Imidazole compounds

http://en.wikipedia.org/wiki/Imidazole

Imidazole has become an important part of many pharmaceuticals. Synthetic

imidazoles are present in many fungicides and antifungal, antiprotozoal, and
antihypertensive medications. Imidazole is part of the theophylline molecule, found in
tea leaves and coffee beans, which stimulates the central nervous system. It is present
in the anticancer medication mercaptopurine, which combats leukemia by interfering
with DNA activities.

The substituted imidazole derivatives are valuable in treatment of many systemic

fungal infections.[9] Imidazoles belong to the class of Azole antifungals, which
includes ketoconazole, miconazole, and clotrimazole.
 Imidazole compounds

2- Clonidine: (Catapress)
It is an imidazoline compound.
Action:
It is a selective partial agonist for α2B (no effect on α2A or α2C) with an α2: α1 ratio of
200: 1 .
It also acts on imidazoline (I) receptors which controls arterial blood pressure.
• It stimulates central presynaptic α2 receptors (in the hypothalamus and
locus caeruleus): resulting in decreased noradrenaline release (i.e. decreased
central sympathetic outflow) which in turn leads to hypotension, bradycardia,
sedation, and anxiolysis.
• It stimulates central postsynaptic α2 receptors and imidazoline (I)
receptors (in the medulla): resulting in decreased blood pressure, heart rate, and
myocardial contractility. This causes reduction of myocardial O2 requirements.
• It stimulates peripheral presynaptic α2 receptors: resulting in decreased
noradrenaline release.
• It stimulates peripheral postsynaptic α1 and α2 receptors (in over dosage
and after rapid i.v. injection): resulting in transient elevation of blood pressure.
• It stimulates central postsynaptic α1 receptors (only in very high doses),
resulting in limitation of its anesthetic action.
• It decreases noradrenaline synthesis by inhibition of dopamine β-
hydroxylase enzyme and N-methyltransferase enzymes.
• It decreases renin activity and renal vascular resistance, therefore; it
maintains renal blood flow.
• It has an analgesic action via action on pre- and postsynaptic α2 receptors
(that not reversed by naloxone) due to:
- stimulation of descending inhibitory pathways from the locus caeruleus.
- inhibition of nociceptive transmission (and inhibition of release of
substance P) at the spinal cord.
and - It potentiates the actions of opioids and local anesthetics.
Uses:
• Moderate and severe hypertension especially in patients with high plasma renin.
• During management of opioid, benzodiazepine, nicotine (tobacco) and alcohol
withdrawal symptoms as it decreases signs of sympathetic over activity.
• As a preanesthetic medication: because it controls blood pressure, attenuates
the stress response, produces sedation, antisialagogue, and potentiate other i.v.
and inhalational anesthetics (up to 50%), but with limits (due to its α 1 action in
high doses).
• With regional anesthesia, because it speeds the onset and prolongs the duration
of the block.
• Clonidine suppression test to differentiate patients with essential hypertension
from those with suspected pheochromocytoma as acute administration of
clonidine decreases the plasma noradrenaline levels in essential hypertension,
but not in pheochromocytoma.
• Postoperative shivering and opioid-induced muscle rigidity, because it
decreases them.
• Diarrhea of autonomic neuropathy.
• Chronic pain e.g. diabetic neuropathy and migraine.
• Menopausal hot flushes.
Side Effects:
• Due to decreased sympathetic activity; as α-methyl dopa (see above).
• Due to sudden clonidine cessation (after 1 months usage); acute withdrawal
syndrome occurs with hypertensive crisis, agitation, and sympathetic overactivity
due to up-regulation of the receptors which is treated by reinstitution of clonidine
therapy or giving α and β blockers.
Drug Interactions:
• With tricyclic antidepressants, hypertension may occur (due to their α-blocking
action).
• With central nervous system depressants, excessive drowsiness occurs.
 Imidazole compounds

Pharmacokinetics:
It is lipid soluble and crosses the blood brain barrier and the placenta. Its
elimination t1/2 is 9-12 hours.
50% of clonidine is metabolized in the liver resulting in inactive metabolites and
50% is excreted unchanged by the kidney.
Doses:
• Oral: 200-300 µg (3-5 µg/kg) for premedication (1 hour preoperatively) and as
antihypertensive (every 12 hours).
• Epidural: 1-2 µg/kg for analgesia and potentiation of other local
anesthetics.
• I.v.: 200-300 µg (3-5 µg/kg) for anesthesia (and decreasing the stress
response).
• Transdermal patch: 0.1 or 0.2 mg released/day patches that are replaced every
7 days for chronic pain and menopausal hot flushes.
It can be taken also by i.m. (2 µg/kg), intrathecal (75-150 µg), sublingual and
rectal routes.

3- Dexmedetomidine: (Precedex)
Action: It is similar to clonidine, with the following differences:
• It is a selective full agonist for α2B and partial agonist on α2A and α2C. The α2: α1
selectivity ratio is 1600: 1 (it has no action on α1 receptors; therefore potentiate
the MAC of inhalational anesthetics up to 90%). It is more selective and effective
on α2 receptors than clonidine
• It also binds to imidazoline (I) receptors.
• It has a shorter duration; its elimination t1/2 is 2 hours only and metabolized in
the liver to metabolites which are excreted in the urine.
Clinical Uses:
It is mainly used for intraoperative sedation e.g. during regional anesthesia or
awake fiberoptic intubation and for short-term sedation in intensive care
especially during mechanical ventilation with the following advantages:
• Although patients are sedated, but they can be easily aroused.
• It blocks sympathetic stimulation with reduction of tachycardia and
hypertension which occur during mechanical ventilation.
• It does not cause respiratory depression, therefore; no need to stop it
before extubation, unlike propofol, benzodiazepines, and opioids.
Side Effects:
They are as clonidine (see above).
Acute withdrawal syndrome occurs after only 48 hours usage due to its increased
affinity to receptors when it is compared to clonidine.
Doses:
• I.v.: loading 1 µg/kg slowly over 10 min then maintenance dose as 0.2-0.7
µg/kg/h.