of Pharmacology Opioid Analgesics
Spring 2011
Harvey Alan Berman, PhD, MPH
Department of Pharmacology and Toxicology [e-mail] 829-2658
Pain
An unpleasant sensory and emotional experience associated with actual or potential tissue damage Distinguish:
Pain as a specific sensation Pain as suffering
Pain is transmitted through
Thin (1-5 m), myelinated A fibers
v = 12-30 m/sec Fast, 1st pain
Very thin (< 1 m), nonmyelinated C fibers
v = 0.5-2 m/sec Slow, 2nd pain
Duller, aching, diffuse pain These fibers also carry sensation of itching
Conduction of pain impulses from the periphery to the brain occurs through a multineuron pathway
Types of Pain
Nociceptive pain results from injury to tissues
Somatic pain Visceral pain
Neuropathic pain results from injury to peripheral nerves. Both types respond differently to analgesic drugs.
Nociceptive pain
Somatic pain
Results from injury to tissues
Bones, joints, muscles
Localized and sharp in quality
Visceral pain
Results from injury to visceral organs
E.g., small intestine
Vaguely localized with a diffuse aching quality
Papaver somniferum
Opium poppy Resin from the poppy is collected and processed into opium
Opium alkaloids
Morphine (9-17 % by weight opium)
Chiefly responsible for pharmacological actions of opium
Codeine (0.3-4 %)
Methylmorphine, has similar but weaker actions
Thebaine (0.2 %)
Practically devoid of analgesic activity No medicinal use, but it provides a synthetic route fo hydroxylated opioids
Morphine
17
N
CH3
3
HO
O
6
OH
17
N
CH3
N
CH3
3
HO
O
6
OH
H3CO
O
OH
MORPHINE
CODEINE
!
Structural relationships among some opiates
N N CH3 O H3CC O H3CO O OCH3 N O
CH3
O O CCH3
HEROIN
CH2CH OH N CH3 OH HO O O CH2
THEBAINE
NALOXONE
H3CO O O
OXYCODONE
A-D-M-E
In general:
Opioids are absorbed well IM, SC, and oral and nasal mucosa Rapid distribution from blood into highly perfused tissues (lung, liver, kidney, spleen)
[Brain] < other tissues, due to BBB
First-pass metabolism in the liver inactivates many opioids (e.g., morphine) Polar metabolites are excreted in urine
Glucuronidation of opioids
COOH O OH OH O OH UDP COOH OO R
+
R
OH
OH OH OH
+
UDP
UDP-glucuronic acid
Pharmacological Actions of Morphine
Actions in the CNS
Analgesia Euphoria Miosis Respiratory depression Cough suppression Nausea / vomiting Mood altering / rewarding properties
Analgesic
Relief of moderate to severe acute pain
renal colic biliary colic acute MI dyspnea associated with LVF and pulmonary edema extensive surgical procedures and post-operative pain severe burns serious wounding severe chronic pain (e.g., associated with malignancy)
Continuous dull pain is relieved more effectively than sharp intermittent pain. In patients suffering from pain, morphine induces a feeling of well being and tranquility (euphoria). In pain-free individuals, the response to morphine is not always pleasant:
General malaise Sensations of anxiety or fear (dysphoria)
Miosis
Due to excitation of the parasympathetic nerve innervating the pupil
Respiration
Morphine depresses respiration, even at normal therapeutic doses. Due to decreased sensitivity of brain stem to increases in PCO2 and [H+]. The main stimulus to breathing at this point becomes hypoxia. This effect is increased by the concurrent use of other CNS-active drugs (alcohol, barbiturates, benzodiazepines) Caution: Pregnancy (neonate)
Respiration Suppression of respiratory drive contributes to usefulness of morphine in relieving difficult or labored breathing in certain conditions such as Left ventricular failure Pulmonary edema
Morphine increases intracranial pressure !
Mechanism: indirect
Respiration pCO2 arteriolar dilatation CSF pressure
But, if respiration is maintained at a normal rate, ICP will remain normal
Antitussive action
Morphine the suppresses cough reflex that originates in the medulla oblongata.
Unrelated to its analgesic action. Unrelated to its respiratory depressant action.
Can modify the morphine molecule to select this single property
Cough suppressant - dextromethorphan
Emesis Morphine stimulates the CTZ in the medulla to cause nausea and vomiting
A vestibular component ?
Cardiovascular System
Blunts the baroreceptor reflex Causes peripheral arteriolar and venous dilatation
Results, in part, from morphine-induced release of histamine
Orthostatic hypotension and fainting
In recumbent individuals, effect is mild In standing individuals, the effect is profound
GI Tract Morphine decreases propulsive peristalsis through GI tract
Leads to constipation
Morphine suppresses awareness of bowel stimuli
Propulsive peristalsis through GI tract is decreased:
Passage of GI contents is delayed. This leads to enhanced absorption of water.
dehydration of feces.
Tone of anal sphincter is increased.
the constipation action of morphine.
Urinary retention Morphine causes urinary hesitancy and urinary urgency
Increased tone of bladder smooth muscle Increased tone of sphincter muscle
Morphine suppresses awareness of bladder stimuli
Biliary colic
Morphine can cause spasm of the lower end of the common bile duct (The Sphincter of Oddi) pressure within the biliary tract. In patients with pre-existing biliary colic, morphine can intensify the pain.
Meperidine a better choice ? Causes less smooth muscle spasm?
Chronic Actions of Morphine Tolerance
Tolerance develops to
Analgesia Respiratory depression
Tolerance does not develop to:
Constipation Pupillary miosis
Dependence
Opioid Poisoning Triad of 3 signs strongly suggests opioid poisoning.
Coma Pinpoint pupils Depressed respiration
Treatment of Opioid Poisoning Maintain patent airway and ventilate the patient Treat with antagonist to reverse CNS effects
Naloxone is drug of choice
Mechanism of Action The Morphine Receptor
Morphine binds to a specific receptor Binding is stereospecific Only the l-isomer is active Implies that binding involves at least three binding sites Regional distribution The regions of highest binding are associated with the limbic system Three principal receptors: , ,
Opiate binding sites (green dots) within the brain and spinal cord
Morphine binds to opiate receptors concentrated within the reward pathway and the pain pathway.
The -Morphine Receptor Spinal and supra-spinal analgesia Miosis Respiratory depression
The k-Morphine Receptor Spinal analgesia Miosis Less intense than Respiratory depression Less intense than Sedation Dysphoria
Euphoria Physical dependence GI motility
The -Morphine Receptor
Much less is known about this receptor Alters affective behaviour ? Main barrier to clinical utility is that most of the -receptor agonists are peptides and do not cross the BBB.
Endogenous Opioids
Opioid drugs produce analgesia by activating the same receptors that are activated on by the endogenous painsuppressing system The enkephalins The endorphins The dynorphins
The enkephalins
Met-enkephalin: H-Tyr-Gly-Gly-Phe-Met-OH Leu-enkephalin: H-Tyr-Gly-Gly-Phe-Leu-OH They mimic the actions of morphine on tissues that contain morphine receptors
The endorphins The dynorphins
Mechanisms of Action
Opioid receptors respond to opioids and to endogenous peptides (suppress painful stimuli) Opioids work both presynaptically and post-synaptically
In general, opioid receptors are G-protein coupled receptors Activation reduces Ca++ influx during the action potential, leading to less neurotransmitter release
Spinal sites of opioid action
, , agonists reduce transmitter release from presynaptic terminals of nociceptive primary afferents. agonists also hyperpolarize second-order neurons by K+ conductance ipsp