OPIOID & ANTAGONIST

Agussalim Ali
FAKULTAS KEDOKTERAN
UNIVERSITAS HALU OLEO
Kendari
 DEFINITION
• Senyawa alami atau sintetik yang
meniru sifat narkotik alami
(morphine-like effects).
• Analgetik yang bekerja dengan cara
berikatan pada reseptor opioid yang
ditemukan terutama pada sistem
saraf pusat dan saluran cerna.
Reseptor ini memberikan efek
menguntungkan dan juga efek
samping yang tidak diinginkan.
 CLASSIFICATION
(opioid agonists)
– Natural opiates
• Alkaloids contained in the resin of the opium poppy
(morphine, codeine, thebaine)
– Semi-synthetic opiates
• Created from the natural opioids (hydromorphone,
hydrocodone, oxycodone,oxymorphone, desomorphine,
diacetylmorphine (Heroin)
– Fully synthetic opioids
• Created from chemical compounds (fentanyl, pethidine,
methadone, tramadol and propoxyphene)
– Endogenous opioid peptides
• Produced naturally in the body (endorphins, enkephalins,
dynorphins, and endomorphins)
OPIOID RECEPTORS
 COMPLEX ACTION OPIOIDS AND
OPIOID ANTAGONISTS

Agonist-antagonists (  analgesics)
• Nalorphine
• Pentazocine
• Butorphanol
Partial/weak  agonist +  antagonist
• Buprenorphine
Pure antagonists
• Naloxone
• Naltrexone
• Nalmefene
 MEKANISME NYERI
Pain

Modulation
Descending
modulation Dorsal Horn
Conduction
Ascending Dorsal root
input ganglion

Transduction
Spinothalamic Peripheral
tract nerve

Trauma
Peripheral
nociceptors

Adapted from Gottschalk A et al. Am Fam Physician. 2001;63:1981, and Kehlet H et al. Anesth Analg. 1993;77:1049.
Modified by AHT
MULTIMODAL ANALGESIA
PHARMACO-
DYNAMICS
 Clinical Use of Opioid Analgesics
• Analgesia → cancer and other terminal
illnesses
– New dosage forms of opioids that allow slower
release eg, sustained-release forms of morphine
(MSContin) and oxycodone (OxyContin). Their
purported advantage is a longer and more stable
level of analgesia.
• Acute Pulmonary Edema
– The relief produced by intravenous morphine in
dyspnea from pulmonary edema associated with left
ventricular failure is remarkable.
– The mechanism is not clear but probably involves
reduced perception of shortness of breath and
reduced patient anxiety as well as reduced cardiac
preload (reduced venous tone) and afterload
(decreased peripheral resistance). Morphine can be
particularly useful when treating painful myocardial
ischemia with pulmonary edema.
• Cough
– Suppression of cough can be obtained at doses
lower than those needed for analgesia.
– In recent years the use of opioid analgesics to allay
cough has diminished largely because a number of
effective synthetic compounds have been
developed that are neither analgesic nor
addictive.
• Diarrhea
– Diarrhea from almost any cause can be controlled
with the opioid analgesics, but if diarrhea is
associated with infection such use must not
substitute for appropriate chemotherapy.
– Crude opium preparations (eg, paregoric) were
used in the past to control diarrhea, but now
synthetic surrogates with more selective
gastrointestinal effects and few or no CNS effects,
eg, diphenoxylate, are used.
• Applications in Anesthesia
– The opioids are frequently used as premedicant drugs
before anesthesia and surgery because of their
sedative, anxiolytic, and analgesic properties.
– Also used intraoperatively both as to other anesthetic
agents and, in high doses (eg, 0.02–0.075 mg/kg of
fentanyl), as a primary component of the anesthetic
regimen.
– opioids can also be used as regional analgesics, by
administration into the epidural or subarachnoid
spaces of the spinal column.
 Contraindications & Cautions in
Therapy
• Use in Patients with Head Injuries
– Carbon dioxide retention caused by respiratory
depression results in cerebral vasodilation. In
patients with elevated intracranial pressure, this
may lead to lethal alterations in brain function
• Use during Pregnancy
– In pregnant women who are chronically using opioids,
the fetus may become physically dependent in utero
and manifest withdrawal symptoms in the early
postpartum period.
– A daily dose as small as 6 mg of heroin (or equivalent)
taken by the mother will result in a mild withdrawal
syndrome in the infant, and twice that much may
result in severe signs and symptoms, including
irritability, shrill, crying, diarrhea, or even seizures
• Use during Pregnancy.....continued
– Need careful history and physical examination
– When withdrawal symptoms are relatively mild,
treatment is aimed at control of these symptoms with
such drugs as diazepam
– With more severe withdrawal, camphorated tincture
of opium (paregoric; 0.4 mg of morphine/mL) in an
oral dose of 0.12–0.24 mL/kg is used.
– Oral doses of methadone (0.1–0.5 mg/kg) have also
been used.
• Use in Patients with Impaired Pulmonary
Function
– In patients with borderline respiratory reserve, the
depressant properties of the opioid analgesics
may lead to acute respiratory failure.
• Use in Patients with Impaired Hepatic or
Renal Function
– Half-life is prolonged in patients with impaired
renal function, and morphine and its active
glucuronide metabolite, may accumulate; dosage
can often be reduced in such patients.
• Use in Patients with Endocrine Disease
– Patients with adrenal insufficiency (Addison's
disease) and those with hypothyroidism
(myxedema) may have prolonged and exaggerated
responses to opioids.
 PHARMACOKINETICS
• Distribution - Widely distributed throughout body
tissue; concentration in kidney, liver and spleen is
higher than that in plasma. Only a small fraction enters
brain rather slowly. Morphine crosses placenta.
• Metabolism - Extensively in the liver. Metabolic-
breakdown is the primary method of opioid duration
• Excretion - Metabolites are excreted by the kidneys. A
small fraction is excreted in stool through the biliary
tract.
• Routes of administration - Oral, Transmucosal,
Transdermal, I.V (most rapid acting), I.M and S.C
 ADVERSE EFFECTS
ACUTE
– Miosis, Respiratory Depression, Nausea and
vomiting, Sedation, Skeletal muscle hypertonus,
Euphoria, Constipation, Vasodilatation, Urinary
retention, Bradycardia, Biliary Spasm, Morphine
poisoning.
CHRONIC
– Tolerance, Physical Dependence and Apnea (in
newborns)
Tolerance and Physical Dependence
Frequently repeated administration of
therapeutic doses → tolerance (gradual loss
in effectiveness)
↓
To reproduce the original response → larger
dose
Tolerance and Physical Dependence
Along with tolerance, physical dependence
Develops

Physical dependence is defined as the

occurrence of a characteristic withdrawal or
abstinence syndrome when the drug is
stopped or an antagonist is administered.
 Withdrawal
Withdrawal is manifested by significant somatomotor and autonomic
outflow-

• agitation • release of all pituitary and

• hyperalgesia adrenomedullary hormones
• hyperthermia
• hypertension • affective symptoms
• diarrhea -dysphoria
• pupillary dilation -anxiety
-depression

These phenomena are highly aversive and motivate the drug

recipient to make robust efforts to avoid the withdrawal state
 DRUG INTERACTIONS
• Drugs that may effect opioid analgesic activity include
amitriptyline, diazepam, phenytoin, protease inhibitors
and rifampin.
• Drugs that may be affected by opioid analgesics include
carbamazepine, warfarin, beta-adrenergic blockers and
calcium channel blockers.
• Use of opioid agonists with other drugs that decrease
respiration, such as alcohol, sedatives, hypnotic and
anesthetics, increase the risk of severe respiratory
depression.
• Taking tricyclic antidepressants, phenothiazines, or
anticholinergics with opioid agonists may cause sever
constipation and urine retention.
The “analgesic ladder”
recommendations for musculoskeletal pain
according to the modified Boger & Jones (2005) guidelines
 Morphine
Central Nervous System Effects
Analgesia
• Pain consists of both sensory and affective (emotional)
components.
• Opioid analgesics reduce both aspects of the pain experience,
especially the affective aspect.
• In contrast, nonsteroidal anti-inflammatory analgesic drugs have no
significant effect on the emotional aspects of pain.

Euphoria
• intravenous drug users experience a pleasant floating sensation
with lessened anxiety and distress (DA release in nucleus
accumbance).
• However, dysphoria, an unpleasant state characterized by
restlessness and malaise, may sometimes occur.
Sedation
• Drowsiness
• clouding of mentation
• little or no amnesia
• No motor incoordination
• Sleep is induced in the elderly (can be easily aroused
from this sleep)
Respiratory Depression
• by inhibiting brainstem respiratory mechanisms.
• Alveolar PCO2 may increase, but the most reliable
indicator of this depression is a depressed
response to a carbon dioxide challenge.
• In individuals with increased intracranial
pressure, asthma, chronic obstructive pulmonary
disease, or cor pulmonale, this decrease in
respiratory function may not be tolerated.
Cough Suppression
• Codeine in particular
• However, cough suppression by opioids may allow
accumulation of secretions and thus lead to airway
obstruction and atelectasis.

Temperature regulating centre depression

• chances of hypothermia

Vasomotor centre depression

• Fall in BP
Morphine stimulates:
• CTZ (nausea, vomiting)

• Edinger Westphal nucleus of III nerve is

stimulated (miosis)

• Vagal centre (bradycardia)

Miosis
• Constriction of the pupils
• By stimulating Edinger Westphal nucleus of III
nerve
• Miosis is a pharmacologic action to which little
or no tolerance develops
• valuable in the diagnosis of opioid overdose.
Truncal Rigidity-
• Truncal rigidity reduces thoracic compliance
and thus interferes with ventilation.
• Truncal rigidity may be overcome by
administration of an opioid antagonist, which
of course will also antagonize the analgesic
action of the opioid.
• Preventing truncal rigidity while preserving
analgesia requires the concomitant use of
neuromuscular blocking agents.
Cardiovascular System
• Bradycardia
Meperidine is an exception (can result in tachycardia)
• Hypotension - due to
-peripheral arterial and venous dilation
-depression of vasomotor centre
-release of histamine.
• Increased PCO2 leads to cerebral vasodilation
associated with a decrease in cerebral vascular
resistance, an increase in cerebral blood flow, and an
increase in intracranial pressure.
Gastrointestinal Tract
Constipation
• no tolerance
• Opioid receptors exist in high density in the gastrointestinal
tract
• constipating effects of the opioids are mediated through an
action on the enteric nervous system as well as the CNS
• gastric secretion of hydrochloric acid is decreased
• propulsive peristaltic waves are diminished
• tone is increased
• this delays passage of the fecal mass and allows increased
absorption of water, which leads to constipation
• so used in the management of diarrhea
Biliary Tract
• sphincter of Oddi may constrict
• contract biliary smooth muscle
• result in biliary colic

Renal
• Renal function is depressed by opioids
• decreased renal plasma flow
• enhanced renal tubular sodium reabsorption
• Ureteral and bladder tone are increased
• Increased sphincter tone may precipitate urinary retention
• ureteral colic caused by a renal calculus is made worse by opioid-
induced increase in ureteral tone
Uterus
• may prolong labor
• both peripheral and central actions of the opioids can
reduce uterine tone
Neuroendocrine
• stimulate the release of ADH, prolactin, and somatotropin
• inhibit the release of luteinizing hormone
Pruritus
• CNS effects and peripheral histamine release may be
responsible for these reactions
• pruritus and occasionally urticaria (when administered
parenterally)
Miscellaneous

The opioids modulate the immune system by

• lymphocyte proliferation
• antibody production
• chemotaxis
 Related drugs
Pethidine
• 1/10th in analgesic potency
• Spasmodic action on smooth muscles is less
• Tachycardia (antimuscarinic action)- it is related to
atropine, even acts on opioid receptors
• Safer in asthmatics (less histamine release)
• Uses- analgesia, preanaesthetic medication
• Preferred opioid analgesic during labour (less
neonatal respi depression)
Codein
- Potensi analgesia 1/10 - 3/20.
Fentanyl
• 80-100 times more potent than morphine
• few cardiovascular effects
• little propensity to release histamine.
• Because of high lipid solubility, it enters brain rapidly
and produces peak analgesia in 5 min after i. v.
injection.
• The duration of action is short: starts wearing off
after 30-40 min due to
redistribution
• Transdermal fentanyl has become available for use in
cancer
Tramadol
– Analgesic action mechanism
• Weak affinity for -opioid receptor
• norepinephrine & 5-HT reuptake Inhibition

– Advantage
• Less respiratory depression, nausea, vomiting,
constipation
• Less abuse potential
• Rapid psychomotor recovery

– Labour pain, injury, surgery (other short lasting pain)

– Moderate pain treatment : as effective as morphine
– Severe pain treatment : less effective than morphine
Naloxone (, ,  antagonist)

• Antagonizes all morphine actions

• Sedation is less completely reversed
• Blocks placebo, acupuncture, stress induced analgesia

Use
• Morphine poisoning
• Diagnostic test for opioid addiction
• Revert neonatal respi depression due to opioid use during
labour