PETHIDINE (Introduction, Mode of action, Pharmacokinetics, Dosage and Adverse effects)

 INTRODUCTION:-

Pethidine is the street name of meperidine. It was firstly synthesized as atropine substitute in 1939. It is relatively weak mu opioid agonist with only around 10% effectiveness of morphine with notable anti-cholinergic and local anesthetic effects and acts primarily as kappa agonist. Pethidine is very lipophilic in nature and its active metabolite is normeperidine which is potentially neurotoxic.

MODE OF ACTION:-

When pethidine binds to its respective receptor which is the G protein coupled receptor, it activates the receptor and converts the GDP into GTP, this GTP activates the G alpha subunit of G protein which is the inhibitory subunit, this G alpha subunit goes and inhibit the adenylate cyclase enzyme which is the effector system and present at the inner surface of the plasma membrane so due to inhibition of adenylate cyclase enzyme, it becomes unable to convert the ATP into CAMP. So because of decreased level of CAMP intracellularly, the release of nociceptive neurotransmitters like acetylcholine, substance P, noradrenaline, GABA and dopamine is inhibited by closing calcium channel so it reduces the propagation of effect and open the potassium channels for hyperpolarization due to which it reduces the neuronal excitability.

PHARMACOKINETICS:-

ü  The oral bioavailability of pethidine in those patients which have normal hepatic function is 50 to 60% due to large first pass metabolism but bioavailability increases up to 80 to 90% in liver impairment patients like in liver cirrhosis.

ü  It can easily cross the placenta and distributed in breast milk.

ü  It is bounded 60 to 80% with the plasma proteins primarily albumin then alpha-1 acid glycoprotein.

ü  Pethidine is metabolized in the liver by hydrolysis to meperidinic acid followed by partial conjugation with glucuronic acid. Pethidine also converts into normeperidine by N-demethylation which then undergoes hydrolysis and partial conjugation.

ü  It is excreted out in urine. Amount of drug that is excreted out as unchanged or as metabolites is dependent on PH. Pethidine and normeperidine are found in the acidic urine, whereas free and conjugated forms of meperidinic acid and normerperidinic acid are found in alkaline urine.

DOSAGE:-

      In ADULTS:-       

ü  Pain:-50 to 150mg PO/IM/SC Q3-4H

ü  Preoperatively:-50 to 100mg IM/SC 30 to 90 minutes before beginning of anesthesia.

ü  Continuous infusion:-15 to 35 mg/hr

ü  Obstetrical analgesia:-50 to 100mg IM/SC repeated Q1-3H (if necessary).

ADVERSE EFFECTS:-

ü  Tolerance and physical dependence

ü  Dry mouth

ü  Tachycardia

ü  Tremors

ü  Mydriasis

ü  Hyperreflexia

ü  Delirium

ü  Myoclonus and convulsions.

MORPHINE (Introduction, Mode of action, Pharmacokinetics, Dosage and Adverse effects)

  INTRODUCTION:-

This drug was first isolated by the German pharmacist “Freidrich Wilhelm Adam Serturner” in 1804 and give the name to this drug is “morphium” (God of sleep). It is a phenanthrene derivative and prototypical strong mu receptor agonist. It is used to control the severe pain. Due to development of hypodermic needle, the use of morphine rapidly increased for relieve of pain. So after the American Civil war, approximately 100000 soldiers got “soldier’s disease” (morphine addiction).

MODE OF ACTION:-

When morphine binds to the mu opioid receptor which is mostly found on the CNS, it activates the alpha G subunit of G protein which is the inhibitory subunit. It goes and inhibit the adenylate cyclase enzyme due to which ATP will not be converted into CAMP, in normal condition CAMP inhibits the potassium channel due to which it blocks the potassium efflux so when CAMP will not formed then there will be no one which inhibit the potassium efflux. Due to continuous potassium efflux it makes the membrane hyperpolarized and stops the action potential due to which pain reduces. And decreased CAMP level also inhibit the Calcium influx due to which it inhibits the release of neurotransmitter from the vesicles of pre-synaptic neuron, which comes in response of noxious stimuli, So it inhibits the signal propagation and produces analgesic effects.

 PHARMACOKINETICS:-

1) Morphine’s absorption occurs in the alkaline environment of the upper intestine and the rectal mucosa. Its bioavailability of morphine is 80 to 100%. Tmax of parental morphine is 15 minutes and oral morphine Tmax is 90 minutes with a Cmax of 283nmol/L. The area under curve (AUC) of morphine is 225-290nmol*h/L and its half-life is 2 to 3 hours.

2) Morphine’s volume of distribution is 5.31L/kg while morhine-6-glucuronide’s volume of distribution is 3.61L/kg.

3) Morphine’s protein binding is 35%, morphine-3-glucuronide’s protein binding is 10% and morphine-6-glucuronide’s protein binding is 15%.

4) Morphine is 90% metabolized by the glucuronidation by UGT2B7 and sulfation at positions 3 and 6. It can also be metabolized into normorphine, morphine ethereal sulfate and codeine.

5) Morphine’s 70-80% of administered dose is excreted within 48hrs. It is mainly eliminated via urine along with 2-10% of administered dose recovered as unchanged parent drug and 7-10% morphine’s dose is eliminated via feces.

DOSAGE:-

ORAL:-short-acting oral dose for severe and chronic pain in adults is 10-30 mg Q4H.

I.M or S.C:-5-20 mg (usually10 mg) Q4H.

I.V:-initial dose is 4 mg-10 mg slowly over 4-5 minutes Q4H. Daily dose range is 12-120 mg.

 ADVERSE EFFECTS:-

1) Miosis

2) Respiratory depression

3) Physical dependence

4) Orthostatic hypotension

5) Increased intracranial tension

6) Nausea

7) Sedation

8) Euphoria

OPIOIDS (Introduction, Receptors and Classification of opioids)

INTRODUCTION:-

Opioid is the broad term which is basically used to describe all the compounds that work on the opioid receptors. In opioids, natural opiates, semi-synthetic and synthetic compounds are included which produce morphine-like actions. Morphine and other different related alkaloids are derived from the opium which is the dark brown and resinous material of the poppy Papaver somniferum. By binding with the different and specific type of opioid receptors, these opioids produce wide range of effects but they are primarily used to relieve the severe pain (unpleasant sensation which is done by an internal or external harmful stimulus) that comes from chronic disease, injury or surgery etc. And also due to the euphoric properties of opioids, these agents are good choice for abuse. In case of opioid overdose, their antagonists are also available to reverse the opioids actions.

Opioid receptors are found within the CNS and throughout the peripheral tissues. These receptors are generally stimulated by the endogenous peptides (enkephalins, endorphins and dynorphins) which are released in response to harmful stimulation. These opioid receptors have Greek letters names which depend on their prototype agonists.

OPIOID RECEPTORS:-

1. Mu receptor:-

·         Mu receptor agonist is morphine. ·         They are found chiefly in brain stem and also in medial thalamus. ·         These receptors cause respiratory depression, sedation, supraspinal analgesia, euphoria, decreased GI motility and also physical dependence. Their subtypes are Mu1 and Mu2, Mu1 receptor is related to euphoria, analgesia and serenity and with Mu2, prolactin release, pruritus, sedation, anorexia, dependence and respiratory depression are related.

These receptors are also known as OP3 or Morphine opioid receptors (MOR).

2. Kappa receptor:-

·         Its agonist is ketocyclazocine. ·         These kappa receptors are present in limbic & other diencephalic areas, spinal cord and brain stem. ·         These receptors are responsible for dyspnea, dsyphoria, sedation, spinal analgesia, respiratory depression and dependence etc.

These receptors are also called as OP2 or Kappa opioid receptors (KOR).

3. Delta receptor:-

·         Delta receptor agonist is (delta-alanine 2-delta-leucine 5-enkephalin). ·         These receptors are found majorly in brain. ·         These delta receptors play important role in analgesia and gastric motility.

They are also known as OP1 and delta opioid receptors (DOR). 

CLASSIFICATION OF OPIOIDS:-

1)      Classification of opioids on the basis of analgesic potency (traditional).

TRADITIONAL
STRONG	INTERMEDIATE	WEAK
Morphine	Buprenorphine	Codeine
Pethidine	Pentazocine
Fentanyl	Butrophanol
Alfentanil	Nalbuphine
Remifentanil
Sufentanil

 
2)      Classification of opioids on the basis of their origin (like naturally occurring or manufactured).

ORIGIN
NATURALLY OCCURING	SEMI-SYNTHETIC	SYNTHETIC
Morphine	Diamorphine	Phenylperidines:- (pethidine, fentanyl, alfentanil, sufentanil)
Codeine	Dihydrocodeine	Diphenylpropylamines:- (methadone, dextropropoxyphene)
Papavarine	Buprenorphine	Morphinans:- (butorphanol, levorphanol)
Thebaine		Benzomorphans:- (pentazocine)

 
3)       Classification of opioids on the basis of their actions on opioid receptors.

FUNCTIONS
PURE AGONISTS	PARTIAL AGONISTS	AGONISTS-ANTAGONISTS	PURE ANTAGONISTS
Morphine	Buprenorphine	Pentazocine	Naloxone
Fentanyl		Nalbuphine	Naltrexone
Alfentanil		Nalorphine
Remifentanil
Sufentanil