PHL331
Prof. Dr/ Gamal A. Soliman
Pharmacy College
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Lecture-4

▓ Some definitions
1- Analgesics
▪ Analgesics are drugs used to relieve pain without causing loss of
consciousness
2- Opiates
▪ Opiates are natural compounds that are extracted from poppy plant
such as morphine and codeine
3- Opioids
▪ Opioids are substance that produce morphine-like effects
▪ Some opioids are widely used medically, some are not.
▪ Ex
o Meperidine, Methadone, Fentanyl
4- Opioid peptides
▪ They are peptides that produced by the body and bind to opioid
receptors in the brain
▪ Ex
o Endorphins.
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▓ Opioid analgesics
[1] Natural
▪ Naturally occurring opioids can be divided into two
classes, phenanthrenes and benzyl isoquinolines
▪ The phenanthrenes are five-ring structures, and the benzyl
isoquinolines are three-ring structures.
(A) Phenanthrene derivatives
▪ Ex: Morphine, Codeine, Thebaine (X)
❖ Characteristics
▪ Potent CNS effect _ Addictive
▪ Spasmogenic effect
▪ Analgesic
(B) Benzyl isoquinoline derivatives
▪ Ex: Papaverine, Noscapine, Narceine
❖ Characteristics
▪ Negligible CNS effect _ Non-addictive
▪ Spasmolytic effect
▪ Non-analgesic
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[2] Semisynthetic
▪ The semisynthetic opioids are morphine derivatives that obtained by chemical modification of natural
opioids
▪ These modifications can produce changes in the pharmacological activity of the opioid.
▪ Ex: Heroin (Acetyl morphine) obtained by acetylation of morphine
[3] Synthetic
▪ The synthetic opioids are opioids that are completely synthesized
▪ The synthetic opioids can be classified according to their effect at opioid receptors into :
(A) Agonists
▪ Opioid agonists are synthetic drugs that interact with the opioid receptors to produce effects that are
similar to morphine
▪ Ex: Meperidine, Methadone, Tramadol
(B) Antagonists Or blockers
▪ Opioid antagonists are synthetic drugs that bind to the opioid receptors but produce no functional
response. At the same time, they prevent an agonist from binding to these receptors.
▪ Ex: Naloxone, Naltrexone
(C) Mixed Agonist-Antagonists
▪ These are drugs that bind to an opioid receptor to produce pain relief and block another receptor that
does not produce a physiological effect.
▪ Ex: Nalorphine, Nalbuphine, Butorphanol, Pentazocine, Naltrexone
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▓ Opioid receptors
▪ Opioid receptors are widely distributed in the body including brain and spinal cord.
▪ All types of opioid receptors mediate very similar effects.
(1) Mu Receptors (μ)
▪ μ receptors are responsible for most of the analgesic effects of opioids, and for some major unwanted
effects (e.g. respiratory depression, constipation, euphoria and dependence).
(2) Kappa Receptors (κ)
▪ κ receptors contribute to analgesia at the spinal cord level in addition to sedation and hallucinations.
(3) Delta Receptor (δ)
▪ δ receptor activation results in analgesia but also can be proconvulsant.
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▓ Ascending and Descending pain pathways
❖ Ascending pain pathway
▪ The ascending pathway is how we feel pain.
▪ The process begins when pain sensory neurons, called nociceptors,
detect a pain stimulus (signal).
▪ These neurons send the pain signal to the dorsal horn of spinal cord
▪ Once the signal reaches the dorsal horn of the spinal cord, the excitatory
neurotransmitters glutamate and substance p are released
▪ Glutamate and substance p transmit pain signals from the spinal cord to
the somatosensory cortex in the brain, which recognizes pain.
❖ Descending pain pathway
▪ Once the signal from the ascending pathway reaches the somatosensory
cortex, it stimulates the descending pain pathway.
▪ The process begins in a region of the midbrain that transmits signals to
the dorsal horn of the spinal cord to release endogenous opioids.
▪ These endogenous opioids further block ascending pain transmission
signals.
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[1] Natural Opioid Analgesics
❑ Morphine
▪ Morphine is a natural alkaloid obtained from Papaver somniferum plant (poppy)
▪ It is one of the a phenanthrene derivative.
❖ Bioavailability : 25% after oral administration (due the first pass metabolism)
o Morphine and most morphine-like drugs undergo considerable first-pass metabolism, and are
therefore less potent when taken orally than when injected.
❖ Half-life :
o The plasma half-life of morphine is 4 – 5 hr.
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❖ Metabolism :
o Hepatic metabolism occurs in the liver usually by conjugation with glucuronide.
o Morphine-6-glucuronide is one of morphine metabolites. It is more active as an analgesic than
morphine itself.
o Because of low conjugating capacity in neonates, morphine and morphine-like drugs have a much
longer duration of action with a possibility of respiratory depression so, these drugs should not be
used in young ages.
❖ Excretion :
o 90% of the dose are excreted through kidney & 10% through biliary route
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❖ Pharmacological actions
1- Effect on CNS
i- Analgesia
▪ Morphine is a potent analgesic.
▪ It is effective in most kinds of pain, either sensory (due to its effect on
pain center) or emotional (due to euphoria)
❖ MOA of morphine as analgesic
▪ 1) At the spinal level, morphine stimulates μ, κ and δ receptors at the
dorsal horn of spinal cord, so decreases the release of the excitatory
neurotransmitters glutamate and substance p and inhibits the
transmission of pain impulses to somatosensory cortex producing
analgesia (Spinal analgesia)
▪ 2) At the brain level, morphine stimulates μ, κ and δ receptors of the
brain that result in activation of the descending inhibitory pain
pathway.
▪ Activation of the descending inhibitory pain pathway results in
release of endogenous opioids at the dorsal horn of the spinal cord to
further block ascending pain transmission signals (Supra-spinal
analgesia)
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NOTE
▪ Morphine inhibits all types of pain except itching.
o It is contra-indicated in case of allergy and itching
o This is because morphine use is accompanied by histamine release which irritates the sensory nerve
endings
ii- Euphoria
▪ Morphine causes a powerful sense of euphoria.
▪ Euphoria is mediated through μ receptors,
▪ Euphoria is not a target for drugs, so no drug is used to induce euphoria
iii- Respiratory depression
▪ Only large dose of morphine can induce respiratory depression
▪ Respiratory depression is mediated by μ receptors.
iv- Suppression of cough
▪ Morphine can suppress chronic cough (antitussive effect)
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v. Vagal stimulation
▪ Morphine stimulates the vagal center in the medulla oblongata causing bradycardia
vi- Pupillary constriction (Miosis)
▪ Pupillary constriction is caused by μ and κ receptor-mediated stimulation of the oculomotor center.
▪ Pinpoint pupils are an important diagnostic feature in opioid poisoning
vii- Nausea and vomiting
▪ Morphine induces nausea and vomiting in up to 40% of patients
▪ The site of action is the chemoreceptor trigger zone in the medulla oblongata
2- Effect on CVS
▪ Hypotension and bradycardia occur with large doses of most opioids, due to :
o Vagal stimulation,
o Histamine release
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3- Effect on smooth muscles (Note that morphine is a spasmogenic drug)
i. Constipation due to :
o Morphine reduce motility of the gastrointestinal system, resulting in constipation
o It increases water absorption so food content become more solid
ii. Bronchoconstriction due to:
o Vagal stimulation,
o Histamine release
o Stimulation of μ and δ receptors of bronchi leads to bronchoconstriction
iii. Urinary bladder
▪ Morphine increases the contractility of urinary bladder muscle that lead to feeling of urgency
▪ It increases the contractility of the bladder sphincter that lead to difficult micturition
o This represents a problem especially in old ages
iv. Gall bladder
▪ Morphine increases the pressure in the gall bladder due to contraction of the gall bladder and
constriction of the gall bladder sphincter (sphincter of Oddi).
o Morphine should be avoided in patients suffering from biliary colic due to gallstones, in whom pain
may be increased.
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❖ Therapeutic uses
1- For severe pain
▪ Given by IV injection to treat acute pain
▪ Given orally to treat chronic pain
2- As pre-anesthetic medication
o in major surgeries
NOTES
▪ In case of severe colic: (Note that morphine is a spasmogenic drug)
o Morphine should be combined with atropine because atropine inhibits the vagal stimulation that
induced by morphine
o The spasmolytic effect of atropine can antagonize the spasmogenic effect of morphine
▪ In case of biliary colic
o Morphine is contra-indicated in case of biliary colic due to the possibility of gall stones
o In this case, morphine can increases the severity of pain
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❖ Adverse effects
▪ The most common adverse effects are nausea, vomiting, constipation and respiratory depression
▪ Other adverse effects include bradycardia & hypotension, feeling of urgency, urine retention, difficult
micturition
▪ Tolerance and physical dependence occurred with repeated administration
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❑ Codeine
▪ Codeine is a natural alkaloid obtained from Papaver somniferum plant (poppy)
▪ It is one of the a phenanthrene derivative.
▪ Chemically, codeine is a methyl morphine
o In the liver, a small amount of codeine is converted to morphine.
▪ Codeine is more absorbed by mouth than morphine with bioavailability of 60%,
o This is due to the presence of methyl group that renders codeine more lipid soluble
▪ Codeine has only 10% of the analgesic potency of morphine.
o So, the analgesic dose of codeine that produce the same analgesic potency of morphine should be
10-time that of morphine, but this large dose may induces respiratory depression
o so codeine used now as analgesic in combination with another analgesic (paracetamol) for more
effective pain relief.
o Codeine is contra-indicated for children less than 12 years because it causes mortalities in children
due to respiratory depression _ in this case, dextromethorphan is the substitute
▪ Unlike morphine, it causes little euphoria and is rarely addictive.
▪ Codeine has marked antitussive activity.
❖ Therapeutic uses
▪ Used mainly for suppression of dry cough due to its strong antitussive effect
▪ Used as analgesic for mild types of pain (in combination with paracetamol).
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[2] Semisynthetic opioids
❖ Heroin (Acetyl morphine)
▪ Produced by acetylation of morphine
▪ It was used as analgesic and antitussive
▪ Now, it is not used clinically because it is highly addictive
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[3] Synthetic opioids
(A) Agonists
❑ Meperidine (Pethidine)
▪ Meperidine is very similar to morphine in most of its pharmacological effects
▪ It has an antimuscarinic action (Atropine-like effect)
▪ The antimuscarinic action of meperidine may cause dry mouth and blurring of vision as side effects.
▪ Bioavailability : 50% _ because it is more lipid soluble
▪ Meperidine has only 10% of the analgesic potency of morphine.
▪ The duration of action of meperidine is slightly shorter than that of morphine
▪ Meperidine is partly N-demethylated in the liver to norpethidine, which has hallucinogenic and
convulsant effects.
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❑ Fentanyl & Alfentanil
▪ Both are meperidine derivatives
▪ Fentanyl and alfentanil are highly potent meperidine derivatives.
▪ They are more potent than morphine as analgesics, but with a more rapid onset and shorter duration of
action (15 – 30 min)
▪ To prolong their duration of action, thy are used in the form of skin batches to be used directly on the
painful area
▪ Ex: Fentanyl skin batch _ with duration of action of 12 hr
▪ Does not prepared for oral administration due to extensive first pass metabolism
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❑ Methadone
▪ It is one of the synthetic opioids
▪ Available for oral administration only
▪ Although the chemical structure of methadone is completely different from the chemical structure of
morphine, it has an analgesic effect equivalent to that of morphine.
▪ The main difference being that its duration of action is considerably longer (>24 h).
▪ It is less addictive
▪ Used only in the hospitals for treatment of opioid addiction
❑ Tramadol
▪ It is a weak agonist at μ receptors
▪ Tramadol has only 10% of the analgesic potency of morphine.
❖ Therapeutic uses:
▪ Not used clinically except as analgesic
▪ Used as post operative analgesic in major surgeries especially in orthopedic surgery
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❑ Loperamide & Diphenoxylate
▪ They are synthetic opioids that bind to opioid receptors in the intestinal wall to slow gut movement.
o They act on peripheral opioid receptors only, not central
o They can not pass through the BBB so produce less CNS side effects
❖ Therapeutic uses
▪ Loperamide and diphenoxylate are two antidiarrheal medications that are used to treat acute and
chronic diarrhea
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(B) Mixed agonist-antagonist
▪ These are drugs that bind to an opioid receptor to produce pain relief and block another receptor that
does not produce a physiological effect.
Ex:
▪ Nalorphine, Nalbuphine, Butorphanol, Pentazocine, Naltrexone
❖ MOA
▪ They act by stimulating kappa receptors, so they are kappa agonists
o This result in spinal analgesia
▪ They act by blocking of mu receptors, so they are mu antagonists
▪ Their analgesic efficacy is less than that of morphine
❖ Therapeutic uses
▪ Used for chronic pain
NOTES
▪ They block mu receptors so no way to induce respiratory depression and addiction
▪ They are contra-indicated for treatment of chronic morphine toxicity (addict patients)
▪ Using of these drugs to addict patients lead to acute withdrawal syndrome
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(C) Opioid Antagonists (Opioid blockers)
▪ Opioid Antagonists act by blocking the opioid receptors (μ, κ and δ).
Ex:
▪ Naloxon _ injection (short duration, for 1 hr)
▪ Naltrexone _ oral (long duration, 10 hr)
▪ They block the actions of endogenous opioid peptides (Endorphins) as well as those of morphine-like
drugs
▪ They produce very little effect in normal persons but produces a rapid reversal of the effects of
morphine and other opioids.
❖ Therapeutic uses
▪ The main clinical uses of opioid antagonists are to treat respiratory depression caused by opioid
overdose, and to reverse the effect of opioid analgesics
▪ Opioid Antagonists have no important adverse effects but precipitates withdrawal symptoms in addicts.
▪ Opioid antagonists are contraindicated in case of chronic addicts with respiratory depression symptoms
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The lecture end
Thank you