg/mL oral solution.
Suggested minimum stocking levels to treat a 70-kg adult for the first 24 hours:
1. Diazepam, 200 mg.
2. Lorazepam, 24 mg.
3. Midazolam, 50 mg (two vials of 5 mg/mL, 5 mL each, or equivalent).