1st used in 1961, & now have displaced barbiturates as sedative/hypnotics due to the remarkably low capacity to produce fatal CNS depression in OD & the main ones marketed are less sedative for the same anxiolytic effect.
they all appear to have pure CNS effects of sedation, hypnosis, anxiolytic, muscle relaxation, anterograde amnesia, anticonvulsant & possibly antidepressant (alprazolam).
Hypnotic actions:
most benzodiazepines lose their hypnotic efficacy after approx. 14 consecutive nights, even though people still keep taking them
quality of sleep is modified - less deep & relaxed sleep; tendency to fall asleep & awake earlier;
day-time: feelings of tiredness; lack of energy; mood disturbances;
in addition, there are only 2 peripheral effects:
coronary vasodilatation &
in high dose, NM blockade.
they are not general neuronal depressants like the barbiturates & also do not cause hyperalgesia but tolerance may develop which limits anticonvulsant usefulness.
Mechanism of action:
potentiates inhibitory GABA neurons & thus in OD, self-limiting effect as need to still actively produce GABA to maintain CNS depressive effect.
Adverse Effects:
Respiratory depression:
at endoscopy doses diazepam or midazolam
⇒ decreased alveolar ventilation, decreased PaO2, increased Pa CO2, & may cause CO2 narcosis if COAD;
apnoea if with opioids or in anaesthesia;
in OD, usually need other CNS drug before there is need for ETT/vent.;
CVS:
at premed doses → decr. BP, increased HR due to either: decr. PR or decr. LV work → decreased cardiac output
doubles risk of road traffic accidents in all age groups, but in addition, in persons over 65yrs, have an additional 50% risk if brief duration Rx or 30% risk if long term Rx.
dependence - mainly abused by those who already abuse other drugs;
Tolerance, dependence & withdrawal:
tolerance & withdrawal symptoms can occur in patients who have been taking benzodiazepines on a regular basis for a duration of 2 or more weeks.
it is difficult to predict which patients will become dependent, so all patients should be considered at risk
tolerance & withdrawal symptoms are experienced by up to 45% of patients discontinuing low therapeutic doses & up to 100% in patients taking high doses.
there is a significant risk of withdrawal symptoms if benzodiazepines are discontinued abruptly, esp. in the sick & the elderly.
withdrawal symptoms may persist for 6-8wks after cessation of benzodiazepines with a peak intensity in the 2nd & 3rd weeks. A minority will experience low grade symptoms intermittently for up to 6 months.
more than 1/3rd of long term benzodiazepine users can successfully cease their medication & another 1/3rd can reduce their dosage by half.
withdrawal symptoms:
insomnia (very common), anxiety/panic, dysphoria, tremor, dizziness, depression, paranoia, hyperacusis, muscle pains, restlessness, fatigue & uncommonly, depersonalisation, derealisation, abnormal perception or sensation of movement, and hallucinations (rare).
seizures may occur if abrupt withdrawal or if a benzodiazepine antagonist is given in patients on long term use of benzodiazepines.
P/K:
all completely absorbed but clorazepate (prodrug) ⇒ nordiazepam by gastric juice;
some (flurazepam) reach systemic circulation only as active metabolites;
hypnotic types reach peak levels 1-3hrs but others up to 8hrs;
IM absorption erratic except for midazolam & lorazepam;
They & their metabolites are strongly bound to pl. proteins (70% → 99% for diazepam)
CSF [ ] approx.= free plasma [ ]; No significant protein-binding compet. drug interactions;
2-compartment models apply (3-compartment for those with highest lipid sol.);
Thus, rapid → brain/organs then redistribute to muscle/fat - main decr. action if IV use
Enterohepatic circulation complicates P/K esp. for diazepam & other increased lipophilics;
Vd large & often increased in elderly; Cross placenta & into breast milk;
Extensively metabolised by several different microsomal enzyme systems:
forming slowly metab. active metabolites - diazepam, flurazepam, nordazepam;
forming inactive metab. first - oxazepam; temazepam; midazolam; triazolam;
benzodiazepines in the elderly:
consider using alternative drugs or none at all
emphasise duration of Rx is to be limited & discuss consequences of long term use
effectiveness is best with intermittent use.
select a benzodiazepine with short half life as in the elderly, long half-life drugs accumulate at regular doses & are associated with falls & hip fractures, etc.
Unusually potent at antag. effects of pentylenetetrazol but almost without action in ECT-induced seizures thus has anticonvulsant activity in wide range of seizure type with notable exception of generalised tonic-clonic seizures & thus useful in absences & myoclonic seizures in children but tolerance to these actions often develop after 1-6mths when no dose of clonazepam will be of use!!;
Plasma Rx range not helpful; Optimal dose hard to predict;
Chronic use → behav. effects, drowsiness, lethargy, hypotonia;
High-dose as in IV 0.25-1mg use (as with IV diazepam) → reduce sustained high-frequency firing of neurons similar to that seen with phenytoin, carbam. & valproate;
After IV dose → redistributed (→ muscle → fat) terminating action;