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benzodiazepines

benzodiazepines

Overview:

  • 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
  • large doses midazolam → decr. decr. cerebral blood flow & O2 assimilation;

GIT:

  • diazepam → marked decr. nocturnal gastric acid secretion;

CNS:

  • persistence next day (& @ peak) of dose-related decr. motor ability, cognition esp. in elderly & with other CNS drugs particularly alcohol;
    • long half-life benzodiazepines (esp. in elderly) result in increased risk of:
      • confusion, drowsiness, memory loss, unsteadiness, falls (thus hip fractures) & incontinence
      • 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.
  • occas. paradoxic effects (esp. nitrazepam) :
    • nightmares; anxiety; irritability; weakness, headache, blurred vision, N&V, diarrhoea, jt pains, PIC, incontinence;
    • increased seizures in some;
  • 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.
  • start low, increase slowly, suggested starting doses are:
    • alprazolam 0.25mg; diazepam 2.5mg; lorazepam 0.25mg; nitrazepam 2.5mg; oxazepam 7.5mg; temazepam 5mg; triazolam 0.125mg;

Examples:

Diazepam:

  • 99% prot. bound; enterohep. circ; metab. to nordazepam → oxazepam;
  • T½= 30-60hrs; Vd = 1.1L/kg; Clearance = 0.38ml/min/kg;
  • redistribution half-times: diazepam 1hr;

Midazolam:

  • 95% prot.bound; T½=2hrs; Vd = 1.1L/kg; Clear. = 6.6ml/min/kg;

Clonazepam:

  • Rivotril
  • 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;
  • To avoid sedation/irritability, keep initial dose low (eg. 0.25mg bd) & increased wkly.
  • 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;
benzodiazepines.txt · Last modified: 2009/04/20 15:51 (external edit)