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Opioids & Their Antagonists I, II (Opioid Agonists (Morphine…
Opioids & Their Antagonists I, II
Overview
Bind to
opioid receptors
, producing morphine-like effects (eg: analgesia)
Primary use:
Analgesic
(pain relief) - mainly for
severe or chronic
pain (eg: cancer, labor)
Natural, semi-synthetic or synthetic
compounds
sometimes
abused
as
recreational drugs (narcotics)
Opiates vs Opioids
Opiates
-
Naturally-occuring compounds
which are extracted from opium poppy (
Papaver somniferum
) that
act on opioid receptors
Opioids
-
All compounds
(natural, semi-synthetic or synthetic) that
act on opioid receptors
Classification
Natural
- alkaloids contained in opium poppy resin (eg:
morphine, codeine
)
Semi-synthetic
- modified from natural opioids (eg:
hydromorphone, hydrocodone, oxymorphone, oxycodone, heroin
Fully-synthetic
- created from chemical compounds (eg:
fentanyl, meperidine (pethidine), methadone, tramadol
Endogenous opioid peptides
- produced naturally in body (eg:
endorphins, enkephalins & dynorphins
Opioid Receptors
Mu (μ)
- Endorphins;
main functions
- analgesia, slowed GIT, modulation of hormone & NT release, sedation, inhibition of respiration
Delta (δ)
- Enkephalins;
main functions
- analgesia, modulation of hormone & NT release
Kappa (κ)
- Dynorphins;
main functions
- analgesia, slowed GIT, psychotomimetic effects
Mechanism of Action
Opioid agonists bind to opioid receptors in
brain & spinal cord
region involved in transmission & modulation of pain; Effects are mediated by opioid receptors on
peripheral nerve endings
that relay pain message to brain & spinal cord regions
Opioids act by
closing voltage-gated Ca2+ channels
on presynaptic nerve terminals,
reducing principal excitatory transmitter (glutamate) release
from nociceptive nerve terminals -->
open K+ channels & cause hyperpolarization
, decrease response to post-synaptic neuron to excitatory glutamate --> lead to
analgesic effect
Opioid Agonist & Antagonist
Full agonist
- binds to & activate
1 or more opioid receptors
(either μ, δ, or κ) to produce biological response
Partial agonist
- binds to & stimulate
one receptor
, but have only
partial efficacy
at receptor relative to full agonist
Antagonist
-
binds
with high affinity to opioid receptors, but
does not activate
receptor-mediated response; no profound effects in normal individuals; in patients-dependent of opioids, antagonist rapidly
reverse the effect of agonists
, such as morphine & precipitate symptoms of opiate withdrawal
Opioid Agonists
Morphine
Therapeutic Use
Analgesia, sedation, treatment of diarrhea, releif of cough
Precautions
Neonates
-
should not receive morphine
due to low conjugating capacity
Elderly patients
- sensitive to analgesic effect of morphine (due to
decreased metabolism
, decreased lean body mass & renal func etc),
should be treated with lower dose
Pharmacokinetic
Absorption
-
IM, SC & IV
injections; if thru
oral
, absorption from GIT is slow, use extended-release oral form to provide more consistent plasma levels
Distribution
- rapidly enters all body tissues; only
small % of morphine crosses BBB
because morphine is the least lipophilic of common opioids;
morphine should not be used for analgesia during labor
Metabolism
- 1st pass metabolism in liver; morphine (primarily) conjugated with glucuronic acid forming
morphine-3-glucuronide (M3G)
; morphine (10%) conjugated to
morphine-6-glucuronide (M6G)
; accumulation of M3G induces seizure (neurotoxic at high dose); high M6G
enhances & prolong opioid action
(4-6x > potent than morphine)
Excretion
- conjugates are excreted primarily in urine, with small quantities in bile
Duration of action
- systemic administration = 4-6 hrs in morphine-naive individuals; longer when injected epidurally, bcos its low lipophilicity prevents redistribution from epidural space
Adverse Effects
Severe
respiratory depression
(may result in death); vomiting; dysphoria; histamine-induced hypotensive effects (due to vasodilation);
elevates intracranial pressure
(can be serious in patients with head injury); enhances cerebral & spinal
ischemia
; cause
acute urinary retention
in benign prostatic hyperplasia (enlarged prostate gland); causes
tolerance & dependence
Overview
prototype;
major analgesic
drug; naturally obtained from opium plant; have high affinity for
μ receptors
; major effects in
CNS, GIT & urinary bladder
Effects
Analgesia
- relieve pain by raising pain threshold/tolerance & alter brain's perception towards pain;
Euphoria
- pleasant, relaxed, dreamy state & freedom from anxiety & distress;
Respiratory depression
- reduce sensitivity to [O2 & CO2] that are outside their normal range (eg: hypoxia);
Depression of cough
- antitussive effects by morphine & codeine
Miosis
- pinpoint pupil thru enhanced parasympathetic stimulation of eye (no tolerance to this effect);
Emesis (vomiting)
- triggered by stimulating chemoreceptor trigger zone in area postrema of brain;
Decreased GI motility
- cause constipation;
Increases ADH
- causes urinary retention
Cardiovascular
- hypotension & bradycardia at high dose;
Histamine release
- urticaria (itchy rash on skin), sweating & vasodilation;
Prolong labor
- decrease strength, duration & frequency of uterine contractions in 2nd stage of labor;
Sedation
- sleep more likely to occur with opiates than with synthetic compounds, but can be easily aroused from sleep
Meperidine
Adverse Effects
Anxiety, tremors, muscle twitches & rarely convulsion due to accumulation of normeperidine (large or repetitive dose)
Causes hyperactive reflexes (large doses)
Severe hypotesion when administered post-operatively
Dilates pupil (mydriasis)
, dry mouth & blurred vision (anti-cholinergic)
Pharmacokinetics
Duration of action
- slightly shorter than morphine; has potential for toxicity, should only be used for
short-term (<48 hrs) management
of pain
active metabolite (
normeperidine or norpethidine
- renally excreted; significant
neurotoxic
actions that can lead to delirium, myoclonus & possibly seizures
Precautions
When used with CNS drugs such as major antipsychotic drugs (eg: haloperidol), antidepressant MAOIs (eg: selegiline) or dextromethorphan (antitussive), can provoke severe reactions such as
convulsion & hyperthermia)
Inappropriate for geriatric patients & patients with impaired renal function, due to
accumulation of normeperidine (neurotoxic)
Adverse effects associated with normeperidine are
NOT REVERSIBLE
by giving
NALOXONE
(opioid antagonist)
Overview
known as
pethidine
,
synthetic
opioid, lower potency than morphine, used for
acute pain, most widely used for labor
,
very lipophilic
& has
anticholinergic effects
resulting in increased incidence of delirium (mental confusion) as compared to other opioids
Fentanyl
Therapeutic Use
Analgesic
(100-fold analgesic potency of morphine)
Anesthetic during cardiac surgery
(adv: negligible effects on myocardial contractility)
Epidural fentanyl
(induce anesthesia) & for
analgesia post-op & during labor
Transmucosal preparation
- treatment of cancer patients with breakthrough pain
As
transdermal patch
Adverse Effects
Death due to
hypoventilation
(breathing at abnormally slow rate, resulting in increased amount of CO2 in blood)
Muscular rigidity
, primarily abdomen & chest wall (during anesthesia)
Causes
pupillary constriction
(miosis)
Overview
Chemically related to meperidine
Sufentanil, Alfentanil, Remifentanil
Related to
fentanyl
, differ in terms of
potency & metabolic disposition
Sufentanil > potent than fentanyl
Alfentanil & remifentanil < potent & shorter acting
Heroin
Pharmacokinetic
Produced by
diacetylation of morphine
,
3-fold
increase in
potency
Greater solubility, can
cross BBB
more rapidly than morphine
Duration of action
: half than morphine
Effects
More exaggerated euphoria
Banned in US, some countries still used for treating severe pain of cancer
Overview
Semi-synthetic
Codeine
Overview
Opiate,
partial agonist
Therapeutic Use
Analgesic
- derived from its
conversion to morphine
by CYP450 2D6 enzyme system;
< potent
than morphine (only 30% of morphine); often used in combination with aspirin or acetaminophen
Antitussive effects
- at doses that do not cause analgesia; now replaced by
dextromethorphan
(synthetic cough depressant- no analgesic action & low potential for abuse); at commonly-used doses, has lower potential for abuse than morphine
Oxycodone, Oxymorphone, Hydrocodone, Hydromorphone
Semi-synthetic
Orally active; oral analgesic effect
> morphine
Tramadol & Tapentadol
Weakly inhibit reuptake of NE & serotonin
, has
anti-depressant effect
, thus contraindicated in patients
currently taking MAOIs
& those who have
taken within 14 days
(additive effect)
Respiratory-depression < than morphine; may cause
anaphylactic reactions
Centrally-acting,
bind to µ receptors
, use for moderate to severe pain
Analgesia produced by tramadol or its active metabolite can only be
PARTIALLY REVERSED
by
NALOXONE
Methadone
Therapeutic Use
Analgesic in nociceptive & neurogenic pain
Used in
controlled withdrawal of dependent abusers from heroin & morphine
- causes
milder but prolonged withdrawal symptoms
Pharmacokinetics
Absorption
-
well absorbed orally
unlike morphine
Distribution
- very
lipophilic, accumulates in fat tissues
, slow release from fat tissues causes half-life to range from
12-40 hrs (may extend up to 150 hrs)
; can lead to toxicity upon repetitive dosing. "
Actual duration of analgesia is 4-8 hrs
"
Metabolism
- liver
Excretion
- via feces
Overview
Synthetic
, orally effective, induce less euphoria, longer duration of action
Adverse Effects
Cause
physical dependence
(less neurotoxicity effect due to lack of metabolites)
Cause
torsades de pointes
(abnormal heart rhythm that can potentially lead to sudden cardiac death) in certain conditions
Overdosing is possible due to
cross-tolerance between methadone & other opioids
&
long half-life
Buprenorphine
Partial agonist
in
naive patients
, used to relieve moderate to severe pain;
Antagonist
in
patient with opioid dependence
, causing withdrawal symptoms
Major use:
Opioid detoxification
with
less severe & shorter duration of withdrawal symptoms
compared to methadone
Adverse effect
:
Respiratory depression
that is
NOT REVERSIBLE
by
NALOXONE
& cause decreased BP, nausea & dizziness
Opioid Antagonists
Naltrexone
Action similar to naloxone but with
longer duration of action
A single oral dose can block effect of heroin for up to 48 hrs
In combination with clonidine (& sometimes with
buprenorphine), is used for
rapid opioid detoxification
Can lead to
hepatotoxicity
Naloxone
Half-life
: 30-81 mins; due to short duration of action, depressed patient may have relapse
Acts as
competitive antagonist at µ, κ & δ receptors
,
with higher affinity to µ receptor than for κ receptors
Used to
reverse coma & respiratory depression of opioid overdose
by
rapidly displaces all receptor-bound opioid molecules
, patients will then
be alert & revived
Readily reverses respiratory depression
with only
minimal reverse of analgesia
No pharmacological effect in normal individual, but
precipitates withdrawal symptoms in opioid abusers
No clinical effect with oral naloxone, but
IV naloxone causes
patients to experience withdrawal
Contraindications
Use in patients with
impaired pulmonary function
- depressant properties of opioids may lead to
acute respiratory failure
Use in patients with
impaired hepatic or renal failure
- prolong half-life of opioids
Use during
pregnancy
- fetus becomes
physically dependent
in utero & manifest
withdrawal symptoms
in early post-partum period
Drug Interaction
Anti-psychotic agents
Increased sedation, enhanced CV effect
Monoamine oxidase inhibitors
(anti-depressants)
Relative contraindication to all opioid analgesic because of high incidence of
hyperpyrexic coma
; Hypertension
Sedative
(hypnotics)
Increased CNS depression, particularly respiratory depression
Tolerance
To achieve original response, higher dose must be administered
Frequent opioid administration causes
gradual loss (diminishing) in analgesic effectiveness
Degree of tolerance that may develop with opioids
High
Analgesia, euphoria, dysphoria, mental clouding, sedation, respiratory depression, anti-diuresis, nausea & vomiting, cough suppression
Moderate
Bradycardia
Minimal or none
Miosis, constipation, convulsion
Dependence
Failure to continue administering opioids may result in
withdrawal or abstinence syndrome
that reflects exaggerated rebound of acute pharmacologic effect of opioids
Withdrawal symptoms
: rhinorrhea (runny nose), lacrimation, yawning, chills, gooseflesh (piloerection), hyperventilation, hyperthermia, mydriasis, muscular aches, vomiting, diarrhea, anxiety, hostility
Physical dependence develops along with tolerance to repeated administration of opioids
Addiction
Risk of inducing dependence & potentially, addiction is important consideration before using opioid drugs
Need to obey certain principles: Once effective dose is established,
LIMIT
the dose to that level only; Use
ALTERNATIVE
non-opioid analgesic
Inability to abstain
consistently, impairment in behavioral control,
craving
, diminished recognition of significant problems with one's behaviors & interpersonal relationship & dysfunctional emotional response