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Opioid analgesics and
antagonist
Pain Management
What is a pain?
– A protective mechanism to warn of damage or the
presence of disease
– Part of the normal healing process
Pain is a warning signal and primarily protective in nature, but causes discomfort. It is the most important symptom that brings the patient to the physician.
Pain can be either acute or chronic and is a consequence of complex neurochemical processes in the peripheral and central nervous systems (CNS).
Analgesic is a drug that selectively relieves pain by
acting in the CNS or on peripheral pain mechanism,
without significantly altering consciousness.
Analgesics relive pain as a symptom, without affecting
its cause. They are used when the noxious stimulus
(evoking pain) cannot be removed or as adjuvants to
more etiological approach to pain.
Analgesics
Opioid (narcotic): Morphine like analgetics
Nonopioid (non-narcotic): 1. Aspirin like -
antipyretic or antiinflammatory analgesics.
2. Antidepressants
3. Antiepileptic drugs
4. General anesthetics and others
Natural
•Morphine
•Codeine
Semi-Synthetic
•Diacetylmorphine
(heroin)
•Naloxone
(antagonist)
Fully Synthetic
•Pethidine
(meperidine)
•Tramadol
•Nalbuphine
•Methadone
•Pentazocine
•Fentanyl
•Alfentanil
•Sufentanil
•Remifentanil
Classification by origin
Classification of OPIOIDS AND
OPIOID ANTAGONISTSStrong (Full) agonists
Morphine
Fentanyl
Diacetylmorphine (Heroin)
Pethidine (Meperidine)
Alfentanil, Sufentanil, Remifentanil
Methadone
Moderate agonist:
Codeine
Partial/weak µ agonist + κ antagonist
Buprenorphine
Classification of OPIOIDS AND
OPIOID ANTAGONISTSAgonist-antagonists ( analgesics)
Nalorphine
Pentazocine
Butorphanol
With mixed mechanism of action
Tramadol
Pure antagonists
Naloxone
Naltrexone
Nalmefene
Receptor Distribution
and Neural Mechanisms
of Analgesia:
Transmission
Mechanism of Action
Opioid analgesics bind to several different opioid receptors in the CNS and spinal cord
Opioid receptors
group of G-protein coupled receptors with
opioids as ligands.
The endogenous opioids are dynorphins,
enkephalins, endorphins, endomorphins and
nociceptin.
Subtypes of opiod receptors:
mu, delta, kappa, epsilon, sigma
Mechanism of action
Closing voltage-gated Ca2+ channels on
presynaptic nerve terminals. As result to Inhibit
release of
Glutamate, acetylcholine, norepinephrine,
serotonin, and substance P
Hyperpolarizing and thus inhibiting postsynaptic
neurons by opening K+ channels
A. Effects due to μ-receptor stimulation:
• Supraspinal, spinal & peripheral analgesia
• Euphoria
• Respiratory depression
• Miosis
• Decreased GIT motility,
• Sedation
• Physical dependence.
.
B. Effects due to қ-receptor stimulation:
• Spinal and peripheral analgesia,
• Dysphoria
• Sedation
• Respiratory depression (less)
• Miosis (less)
• Decrease GIT motility
• Physical dependence
C. Effects due to δ-receptor stimulation:
• Spinal analgesia
• Respiratory depression
• Decrease GIT motility .
• They are not true opioid receptors only
some opioids react with them .
D. Effects due to other receptors stimulation:
Stimulation of σ receptors produces autonomic stimulation, dysphoria, hallucinations, nightmares, and anxiety.
Stimulation of ε receptors produces analgesia.
4
Opiod Receptor Activation
Response Mu-1 Mu-2 Kappa Delta Sigma
Analgesia
Respiratory depression
Euphoria
Dysphoria
Decrease GI motility
Physical Dependence
Mania, hallucination
Effects of opioid analgesics
(morphine)
Central effects
Inhibitory Effects
1. Analgesia. The analgesic action has spinal and
supraspinal components. It acts in the substantia
gelatinosa of dorsal horn to inhibit release of excitatory
transmitters from primary afferents carrying pain impulses.
Action at supraspinal sites in medulla, midbrain, limbic and
cortical areas may alter processing and interpretation of
pain impulses as well as send inhibitory impulses through
descending pathways to the spinal cord.
Inhibitory Effects
2. Sedation. This effect is different from that produced by
hypnotics. Drowsiness and indifference to surrounding as
well as own body occurs without motor incoordination,
ataxia or apparent excitement (contrast alcohol). Higher
doses progressively cause sleep and coma. It has no
anticonvulsant action.
3. Respiratory Depression
- Significant respiratory depression by reduction of the
sensitivity of respiratory center neurons to carbon dioxide
Influenced significantly by the degree of sensory input
Respiratory depression is the most common cause of death
in acute opioid overdose.
Inhibitory Effects
4. Cough Suppression
Depression of cough reflex by depression cough center(Codeine more effective)
5. Temperature regulation. Morphine cause depression
of temperature regulating centre, hypothermia occurs,
but no antipyretic action.
-opioid receptor agonists hyperthermia
-opioid receptor agonists hypothermia
6. Vasomotor center is depressed at higher doses and
contributes to the fall in BP.
Inhibitory Effects
7. Hormones. Inhibiting of secretion of ACTH, GTH and
LH
8. Vomiting center is depressed.
Stimulating Effects
1.Euphoria Mood and subjective effects. These are
prominent. It has a calming effect, very pleasurable –
akin to orgasm. Pleasant floating sensation. Lessened
anxiety and distress
Dysphoria may occure
2. Emesis. Directly stimulation of the chemorecetor
trigger zone in the area postrema that causes vomiting.
Stimulating Effects
3.Miosis as result of III nerve stimulation (from stimulation
of μ and κ receptors). There is little tolerance to the
effect, and all addicts demonstrate pin-point pupils. This
is important diagnostically, because most other causes
of coma and respiratory depression produce dilation of
the pupil.
4. Vagal center is stimulated too – can cause bradycardia
and hypotension.
5.Hormonal action. Stimulation of releasing ADH, GH,
PL.
6. Truncal Rigidity
Intensification of tone in the large trunk muscles
Peripheral effects
Inhibitory Effects
1. GIT. Decreasing motility of smooth muscle. As result
produces constipation, with little tolerance developing.
2. Venodilation. Because of respiratory depression and
carbon dioxide retention, cerebral vessels dilate and
increase the cerebrospinal fluid (CSF) pressure.
Therefore, Morphine is usually contraindicated in
individuals with severe brain injury.
Stimulating Effects
1. CVS. Morphine has no major effects on the blood
pressure or heart rate except at large doses, when
hypotension and bradycardia may occur.
Except agonist-antagonists, that have sympathetic activity
and lead to hypertension and tachycardia.
2. GIT. Increasing tone of smooth muscle. It increases
pressure in the biliary tract, because causes spasm of
sphincter Oddi ( may cause biliary colic). It also increases
the tone of the anal sphincter.
3.Urinary bladder. Tone of both detrusor and sphincter is
increased, urinary urgency and difficulty in micturition are
occur.
Stimulating Effects
4. Bronchi. It causes histamine release which can cause
bronchoconstriction.
5. Histamine release. Releasing histamine from mast
cells, causing urticaria, sweating and vasodilation.
Because it can cause bronchoconstriction, asthmatics
should not receive the drug.
Morphine
It is the principal opium alkaloid, therefore described as
prototype. It shows a high affinity for μ receptors, varying
for δ and κ receptors, and low affinity for σ receptors
(The major effects of the opioids are mediated by these
receptors).
1. Analgesia:
- Used for various pain, especially acute, obstinate constant
pain (e.g. burn, cancer pain);
2. Cardiac asthma:
Acute left ventricular heart failure induces pulmonary edema
- Reduces anxiety, cardiac preload and afterload.
- Particularly useful for painful myocardial ischemia with
pulmonary edema.
3. Treatment of diarrhea (Loperamide)
4. Relief of cough
5. Premeditate drugs before anesthesia : sedative,
anxiolytic, and analgesic properties. For high-risk surgery
administered systemically; for local (epidural) anesthesia.
Indications
1. respiratory depression, apnea2. nausea and vomiting3. Dysphoria4. dizziness, orthostatic hypotension, edema5. mental clouding, drowsiness6. constipation, ileus7. biliary spasm (colic)8. dry mouth9. urinary retention, 10. hypersensitivity reactions (contact dermatitis, urticaria)11. Elevation of intracranial pressure (head injury)12. Tolerance and Physical Dependence
Adverse Reactions
Withdrawl Reactions
Acute Action• Analgesia
• Respiratory Depression
• Euphoria
• Relaxation and sleep
• Tranquilization
• Decreased blood pressure
• Constipation
• Pupillary constriction
• Hypothermia
• Drying of secretions
• Reduced sex drive
• Flushed and warm skin
Withdrawl• Pain and irritability
• Hyperventilation
• Dysphoria and depression
• Restlessness and insomnia
• Fearfulness and hostility
• Increased blood pressure
• Diarrhea
• Pupillary dilation
• Hyperthermia
• Lacrimation, runny nose
• Spontaneous ejaculation
• Chilliness and “gooseflesh”
Meperidine
It is a synthetic opioid with a structure unrelated to Morphine.
It is used for acute pain.
It binds to opioid receptors, particularly κ receptors.
It causes a depression of respiratory similar to that of Morphine, but there is no significant cardiovascular action when the drug is given orally.
Meperidine
It is a synthetic opioid with a structure unrelated to Morphine.
It is used for acute pain.
It binds to opioid receptors, particularly κ receptors.
It causes a depression of respiratory similar to that of Morphine, but there is no significant cardiovascular action when the drug is given orally.
It dilates cerebral vessels and increases cerebrospinal fluid pressure similar to that of Morphine and in contrasts it does not cause pinpoint pupils and has a little effect on gastrointestinal tract and urinary bladder.
Meperidine provides analgesia for any type of severe pain, but is not clinically useful in the treatment of diarrhea or cough. It produces less of an increase in urinary retention than does Morphine.
Meperidine
Fentanyl
It is chemically related to Meperidine, has 80 -
100 times more potent than Morphine, both in
analgesia and respiratory depression.
The duration of action is short: starts wearing
off after 15-30 minutes.
It is almost exclusively used in anesthesia,
mostly in combination with Droperidol.
Codeine
It is a much less potent analgesic than
Morphine, but it has a higher oral efficacy. It
shows good antitussive activity at doses that do
not cause analgesia.
It rarely produces dependence, because
causes less euphoria than Morphine.
It is often used in combination with Aspirin and
as antitussive drug.
Pentazocine
It acts as an agonist on κ receptors and is a weak antagonist at μ and δ receptors. It also binds to σ receptors, which may account for its dysphoric properties.
In higher doses, the drug causes respiratory depression and decreases the activity of the gastrointestinal tract. High doses increase blood pressure and can cause hallucinations, nightmares, tachycardia and dizziness.
Pentazocine
Despite its antagonist action, Pentazocine does not
antagonize the respiratory depression of Morphine,
but it can precipitate a withdrawal syndrome in a
Morphine abuser.
It can used as analgesic.
AntagonistsNaloxone and Naltrexone
They are used to reverse the coma and
respiratory depression of opioid overdose.
Naltrexone has a longer duration of action than
Naloxone (48 hours and 6 hours).
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