Lecture 3 - NSAIDs and Opioids Flashcards
Opioid agonists:
- what is the natural ligand to opioid receptors ?
- where in the brain are opioid receptors found?
-
Natural Ligand: Endorphins
Locations of Receptors:
Brain – PAG, Amydala, Hypothalamus, corpus stiratum
Spinal cord
Mu Opioid Agonists –
what is the mechanism of action of most opioid agonists ?
Receptors are both pre and post synaptic:
* Pre synaptic: When Mu agonist binds, decreased conductance of voltage gated calcium channels/less likely for the vesicles to merge and release contents to synaptic cleft * Post Synaptic level -- Increase in K conductance; hyperpolarization of the post synaptic membrane; less likely to reach action potential
what are the three different classes of opioid receptors? which is most likely to cause side effects?
- Mu – the workhorse for pain relief; also most of the associated unwanted side effects from these drugs (respiratory depression, for example)
* Kappa – contribute to spinal analgesia; also some unwanted side effects such as constipatin, miosis, sedation
Delta – contribute to analgesia
Opioid agonist effects/side effects at the CNS level?
Analgesia
Sedation
Respiratory System – Dost dependent depression (depressant effect on brain stem ventilation centers; loss of CO2 responsiveness)
Muscle rigidity
Miosis
Opioid agonist effects/side effects at the cardiovascular level?
– describe the potential mechanisms for this
CVD– Hypotension
Mechanism:
Bradycardia – from decreased central sympathetic tone
Increased activity of vagal nerves –
Depressant at the SA node
Histamine Release – vasodilation; decreased preload via venous pooling
Opioid agonist effects/side effects at the GI level?
constipation – decreased peristalsis; increased sphincter tone; more water resorption
Nausea and Vomiting – direct stimulation of chemo-receptor trigger zone on the 4th ventricle
side of effects of Mu agonists at the level of the GU, skin and placenta?
- The GU – increased tone and peristalsis of the ureter; tone of vascular sphincter is enhanced; urinary retention
- The Skin – histamine release, cutaneous vasodilation, urticaria
- Placenta – No a barrier for transfer; neonatal ventilator depression or even neonatal dependence is a possibility
what three factors influence ability of a drug to cross the BBB
Lipid Solubility (higher lipid solubility, the easier the cross)
Charge
Drug is un bound to protein
MORPHINE
- - mechanism? CNS penetration? - Onset? Peak effect? Duration? Metabolism/metabolites? excretion? be careful giving this drug to patients with....
Mu agonist
CNS Penetraton – poor – delay in the crossing BBB
* Onset -- 15 to 30 minutes; * Peak effect: (Blood to brain); 45-90 minutes * Duration: 4 hours
Metabolism via the Liver
15-25% M6G Metabolite – still active; prolonged effects in the body;
Excreted via the kidneys
Becareful giving to patients with Renal insufficiency
• Meperidine (Demerol)
- Mechanism?
- potency compared to morphine/
- Duration?
- side effects?
- Metabolism/MEtabolites?
- Clinical uses?
- Synthetic opioid agonist that also has anti-muscarininc effects
- 10% as potent as morphine
- duration - 2-4 hours
- Metabolism: Normeperidine, which can cause clonus and seizures
- Side effcts: Antimuscarinics effects, histamine release, decreaed myocardial contractility
- Only current clinical use: Post operative shivering
Fentanyl
Potency compared to morphine? why?
onset vs dduration?
Metabolism?
100x more potent that morphine – more lipid soluble, fast onset, long context sensitivehalf life
Fast onset –
Short duration – redistributes quickly bc of thoses same properties
no active metabolites
No histamine release
which two opioid agonists can cause histamine release?
Morphine, Meperidine
Sufentanil - potency compared to fentanyl - onset? - duration ? - Metabolsim? Clinical uses?
10x more potent than fentayl Very lipopholic very fast Onset Short duration (rapid redistribution) No active metabolites Used for intra-operative infusions
Remifentanil
- potency compared to fentayl
- Chemical structure? what is the significance of this?
- peak effect?
- Duration?
- Metabolism?
Similar potency to fentanyl
Ester linkage – metabolised by estase in the blood stream
therefore can be used in patients with liver or kidney failure
No toxic metabolites
Peak effect - 1 minute
extremely short, and very predictable, duration
Methadone - mechanism? - uses? Metabolims? considerations of dosaging?
Mu opioid agonist; also an NMDA receptor Antagonist; both help with pain modulation
• Used for chronic pain; used for weaning off heroin * Half-life is unpredictable (16-120 hours?) * The drug can accumulate; can result in respiratory arrest * Have to start off on small doses;
