Benzodiazepines: pros and cons (Proceedings)

Dea class IV

• Rapid onset of action

• Only acts for a few hours

• Potential for human abuse: Psychological dependency, Physical dependency

• Can be safely used with many other psychoactive medications

Action

• Facilitates GABA in the CNS by binding to GABAA receptors.

• Behavioral effects due to action on the hypthalamus and limbic system

Uses

• Anxiety and phobias in all species

• Behavioral disorders in which anxiety is a contributing factor

Aggression

• Evidence in literature is contradictory.  Aggression may increase or decrease depending on

• Species, Sex, Type of aggression, Specific benzodiazepine, Specific dose, Single-dose vs. repeated dosing

• Lack a specific anti-aggressive mechanism

• May help with fear-induced aggression

• Use with caution in fear aggression.  Learned inhibition of aggression may be lost.

Affiliative behavior

• May increase, depending on

• Species, Sex, Type of aggression, Specific benzodiazepine, Specific dose, Single-dose vs. repeated dosing

Side-effects

• Sedation, Muscle relaxation, Increased appetite, Paradoxical excitation, Increased friendliness, Anxiety,

• Hallucinations, Muscle spasticity, Insomnia, Idiopathic hepatic necrosis in cats (Diazepam)

Excreted in milk

• Passes through the placenta

• Changes in absorption, distribution, metabolism and excretion occur in various disease states, e.g. impaired hepatic or renal function

• Decrease dose in patients that are,Old,Obese,Impaired renal function,Impaired liver function,

• Taking other medications that are metabolized by the cytochrome P450 enzyme system

• Do not give to patients with narrow angle glaucoma

May or may not interfere with learning

• Can have an amnestic effect

Wide variation in optimum dose for individual animal

• Tolerance can develop in patients that are on a benzodiazepine for a long period of time, resulting in the need to repeatedly raise the dose to maintain efficacy.

Withdraw gradually

• If patient has been on higher dose daily for several weeks, eventually becomes physically addicted.  Gradual withdrawal can avoid side-effects that abrupt withdrawal can cause.

• Gradual reduction allows identification of specific dose that may still be required to control the problem.

• Sudden termination in a patient that has been on continuously for a long period of time can result in rebound, i.e. a resumption of symptoms which may be more intense than prior to treatment. Most likely if has been on a short-acting benzodiazepine.

To begin

• Begin when situation for which drug is being used does not exist, e.g. owner home and no storms.

• Test lowest dose to make sure animal is not unusually sensitive (ataxic, sedated) and does not show paradoxical excitement.

• Test in actual situation, e.g. thunderstorm, owner leaves (videotape)

• If sufficient, maintain that dose

• If insufficient, incrementally increase the dose until

• Find effective dose or

• Experience unacceptable side-effects

• If cannot find effective dose without side-effects, change medication.

• Diazepam → Alprazolam

• Alprazolam → Diazepam

The fact that one medication does not work well does not mean that another will not.

• When discontinuing, common rule of thumb is to decrease dose no faster than 25% each week

• Do more slowly if

• Patient has been on medication a long time (months)

• Particular concerns about relapse

Alprazolam (Xanax and generic)

• Available as 0.25, 0.5, 1.0 and 2.0 mg tablets

• Dogs: 0.02-0.1 mg/kg q4h

• Cats: 0.0125-0.025 mg/kg q8h

• Clinical Pharmacology

• Readily absorbed following oral administration

• Peak concentrations in plasma occur in 1-2 hours (humans)

• Plasma levels proportionate to dose given

• Mean plasma elimination half-life (healthy humans) 11.2 hours

• Half-life in African green monkeys is 5.7 hours

• For veterinary patients

• Sporadic use, as in thunderphobia

• Regular use, as in SA

• Alone or as a supplement to another medication with anxiolytic properties such as a TCA or SSRI.

• Short term use in severe cases until a delayed onset of action medication has time to take effect.

• Use in thunderstorms

• Most effective if given 30-60 minutes BEFORE occurrence of the earliest stimuli that elicit fear responses.  Owners must monitor weather conditions closely.  If in doubt, medicate.

• If dog is already showing fear, give anyway as may help some, but not as effective

• Dogs given escalating dose over 18 to 26 until achieve a dose of 12 mg/kg q.i.d., then maintained on that dose for three weeks become physically addicted.

• Liver failure?

• Not yet reported in veterinary patients, but has occurred as a rare event in humans.

Chlordiazepoxide (Librium and generic)

• Available as 5, 10 and 25 mg capsules

• Dogs: 2.0-6.5 mg/kg q8h

• Cats: 0.2-1.0 mg/kg q12h

Dog

• Plasma levels peak around 2-5 hours after a single dose of 0.5-0.8 mg/kg

• Plasma levels peak around 7-8 hours after a single dose of 4 or 20 mg/kg.

• Doses of 2.5-20 mg/kg stimulate appetite

• Doses of 10-40 mg/kg cause ataxia

• Given doses up to 50 mg/kg PO for 6 months have not shown adverse effects.

Cats: Dose of 200 mg/kg PO fatal in 5 days

• Dogs given 80 mg/kg showed non-specific toxic changes

• 2/6 dogs given 127 mg/kg died from circulatory collapse

• 6/6 dogs given 200 mg/kg died

• Nervous/timid dogs become less timid at 3.5 mg/kg daily in the morning

• Used to tame zoo animals for handling

Clonazepam (Klonopin and generic)

• Available as 0.5, 1.0 and 2.0 mg tablets

• Dogs: 0.1-0.5 mg/kg q8-12h

• Cats: 0.15-0.2 mg/kg q8h

• Extensive metabolism in the liver to various inactive metabolites.  Not the best choice for patients with liver disease

• Dogs given 0.5 mg/kg q12h

• Week 1; half-life 2 hours

• Week 3; half-life 8 hours

• Dogs given clonazepam q12h for three or more weeks, then acutely withdrawn, exhibit anorexia, hyperthermia and weight loss

• Cats given 1000 mg/kg survived

Clorazepate dipotassium (Tranxene® & generic)

Available as 3.75, 7.5, 11.25, 15.0, 22.5 and 5.0 mg tablets and 3.75, 7.5 and 15 mg capsules

• Clorazepate

• DOGS: 0.5-2.0 mg/kg q4h

• CATS: 0.5-2.0 mg/kg q12h

• In the acidity of the GI tract, it is decarboxylated to form nordiazepam (active)

• Plasma nordiazepam is metabolized by hydroxylation to conjugated oxazepam (3-hydroxynordiazepam) and r-hydroxynordiazepam.

• Dogs given a single dose of 2 mg/kg PO have peak plasma concentrations of nordiazepam at 1-3 hours.

• Mean elimination half-life of nordiazepam is 284 minutes (almost 5 hours) after a single dose and 355 minutes (almost 6 hours) after multiple doses given q12h.

• Half-life much longer in humans.

Diazepam (Valium® & generic)

• Available as 2, 5, and 10 mg tablets; 1 mg/ml and 5 mg/ml oral suspension; 5 mg/ml injectable solution; 2.5, 5, 10 , 15 and 20 mg rectal gel

• Dogs       0.5-2.0 mg/kg q4h

• Cats         0.1-1.0 mg/kg q4h

• Rabbit      0.1-0.6 mg/kg

Blood concentrations are proportional to dose given.

• Half-life

• Dog         2.5-3.2 hours

• Cat           5.5 hours

Multiple metabolites: nordiazepam, oxazepam, temazepam

• Half-life of nordiazepam

• Dog         3-5.7 hours

• Cat           21.3 hours

• Half-life of oxazepam

• Dog         3-5.7 hours

Cats: 500 mg/kg PO is fatal within 1 day

• Acute withdrawal of diazepam dependent dogs by administration of flumazenil.

• Tremors, twitches, jerks, seizures

• Reports of death due to acute hepatic necrosis reported in cats beginning in 1994.

• Clinical signs as soon as 5 days after beginning daily administration.

• Death within 24 hours in spite of aggressive supportive treatment.

• Some do survive

• Various brands

Possible cause?

• Substance incorporated during tablet production?

• Multiple brands have caused the problem

• Speculation that there is accumulation of a toxic intermediate metabolite unique to some cats?

• In a study of “Acute hepatic necrosis and liver failure associated with benzodiazepine therapy in six cats”, all the subjects had cardiac, pancreatic or renal disease.

• Incidental finding?

• Prior disease potentiating hepatotoxic insult?

• Speculation that a virus was occurring in cats at the time of these deaths?

• No conclusive evidence as to why diazepam caused fatal hepatic necrosis.

• Take baseline blood chemistry before start.

• Check at 3-5 days.

• If elevated Alanine Transaminase (ALT) or Aspartate Transaminase (AST), discontinue.

• While there is a real risk of fatal liver disease when using diazepam, it is RARE.

Lorazepam (Ativan and generic)

• Available as 0.5, 1.0 and 2.0 mg tablets and 2 mg/ml oral solution

• Dogs: 0.02-0.5 mg/kg q18-12h

• Cats: 0.03-0.08 mg/kg q12h            

• Major metabolite is lorazepam glucuronide, which has no significant CNS activity.

• Formation of lorazepam glucuronide is much faster in dogs than in humans.  Peak plasma levels of unchanged lorazepam are almost identical in humans and dogs if dogs are given a dose 30X higher than humans on a per kg basis.

• Cats do glucuronidate lorazepam!

• Peak plasma concentration

• Dog: 0.5 hours at 1 mg/kg PO

• Cat: 12 hours at 20 mg/kg PO

• Good separation between anxiety-reducing doses and sedative-hypnotic doses

Oxazepam (Serax and generic)

• Available as 10, 15 and 30 mg capsules and as 15 and 30 mg tablets.

• Dog: 0.04-1.0 mg/kg q6h

• Cat: 0.2-1.0 mg/kg q12h

• No active intermediate metabolites

• Main metabolite is an inactive glucuronide conjugation of oxazepam.

• May be best benzodiazepine for geriatric patients and patients with liver disease or obesity.

• Dogs given 5-10 mg/kg oxazepam PO exhibit peak plasma levels in 4-6 hours.

• Wide separation of clinically effective doses and doses that produce side-effects

• Has a larger spread between clinically effective dose and dose that produces side-effects than chlordiazepoxide or diazepam.

• Dogs given 480 mg/kg daily for 4 weeks or 120 mg/kg daily for 52 weeks showed no specific toxic changes.

At doses of 960 mg/kg 25% of dogs die with circulatory collapse.

• Cats: Good appetite stimulant with longer duration of action than diazepam.  No reported incidents of liver failure.  If liver failure is due to problems of metabolism in some individuals, oxazepam is probably unlikely to cause this problem.