Pharmacology - Zolpidem

[Jatelka]

Zolpidem is a non-benzodiazepine hypnotic of the imidazopyridine class.

Chemically it’s structure is N,N,6-trimethyl-2-p-tolylimidazo[1,2-a] pyridine-3-acetamide. It’s chemical formula is C19H21N3O and it has a molecular weight of 307.395

It is a white to off-white crystalline powder that is sparingly soluble in water, alcohol, and propylene glycol.

Mechanism of action

Zolpidem interacts with a GABA-BZ receptor complex and shares some of the pharmacological properties of the benzodiazepines. (Benzodiazepines non-selectively bind to and activate all omega receptor subtypes whereas Zolpidem binds to the (ω1) receptor preferentially with high affinity for alpha1/alpha5 subunits.)

This selective binding of zolpidem on the (ω1) receptor is not absolute, but it may explain the relative absence of myorelaxant and anticonvulsant effects in animal studies as well as the preservation of deep sleep in human studies

Pharmacokinetics

Zolpidem is rapidly and completely absorbed after oral administration. With a 5mg oral dose the mean peak concentration is 59 ng/ml, and, with a 10mg oral dose it is 121 ng/ml, both occurring at 1.6 hours. The mean elimination half-life is 2.6 hours (Range 1.4 – 4.5 hours), and 2.5 hours (range 1.4-3.8 hours) for the 5 and 10mg doses respectively.

Zolpidem is converted to inactive metabolites that are eliminated by the kidneys. Zolpidem demonstrates linear pharmacokinetics over the 5-20mg dosage range. It is 92% protein bound., and has not been found to accumulate (in young adults) following nightly dosies of 20 mg for 2 weeks.
When taken on a full stomach the maximum plasma concentration is reduced 25%, and the mean elimination half-life is prolonged by 60% (from 1.4 to 2.2hr).

In the elderly (over 70) maximum plasma concentration, and elimination half-life are increased, by 50% (255 vs 384 ng/mL) and 32% (2.2 vs 2.9 hr), respectively, as compared to younger adults (20 to 40 years) following a single 20 mg dose. Zolpidem does not accumulate in older adults given a dose of 10mg nightly for 1 week.

Hepatic Insufficiency: Following a single 20 mg oral dose, the mean maximum plasma concentration is approximately twice as high as in normal subjects, although the time to maximum concentration is not significantly different. The mean half-life is 9.9 hr (range: 4.1 to 25.8 hr).

Renal Failure: Zolpidem is not significantly affected by renal failure or dialysis and no dosage adjustments are recommended, although these patients should be closely monitored.

Indications:

Zolpidem is indicated for short term treatment of insomnia. Clinical trials have only shown efficacy for 35 days.

Dosage

Recommended starting dose is 10mg immediately before retiring. In the elderly, and those with hepatic insufficiency, and those taking other sedatives (including alcohol) the recommended therapeutic dose is 5mg.
Maximum licensed dose is 10mg per day.

Adverse Effects

Common/frequent: Drowsiness, dizziness, amnesia, double vision, nausea/vomiting, diarrhoea, hiccups, myalgia, headache, euphoria, ataxia, and falls.

Infrequent: Increased sweating, postural hypotension, syncope, oedema, malaise, tachycardia, agitation, paradoxical reactions including hallucinations, mania and suicidal ideation, migraine, hangover effect, constipation,

Rare: Glaucoma, allergy/anaphylaxis, restless legs syndrome, weight loss, reduced libido, delusions, depersonalization, panic attacks, complex sleep-behaviours (Eg: driving, eating, sex), haematological reactions (including reduced blood, platelet and white cell counts), raised liver function tests. acne and dermatitis, acute renal failure

Interesting Note: Paradoxical Reactions, including agitation and hallucinations occur seven times more frequently in people with insomnia associated with ADHD than in those who do not have ADHD. Complex sleep-behaviours are more frequent when taken with other CNS Depressants.

Interactions

As with all sedatives, Zolpidem has an additive CNS depressant effect when administered with other CNS depressants (including alcohol).

Fluoxetine: Co-administration increases Zolpidem’s half-life by approximately 20%
Sertaline: Co-administration increases maximum plasma levels of Zolpidem by 43% and time taken to reach maximum level was significantly reduced (43%)

Drugs which affect metabolism by Cytochrome P450

Itraconazole: Co-administartion results in a 34% increase in maximum plasma levels
Rifampicin: Co-administration results in significant reductions in maximum plasma concentration, and elimination half life of Zolpidem (58% and 36% respectivel)

Cimetidine and ranitidine do not appear to affect the pharmacokinetics or Zolpidem.

Flumazenil reverses the sedative/hypnotic effects of Zolpidem.

Abuse Potential

Studies have demonstrated that, in “drug-abusers”, the effects of 40mg Zolpidem are similar (but not identical) to 20mg diazepam, whereas Zolpidem 10mg is indistinguishable from placebo for most.

Dependence and Withdrawal

Zolpidem does cause physical dependence, even after short-term use, and a subsequent withdrawal syndrome is well-documented, consisting of:

Fatigue, nausea, flushing, light-headedness, emotional lability, panic attacks, stomach cramps, nervousness and GI upset.

Zolpidem should therefore not be discontinued suddenly.

Carcinogenesis

There is no evidence of carcinogenesis (in mice or rats) at doses up to 115 times the maximal human dose, over prolonged periods.

Impairment of fertility

In a study in rats, high dose Zolpidem (100mg/kg) resulted in irregular cycles. But there was no reduction in fertility in males or females at doses between 4 and 100mg/kg

Pregnancy and Lactation

There are no trials in pregnant women, therefore Zolpidem should only be used in pregnancy if the benefit to the mother out weighs the risk to the foetus.

In rats at doses of 20mg/kg, incomplete ossification of bones has been demonstrated.

In rats, Zolpidem has been shown to inhibit secretion of milk, and is secreted in the milk that is produced, therefore use by nursing mothers is not recommended.

Sources: Rxlist, BNF, Clinical Evidence.

Reputation Comments on this post:

Good post.