Unit 3: Drugs Affecting the Central Nervous System
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Lecture 8 - Opioids
Narcotic analgesics
Analgesic drug: Is a drug that relieves of pain.
Analgesic drugs are divided into 2-types
1-Narcotic 2-Non-narcotic
The narcotic analgesics are divided into two classes:
1. Narcotic analgesics obtained from raw opium.
2. Synthetic narcotic analgesics.
Narcotic analgesic drugs are called opiates or opioids
Opiates: An alkaloid narcotic analgesic derived from
opium (dried juice of the seed head of opium poppy).
Opioids: Analgesic drugs with morphine like action.
Actions of narcotic analgesic drugs:
1) They relieve pain usually by depressing CNS pain
transmitter.
2) They have other pharmacological effects: sedation,
constipation and antitussive.
3) Narcotic drugs interact or bind with specific receptors in
the brain and spinal cord; these specific receptors appear
to be the normal sites of action of several endogenous
ligands as: Endorphins, Dynorphins and Enkephalins.
The opioid peptides receptors are:
μ(mμ), κ(Kappa), δ(delta), σ(sigma)
1. μ(mμ): Causes analgesia, miosis, respiratory
depression, euphoria and physical dependence.
2. κ(Kappa): Causes sedation and miosis.
3. δ(delta): Its function is not fully defined (may be
involved in changes of effective behavior).
4. σ(sigma): Unpleasant feelings and hallucination.
Classification of opioids according to analgesic efficacy
1) High efficacy for severe pain (agonist action).
e.g
Morphine, Pethidine, Methadone, Diamorphine &
Fentanyl
2) Low efficacy for mild & moderate pain (agonist action)
e.g.
Codeine, Dihydrocodeine & Dextropropoxyphene.
3) Partial agonist (mixed agonist-antagonists).
e.g
Pentazocin, Buprenorphine & Meptazinol.
4) Pure competitive opioid antagonist.
e.g.
Naloxone and Naltrexone.
1) High efficacy for severe pain (agonist action).
Morphine and other opioids
Morphine will be described in detail and other opioid
analgesics principally in so far as they differ.
Morphine acts mainly on:
μ
1
receptors (analgesia, euphoria, dependence)
μ
2
receptors( respiratory depression, Gut motility)
Pharmacological actions:
On the central nervous system.
Depression leading to:
o analgesia (that means suppers pain)
o sedation or sleep
o respiratory depression (rate and depth, in over dose the
respiratory rat may reach to 2/min)
depression of cough reflex.
Excitation (stimulant) leading to:
o Vomiting (acts on CRTZ in medulla)
o Miosis (it stimulates the third nerve-nucleus, in
poisoning, it leads to pin-point pupil)
o Hyperactive spinal cord reflexes (not all).
Convulsion (very rare)
Changes of mood: euphoria or dysphoria
Dependence
On smooth muscle:
Gastrointestinal muscle spasm (delay gastric emptying
with constipation, so it is used in case of diarrhea).
Bilary tract spasm (spasm sphincter of oddi)
Bronchospasm (due to histamine release), increases
the viscosity of secretion, so morphine is harmful to
asthmatic patient.
Urine retention (the patient will ignore afferent
message from full bladder).
Uterus: labor is prolonged (slow of contraction by
central action).
On cardiovascular system:
Dilatation of blood vessels (direct action), so unfavorable
in hemorrhogic shock.
Other effects:
It has antidiuretic action (it releases ADH)
Decreases the action of diuretic drugs.
Sweating
Itching
Unit 3: Drugs Affecting the Central Nervous System
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Uses of Morphine:
Relief of moderate to severe acute pain. Is either visceral
(renal colic, MI) or it is somatic (as post-operative, burns,
fractures)
Brief relief of anxiety in serious and frightening disease
accompanied by pain e.g trauma.
Relief of dyspnoea in acute left ventricular failure and in
terminal cancer.
Pre-medication for surgery.
Symptomatic control of acute non serious diarrhoea e.g
travellers diarrhoea.
Suppression of cough (more for codeine).
Notes:
Dependence: physical dependence begins to occur within
24hrs if morphine is given 4-hourly.
It is very harm to the person and may change him to
criminal in order to get the drug.
Pharmacokinetic:
Morphine is absorbed readily after S.C or I.M injection. It
is unreliable oral absorption due to 1
st
pass metabolism in
the liver and gut.
Oral efficacy 1/6 to 1/8 than I.M or S.C. administration.
The period of effective analgesic is 4 to 5 hrs.
Morphine crosses placenta and depresses respiration in
the fetus at birth.
Tolerance:
Chronic use of morphine and other opioids is marked by a
cquired tolerance.
Tolerance occurs to analgesic, sedative, euphoria and
respiratory depression, but not to some stimulant agonist
effects as in case of constipation and miosis.
There is cross-tolerance to other opioid e.g methadone,
meperidine and other CNS depressant like alcohol and
barbiturates will cause sedation.
Opioids that have partial agonist induce tolerance with
agonist action but not to the antagonist action.
Withdrawal syndrome:
When the drug (like morphine) is withdraw from addict
person or if the addict person receives narcotic antagonist.
During the first 8-16 hrs the addict becomes (distress,
fear, anxiety, pupil dilatation, lacrymation and sweating.
Then within 36hrs, there are painful cramps in the back of
the legs and in the abdomen, salivation, vomiting,
diarrhoea and insomnia.
Then between the third and fourth day the systolic and
diastolic blood pressure increase to a maximum and temp.
rises an average 0.5°C.
For the next 5-10 days. These signs are subsiding.
Complete recovery requires from 3-6 months.
Treatment of withdrawal syndrome (morphine):
It is by giving the patient:
1. Methadone (with long half-life opioid) + benzodiazepine.
2. Clonidine (reduces the effect of nor-adrenergic
hyperactivity).
Why withdrawal syndrome occurs:
Morphine binds to the receptor (the neuron activity
decreases).
Enkephalins are switched off gradually.
On stopping morphine, the neurons are released from
inhibition due to the upsent of endogenous enkephalines.
With the time endogenous enkephalines become available
and hyperactive neurons return to normal state.
Acute morphine poisoning:
50mg morphine I.M produces serious toxicity:
Coma, pin point pupils, fall in blood pressure, respiratory
failure, death from overdose due to respiratory failure.
Drug interaction:
Morphine is potentiated by MAOI
s.
Any C.N.S depressant drugs (including alcohol) will have
additive effect.
Morphine releases of ADH so the effect of diuretic drugs
may be reduced.
Potentiate the effect on pain relief by tricyclic
antidepressants and dexamphetamine (C.N.S stimulants).
The respiratory depressant effects of morphine is
potientiated by NM-blocking agents.
Pethidine (meperidine)
It was introduced as antispasmodic cause smooth muscle
relaxants like atropine (it has atropine like action).
The analgesic potency of pethidine is 50mg which is
equivalent to 8mg of morphine (so it has lower
therapeutic efficacy)
Pethidine differs from morphine in that it:
Does not suppress cough usefully.
Does not constipate. So it is not used in case of diarrhea.
Is less to cause urinary retention & to prolong childbirth
(widely used in obstetric because it does not delay labour)
Has little hypnotic effect.
Duration of analgesic is shorter (2-3 hrs).
Dependence is less than morphine.
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Methadone
It is a synthetic drug, the analgesic potency similar to
morphine but with a longer duration.
It causes less sedation and euphoria than morphine.
Vomiting & constipation actions are less than of morphine
very effective orally (analgesia may last more than 24hrs).
It is useful for sever cough.
Diamorphine (heroin)
Semisynthetic drug.
It is converted in the body to morphine.
It is considered to be more euphorient.
It is 3-5 times more potent than morphine.
Fentanyl
80 to 100 more potent analgesia than morphine, short
duration of action (30-40 min).
Tramadol
Is an oral, synthetic, centrally active analgesic for moderate
to severe pain. It is not chemically related to opioids.
Its mechanism of action is unclear but includes binding to
mu opioid receptors and inhibiting re-uptake of nor-
epinephrine and serotonin in the brain.
Tramadol causes significantly less respiratory depression
than morphine.
2) Low efficacy for mild & moderate pain (agonist
action).
Codeine
It is less analgesic than morphine.
It lacks efficacy for severe pain (about 1/8 of that
morphine).
Uses for mild and moderate pain and cough.
Long term use is accompanied by chronic constipation.
Codeine is converted (10%) in the body to morphine.
Uses:
Analgesic for moderate pain & can be combined with other
analgesic like aspirin or paracetamol for potentiation.
Antitussive (cough suppressant).
In acute diarrhea.
Dihydrocodeine (Df 118) & Dextropropoxyphene
Are low efficacy opioid with analgesic efficacy similar to
that of codeine.
3) Partial agonist (mixed agonist-antagonists).
Pentazocin
Its analgesic effect is due to agonist action at k-receptors.
It causes dysphoria due to activation σ-receptors.
It is a weak antagonist at u-receptor.
It can cause withdrawal syndrome in addict person.
It can induce psychological and physical dependence
(agonist effect).
Its analgesic efficacy approximately to that of morphine.
Buprenorphine:
It is a high-efficacy partial agonist at the u-receptors and
an antagonist at the k-receptors.
It has less to induce dependence and respiratory
depression than pure agonists with little effect on CVS.
Meptazoline:
It is with a high efficacy partial agonist.
It has central cholinergic activity.
It does not cause euphoria and withdrawal effects.
4) Pure competitive opioid antagonist.
Naloxone
Is a pure competitive antagonist at the u, k and σ opioid
receptors (both agonist and partial agonist opioids).
It has no agonist activity.
It revers opioid induced respiratory depression within 1-2
min. The duration of action is 1hr.
It is also used to counter excess opioid after surgical
analgesia or child birth.
Naltrexone:
It is similar to nalaxone but longer acting with duration of
effect 1-3 days according to the dose.