Midazolam

Last generation hypnotic benzodiazepine.

Midazolam 5mg/mL. Hydro-soluble painless solution.

MIDAZOLAM is an agent that comes from a last generation group of benzodiazepines; it can be used as anti-anxiety, tranquillizer, sedative, hypnotic, anticonvulsive and muscular relaxing. It is indicated alone or combined with analgesic, parasympathicolytics and anesthetics agents according to different protocols.

MIDAZOLAM is twice as powerful as Diazepam and its toxicity gets reduced to a half. 

MIDAZOLAM has a unique solubility characteristics; it is hydro-soluble in its original formulation situation and fat-soluble at body PH level, which gives it a quick action after the injection.

MIDAZOLAM is an hypnotic benzodiazepine of quick action, its effects lasts 2-4 hours, which is in favour of the maneuverability of the medicine and its effects control. It gives a minor anesthesia induction time, thus allowing the reduction of doses of inducer and maintenance (halothane) agents.

MIDAZOLAM gives the patient a calm and wide wake up.

Bioactivity:

MIDAZOLAM acts selectively on the polysynaptic neuronal via influenced by the essential action of gamma amino butyric acid or glycine.

MIDAZOLAM acts over all the central nervous system and its inhibitory action is –almost exclusively- presynaptic. This presynaptic inhibitory action has the same power than Diazepam, but it is more effective.

MIDAZOLAM acts on the ascending reticular system and its action over this centre is responsible of its anti-anxiety, tranquillizer, hypnotic y sedative effects.

The hypnotic effect of MIDAZOLAM is given by the depression of the cortical centers and the muscular relaxation is due to the depression caused by MIDAZOLAM over the spinal motor centers.

Pharmacokinetics:

After intramuscular injection, MIDAZOLAM is quickly and almost completely absorbed (91%). Although, there are no oral administration products that contain this drug, MIDAZOLAM is well absorbed after its oral administration. However, because of its quick effect at first step, its bioavailability varies between 31 - 72%. The latency time after IV administration is very fast because the agent has a high property of been assimilated to the lipids.

The drug is highly related to the plasmatic proteins (94 – 97%) and goes quickly across the hemato-brainstem barrier.

MIDAZOLAM is metabolized in the liver because of mycrosomal oxidation. It does not produce clinical effects because it active metabolite has a short average life and low pharmacological activity.

MIDAZOLAM´s serum average life and activity duration are considerable shorter than diazepam’s.

Compatibility:

MIDAZOLAM is compatible with the following products: atropine sulfate, glycopirrolate, Ketamine, morphine, fentanyl and Nalbufine.

Compatibility depends on many factors such as PH, concentration, temperature, solvents.

MIDAZOLAM precipitates in solutions containing Sodium Bicarbonate.

 

DOSAGE:

• Maximum suggested dose: until 1 mg/kg.

Canines: 0,1 to 0,2 mg/kg - 0,25 to 0,5 ml/10 kg - 2 to 4 hours - IM, IV.

Felines: 0,1 to 0,2 mg/kg - 0,125 to 0,25 ml/5kg - 2 to 4 hours - IM, IV.

Sports Equines: 0,1 to 0,02 mg/kg - 2,0 to 4,0 ml/100 kg - 2 to 4 hours - IM, IV.

Hypnotic dose: all species, to reach a hypnotic effect, the dose mentioned above should be doubled.

In contrast to Diazepam, MIDAZOLAM IM administration is well tolerated and so is its response.

In these doses and using Midazolam as anaesthetics pre-medication, the doses in inductive agents should be reduced to 50% without pre-medication for those agents.

  • Diagnostics and minor surgical proceedings:

Canines: 0,28 mg/kg - 0,56 ml/10 kg - IM - + Ketamine: 5, 6 mg/kg IM

Felines: 0,2 mg/kg - 0,2 ml/5kg - IM - + Ketamine: 10 mg/kg IM

• Anesthesia induction:

These protocols can be complemented with infiltrative local anaesthesia for minor surgical proceedings or when epidural or regional anaesthesia is used.

Midazolam/Ketamine

Midazolam 0,28 mg/kg IV equivalent to 0,056 ml/kg + Ketamine 5,6 mg/kg IV.

Midazolam/Thiopental

Midazolam 0,28 mg/kg IV equivalent to 0,056 ml/kg + Thiopental 3 to 8 mg/kg IV.

Midazolam /Propofol

Midazolam 0,28 mg/kg IV equivalent to 0,056 ml/kg + Propofol 2 mg/kg slow IV.

Administer supplementary doses of Propofol (0.5 mg/kg every 60 seconds) until the palpebral reflex despairs.

• Ambulatory surgery in felines:

- Protocol A:

Acepromazine 0,01 mg/kg IM

Midazolam 1 mg/kg IM (0.2 ml/kg)

Ketamine 20 mg/kg IM

Fentanyl 0,02 mg/kg IM

Latency:  4.5 +/- 0,7 min.

Analgesia: 50 +/- 6 min.

Head movements: 54 +/- 9 min.

Recovery: 83 +/- 13 min.

- Protocol B:

Acepromazine 0,01 mg/kg IM

Midazolam 1 mg/kg IM (0,2 ml/kg)

Ketamine 20 mg/kg IM

Latency: 4 +/- 1 min.

Analgesia: 54 +/- 12 min.

Head movements: 57 +/- 9 min.

Recovery: 85 +/- 18 min.

  • In canine patients with heart disease:

a- Hypertrophic cardiomyopathy:

- Pre-medication:

Midazolam 0,1 mg/kg IM (0,02 ml/kg)

Nalbufine 0,4 mg/kg IM

- Induction:

Thiopental 3 to 8 mg/kg IV or Propofol 1 to 2 mg/kg IV with supplementary doses of 0,5 mg/kg every 60 seconds.

- Maintenance:

 Halothane + Oxygen.

b- Dilated cardiomyopathy:

- Pre-medication:

Midazolam 0,1 mg/kg IM(0,02 ml/kg)

- Induction:

Thiopental 3 to 8 mg/kg IV or Propofol 1 to 2 mg/kg IV with supplementary doses of 0,5 mg/kg every 60 seconds.

- Maintenance:

Halothane 0,5 to 1,5 % + Oxygen

  • Continuous infusion:

a- Thorax surgery in canines:

Midazolam 0,55 µg/kg min. + fentanyl 0,7 µg/kg min.

b- Intraocular surgery in equines:

- Pre-medication:

Romifidine 0,08 mg/kg IV.

- Induction:

Glyceryl  guaiacolate ether 100 mg/kg IV + Midazolam 0,1 mg/kg IV + Ketamine 1 mg/kg IV.

- Maintenance:

Halothane + Oxygen

With this protocol, there are no registered intraocular pressure increases.

  • Muscular contractures:

In patients with post-traumatic sympathetic syndrome.

In patients with painful syndrome because of intervertebral disk disease.

MIDAZOLAM could be used IM via combined with AINES (Aspirin, Phenylbutazone, Flunixin Meglumine, etc.).

In indicated species, the interval to administrate the repeated treatment is of 2 to 4 hours.

 

ADMINISTRATION:

Sterile injectable solution ready to use.

 

PRESENTATION:

20 ml vials. Sterile injectable solution.

 

OBSERVATION:

MIDAZOLAM has a quick, intense and short sedative and hypo-inducer action. It also has anti-anxiety, anticonvulsive, tranquillizing and mio-relaxing properties.

• Pre-anesthetics: it can be used alone or in combination with analgesics, parasympathicolytics (atropine), etc.

• Minor surgical and diagnostic proceedings: combined with Ketamine or Xylazine.

• Anesthesia inducer in normal or critic patients: it can be combined with Ketamine, thiopental and propofol.

• Minor surgeries in felines: combined with acepromazine or Ketamine

• In cardiac canines patients.

• During thorax surgery in canines.

• Intra-ocular surgery in equines.

• Muscular contractures: in patients with post-traumatic sympathetic syndrome, in patients with painful syndrome because of intervertebral disk disease.

MIDAZOLAM is compared with thio-barbiturate induction agents (thiopental): it has a minor cardiopulmonary depressor effect, it is hydro-soluble, it can be mixed with other agents, and it is not prone to be accumulated in the organism after repeated doses.

 

CONTRAINDICATED:

• Do not administrate in patients with severe hypersensitiveness to the drug, acute liver failure, acute kidney failure, pregnant females and weak or old patients.

• It is possible that the patients with congestive heart failure eliminate the drug slowly. In patients with coma, shock or significant respiratory depression MIDAZOLAM should be very carefully administrated.

Pharmacological interactions:

Midazolam could empower the central depressive effect when it is administrated with anti-psychotics, hypnotics, anti-anxiety medication, anti-depressants, analgesics, narcotics, antiepileptic medication, anesthetics and sedative antihistamines.

There is a potentially significant interaction among Midazolam and other compounds that inhibit some hepatic enzymes (in particular, cytochrome P 450 III A). Experiences clearly indicate that these compounds modify midazolam and could induce to an extended sedation.

This reaction has been verified with cimetidine, erythromycin, verapamil, ketoconazole, e itraconazole. Therefore, patients who receive the mentioned compounds and others that inhibit P 450 III A at the same time that receive midazolam should be carefully controlled during the firsts hours after midazolam administration (tests have shown that ranitidine does not influence on midazolam pharmacokinetic, parenteral via).

During an in vitro test, several substances (among them, cyclosporine, amiodarone, neuroleptics) inhibited midazolam hydroxylation which leads to the conclusion that –in theory- interaction among lot of drugs is possible.

 

Suggestions:

It is recommended to establish a 12 hours solid and liquid fasting, previously to the general anaesthetics administration; in summer, this time could be reduced to a 6 hours liquid fasting.

It is necessary to emphasise on the fact that in some species fasting provokes adverse effects. Some mammals, birds and neonates could show hypoglycaemia even after not many hours of fasting; and glycogen stores mobilization could alter metabolism parameters and drugs clearance. This is an important point in ruminants.

In contrast, feeding canines before induction increases the metabolic rate for over 18 hours.

Anaesthesia induction in animals with full stomach should be avoided, if possible, due to the breathing in risks that could be run. Rumen strain in small and large ruminants prejudices normal ventilation and, therefore, it provokes hypoxemia and hypercapnia. Although food limitation does not empty the rumen, the possibility of regurgitation is reduced if, besides, 12-24 hours before anesthesia induction a liquid fasting is realized.

In equines, full stomach could get broken during induction, therefore, it is recommended to establish a solid and liquid fasting for not less than 6 hours. In very young or very old animals, water is usually offered until the last moment before pre-anesthetics agents administration.

Remember that nephritis is common in old canines; those patients should compensate under normal conditions, and stress because of hospitalization, water privation and anesthesia (sometimes, without surgery) could produce acute de-compensation.

Normal diuresis could be reestablished with fluids by continuous IV administration before anesthetic drugs administration.

In any case, fluids administration during anesthetic drugs administration turns out to be a good anesthetic practice; to help blood pressure and urine production keep suitable and to provide a permeable via to drugs administration.

Systemic pre-surgical wide spectrum antibiotics administration (e.g. sodium Ampicilline IV) is a prophylactic measure useful before mayor surgeries or those in which the place to be operated is under the risk of contamination.

 

Precautions:

• Midazolam potentates barbiturates and neuroleptics, diphenylhydantoin and phenobarbital effects.

• Midazolam provokes respiratory depression; its severity depends on the administration speed, that’s why it should never be less than 30 seconds; otherwise, an apnoea phenomenon will be observed.

• Check that the safety seal and the storage conditions of the product are the adequate to its correct use.

• In all cases, doses and warnings suggested are to be determined by the veterinarian in charge.

• Keep the product between 5 and y 30º C, protected from the direct sunlight, in a dry and hygienic place.

• Throw administration residues and disposable materials into pathogenic residues container.

• Recyclable container, destroy and throw in residues collectors after use.

• Protect the environment.

• Do not eat. Keep out of the reach of children.

• Sell under receipt and exclusively to Registered Veterinarians.