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promethazine HCL / PhenegranTM
ANTI-EMETIC: Antihistamine:Antipsychotic:
MODERATE RISK
Description: Promethazine is a phenothiazine-type antihistamine. It is an HA-antagonist with considerable anticholinergic, sedative, and antiemetic effects and some local anesthetic properties. Promethazine is a versatile drug but is used predominantly as an antiemetic or to prevent motion sickness. Despite belonging to the phenothiazine class, it is rarely used as a neuroleptic. Promethazine was approved by the FDA in 1951.
Mechanism of Action: Promethazine's predominant action is antagonism of HA-receptors. Although promethazine is classified as a phenothiazine, its ability to antagonize dopamine is approximately one-tenth that of chlorpromazine. For this reason, promethazine is not used as a neuroleptic.
Like other antihistamines, promethazine does not prevent the release of histamine, as do cromolyn and nedocromil, but competes with free histamine for binding at HA-receptor sites. Histamine receptors in the GI tract, uterus, large blood vessels, and bronchial muscle are blocked. The relief of motion sickness and nausea/vomiting appear to be related to anticholinergic actions and may implicate activity on the medullary chemoreceptor trigger zone. Other CNS receptor sites can also be affected, since promethazine is believed to indirectly reduce stimuli to the brain stem reticular system. Sedation is significant at concentrations achieved from therapeutic dosages. Antitussive activity has been attributed to promethazine, but this effect probably results from anticholinergic and sedative actions. Local anesthetic activity requires higher concentrations than those required to antagonize histamine receptors.
Pharmacokinetics: Onset of action occurs within 15-60 minutes after oral or rectal administration and within 20 minutes after intramuscular administration. Following intravenous administration, onset of action occurs within 3-5 minutes. Antihistaminic effects last for 4-6 hours, and sedative effects last for 2-8 hours. Promethazine is highly protein-bound. It is widely distributed in body tissues and fluids, and it crosses the placenta and is excreted into breast milk. Metabolism occurs in the liver; the elimination half-life is 10-14 hours. Inactive metabolites-promethazine sulfoxide and other glucuronides-are excreted slowly in the urine and the feces.
CONTRAINDICATIONS/PRECAUTIONS: Promethazine is relatively contraindicated in patients with asthma and COPD, especially during acute attacks, because anticholinergic actions can thicken secretions and reduce expectoration.
Promethazine is classified as pregnancy category C. Antihistamines generally are not recommended for use in pregnancy, especially during the third trimester, because there is a risk of seizures in the fetus, although promethazine may be used as a sedative during labor. Risks-benefits should be considered during pregnancy and in women expecting to become pregnant. Antihistamines are contraindicated for use in women who are breast-feeding because they can induce hyperexcitability in the infant, seizures in premature infants, and inhibited lactation. Alternative methods of feeding are recommended if promethazine therapy is deemed necessary.
Promethazine should be used with extreme caution in children. Children can experience paradoxical CNS stimulation and should be supervised in their activities to ensure safety. Some children have experienced respiratory depression and sleep apnea while taking antihistamines; SIDS has occurred. The drug should be used with extreme caution in children who have a family history of SIDS or sleep apnea. Antihistamines are contraindicated in neonates because they may experience paradoxical CNS stimulation and there is an increased risk of seizures.
Promethazine should be used with extreme caution in patients predisposed to or with closed-angle glaucoma. Due to its anticholinergic actions, it can increase intraocular pressure, precipitating an acute attack of glaucoma. Promethazine must also be used cautiously in patients with open-angle glaucoma; glaucoma therapy may need to be adjusted.
Promethazine should be used cautiously in patients with hepatic disease. Promethazine is extensively metabolized in the liver, hepatic impairment may lead to a decrease in metabolism, a subsequent increase in drug levels, and an added risk of toxicity.
Because of anticholinergic effects, promethazine should be used with extreme caution in patients who have bladder obstruction, GI obstruction, prostatic hypertrophy, or urinary retention.
Phenothiazines have a quinidine-like action as well as anticholinergic action and should be used with caution in patients with cardiac disease because they can cause tachycardia, palpitations, and/or arrhythmias.
Promethazine has been reported to affect control of blood glucose in diabetic patients. Since promethazine is a phenothiazine, it should be used cautiously in patients with diabetes mellitus.
Promethazine should be used with caution in patients with hyperthyroidism or hypertension since it can exacerbate these conditions.
Promethazine should be used cautiously in patients with seizure disorder because phenothiazine can precipitate epileptiform seizures in patients with focal lesions of the cerebral cortex.
Antihistamines should be used with caution in patients undertaking tasks requiring mental alertness. Drowsiness can be severe in some patients, especially in the elderly. Patients should exercise extreme caution until the effects are known. Alcohol can add to sedation caused by promethazine.
In addition, antihistamines can mask signs of allergic reactions, thus delaying the diagnosis of a hypersensitivity reaction.
DRUG INTERACTIONS: Epinephrine and promethazine should be used together cautiously. Many references warn that if epinephrine is given to patients receiving chlorpromazine, epinephrine can paradoxically lower blood pressure. This has not been a consistent finding; nevertheless, since promethazine is also a phenothiazine, patients should be monitored for paradoxical responses to epinephrine administration. If hypotension occurs, a vasopressor with predominantly ›-agonist effects (e.g., norepinephrine or phenylephrine) should be used.
If promethazine is used concomitantly with other CNS depressants, additive CNS effects, such as drowsiness and sedation, can occur. Patients taking promethazine should be warned not to self-medicate with other antihistamines, ethanol, barbiturates, or anxiolytics, sedatives, and hypnotics.
MAOIs can increase and prolong the anticholinergic and CNS depressant effects of promethazine. Their concurrent use is not recommended.
Drugs with anticholinergic activity can add to the anticholinergic side effects of promethazine. These drugs include direct anticholinergics, tricyclic antidepressants, and phenothiazines.
A pharmacodynamic interaction can occur if promethazine is administered concomitantly with other medications that commonly cause extrapyramidal symptoms. These drugs include butyrophenones such as haloperidol, other phenothiazines, and metoclopramide.
Chlorpromazine has been reported to affect control of blood glucose in diabetic patients. It is unclear if phenothiazines directly interact with oral hypoglycemics. Since promethazine is a phenothiazine, it should be used cautiously in patients receiving oral hypoglycemics.
Concomitant use of antithyroid agents and phenothiazines can increase the risk of developing agranulocytosis. Promethazine should not be used with propylthiouracil.
In general, phenothiazines block the dopamine receptors in the brain. Although promethazine is a weak dopamine antagonist, it can counteract the actions of dopamine agonists such as levodopa and bromocriptine.
Concurrent use of intrathecal metrizamide with promethazine can lower the seizure threshold. The phenothiazine should be discontinued at least 48 hours before myelography and not resumed until at least 24 hours afterwards.
ADVERSE REACTIONS: Antihistamines sometimes cause CNS stimulation. This reaction is more likely to occur in children, particularly with a phenothiazine. Symptoms include restlessness, insomnia, palpitations, or seizures. Extrapyramidal effects are more likely to be dose-related and may disappear with a reduction in dosage.
Extrapyramidal symptoms (EPS) occur frequently during treatment with phenothiazines and appear to be the result of DA-receptor blockade. These symptoms occur with greater severity and frequency during high-dose therapy. Extrapyramidal symptoms are categorized as dystonia, akathisia (subjective and objective motor restlessness), and parkinsonism. Parkinsonian symptoms are more common in the elderly, whereas children most often develop dystonic reactions, which can be worsened by acute infections or severe dehydration. Dystonic reactions are seen during the first week of treatment. Akathisia and parkinsonian symptoms usually develop several days to weeks into therapy. Dystonia and pseudoparkinsonism usually are easily treated with concomitant benztropine, diphenhydramine, lorazepam, or amantadine. Akathisia may respond to dosage reduction or concomitant administration of a benzodiazepine (usually lorazepam) or propranolol. In rare patients, an alternate antipsychotic may be necessary. Neuroleptic malignant syndrome (NMS) can occur in patients receiving phenothiazines. NMS is characterized by hyperthermia, severe extrapyramidal dysfunction, alterations in consciousness, altered mental status, and autonomic instability (sinus tachycardia, low blood pressure or hypertension, diaphoresis). Increased serum creatine phosphokinase (CPK), acute renal failure, and leukocytosis also have occurred. NMS does not appear to be dose-related. Severe cases have resulted in death 3- 30 days after the onset of the syndrome. Several predisposing factors may contribute to the development of NMS including heat stress, physical exhaustion, dehydration, and organic brain disease. NMS occurs more frequently in young men. The phenothiazine should be immediately discontinued and appropriate supportive therapy initiated as soon as symptoms of NMS are discovered. Hypothermia and hyperthermia have been reported with phenothiazines independent of the neuroleptic malignant syndrome and may be caused by the effect of the phenothiazine on the hypothalamic control of temperature regulation. Hyperpyrexia and heat stroke unrelated to NMS also have occurred.
Tardive dyskinesia (TD) is characterized by involuntary movements of the perioral region (tongue, mouth, jaw, eyelids, or face) or choreoathetoid movements in the extremities. It can develop during long-term therapy or following discontinuation of phenothiazine therapy, and it is observed more frequently in elderly women. The incidence of TD may be higher in patients with bipolar disorder than with schizophrenia. Some cases can be irreversible. While contradictory evidence exists, it has been suggested that the likelihood of developing TD increases with prolonged treatment and cumulative doses. Although this complication often occurs following prolonged treatment or with administration of high dosages, it also has been reported to occur after short periods of time and with low dosages. Routine monitoring (at 3- to 6-month intervals) of movement disorders is considered the standard practice when using phenothiazines. If signs or symptoms of TD develop, the neuroleptic should be reevaluated and possibly discontinued.
Phenothiazines can cause a variety of CNS effects. Drowsiness occurs occasionally during initial treatment with some phenothiazines. Tolerance usually develops with continued therapy. Dizziness may occur as a result of orthostatic hypotension. Other CNS effects reported less frequently include restlessness, insomnia, depression, headache, and cerebral edema. Seizures can occur and are of special significance in patients with preexisting seizure disorders or EEG abnormalities.
Anticholinergic effects of phenothiazines include blurred vision, xerostomia, mydriasis, nausea, adynamic ileus, urinary retention, impotence, and constipation. These effects can be enhanced by the concomitant administration of anticholinergic antiparkinsonian drugs, antidepressants, or other anticholinergic agents.
Leukopenia including agranulocytosis is the most common hematologic disturbance that has been reported during phenothiazine administration. Agranulocytosis has occurred rarely and has been associated with combination treatment with other agents. Other hematologic abnormalities that have been associated with phenothiazine therapy include leukocytosis (usually in association with the neuroleptic malignant syndrome), eosinophilia, thrombocytopenia, pancytopenia, aplastic anemia, and anemia.
Prolonged therapy with phenothiazines can lead to skin hyperpigmentation. Hyperpigmentation generally is restricted to areas of the body exposed to sunlight. Photosensitivity can result, and patients should be warned either to keep out of the sun or to use effective sunscreens (SPF 15+) on exposed areas of the body. Withdrawal of the drug can reverse the effects. Contact dermatitis is also possible in predisposed individuals if they come in contact with liquid dosage forms of phenothiazines.
Phenothiazines can cause ocular changes. Pigmentary retinopathy can occur with or without pigmentary changes in the skin during therapy with phenothiazines. Symptoms of blurred vision, difficulty with nighttime vision, or defective color vision should be investigated promptly. Wearing protective dark glasses can reduce the possibility of this reaction. Phenothiazines have been associated with deposition of fine particles in the lens and cornea, which can lead to corneal opacification and visual impairment.
Liver impairment in the form of cholestasis has been reported rarely with administration of phenothiazines. Jaundice is also possible and may even occur in neonates of mothers who received phenothiazines during pregnancy. Cholestatic jaundice from phenothiazines is generally considered a hypersensitivity reaction.
Adverse cardiovascular reactions that have occurred during antipsychotic therapy include hypotension, hypertension, ventricular tachycardia, ECG changes such as QT prolongation, and other cardiac arrhythmias such as torsade de pointes. Cardiac arrhythmias such as torsade de pointes secondary to antipsychotic therapy have mainly been associated with thioridazineI and haloperidol.
Dopamine blockade can lead to hyperprolactinemia. As a result, neuroleptics can cause galactorrhea. Other endocrine changes that can occur during therapy with neuroleptics include amenorrhea or other menstrual irregularity, breast enlargement or mastalgia, libido decrease, impotence, ejaculation dysfunction (no ejaculation), and priapism. Weight gain may also occur during therapy with phenothiazines.
Promethazine can cause an injection site reaction. Inadvertant intra-arterial injection can result in arteriospasm, with a possible impairment in circulation and development of gangrene.
PATIENT INFORMATION:
What does promethazine injection do?
Promethazine (PhenerganTM ) is an antihistamine. It relieves moderate to severe allergic reactions; reduces or prevents nausea and vomiting, including motion sickness; helps to make you sleep before surgery, and helps with pain relief after surgery. Generic promethazine injections are available.
What should my doctor, dentist, or pharmacist know before I receive promethazine?
They need to know if you have any of these conditions:
How should I use this medicine?
Promethazine is for injection into a muscle, or into a vein.
Special precautions for use in children:
Promethazine is not for children under 2 years old.
What if I miss a dose?
The injection is usually given as needed.
What other medicines can interact with promethazine?
Tell your doctor or pharmacist: about all other medicines you are taking, including non-prescription medicines; if you are a frequent user of drinks with caffeine or alcohol; if you smoke; or if you use illegal drugs. These may affect the way your medicine works. Check before stopping or starting any of your medicines.
What side effects may I notice from receiving promethazine?
Serious side effects with promethazine include;
Call your doctor as soon as you can if you get any of these side effects.
Minor side effects with promethazine include:
Let your doctor know about these side effects if they do not go away or if they annoy you.
What do I need to watch for while I receive promethazine?
Tell your doctor if your symptoms do not improve in 1 to 2 days.
You may get drowsy or dizzy. Do not drive, use machinery, or do anything that needs mental alertness until you know how promethazine affects you. To reduce the risk of dizzy or fainting spells, do not stand or sit up quickly, especially if you are an older patient. Alcohol may increase dizziness and drowsiness. Avoid alcoholic drinks.
Your mouth may get dry. Chewing sugarless gum or sucking hard candy, and drinking plenty of water will help.
Keep out of the sun, or wear protective clothing outdoors and use a sunscreen. Do not use sun lamps or sun tanning beds or booths.
If you are diabetic, check your blood-sugar levels regularly.
Where can I keep my medicine?
Keep out of the reach of children.
Store at room temperature between 15 and 25C (59 and 77F). Protect from light. Do not use injection if the solution is discolored or contains a precipitate.
The P-I-E-N-O Parkinsn's List Drug Database Index
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