Pethidini HCl

Uses

Pethidine is used for short-term (24-36 hours) relief of moderate to severe pain. It can be given via the following routes of administration: intramuscular, subcutaneous, slow intravenous bolus injection, intravenous infusion and patient controlled analgesia (PCA).

Pethidine is used for administration as an anaesthetic adjunct and for obstetric analgesia. An opioid antagonist and facilities for administration of oxygen and control of respiration should be immediately available during and immediately following intravenous administration of pethidine

Pethidini HCl is also used to associated treatment for these conditions: Severe Pain, Moderate Pain

How Pethidini HCl works

Pethidini HCl is primarily a kappa-opiate receptor agonist and also has local anesthetic effects. Pethidini HCl has more affinity for the kappa-receptor than morphine. Opiate receptors are coupled with G-protein receptors and function as both positive and negative regulators of synaptic transmission via G-proteins that activate effector proteins. Binding of the opiate stimulates the exchange of GTP for GDP on the G-protein complex. As the effector system is adenylate cyclase and cAMP located at the inner surface of the plasma membrane, opioids decrease intracellular cAMP by inhibiting adenylate cyclase. Subsequently, the release of nociceptive neurotransmitters such as substance P, GABA, dopamine, acetylcholine and noradrenaline is inhibited. Opioids also inhibit the release of vasopressin, somatostatin, insulin and glucagon. Opioids close N-type voltage-operated calcium channels (OP2-receptor agonist) and open calcium-dependent inwardly rectifying potassium channels (OP3 and OP1 receptor agonist). This results in hyperpolarization and reduced neuronal excitability.

Dosage

Pethidini HCl dosage

Adult Dosage:

Analgesia:

• Dosage should be adjusted according to the severity of pain and the response of the patient and also depends on patient profile eg: age, weight, sex, previous exposure to narcotics.
• 25 to 100 mg by IM (preferred) or S.C. injection, every 3 to 4 hours.
• 25 to 50 mg slow IV injection, every 3 to 4 hours
• Usual dose is 200 mg/day by the IV route. Intravenous injection should be made very slowly, preferably using a diluted solution.
• For continuous intravenous infusion adequate analgesia should be established prior to commencement of the infusion. A dosage of 0.3 mg/kg/hr is recommended as the initial intravenous infusion rate.
• Clinical experience suggests that patients with normal renal function receiving more than 1000 mg/24 hrs pethidine are at particular risk of developing pethidine associated neurotoxicity (PAN). Patients receiving over 800 mg/24 hrs pethidine should usually be monitored for early signs of norpethidine toxicity

Obstetric Analgesia: 50 to 100 mg by IM (preferred) or S.C. injection, administered when pain becomes regular. May be repeated 3 to 4 times at one to three hour intervals if necessary. Maximum of 4 doses in 24 hours

Anaesthesia Adjunct: As premedication, intramuscular (preferred) or subcutaneous, 50 to 100 mg thirty to ninety minutes prior to anaesthesia. As an adjunct to anaesthesia, intravenous, by repeated slow injection of fractional doses of a solution diluted to 10 mg per mL. Dosage by this route should not exceed 25 to 50 mg.Dosage must be titrated to the needs of the patient, depending on the premedication given, the type of anaesthesia, and the nature and duration of the surgical procedure.

Patient-Controlled Analgesia:

• Patient-controlled analgesia (PCA) allows patients to assess their own level of pain and consequently titrate the amount of pethidine they require for adequate pain control against sedation and other side effects. Adequate analgesia should be established prior to commencement of PCA.
• The dosages and time intervals are preset into a microprocessor-controlled infusion pump. When the patient experiences pain, a button is depressed by the patient and a dose of pethidine is administered intravenously. If the patient should depress the button before the preset time interval (lockout interval) has elapsed, no extra drug is administered. For adults, demand doses, of 5 mg to a maximum of 20 mg pethidine have been given via PCA using a lockout interval of 6 to 20 minutes. Along with the self-administered dose of pethidine, some syringe pumps also deliver a background continuous infusion of pethidine at a basal rate. Some PCA pumps allow a maximum dosage over a defined period to be preset in order to avoid patient overdosage.
• The demand dosage and lockout interval should be determined according to the patient’s analgesic requirements. Patients receiving a background infusion of pethidine should generally receive a smaller demand dose relative to equivalent patients utilising a demand dose only.
• Clinical experience suggests that patients with normal renal function receiving more than 1000 mg/24hrs pethidine are at particular risk of developing pethidine associated neurotoxicity (PAN). Patients receiving over 800 mg/24hrs pethidine should usually be monitored for early signs of norpethidine toxicity. Pethidine-associated neurotoxicity is dose related, so pethidine should not be used for periods greater than 24 to 36 hours

Paediatric Dose:

• Analgesia: Intramuscular (preferred) or subcutaneous, 0.5 to 2 mg per kg of body weight, not to exceed 100 mg, every three to four hours as needed.
• Preoperative: Intramuscular (preferred) or subcutaneous, 1 to 2 mg per kg of body weight, not to exceed 100 mg, thirty to ninety minutes prior to anaesthesia.
• Neonates: Excretion and metabolism of pethidine in the neonate is reduced compared with adults. Safety has not been established in neonates and due to lack of data, no dosage regimen can be recommended.

Intravenous: Dilute with water for inj to a concentration of 5-10 mg/ml.

Parenteral: Moderate to severe acute pain:

• IV infusion: Dilute with glucose 5% or sodium chloride 0.9% to required volume.
• IV inj: Dilute with water for inj to a concentration of 5-10 mg/ml.

Side Effects

Central Nervous System: Lightheadedness, dizziness, sedation, sweating, bizarre feelings, disorientation, hallucinations, psychosis. Some of these effects seem to be more prominent in ambulatory patients and those not experiencing severe pain, and may be relieved by reducing the dose slightly and lying down.

Gastrointestinal: Nausea and vomiting, constipation.

Precaution

Serious or life-threatening reactions such as respiratory depression, coma, convulsions, possibly due to elevated levels of norpethidine and hypotension have been associated with the use of pethidine. Therefore the recommendations in the Warnings and Precautions sections should be carefully observed.

Pethidine should be used with caution in patients taking other CNS depressant drugs such as hypnotics and sedatives including barbiturates and benzodiazepines, phenothiazines, and other tranquillisers, anaesthetics, alcohol and antidepressants.

Patients with severe pain may tolerate very high doses of pethidine but may exhibit respiratory depression should their pain suddenly subside.

The elderly demonstrate an increased sensitivity to opioids relative to younger patients. Reduced liver function, renal function and plasma protein binding may contribute to the elevated plasma levels found in elderly subjects.

Since pethidine is metabolised in the liver and excreted via the kidneys, the possibility of accumulation of the toxic metabolic norpethidine should be considered in patients with hepatic and/or renal impairment

Reduced cardiac output may lead to reduced hepatic perfusion and diminished metabolism of pethidine leading to accumulation of pethidine with possible toxic results.

Pethidine may cause a transient rise in blood pressure and systemic vascular resistance and increased heart rate. Therefore, it is not recommended for pain relief in cardiac infarction.

Pethidine in patients with phaeochromocytoma may result in a hypertensive crisis.

In an individual physically dependent on opioids, the administration of the usual dose of an opioid antagonist will precipitate an acute withdrawal syndrome. The severity of this syndrome will depend on the degree of physical dependence and the dose of antagonist administered. The use of opioid antagonists in such individuals should be avoided if possible. If an opioid antagonist must be used to treat serious respiratory depression in the physically dependent patient, the antagonist should be administered with extreme care and only 10 to 20% of the usual initial dose administered.

Pethidine may aggravate pre-existing convulsions in patients with convulsive disorders. If dosage is escalated substantially above recommended levels because of tolerance development, convulsions may occur in individuals without a history of convulsive disorders.

In eclampsia the combination of pethidine with phenothiazines has been reported to induce recurrence of seizures rather than stopping them. Therefore, the use of pethidine in eclampsia and pre-eclampsia is not recommended.

Pethidine, while commonly used for pain relief in obstetrics, is known to pass the placenta and may cause neonatal depression, including respiratory depression. An opioid antagonist such as naloxone may be required to reverse such depression. In the neonate, pethidine is excreted and metabolised at a significantly reduced rate compared to adults.

Orthostatic hypotension has been reported in ambulatory patients administered pethidine.

Pethidine should be given with caution and the initial dose should be reduced in patients with hypothyroidism or Addison’s disease.

Pethidine should be used with caution in patients with prostatic hypertrophy or urethral stricture.

As opiate agonists may produce hyperglycaemia, this effect should be considered when diabetics require pethidine.

There are conflicting reports about the effect of pethidine on the eye. Some reports state that pethidine and its congeners produce miosis, whereas others indicate that these drugs tend to produce mydriasis or no pupillary change. Until the effects are better defined intraocular tension should be monitored in patients with glaucoma who received pethidine.

Interaction

Increased pethidine metabolite levels with aciclovir, cimetidine, ritonavir. Reduced analgesic effects with phenytoin, barbiturates. Additive sedative and/or respiratory depressive effects with alcohol, barbiturates, benzodiazepines, phenothiazines, TCAs, other CNS depressants.

Food Interaction

• Avoid alcohol.
• Take with or without food. Food does not significantly affect absorption.

Pethidini HCl Alcohol interaction

[Moderate] GENERALLY AVOID:

Ethanol may potentiate the central nervous system (CNS) depressant effects of opioid analgesics.

Concomitant use may result in additive CNS depression and impairment of judgment, thinking, and psychomotor skills.

In more severe cases, hypotension, respiratory depression, profound sedation, coma, or even death may occur.

Concomitant use of opioid analgesics with ethanol should be avoided.

Pethidini HCl Drug Interaction

Major: zolpidem, duloxetine, morphine, gabapentin, acetaminophen / hydrocodone, oxycodone, diazepam, alprazolamModerate: furosemide, promethazineUnknown: aspirin, amoxicillin / clavulanate, celecoxib, enoxaparin, esomeprazole, acetaminophen, acetaminophen, cyanocobalamin, ascorbic acid, cholecalciferol

Pethidini HCl Disease Interaction

Major: impaired GI motility, infectious diarrhea, liver disease, prematurity, acute alcohol intoxication, drug dependence, gastrointestinal obstruction, hypotension, intracranial pressure, respiratory depressionModerate: adrenal insufficiency, biliary spasm, hypothyroidism, renal dysfunction, seizure disorders, urinary retention, arrhythmias

Volume of Distribution

Pethidini HCl crosses the placenta and is distributed into breast milk.

Elimination Route

The oral bioavailability of meperidine in patients with normal hepatic function is 50-60% due to extensive first-pass metabolism. Bioavailability increases to 80-90% in patients with hepatic impairment (e.g. liver cirrhosis). Pethidini HCl is less than half as effective when administered orally compared to parenteral administration. One study reported that 80-85% of the drug administered intramuscularly was absorbed within 6 hours of intragluteal injection in health adults; however, inter-individual variation and patient-specific variable appear to cause considerable variations in absorption upon IM injection.

Half Life

Initial distribution phase (t_{1/2 α}) = 2-11 minutes; terminal elimination phase (t_{1/2 β}) = 3-5 hours. In patients with hepatic dysfunction (e.g. liver cirrhosis or active viral hepatitis) the t_{1/2 β} is prolonged to 7-11 hours.

Elimination Route

Excreted in the urine. The proportion of drug that is excreted unchanged or as metabolites is dependent on pH. When urine pH is uncontrolled, 5-30% of the meperidine dose is excreted as normeperidine and approximately 5% is excreted unchanged. Pethidini HCl and normeperidine are found in acidic urine, while the free and conjugated forms of meperidinic and normperidinic acids are found in alkaline urine.

Pregnancy & Breastfeeding use

Pregnancy Category C. Opioid analgesics may cause respiratory depression in the newborn infant. These products should therefore only be used after weighing the needs of the mother during labour against the risk to the foetus. Animal reproduction studies have not been conducted with pethidine hydrochloride and safe use in pregnancy prior to labour has not been established with regard to possible adverse effects on foetal development.

Breast-feeding: Pethidine is excreted in breast milk; however, clinical data on the rate of excretion or concentration of pethidine in breast milk is not available. The clinical significance of these findings is yet to be determined. It is not recommended that pethidine be administered to nursing mothers.

Contraindication

Hypersensitivity to Pethidine.

Respiratory depression, or where respiratory reserve is depleted (acute bronchial asthma, chronic airway disease, severe emphysema, severe chronic bronchitis, kyphoscoliosis).

Head injury, raised intracranial pressure (apart form introducing monitoring and diagnostic problems, hypercapnia associated with respiratory depression can itself result in elevated intracranial pressure), brain tumour.

Cardiac arrythmias, especially supraventricular tachycardias, cor pulmonale. Pethidine has a vagolytic action and may produce a significant increase in the ventricular response rate.

Concurrent use of monoamine oxidase inhibitors (MAOI’s), including selegeline, or use of MAOI’s within two weeks prior. The combination of monoamine oxidase inhibitors and pethidine has caused hypotension, hypertension, excitation, rigidity, hyperpyrexia and/or convulsions and in some cases fatalities have been reported. This combination should be avoided.

Pre-eclampsia, eclampsia.

Convulsive states such as status epilepticus, tetanus and strychnine poisoning, due to the stimulatory effects of pethidine on the spinal cord.

Diabetic acidosis where there is a danger of coma.

Acute alcoholism or delirium tremens.

Severe liver disease, incipient hepatic encephalopathy.

Patients with a low platelet count, coagulation disorders or receiving anticoagulant treatment.

Continuous Intravenous Infusion: The administration of pethidine via continuous intravenous infusion in patients with renal impairment is contraindicated.

Patient-Controlled Analgesia: The administration of pethidine via patient-controlled analgesia (PCA) in young children and adults with poor cognitive function is contraindicated. The administration of pethidine via PCA in patients with renal impairment is contraindicated.

Special Warning

Geriatric patients: Dose reduction to half normal adult dose is recommended in geriatric patients (over 70 years).

Liver impairment: Dosage reduction and/or increased dosage intervals are recommended.

Renal impairment: Due to the possibility of accumulation of norpethidine in patients with renal failure, caution should be exercised when pethidine is administered to these patients, especially over prolonged periods of time. Therefore, a decrease in the dose or increase in the dosing interval is recommended

Acute Overdose

Symptoms: CNS/respiratory depression, mydriasis, bradycardia, pulmonary oedema, chronic tremor, CNS excitability, seizures.

Treatment: Symptomatic. Naloxone can be used to reverse opioid effects. Do not use naloxone for pethidine-induced seizures.

Storage Condition

Store at room temperature. Do not freeze and protect from light.

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