VERPAT

Mechanism of action

Pethidine primarily acts as a kappa-opiate receptor agonist, with some local anesthetic effects. It has a greater affinity for the kappa-receptor compared to morphine. Opiate receptors are coupled with G-protein receptors and regulate synaptic transmission, leading to decreased intracellular cAMP levels by inhibiting adenylate cyclase. This action results in the inhibition of nociceptive neurotransmitter release, including substance P, GABA, dopamine, acetylcholine, and noradrenaline. Additionally, pethidine inhibits the release of vasopressin and other hormones, while closing N-type voltage-operated calcium channels and opening calcium-dependent inwardly rectifying potassium channels, leading to hyperpolarization and reduced neuronal excitability.

Pharmacodynamics

As a synthetic opiate agonist, pethidine is recognized for its analgesic effects and is effective in relieving moderate to severe pain. It has a rapid onset of action and a slightly shorter duration than morphine, making it suitable for acute pain management. Pethidine may also produce less smooth muscle spasm and constipation compared to morphine, and it is indicated for use in various anesthesia techniques including intravenous regional anesthesia and peripheral nerve blocks. Its unique ability to alleviate postoperative shivering enhances its utility in clinical settings.

Pharmacokinetics

Pethidine is absorbed following parenteral administration and is metabolized in the liver. It has a relatively short half-life, which necessitates more frequent dosing compared to other opioids. The primary metabolic pathway involves conversion to normeperidine, which has its own pharmacological activity but may accumulate and lead to toxicity, particularly in patients with renal impairment. Pethidine is excreted via the kidneys, and its pharmacokinetic profile supports its use in acute pain management, although caution is advised

Contra-indications

• Hypersensitivity to pethidine or any component of the formulation
• Severe respiratory depression
• Acute or severe bronchial asthma
• Known or suspected gastrointestinal obstruction, including paralytic ileus
• Concurrent use with monoamine oxidase inhibitors (MAOIs)

Adverse effects

• Drowsiness
• Dizziness
• Nausea
• Vomiting
• Constipation
• Respiratory depression
• Hypotension
• Dry mouth
• Urinary retention

Interactions

• ritonavir+pethidine: Severe (increases risk of central nervous system toxicity)
• selegiline+pethidine: Severe (increases risk of adverse effects)
• rasagiline+pethidine: Unknown (increases risk of adverse effects)
• safinamide+pethidine: Unknown (increases risk of adverse effects)

Precautions

• Use with caution in elderly patients
• Caution in patients with head injuries or increased intracranial pressure
• Caution in patients with a history of substance use disorder
• Monitor for signs of respiratory depression, especially in opioid-naïve patients
• Consider potential for abuse and misuse

Pregnancy

Pethidine should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus. It crosses the placenta and can cause respiratory depression in the newborn.

Breast-feeding

Pethidine is excreted in breast milk; caution should be exercised when administering to nursing mothers as it may cause sedation or respiratory depression in the breastfed infant.

Storage

Store at room temperature, away from light and moisture. Keep out of reach of children.

Formulations

• Injection solution
• Oral solution
• Tablets

Indications

• Moderate to severe acute pain
• Obstetric analgesia
• Premedication before surgical procedures
• Postoperative pain management

Dosage

Adults: For adults, pethidine is typically administered as follows: 50 to 150 mg every 4 hours for pain management. For moderate pain, the usual dose is 25 to 100 mg every 3 to 4 hours, with a

Mechanism of action

Pethidine exerts its analgesic effect primarily through the activation of the mu-opioid receptors in the central nervous system. This leads to the inhibition of pain pathways and the modulation of neurotransmitter release in the brain and spinal cord, resulting in reduced perception of pain. Additionally, it has anticholinergic properties, which can lead to effects such as urinary retention and dry mouth.

Pharmacodynamics

The pharmacodynamics of pethidine involve dose-dependent analgesia, sedation, and respiratory depression. Its effects can vary based on individual patient factors such as tolerance and metabolism. Pethidine also has a shorter duration of action compared to other opioids, which may necessitate more frequent dosing. The drug's side effects can include dizziness, nausea, vomiting, and constipation, alongside risks of dependence and potential for abuse.

Pharmacokinetics

Pethidine is absorbed rapidly after parenteral administration, with peak plasma concentrations reached within 30 to 60 minutes. The drug is metabolized primarily in the liver by the cytochrome P450 system, producing norpethidine, an active metabolite that can accumulate and lead to toxicity, especially in cases of renal impairment. The elimination half-life of pethidine is approximately 3 to 5 hours, and it is excreted predominantly through the urine. Adjustments in dosing may be required in patients with hepatic or renal dysfunction.

Contra-indications

• Acute porphyrias
• Severe respiratory depression
• Heart failure secondary to chronic lung disease
• Patients dependent on opioids (risk of withdrawal)
• Severe renal impairment

Adverse effects

• Nausea
• Vomiting
• Dizziness
• Sedation
• Constipation
• Respiratory depression
• Hypotension
• Biliary spasm
• Mood alterations

Interactions

• Increased effects with other CNS depressants
• Potential for increased sedation with alcohol
• Interactions with MAO inhibitors

Precautions

• Caution in patients with renal impairment
• Caution in elderly patients
• Caution in patients with a history of substance abuse
• Caution in patients with hypotension
• Caution in patients with cardiac arrhythmias

Pregnancy

Pethidine should only be used in pregnancy if clearly needed, as it may affect the fetus.

Breast-feeding

Therapeutic doses may be excreted in breast milk; caution is advised.

Storage

Store in a cool, dry place away from light. Keep out of reach of children.

Formulations

• Pethidine hydrochloride 50 mg/mL solution for injection
• Pethidine hydrochloride 100 mg/2 mL solution for injection

Mechanism of action

Meperidine is primarily a kappa-opiate receptor agonist and also has local anesthetic effects. Meperidine 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. Meperidine is a mu (OP3)-receptor (MOR) agonist opioid with approximately 20-25% the potency of morphine. Receptors for opiate analgesics are found in high concentrations in the limbic system, spinal cord, thalamus, hypothalamus, striatum, and midbrain. They are also found in tissues such as the gastrointestinal tract, urinary track, and in other smooth muscle. The morphine-like agonists (morphine, meperidine, oxymorphone) have primary activity in the mu receptors, with some activity possible in the delta receptor. ... Meperidine produces equivalent respiratory depression at equi-analgesic doses as morphine. Like morphine, it can cause histamine release. It does not have antitussive activity at doses lower than those causing analgesia. Meperidine is the only used opioid that has vagolytic and negative inotropic properties at clinically used doses. One study in ponies demonstrated jejunal activity after meperidine administration, but no effects on transit time or colonic electrical activity were noted. The purpose of the present study was to investigate the effect of meperidine on rat ventricular muscle. Cardiac function was assessed in Langendorff-perfused rat hearts and intracellular calcium level was recorded in enzymatically isolated rat ventricular myocytes using spectrofluorometric techniques. To explore the underlying mechanism, whole-cell configuration of patch-clamp technique was used to record L-type Ca(2+) current. The results showed that meperidine decreased the product of heart rate and left ventricular developed pressure (LVDP HR), maximal rate of the left ventricular pressure increase (LV +dP/dt(max)) and decrease (LV -dP/dt(max)), but increased left ventricular end-diastolic pressure in a dose-dependent manner (0-1000 umol/L). Meperidine also produced a dose-dependent reduction in electrically induced [Ca(2+)](i) transient amplitude and an increase in diastolic [Ca(2+)](i) baseline level, but did not alter the caffeine (20 mmol/L) induced Ca(2+) release from intracellular ryanodine-sensitive Ca(2+) stores. Meperidine at 100 umol/L inhibited L-type Ca(2+) current to 67.4 10.1% of control but did not affect the voltage dependency of activation and inactivation. The inhibitory effect of meperidine on Ca(2+) current could not be prevented by pretreatment with the opioid receptor antagonist naloxone. These data suggest that meperidine exerts a negative inotropic effect by inhibiting L-type Ca(2+) current. The lack of effect of naloxone implies that the action is independent of the opioid receptor. In addition to local anesthetics, meperidine has been successfully used for local anesthesia. When applied intrathecally, the dorsal horn neurons of the superficial laminae are exposed to high concentrations of meperidine. These cells represent an important point for the transmission of pain information. This study investigated the blocking effects of meperidine on di

Pharmacodynamics

Meperidine is a synthetic opiate agonist belonging to the phenylpiperidine class. Meperidine may produce less smooth muscle spasm, constipation, and depression of the cough reflex than equivalent doses of morphine. The onset of action is lightly more rapid than with morphine, and the duration of action is slightly shorter. The chemical structure of meperidine is similar to local anesthetics. Meperidine is recommended for relief of moderate to severe acute pain and has the unique ability to interrupt postoperative shivering and shaking chills induced by amphotericin B. Meperidine has also been used for intravenous regional anesthesia, peripheral nerve blocks and intraarticular, epidural and spinal analgesia. Meperidine is considered a second-line agent for the treatment of acute pain.