Signal Transduction 5: Opioids Flashcards
Explain how natural activities of receptors can be harnessed to treat disease: Two factors required in drug design
From knowing a signalling pathway a drug can be designed to enhances it (agonist) or block it (antagonist)
Explain what binding affinity means and how to determine the affinity of a ligand.
Affinity: a measure of how tightly ligand will bind to receptor. This is measured by Kd dissociation constant (or Ki for inhibitor).
The Kd is the ligand concentration (nM) at which 50% of receptor is saturated with ligand.
What is the relative Kd of high affinity substance (high or low)
low
Compare 2 medications that treat asthm.
Salbutamol: low affinity for acute attacks.
Salmeterol: high affinity- long acting for prevention.
Both are agonists for the b-adrenoreceptor
What is the signalling pathway of the asthma medications
- Agonist binds to B adrenoreceptor causing G protein -a-subunit to bind to Adenylate cyclase
- Adenylate cyclase-> increased cAMP.
- cAMP activates Protein kinase A
- PKA activates phosphorylated myosin light chain kinase. This leads to muscle relaxation.
If an antaogonist binds to ga1 protein what happens to cAMP concentration
increases
What is the normal pathway for pain reception (nociceptor pain)
- Through a cut -> inflammation -> this increases prostagladins
- Nociceptor senses increase in prostaglandins which leads to AP initiated
- AP propogated to spinal cord interneurons where it is modulated . Releases neurotransmitter glutamate or substance P
- Neurotransmitter triggers AP in spinothalamic tract of neurons to the thalamus where pain is sensed
Name two different strategies that can be used to target pain relief and give examples of medicines
- Change the initiator of pain ( amount of prostaglandins)
2. Change the CNS modulation of pain at the synapse of interneuron
What is the WHOs pain relief ladder reccomend to use
1st non opioids,
- Opioids mild to moderate
- Strong Opioid
Explain how the signaling pathway of opioid receptors work, leading to a decrease in pain perception.
- Signal: opioids eg. endorphins are released by an interneuron
- They bind to GPCR Opioid receptor: (nyuu, kappa and delta) at the presynaptic neuron
- Goes through G-ai signal cascade
- Inhibits Adenylate cyclase
- reduced cAMP
- Decreases the Ca2+ coming into the cell and increases the amount of K+ leaving the cell in both neurons, so makes it more negative overall
- Less depolarisation of the presynaptic neuron to transmit the pain signal
What are the drawbacks of Opioid use
- Also works on receptors in the bowel/ anal sphincter and in the area of brain responsible for respiration leading to Constipation and death
- Tolerance to Opioids occurs through adaption of the receptor and effectors so need increasingly higher doses
- Addiction: Opioids cause a feeling of reward or pleasure
How did the Opioid crisis come about
In trying to treat pain in patients, opioids were prescribed as they were effective and supposedly addiction was rare.
However
increased misuse of prescriptions lead to increased overdose deaths and when they tried to shut down prescription drug misuse users moved to stronger forms including heroin, fentanyl and synthetic opioids that caused even more deaths because of high affinity and potency
What are the suggested potential solutions to the opioid crisis
- Development of antidote
- Change in policy
- Change doctor pain management practices
- develop better pain medication
How does antidote eg naloxone help against opioid crisis
Antidote is competitve antagonist that doesn’t lead to tolerance or addiction so can reverse addiction but is temporary solution
How does Change in policies help against opioid crisis
Policies
- monitoring of prescription drugs
- increase access to antidote for first responders
- increase access to drug abuse treatment
- enforce rules for drug makers
