Discussion on Analgesic
Drugs

- Dr. Tarun Yadav
Pain



"Pain is an unpleasant
sensory and emotional
experience associated
with actual or potential
tissue damage, or
des...
Opioids Analgesics and
Antagonists


Algesia : is an ill defined , unpleasent
sensation, usually evoked by an external or...
Opioid Analgesics


Opium : A dark brown ,resinous material obtained from
poppy(Papaver somniferum) capsule.

It contains...
Classification of Opioids


1.Natural opium alkaloids: Morphine,
Codeine.



2.Semisynthetic opiates:
Diactylmorphine(He...
MORPHINE


Morphine is the
principal alkaloid in
opium Therefore it is
described as prototype.



Sertuner a pharmacist,...
Pharmacological Actions of
Morphine.
1. CNS :Morphine has site specific depressant
and stimulant actions in the CNS by int...
Contt..
Morphine stimulates
a) CTZ : Nausea & vomiting
b) Edinger Westphal nucleus of III nerve
producing miosis. This is ...
Contt..


2 Neuro-endocrine :
Hypothalamic activation by afferent
collaterals is dampened. Hypothalamic
influence on pitu...
Contt..
3 CVS : Morphine causes vasodilatation due
to
a) Histamine release
b) Depression of vasomotor centre
c) Direct act...
Contt..
4 GIT : Constipation is a prominent feature of
morphine action due to
a) Action directly on intestines and in CNS
...
Contt..
5 Other smooth muscles :
a) Biliary tract :
spasm of spincter of Oddi -> intrabiliary pressure to
increase -> bili...
Pharmacokinetics of
Morphine








Absorption: oral absorption is unreliable cz of high and
variable first pass meta...
Miscellaneous
Side effects: Sedation, mental clouding,
lethargy, dysphoric effects, vomiting
constipation, respiratory dep...
Codeine
It is methyl-morphine, occurs naturally
in opium and is partly converted in
body to morphine.It is analgesic and
c...


Pholcodeine : It has a codeine like
properties and has been used mailnly as
antitussive; claimed to be less
constipatin...
Pethidine(Meperidine)









Pethidine is indicated for the treatment of moderate to severe
pain, and is delivered ...
Fentanyl








Short acting potent analgesic generally given i.v. at the
begninning of painful surgical procedures....
Methadone
used medically as an analgesic and a
maintenance anti-addictive for use in patients
with opioid dependency.
 Me...
Tramadol
It is centrally acting analgesic relieves
pain as well as additional mechanism.
 Injected i.v. 100 mg tramadol i...
Opiod Receptors
•

Receptors: Many subtypes: ALL are G-proteincoupled receptors. Most important for our
discussion:
1. Mu ...
Opioid receptor transducer
mechanism
All three types of opioid receptors (mu, kappa
,delta) have been cloned; all are G pr...
Opioid receptor transducer
mechanism
Complex Action Opioids and
Opioid Antagonists
1. Agonist- antagonists( k analgesics)
Nalorphine, Pentazocine,Butorphanol.
...
Nalorphine


It 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 a...
Butorphanol
It is k analgesic, similar to but more potent than
pentazocine( 2 mg butorphanol = 30mg
pentazocine) > likewis...
Buprenorphine













It is highly lipid soluble Mu analgesic that is 25 times potent than
morphine. It has s...
Pure Opioid Antagonists








Naloxone: it is the drug of choice in
morphine poising (0.4-.8mg iv every 2-3 min:
ma...
Naltrexone it is chemically related to
naloxone and used to prevent relapse
of heavy drinking.Side effects are
nausea , vo...
References
1 Essentials of Medical Pharmacology
6th edition – K.D. Tripathi
 Basic & Clinical Pharmacology, 12e.
Bertram ...
Opioids analgesics and antagonists
Opioids analgesics and antagonists
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Opioids analgesics and antagonists

  1. 1. Discussion on Analgesic Drugs - Dr. Tarun Yadav
  2. 2. Pain  "Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage”
  3. 3. Opioids Analgesics and Antagonists  Algesia : 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.  a) b)  Analgesics are of two types Opioid Nonopioid Today we will be discussing Opioids.
  4. 4. Opioid Analgesics  Opium : A dark brown ,resinous material obtained from poppy(Papaver somniferum) capsule. It contains two types of alkaloids. a) Phenanthrene derivatives Morphine(10 % in opium) Codeine( 0.5% in opium) Thebaine ( 0.2 % in opium)(Nonanalgesic) b) Benzoisoquinoline derivatives Papaverine (1%)(nonanalgesic) Noscapine(6%) (nonanalgesic)
  5. 5. Classification of Opioids  1.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.
  6. 6. MORPHINE  Morphine 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.
  7. 7. 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. Analgesia b. Sedation c. Mood and subjective effects : euphoric effect. d. Respiratory centre : depression e. Cough centre : depression f. Temperature regulating centre: depression :hypothermia g. Vasomotor centre : depression : fall in bp 
  8. 8. Contt.. Morphine stimulates a) CTZ : Nausea & vomiting b) Edinger Westphal nucleus of III nerve producing miosis. This is central action not produced by tropical application. Vagal centre: leading : bradycardia c) Certain cortical areas & hippocampal cells. 
  9. 9. 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.
  10. 10. Contt.. 3 CVS : Morphine causes vasodilatation due to a) Histamine release b) Depression of vasomotor centre c) 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 stimulation Cardiac work is reduced due to decrease in peripheral resistance 
  11. 11. Contt.. 4 GIT : Constipation is a prominent feature of morphine action due to a) 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 secretions d) Central action causing inattention to defecation reflex. No tolerance develops to this effects and subject remains constipated. 
  12. 12. Contt.. 5 Other smooth muscles : a) Biliary tract : spasm of spincter of Oddi -> intrabiliary pressure to increase -> biliary colic This 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. 
  13. 13. 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.
  14. 14. Miscellaneous Side 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 
  15. 15. Codeine It 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 
  16. 16.  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.
  17. 17. 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.
  18. 18. 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.
  19. 19. Methadone used 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 
  20. 20. Tramadol It 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. 
  21. 21. Opiod Receptors • Receptors: Many subtypes: ALL are G-proteincoupled receptors. Most important for our discussion: 1. Mu – ( ) receptor – primarily responsible for analgesia, euphoria, respiratory depression and physical dependence  Agonists: Endorphins, enkephalins, morphine, fentanyl, methadone, meperidine, and others 2. Kappa ( ) receptor - responsible for mixed-action agonists and analgesia at the level of the spinal cord, sedation and dysphoria  Agonists: Dynorphins, pentazocine, butorphanol 3. Delta ( ) receptor - MAY contribute to analgesia  Agonists: Enkephalins, endorphins, morphine, codeine
  22. 22. Opioid receptor transducer mechanism All 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 
  23. 23. Opioid receptor transducer mechanism
  24. 24. Complex Action Opioids and Opioid Antagonists 1. Agonist- antagonists( k analgesics) Nalorphine, Pentazocine,Butorphanol. 2. Partial/weak mu agonist + k antagonist Buprenorphine 3. Pure antagonists Naloxone, Naltrexone,Nalmefene
  25. 25. Nalorphine  It is N allyl – normophine and not used now because of its dysphoric and psychotomimetic effects.
  26. 26. 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
  27. 27. 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. 
  28. 28. 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
  29. 29. Pure Opioid Antagonists      Naloxone: 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 0.10.2 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.
  30. 30. 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. 
  31. 31. References 1 Essentials of Medical Pharmacology 6th edition – K.D. Tripathi  Basic & Clinical Pharmacology, 12e. Bertram G. Katzung  Miller’s Anesthesia 7th edition  2.www.wikipaedia.com  3. www.ncbi.nlm.nih.gov 
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