Discussion on Analgesic Drugs

- Dr. Tarun Yadav

Pain

"Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage”

Opioids Analgesics and AntagonistsAlgesia : is an ill defined , unpleasent sensation,

usually evoked by an external or internal noxious stimulus.

Analgesic: is a drug that selectively relieves pain by acting in CNS or on peripheral pain mechanism , without significantly altering consciousness.

Analgesics are of two typesa) Opioidb) Nonopioid Today we will be discussing Opioids.

Opioid Analgesics Opium : A dark brown ,resinous material obtained

from poppy(Papaver somniferum) capsule.

It contains two types of alkaloids.

a) Phenanthrene derivativesMorphine(10 % in opium)Codeine( 0.5% in opium)Thebaine ( 0.2 % in opium)(Nonanalgesic)

b) Benzoisoquinoline derivatives Papaverine (1%)(nonanalgesic)Noscapine(6%) (nonanalgesic)

Classification of Opioids1.Natural opium alkaloids: Morphine,

Codeine.

2.Semisynthetic opiates: Diactylmorphine(Heroin) , Pholcodeine, Oxycodone ,Hydrocodone.

3.Synthetic opioids:Pethidine(Meperidine), Fentanyl, Methadone, Dextropropoxyphene, Tramadol, Afentanil , Sufentanil, Remifentanil etc.

MORPHINEMorphine is the principal

alkaloid in opium Therefore it is described as prototype.

Sertuner a pharmacist, isolated the active principle of opium in 1806 and named it ‘morphine’ after the greek god of dreams Morpheus.

Pharmacological Actions of Morphine.1. CNS :Morphine has site specific depressant

and stimulant actions in the CNS by interacting primarily with the μ opioid receptors as a full agonist.

The depressant actions are:a. Analgesiab. Sedationc. Mood and subjective effects : euphoric effect.d. Respiratory centre : depressione. Cough centre : depressionf. Temperature regulating centre:

depression :hypothermiag. Vasomotor centre : depression : fall in bp

Contt..Morphine stimulatesa) CTZ : Nausea & vomitingb) Edinger Westphal nucleus of III

nerve producing miosis. This is central action not produced by tropical application.

Vagal centre: leading : bradycardiac) Certain cortical areas &

hippocampal cells.

Contt..2 Neuro-endocrine :

Hypothalamic activation by afferent collaterals is dampened. Hypothalamic influence on pitutary is reduced. As a result FSH, LH, ACT levels are lowered, while prolactin and GH levels are raised(these are under predominant inhibitory control. The sex harmone and corticosteriods are lowered for short term but then tolerence develops in longterm.It can release ADH and reduce urine output.

Contt..3 CVS : Morphine causes vasodilatation due

toa) Histamine release b) Depression of vasomotor centrec) Direct action decreasing tone of blood

vessels.There is a shift of blood from pulmonary to systemic circuit due to greater vasodilatation in the latter. HR decreases due to vagal stimulationCardiac work is reduced due to decrease in peripheral resistance

Contt..4 GIT : Constipation is a prominent feature of

morphine action due toa) Action directly on intestines and in CNS

increases tone and segmentation but decreases propulsive movements.Tone of duodenum and colon may be increased to the level of spasm.

b) Spasm of pyloric, ileocaecal and anal shhinters.c) Decrease in all gastrointestinal secretionsd) Central action causing inattention to defecation

reflex.No tolerance develops to this effects and subject

remains constipated.

Contt.. 5 Other smooth muscles :a) Biliary tract :spasm of spincter of Oddi -> intrabiliary pressure to

increase -> biliary colicThis action is only partly counteracted by atropine but

more completely by naloxone and nitrates.b) Urinary bladder: tone of detrusor and sphinter is

increased -> urinary urgency and difficulty in micturition.

c) Uterus : may slightly prolong labour.d) Bronchi : morphine releases histamine that causes

bronchoconstriction.6.ANS : It causes mild hyperglycemia due to central

sympathetic stimulation. It has weak anticholinestrase action.

Pharmacokinetics of Morphine Absorption: oral absorption is unreliable cz of high and variable

first pass metabolism. Oral bioavailablity id 1/6th to 1/4th of parenterally administered drug. About 30 % is bound to plasma proteins.

Distribution : is wide conc. In liver, kidney spleen is higher than plasma. Only a small fraction enters brain slowely. Morphine crosses placenta freely and can effect foetus.

Metabolism : primarily metabolised in liver by glucuronide conjugation.Morphine -6-glucuronide is an active metabolite(more potent than morphine) which accumulates during chronic dosing and contributes to analgesia but can not cross BBB. Another metabolite morphine-3-gluronide is neuroexitatory.

Elimination:Plasma t ½ 2-3 hours. Parental dose lasts for 4-6 hours.Elimination is complete in 24 hours and morphine is noncumumulative. Small amount may persist due to entrohepatic circulation.

MiscellaneousSide effects: Sedation, mental clouding, lethargy,

dysphoric effects, vomiting constipation, respiratory depression, blurring of vision, urinary retention, hypotension, allergy, apnoea,

Acute morphine poisoning: lethal dose is 250 mg : coma, stupor, flaccidity, shallow and ocasional breathing,cyanosis,pinpoint pupil,fall in bp nd shock,covulsions may be seen nd pulmonary edema occurs at terminal stage.

Tolerance and dependence is the major side effect.

Dose 10-50 mg oral/ 10-15 mg i.m. or sc, 2-6 mg iv/ 2-3 mg epidural/intrathecal. Children 0.1-0.2 mg/kg

CodeineIt is methyl-morphine, occurs

naturally in opium and is partly converted in body to morphine.It is analgesic and can relieve mild to moderate pain.

It is cough supressor(only 1/3rd as potent as morphine).

Coedine has a good activity by oral route. Single oral dose acts for 4-6 hours.

Constipation is a prominent side effect.

Pholcodeine : It has a codeine like properties and has been used mailnly as antitussive; claimed to be less constipating.

Heroin : It is about 3 times more potent than morphine, more lipid soluble ,enters brain more rapidly.It is considered more euphorient and highly addicting.It has no outstanding therapeutic advantage over morphine and has been banned in most of countries except uk.

Pethidine(Meperidine) Pethidine is indicated for the treatment of moderate to severe

pain, and is delivered as a hydrochloride salt in tablets, as a syrup, or by intramuscular, subcutaneous or intravenous injection. For much of the 20th century, pethidine was the opioid of choice for many physicians

Compared to morphine, pethidine was supposed to be safer and carry less risk of addiction, and to be superior in treating the pain associated with biliary spasm or renal colic due to its putative antispasmodic effects. In fact, pethidine is no more effective than morphine at treating biliary or renal pain, and its low potency, short duration of action, and unique toxicity (i.e., seizures, delirium, other neuropsychological effects) relative to other available opioid analgesics have seen it fall out of favor in recent years.

It is used as an analgesic and in preanaesthetic medication. It has also been used to control shivering during recovery from

anaesthesia. It is preffered analgesic during labour as neonatal respiratory

depression is less marked.

Fentanyl Short acting potent analgesic generally given i.v. at the

begninning of painful surgical procedures. Reflex effects of painful stimuli are abolished. It is frequently used to suppliment anaesthetics in balanced anaesthesia. This permits use of lower anaesthetics concentrations with better haemodynamic stability.Combined with BZDs, it can obviate the need of inhaled anaesthetics for diagnostic, endoscopic, angiographic and other minorprocedures.

Anaesthetic awareness with dreadful recall is a risk. After iv fentanyl (2-4 microgrm/kg) the patient remains

drowsy but conscious.Respiratory depression is marked. Tone of chest muscle may be increased so a muscle relaxant is then required to facilitate mechanical ventilation.

HR decreased : due to stimulation of vagus, fall in BP is slight.

Nausea, vomiting and itching often occurs during recovery. It is also used as an adjunt to spinal and nerve block

anaesthesia.

Methadoneused medically as an analgesic and a maintenance

anti-addictive for use in patients with opioid dependency.

Methadone is useful in the treatment of opioid dependence. It has cross-tolerance with other opioids including heroin and morphine, offering very similar effects and a long duration of effect. Oral doses of methadone can stabilise patients by mitigating opioid withdrawal syndrome. Higher doses of methadone can block the euphoric effects of heroin, morphine, and similar drugs.

A majority of patients in outpatient treatment programs require 80–125 mg/d of methadone, or more, to achieve these effects and require treatment for an indefinite period of time, since methadone maintenance is a corrective but not a curative treatment for opiate addiction

TramadolIt is centrally acting analgesic relieves pain

as well as additional mechanism.Injected i.v. 100 mg tramadol is

equianalgesic to 10 mg im morphine. Oral bioavailablity is good. T1/2 is 5 hours and effect lasts for 5-6 hours.

Causes : respiratory depression, sedation, constipation, urinary retention, rise in intrabiliary pressure.

Side effects : dizziness, nausia, vomiting, dry mouth, sweating, lowering of seizure threshold.

Opiod Receptors• Receptors: Many subtypes: ALL are G-protein-

coupled receptors. Most important for our discussion:

1. Mu – (m) receptor – primarily responsible for analgesia, euphoria, respiratory depression and physical dependence Agonists: Endorphins, enkephalins, morphine,

fentanyl, methadone, meperidine, and others

2. Kappa (k) receptor - responsible for mixed-action agonists and analgesia at the level of the spinal cord, sedation and dysphoria Agonists: Dynorphins, pentazocine, butorphanol

3. Delta (d) receptor - MAY contribute to analgesia Agonists: Enkephalins, endorphins, morphine,

codeine

Opioid receptor transducer mechanismAll three types of opioid receptors (mu,

kappa ,delta) have been cloned; all are G protein coupled receptors located mostly on prejunctional neurons. They generally excerise inhibitory modulation by decreasing release of the junctional transmitter. As such various monoaminergic (NA,DA, 5-HT),GABA , Glutamate (NMDA/AMPA) pathways are intricately involved in opioid actions.

Opiod receptor activation reduces intracellular cAMP formation and opens K+ channels (mainly through mu and delta receptors) or supressess voltage gated N type Ca2+ channels(mainly kappa receptors). These actions result in neurohyperpolarization and reduced availability of intracellular Ca2+ -> decreased neutotransmitter release by CNS and myentric neurons(e.g. glutamate from primary nociceptive afferents).

Opioid receptor transducer mechanism

Complex Action Opioids and Opioid Antagonists

1. Agonist- antagonists( k analgesics)Nalorphine, Pentazocine,Butorphanol.

2. Partial/weak mu agonist + k antagonist

Buprenorphine

3. Pure antagonistsNaloxone, Naltrexone,Nalmefene

NalorphineIt is N allyl – normophine and not

used now because of its dysphoric and psychotomimetic effects.

Pentazocine It is the first agonist-antagonist to be used as an analgesic. It has a weak mu anatagonistic and more marked k agonistic actions. Profile action is similar to morphine ; important differences are a) Analgesia caused by pentazocine is primarily spinal(k1) and has a

different character than that caused by morphine. Parenterally 30 mg pentazocine = 10 mg morphine; but ceiling effect is lower i.e. @ higher doses increase proportionate increase in analgesia does not occur.

b) Sedation and respiratory depression is 1/3 to ½ of morphine at lower doses, and has a lower ceiling , doesn’t increase much beyond 60 mg dose.

c) Trachycardia and rise in Bp are produced due to sympathetic stimulation. This may increase cardiac work so it is avoided in cardiac ischemia & MI

d) Biliary spasm and constipation are less serve. e) Vomiting is less frequent. f) Subjective effects are pleasurable(morphine- like) at low doses but

becomes unpleasurable at high dosage. Tolerance , psychological and physical dependence to pentazocine develops

on repeated use. It is indicated in moderately severe pain in burns , trauma, fracture. Also used as anaesthetic premedication in children. Dose oral: 50-100mg, parental 30-60 mg im.sc //0.5 mg/kg IV

Butorphanol It is k analgesic, similar to but more potent than

pentazocine( 2 mg butorphanol = 30mg pentazocine) > likewise analgesia and respiratory depression have a lower ceiling than morphine. Sedation nausea, cardiac stimulation and other side effects are similar to pentazocine, but subjective effects are less dysphoric. Psychotomimetic effects are less marked. BP is not increased.

It may produce physical dependence; withdrawal can be done with high dose of naloxone,but syndrome is mild.

The most outstanding feature is it can neither substitute nor antagonize morphine.

It should be avoided in patients with cardiac ischemia.

It is used as a premedication in anaesthesiaDose 1-4 mg im/iv

Buprenorphine It is highly lipid soluble Mu analgesic that is 25 times potent than morphine.

It has slower oncet and longer duration of action.After single dose analgesia lasts for 6-8 hours; but with repeated use, duration of action increases upto 24 hours.

Sedation , vomiting ,miosis, subjective effects are similar to morphine but constipation is less marked. Postural hypotension is prominent. Respiratory depression exhibit ceiling effect. It is substitutes for morphine at low level of dependence but precipitates withdrawal in highly dependent subjects.

Lower degree if tolerance and physical dependence develops on chronic use.withdrawal resembles morphine but delayed.

Naloxone only partially reverses buprenorphine. It has good efficacy by sublingual route, is highly plasma protein bound and

remains in tissue for several days. T1/2 is 40 hours. Mostly excreated unchanged in bile and finds its way out of body in faeces

Indicated for long lasting painful conditions. It has been recommended for premedication,postoperative pain, in mycardial infarction and in treatment of morphine dependence.

It is not suitable in labour as causes respiratory depression in the neonate. Also used as a additive to spinal anaesthetic drung to prolong its action.

Pure Opioid AntagonistsNaloxone: it is the drug of choice in

morphine poising (0.4-.8mg iv every 2-3 min: max 10 mg) and for neonatal asphyxia due to opioid use during labour (10 microgm /kg in the cord)

Used to reverse respiratory depression 0.1-0.2 mg in this dose also provide analgesia.

Used as a adjunct to intra spinal opioid analgesia: reverses respiratory depression without abolishing pain relief.

It partially reverses alcohol intoxication.It has been found to elevate BP in endotoxic

or hypovolumic shock,stroke and spinal injury.

Naltrexone it is chemically related to naloxone and used to prevent relapse of heavy drinking.Side effects are nausea , vomitting and headache, hepatotoxicity in high dosage.

Nalmefene: Pure opioid antagonist lacks hepatotoxicity of naltrexone, has higher oral bioavailability and is longer acting.

References1 Essentials of Medical

Pharmacology 6th edition – K.D. Tripathi

Basic & Clinical Pharmacology, 12e. Bertram G. Katzung

Miller’s Anesthesia 7th edition2.www.wikipaedia.com3. www.ncbi.nlm.nih.gov

THANKS ……..