Seminar 10. Opioid analgesics and antagonists & General anesthetics. PDF

Preview

Summary

Seminar 10.Opioid analgesics andantagonists.General anesthetics.I. Opioid analgesics andantagonists. The word opioid comes from opium ⇾ this is the main source of morphine → comes from the poppy flower - Opium itself contains a lot of alkaloids ⇾ basic in their chemical reaction - The poppy flower i...

Description

Seminar 10. Opioid analgesics and antagonists. General anesthetics. I. Opioid analgesics and antagonists. • The word opioid comes from opium ⇾ this is the main source of morphine → comes from the poppy flower# • Opium itself contains a lot of alkaloids ⇾ basic in their chemical reaction • The poppy flower itself contains a low concentration of these alkaloids (less than 2%)# • Unlike steroid analgesics, opioid analgesics are used in severe types of pain# • Used in final stages of cancer, when nothing else can be done# • Used to relieve pain in severe traumas or after surgery# • Analgesia not only due to blockage of the painful signal, morphine also changes the emotional perception to pain# • Pain will not arise, patient wont feel pain# • Patient won’t recognise pain stimulus as negative ➞ ‘dissociative analgesia’# • Especially useful in end stages of cancer when nothing else can be done, helps the patient to accept the condition • Euphoria (feeling of self-satisfaction, less stress and anxiety), sedation#

!

1 

3 types of opioid receptors • 3 types: mu, delta, kappa • Nowadays we mostly care about the mu receptor → Gi receptor • Effects of drugs are due to stimulation of the mu receptors (drugs are activators of the receptors)#

• 3 Types endogenous opioid substances (opioid peptides):# 1. Endorphins → have higher affinity for the mu receptor 2. Enkephalins → have higher affinity for the delta receptor# 3. Dynorphins → have higher affinity for the kappa receptor#

• All of these receptors mediate analgesia → receptors are located on different places and mediate a different type of analgesia# • mu receptors mediate supraspinal and spinal analgesia ➞ mu receptors produce CNS analgesia & peripheral analgesia • mu receptors are highly abundant in the spinal cord (dorsal horn of the SC)#

!

2 

Mechanism of action

• Pain stimulus travels to nerve ending# • 1st mu receptor in the periphery, while the 2nd one is much closer to the nerve ending, 3rd is on the secondary neuron# • Morphine is going to bind and stimulate the mu receptors 1. mu receptor is a Gi receptor ➞ decreases cyclic AMP levels ➞ we expect inhibition of the pain signal propagation in the periphery# 2. Morphine binds mu receptor close to nerve ending → stimulation of this receptor decreases the entry of calcium → calcium will not bind the vesicle → will reduce the release of painful mediators# 3. Morphine binds mu receptor on secondary neuron → causes decreased potassium leaving the cell ➟ causes hyperpolarization of the cell membrane ➟ will cause block ➟ block of propagation of the painful signal# !

3 

#

#

Whalen, K. (z.d.). Figure 14.4 Mechanism of action of μ opioid receptor agonists in the spinal cord. [figure]. Retrieved from Lippincott Illustrated Reviews Pharmacology p. 182

Effects of opioid analgesics

CNS Main effects on CNS: Analgesia, sedation, euphoria, respiratory depression

• Analgesia • Unlike the non-opioid analgesics, opioid analgesics also affect the emotional effect of pain → they don’t simply diminish the sensation of pain, they also decrease the emotional response to pain ➞ opioids change the emotional perception of pain# • Non-opioid analgesics decrease the sensory aspect of pain, but they do not have any effect on the emotional part of pain# • Sedation • Common finding in elderly patients and people suffering from some conditions# • Sedation is pretty rare in young and healthy individuals → sleepiness won’t be observed in younger people # # This is the reason why compounds like heroin are abused ⇾ they don’t cause sedation in a young & healthy person • Often observed together with euphoria# • Sedation might be a problem → morphine and morphine-like drugs disrupt the normal sleeping cycle (especially disrupt the REM sleep) → Problem next morning: patient still feels tired# • Euphoria • Frequent finding in people on injectable opioids (euphoria develops pretty slowly if opioid is given in tablet form)# • Causes less anxiety and stress (inner peace & satisfaction)# • Respiratory depression • Opioid analgesics inhibit the respiratory centre in the brainstem # • Patient forgets to breath → main death reason opioid overdose# • Breathing centre in highly sensitive to partial levels of O2 & CO2 → opioids decrease the sensitivity of the respiratory centre for the partial levels of CO2#

!

5 

• Cough suppression (supression of cough reflex)# • Especially with the drug codeine# • Blocking dry cough, type of cough due to some irritation on the airways without the accumulation of bronchial secretions# • Miosis (pin-point pupils) • One of the effects of opioids where we have no tolerance → miosis does not only occur in opioid overdose, it occurs at every dose • We have tolerance for other opioid effects → example: after 5th day of using morphine, the euphoria and algesia will get weaker# • Nausea & vomiting • Opioid analgesics activate the brainstem chemoreceptor trigger zone → this produces nausea and vomiting • This effect is mainly due to dopamine receptor stimulation → opioids don’t stimulate the dopamine receptors by themselves, they increase the release of dopamine in the CNS • The increased levels of dopamine are also responsible for the euphoria → due to increased levels of dopamine in the ‘reward center’ (center for pleasure, motivation, self-esteem)# • Hyperthermia • Caused by stimulation of the mu receptor# • Sleep pattern • Caused by stimulation of the mu receptor#

Cardiovascular system • Opioids have no direct effect on the cardiac function • Bradycardia (not a major effect) • Caused by stimulation of the mu receptor# • Effect on blood pressure • Due to histamine release → arterial and venous dilation ➞ Hypotension#

!

6 

GIT • Constipation → no tolerance 1 (occur at every dose) • Abdominal pain • Billiary tract contraction → biliary colics

Renal system • Its function is depressed → due to decreased renal flow (decreased volume of the urine)# • Opioids have direct anti-diuretic effect • Opioids can also enhance the renal sodium absorption → might lead to fluid retention

Uterus • Opioids prolong labor → due to relaxation of smooth muscle#

Endocrine system • Opioids inhibit the release of LH • Males: decreased testosterone levels → leads to decreased libido, energy and mood • Females: dysmenorrhea

Immune system • Opioids decrease immune response • Decreased lymphocyte proliferation & decreased production of antibodies #

1

!

No tolerance: miosis (pin-point pupils) & constipation

7 

Clinical use of opioid analgesics • Treatment of severe pain (high intensity pain)# • Renal pain → drug of choice in renal pain# • Biliary colic pain → Watch out: opioids worsen the biliary colics! • Pulmonary edema • Opioids decrease anxiety associated with pulmonary edema → they modulate the perception of shortness of breath ⇾ there will still be shortness of breath, but patient won't think about this • Decreased cardiac work • Pain associated with myocardial infarction • Suppression of cough (codeine) • Anesthesia → pre-medication before general anesthesia • Most frequently used in cardiovascular surgery (minimise the cardiovascular depression)# • Regional analgesia (opioids have direct effect on neurons dorsal horn spinal cord) → epidural analgesia during labor#

Pharmacokinetics of morphine

• Routes of administration: injected, oral, nasal (inhalation) # • Easily penetrate blood-brain barrier# • Do tend to accumulate → can lead to respiratory depression due to accumulation in adipose tissue • Metabolism: metabolised in the liver → glucuronidation • 2 morphine metabolites: !3-glucuronide → neuroexcitatory! ! ! ! ! ! ! ! 6-glucuronide → potent analgesics (more potent than # # # # # morphine itself) !

8 

Opioid tolerance, dependence & addiction

Tolerance • When we use opioid drugs repeatedly at limited time # • No tolerance in miosis (pin-point pupils) & constipation • Occurs at 4th-5th day of its use# • Opioid receptors become insensitive to stimulation → we should increase the dose to achieve the initial analgesic effect# • The longer the plasma half-life of the drug, the longer it takes for the tolerance to occur • The shorter the plasma half-life of the drug, the shorter it takes for the tolerance to occur • The larger the dose of the drug, the faster the tolerance will occur • The smaller the dose of the drug, the more slowly the tolerance will occur • The stronger the drug is, the faster the tolerance will occur • The weaker the analgesic is, the more slowly the tolerance will occur

Dependence • Definition: Fast adaptation of the homeostasis of the organism to the administration of some drug# • Withdraw effects: opposite effects of opioids# • Can only be observed when we patient suddenly stopped the use of the opioid analgesics#

Addiction • Definition: chronic disease of the brain reward, motivation and memory centres# !

9 

Opioid drugs

Pethidine / Meperidine • Exceptions: # • Only drug that can be used in the treatment of biliary colics# • Only drug that has significant cardiac effect • Does not produce miosis, it produces mydriasis (dilation of the pupils)# • Does not cause abdominal pain • The only drug from this group that has anti-muscarinic effect → blocks muscarinic receptors • Reason why it causes relaxation of the biliary smooth muscles • Atropine-like effects ➞ tachycardia

!

 10

Fentanyl • The most potent analgesic → much more potent than morphine# • Plasma half-life: 20 minutes# • Fentanyl is used as a single-dose drug # • Used during or before general anesthesia# • Drug of choice in myocardial infarction associated pain# • Tolerance, dependence and addiction occur very fast → not produced by single dose, will occur if fentanyl is used 4-5 days after each other# • Transdermal patches → fentanyl penetrates very fast through the skin → Danger: this will cause dependence and addiction# • Transdermal patches of fentanyl are only used for patients in terminal stages of some condition (eg cancer) → there is the danger of addiction, but these patients will die soon and we want to make sure these patients have some quality of life#

Methadone • Has one of the longest plasma-half lives# • Rarely causes tolerance, dependence and addiction (happens very slowely)# • Used in treatment of opioid addiction → because it doesn’t cause addiction itself# • Used as substitution-therapy# • Much easier to stop the treatment of methadone#

Naloxone • Injectable# • Drug supposed to use in case of respiratory depression# • Capable of very fast reversing the respiratory depression# • Acts as an inhibitor → blocks mu receptors#

!

 11

II. General anesthetics. #

!

 12...