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Pethidine

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Collated from PsychonautWiki, TripSit, Pharmacology, DrugCentral. Where sources differ (e.g. dosing), Compare shows them side by side.

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OpioidSubstituted piperidinesHabit-formingDepressantPW

Also known as Pethidine, Meperidine, Demerol, Dolantin, DolcontralPW

Fatal overdose may occur when opiates are combined with other depressants such as benzodiazepines, barbiturates, gabapentinoids, thienodiazepines, alcohol or other GABAergic substances.[1] It is strongly discouraged to combine these substances, particularly in common to heavy doses.PW

Addiction potentialPW
extremely addictive with a high potential for abuse
ToxicityPW
high toxicity; potentially lethal when mixed with depressants like alcohol or benzodiazepines
TolerancePW
full tolerance develops with prolonged and repeated use; half after 3 - 7 days; baseline after 1 - 2 weeks
Cross-tolerancePW
opioids

Oral

Route dataPsychonautWiki

Dose
WeakerStronger
ThresholdLightCommonStrongHeavy
25 mg50–100 mg100–200 mg200–400 mg—+
0400 mg
LightCommonStrongHeavy
Duration
ShorterLonger
Onset30–60 minutes
Peak4–6 hours
After-effects2–10 hours
OnsetCome-upPeakOffset

Caution / uncertainPW

MAOIsNitrousPCPStimulants

🧬 Receptor activityPHDC

TargetActionAffinitySource
Sodium-dependent serotonin transporter—Ki 412 nMCHEMBL
Mu-type opioid receptor—Ki 451 nMCHEMBL
Sodium-dependent dopamine transporter—Ki 17800 nMCHEMBL
Kappa-type opioid receptor—Ki 100000 nMCHEMBL
Mu-type opioid receptor (OPRM1)Agonist6.04 KiDRUGCENTRAL
Glutamate receptor ionotropic, NMDA 3A (GRIN3A)——DRUGCENTRAL
Kappa-type opioid receptor (OPRK1)—5.625 KiDRUGCENTRAL
Mu-type opioid receptor (OPRM1)—6.35 KiDRUGCENTRAL
Opioid receptor (Oprd1)—6.15 EC50DRUGCENTRAL
Potassium voltage-gated channel subfamily H member 2 (KCNH2)—6.49 IC50DRUGCENTRAL
Sodium-dependent dopamine transporter (SLC6A3)——DRUGCENTRAL
Sodium-dependent serotonin transporter (Slc6a4)—6.39 KiDRUGCENTRAL
Solute carrier family 22 member 1 (SLC22A1)—4.65 IC50DRUGCENTRAL
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Mechanism of actionPH

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 different ionic currents of spinal dorsal horn neurons and, in particular, its impact on the generation of action potentials. Using a combination of the patch clamp technique and the entire soma isolation method, the action of meperidine on voltage-gated Na+ and K+ currents in spinal dorsal horn neurons of rats was described. Current clamp recordings from intact neurons showed the functional relevance of the ion current blockade for the generation of action potentials. Externally applied meperidine reversibly blocked voltage-gated Na+ currents with a half-maximum inhibiting concentration (IC50) of 112 uM. During repetitive stimulation, a slight phasic block occurred. In addition, A-type K+ currents and delayed-rectifier K+ currents were affected in a dose-dependent manner, with IC50 values of 102 and 52 uM, respectively. In the current clamp mode, single action potentials were suppressed by meperidine. The firing frequency was lowered to 54% at concentrations (100 uM) insufficient for the suppression of a single action potential. Meperidine inhibits the complex mechanism of generating action potentials in spinal dorsal horn neurons by the blockade of voltage-gated Na+ and K+ channels. This can contribute to the local anesthetic effect of meperidine during spinal anesthesia.

PharmacodynamicsPH

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.

Pharmacokinetics

Half-lifePH

Initial distribution phase (t<sub>1/2 &alpha;</sub>) = 2-11 minutes; terminal elimination phase (t<sub>1/2 &beta;</sub>) = 3-5 hours. In patients with hepatic dysfunction (e.g. liver cirrhosis or active viral hepatitis) the t<sub>1/2 &beta;</sub> is prolonged to 7-11 hours.
Plasma meperidine concentrations decline in a biphasic manner, with a half-life in the initial distribution phase (t1/2alpha) of 2-11 minutes and a half-life in the terminal elimination phase (t1/2beta) of 3-5 hours in individuals with normal renal and hepatic function. The elimination half-life is prolonged in patients with hepatic dysfunction, averaging about 7-11 hours in patients with liver cirrhosis or active viral hepatitis.
After single rapid iv injection in man, 0.8 mg/kg, plasma meperidine concentration declined biexponentially with fast (alpha) and slow (beta) phases having half-lives in normal group of 0.19 hr and 3.2 hr (mean values), respectively. In cirrhotics half-life-alpha was not changed but half-life-beta increased to 7.0 hr.
Pharmacokinetics of morphine, buprenorphine and pethidine were determined in 10 cats. ... Six received pethidine (5 mg/kg) intramuscularly. Jugular venous blood samples were collected at time points to 24 hr, and plasma morphine concentrations were measured by high performance liquid chromatograpy (HPLC), buprenorphine by radioimmunoassay (RIA) and pethidine by gas chromatography. ... For i.m. pethidine, elimination half-life /was/ 216.4 min ... .
Following intravenous administration of meperidine in healthy individuals, the volume of distribution at steady state was 269 L (range, 198 to 333 L); plasma clearance was 1.06 L/min (range, 0.71 to 1.32), and the elimination half-life was 3.6 hours (range, 3.1 to 4.1). Liver disease, eg, cirrhosis, acute viral hepatitis, doubles the half-life. There is evidence that the disposition of meperidine varies between day and night, with the elimination half-life being shorter and the plasma clearance greater at night. This suggests that larger doses might be required at night. Bioavailability after oral administration is about 50% due to first-pass metabolism in the liver, but increases to 80% to 90% in patients with cirrhosis. The elimination half-life in the neonate is 22.7 hours.
For more Biological Half-Life (Complete) data for Meperidine (7 total), please visit the HSDB record page.

AbsorptionPH

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). Meperidine 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.
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. Meperidine and normeperidine are found in acidic urine, while the free and conjugated forms of meperidinic and normperidinic acids are found in alkaline urine.
Meperidine crosses the placenta and is distributed into breast milk.
Following oral administration, meperidine undergoes extensive metabolism on first pass through the liver, with approximately 50-60% of a dose reaching systemic circulation unchanged. In patients with hepatic impairment (e.g., liver cirrhosis), oral bioavailability of meperidine increases to approximately 80-90%. Meperidine is less than one-half as effective when given orally as when given parenterally. Approximately 80-85% of an IM dose of the drug reportedly was absorbed within 6 hours after intragluteal injection in healthy adults in one study; however, absorption from the IM injection site appears to show considerable interindividual variation and may depend on the site of injection, dose, and patient-specific variables. Meperidine appears to have a more rapid onset and shorter duration of action than does morphine. Following oral administration of meperidine, peak analgesia occurs within one hour and gradually declines over 2-4 hours. Peak analgesia occurs about 40-60 minutes after subcutaneous administration and 30-50 minutes after IM administration. Analgesia may be maintained for 2-4 hours following subcutaneous or IM administration.
Meperidine is approximately 60-80% bound to plasma proteins, principally albumin and alpha1-acid glycoprotein (alpha1-AGP). There is some evidence that the ratio of bound to free drug is correlated with plasma alpha1-AGP concentrations. In patients with cirrhosis or active viral hepatitis, the extent of protein binding does not appear to be affected.
/MILK/ Meperidine crosses the placenta and is distributed into milk.

MetabolismPH

Meperidine is metabolized in the liver by hydrolysis to meperidinic acid followed by partial conjugation with glucuronic acid. Meperidine also undergoes N-demethylation to normeperidine, which then undergoes hydrolysis and partial conjugation. Normeperidine is about half as potent as meperidine, but it has twice the CNS stimulation effects.
Meperidine is metabolized principally in the liver. The drug is biotransformed mainly by hydrolysis to meperidinic acid followed by partial conjugation with glucuronic acid. Meperidine may also undergo N-demethylation to normeperidine followed by hydrolysis and partial conjugation. Other metabolites also have been identified, but only normeperidine has been detected in blood or plasma. When urine pH is uncontrolled, approximately 5-30% of a dose of meperidine is excreted in urine as the N-demethylated derivative and about 5% is excreted unchanged; however, the relative proportion of the drug excreted in urine unchanged and as metabolites is pH dependent. Meperidine and normeperidine are found in acid urine whereas meperidinic and normeperidinic acids in the free and conjugated form are present in alkaline urine. Excretion of the unchanged drug and normeperidine is enhanced by acidifying the urine. Normeperidine is pharmacologically active, reportedly exhibiting about half the analgesic potency of meperidine but twice the CNS stimulant (e.g., seizure-inducing) potency. Various toxic effects secondary to CNS stimulation (e.g., seizures, agitation, irritability, nervousness, tremors, twitches, myoclonus) have been attributed to accumulation of this metabolite. The elimination half-life of normeperidine is substantially longer than that of meperidine, reportedly ranging from 8-21 hours, and may be prolonged (e.g., to longer than 30 hours) in patients with renal impairment. Accumulation of this metabolite may occur with repeated, high doses of the drug and in patients with renal or hepatic impairment.
Meperidine (Demerol) is a mu- and kappa-opiate receptor agonist used for moderate to severe pain. Overdose can result in respiratory depression, hypotension and coma, while accumulation of its toxic metabolite, normeperidine, can cause delirium and seizures. Little data exist examining the inter- and intrasubject variability of the normeperidine-to-meperidine metabolic ratio (MR) in urine. This retrospective data analysis examined meperidine and normeperidine urine concentrations collected from chronic pain patients. In 98 subjects with multiple visits, the geometric mean urinary MR = 6.1 (coefficient of variation, %CV = 68%). From single specimens obtained from 799 subjects, the geometric mean urinary MR = 6.2 (%CV = 212%). The urinary MR increased in young subjects compared with elderly (P = 0.004) and middle-aged subjects (P = 0.01). A 27% difference was found between the male and female urinary MR (male geometric mean MR = 5.1, female geometric mean MR = 7.0, P = 0.02). Intersubject variability in meperidine metabolism was 3-fold greater than intrasubject variability. A significant difference in the urinary MR was found between males and females. The substantial variability in meperidine metabolism and the serious side effects of its metabolite normeperidine require greater vigilance in patient medication monitoring.
Human liver carboxylesterases catalyze the hydrolysis of apolar drug or xenobiotic esters into more soluble acid and alcohol products for elimination. Two carboxylesterases, hCE-1 and hCE-2, have been purified and characterized with respect to their role in cocaine and heroin hydrolysis. The binding of meperidine (Demerol) and propoxyphene (Darvon) was examined in a competitive binding, spectrophotometric assay. The hCE-1 and hCE-2 bound both drugs, with Ki values in the 0.4- to 1.3-mM range. Meperidine was hydrolyzed to meperidinic acid and ethanol by hCE-1 but not hCE-2. The Km of hCE-1 for meperidine was 1.9 mM and the kcat (catalytic rate constant) was 0.67 min-1. Hydrolysis of meperidine by hCE-1 was consistent with its specificity for hydrolysis of esters containing simple aliphatic alcohol substituents. Hence, hCE-1 in human liver microsomes may play an important role in meperidine elimination. Propoxyphene was not hydrolyzed by hCE-1 or hCE-2. This observation is consistent with the absence of a major hydrolytic pathway for propoxyphene metabolism in humans.
Meperidine is metabolized to N-methyl-4-phenylpiperidine-4-carboxylic acid in rat. /From table/
For more Metabolism/Metabolites (Complete) data for Meperidine (13 total), please visit the HSDB record page.

Protein bindingPH

60-80% bound to plasma proteins, primarily albumin and &alpha;<sub>1</sub>-acid glycoprotein. The presence of cirrhosis or active viral hepatitis does not appear to affect the extent of protein binding.

Plan when to take Pethidine — see where onset, peak and comedown land on the clock

Fact-sheets from PsychonautWiki. Harm-reduction reference only — not medical advice.