Pharmacokinetics of Insomnia Medicines

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The ideal sleeping pill should have the following properties

  • High affinity for the active sites for the neurotransmitters the drug is trying to stimulate or inhibit
  • Low systemic availability of inhibitors
  • The correct duration of effect – long enough to keep the patient asleep all night, but not so long that sleep inertia in the morning is a major problem.

Especially for cases of secondary insomnia, when sleepiness is a symptom of another disorder, use of sleeping pills can cover up other problems and cause the patient to forgo complaining to the doctor.

Pharmacists and the wider medical community refer to sedative-hypnotics to signify a range of drugs that make people more relaxed and/or sleepy.  Drugs in this class may have completely different mechanisms from each other.  “Sedative” means the drug calms an awake patient and makes him or her less excited.  “Hypnotic” (from Hypnos, Green god of sleep) is a drug that makes people drowsy and promotes sleep.

The line between the two is not firm and many drugs act in both ways.

Even within the sedative-hypnotic class, there is a lot of variation. Benzodiazepines (e.g. Xanax) are great at reducing anxiety and are more often prescribed for that purpose today.  In the past doctors routine administered benzodiazepines for insomnia but newer drugs have displaced them from the marketplace.

The pharmacokinetics of insomnia medicines play a large part in how effective they are.  Drugs enter and are eliminated from the body by several processes that physiologists conveniently call ADME (absorption, distribution, metabolism, and excretion).  For the drugs we discuss at Tuck, absorption is through the digestive system. Drugs for insomnia or restless leg syndrome or other parasomnias and dyssomnias are generally not administered intravenously, nasally, or otherwise.  They are swallowed in pill form.  The rate of absorption varies but usually the patient’s bloodstream sees significant increases within an hour.  (In the case of liquid sodium oxybate, the absorption is so fast that patients are advised to be in bed when they swallow the medicine.)

Drugs exit the body either through breakdown in the liver (metabolism) or excretion.  The blood concentrations of drugs like these follow a roughly exponential decay and the rate they leave the body is characterized by a half-life.  This is short-hand for how long a drug lasts.  For insomnia drugs, a too-long half-life means the patient is still groggy in the morning, and a too-short half-life means the patient goes to sleep right away and then awakes in the middle of the night.  Getting the dosage and the half-life right is a large part of developing a new drug.

Elderly people typically have longer half-lives for the same drug than young adults.  This makes it tricky for those elderly people and their doctors.  If data about a drug has been developed by tests on young people, the pharmacokinetics could be different on the old.  This is one reason benzodiazepines and z-drugs are discouraged for seniors, and one reason ramelteon is preferentially given to them.

The Australian Prescriber Journal has a chart with pharmacokinetic parameters of some hypnotics. We like it so much we are presenting it here:

MedicineHalf life in body (typical adult)Time to max concentration
Z drugs
Zaleplon1 hour1 hour
Zolpidem2.4 hours0.5 to 3 hours
Zopidone5.3 hours1.75 hours
Benzodiazepine Receptor Agonists
Flunitrazepam25 hours1 to 2 hours
Temazepam10 hours0.5 to 2 hours
Nitrazepam27 hours1 hour
Triazolam7.8 hours (terminal phase)1.5 hours
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