WEEK 3: Pharmacology of pain control Flashcards
A thin 55-year-old female presents to the clinic for routine examination. X-ray absorptiometry studies
demonstrate abnormally decreased bone density in the lumbar vertebrae.
The patient ultimately had a vertebral compression fracture and complains of
back pain.
What is ‘pain’?
Pain is an unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage.
What are analgesics?
State types of analgesics.
Analgesics are a class of medications that are primarily designed to relieve pain.
These drugs work by altering the perception of pain in the brain or by reducing the sensitivity of the nerves that transmit pain signals.
*Non-steroidal anti-inflammatory drugs
*Paracetamol
*Opioids
* Adjuvants
Nonsteroidal Anti-Inflammatory Drugs (NSAIDs):
Describe the MOA of NSAIDS.
State the function of COX-1 and COX-2.
State 3 adverse reactions associated with COX-1 inhibition.
Examples: Ibuprofen, naproxen, aspirin.
Mechanism of action: NSAIDs reduce pain, inflammation, and fever by inhibiting the activity of enzymes called cyclooxygenases (COX), which are involved in the production of prostaglandins.
Aspirin (Irreversible non-selective COX inhibitor)
Other NSAIDS (Reversible non-selective COX inhibitors).
Adverse effects associated with COX 1 inhibition: GI ulcers, renal insufficiency, prolonged bleeding time.
Selective COX-2 inhibitors: Celecoxib have lower risk of cox-1 mediated adverse effects such as GIT irritation.
CYCLOOXYGENASE (COX) ENZYMES
COX-1 regulates physiologic activities such as vascular homeostasis, maintenance of renal and gastrointestinal blood flow, intestinal mucosal proliferation and platelet function (Constitutive)
COX-2 is primarily found at sites of inflammation. (Inducible)
NSAIDs are cyclooxygenase inhibitor.
Occurs in children with viral infections.
Most of the cases are associated with aspirin.
Manifested by liver failure and encephalopathy.
Poor prognosis (Death occurs in 20–40% of the cases.
Name the disorder.
Avoid aspirin in pediatric patients!
Reye syndrome
What is the other name for Paracetamol?
Describe the MOA of paracetamol.
Acetaminophen (Paracetamol):
Mechanism of action: Acetaminophen is believed to work by inhibiting an enzyme in the brain (cyclooxygenase), but its exact mechanism is not fully understood.
Inhibits prostaglandin synthesis in the central nervous system.
Limited effects on cyclooxygenase in peripheral tissues
It has weak anti-inflammatory properties.
It does not affect platelet function or increase the bleeding time.
Minimal GIT distress
Safe in pediatric patients.
Paracetamol is generally safe when used at therapeutic doses, but exceeding the recommended dosage can lead to severe hepatotoxicity.
It is essential for individuals to follow the recommended dosages and guidelines when using paracetamol to avoid unintentional overdose.
If there is any suspicion of paracetamol overdose, immediate medical attention should be sought to initiate appropriate treatment and prevent severe liver damage.
Describe how overdose of paracetamol can lead to liver failure.
Metabolism of Paracetamol:
Paracetamol is metabolized in the liver through various pathways. One of the primary pathways involves the conversion of paracetamol to a highly reactive metabolite called N-acetyl-p-benzoquinone imine (NAPQI).
Normal Detoxification by Glutathione:
At therapeutic doses of paracetamol, NAPQI is efficiently detoxified by the antioxidant molecule glutathione. Glutathione helps neutralize NAPQI and prevent its harmful effects on liver cells.
Depletion of Glutathione at Higher Doses:
In cases of paracetamol overdose or when taken in excess of recommended doses, the normal detoxification process can be overwhelmed. The high levels of NAPQI can deplete the available glutathione in the liver.
NAPQI Reaction with Hepatic Proteins:
When glutathione becomes depleted, NAPQI can react with hepatic proteins, leading to oxidative stress and damage to liver cells. This can result in inflammation, hepatocellular injury, and cell death.
Liver Failure:
If the damage is severe and widespread, it can progress to acute liver failure, a serious and potentially life-threatening condition. Liver failure can have systemic consequences and may require emergency medical intervention, including liver transplantation in severe cases.
OPIOIDS
Give examples of endogenous opioids.
Give examples of opioids receptors.
What type of receptors are they?
Describe their MOA.
Describe the MOA of opioids.
Endogenous Opioids:
Endorphins, enkephalins, and dynorphins are examples of endogenous opioids.
These are naturally occurring substances in the body that bind to and activate opioid receptors.
Opioid Receptors and G-Protein Coupling:
Opioid receptors, such as mu (μ), delta (δ), and kappa (κ) receptors, are G protein-coupled receptors.
When an opioid binds to its receptor, it activates the associated G protein (usually Gi/o), initiating intracellular signaling cascades.
Gi Protein Coupling:
Gi proteins inhibit adenylate cyclase, leading to a decrease in the production of cyclic adenosine monophosphate (cAMP). This inhibition of cAMP has downstream effects on cellular function.
Mechanisms of Action:
Opioid receptors exert their effects through multiple mechanisms:
Closure of Voltage-Dependent Calcium Channels (VDCCs) on Prejunctional Nerve Terminals: Opioid binding inhibits the opening of VDCCs, reducing the influx of calcium ions.
This inhibits the release of neurotransmitters, such as substance P, from presynaptic nerve terminals.
Opening of Potassium Channels (K+ Channels) in Postjunctional Cells:
Opioid receptor activation opens potassium channels, leading to an efflux of potassium ions from the cell. This hyperpolarizes the cell membrane, making it less excitable and reducing the likelihood of action potential generation.
OPIOD»_space;»MORPHINE
Describe the MOA of morphine.
Describe a diagnostic test used to check for morphine overdose.
State some of the adverse effects of morphine.
Analgesia:
Morphine provides pain relief by binding to opioid receptors in the brain and spinal cord. It increases the pain threshold and alters the perception of pain, leading to a reduction in the sensation of pain.
Meiosis:
Morphine causes constriction of the pupil (miosis) by stimulating the oculomotor nucleus. This effect is often used as a diagnostic sign in cases of suspected opioid overdose.
Constipation:
Morphine can lead to constipation by increasing smooth muscle tone in the gastrointestinal (GI) tract and reducing GI motility. Opioid-induced constipation is a common side effect of opioid medications.
Depression of Cough Reflex:
Morphine suppresses the cough reflex by centrally acting on the medullary cough center. This can lead to the accumulation of respiratory secretions, which may be a concern in certain clinical situations.
Nausea and Vomiting:
Morphine can stimulate the chemoreceptor trigger zone in the brain, leading to nausea and vomiting. This side effect is common, especially during the initial administration of opioids.
Respiratory Depression:
One of the most serious side effects of morphine is respiratory depression. Morphine acts on the respiratory centers in the brainstem, reducing the responsiveness to elevated carbon dioxide levels and impairing the drive to breathe. This effect can be life-threatening in overdose situations.
Euphoria, Tolerance, and Dependence:
Morphine has psychoactive effects, including a sense of euphoria or well-being. Prolonged use of morphine can lead to the development of tolerance, where higher doses are needed to achieve the same analgesic effect. Additionally, dependence can occur, leading to withdrawal symptoms upon discontinuation.
OTHER OPIODS (morphine-like drugs)
Pethidine/ meperidine (demethylated in the liver to norpethidine
hallucinations and convulsions)
Fentanyl (More potent than morphine. Rapid onset and shorter duration of
action. Peri-operative analgesia)
Codeine (Weaker analgesic than morphine. Mild-moderate pain. Cough
suppressant )
Pethidine/ meperidine (demethylated in the liver to norpethidine
hallucinations and convulsions) 2024
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Others: Tramadol (5HT-NE reuptake inhibitor), Buprenorphine
(partial receptor agonist),
What are ADJUVANT ANALGESICS?
State the 3 main adjuvant analgesics and their MOA.
Drugs that are used primarily for treating conditions other than pain but may be analgesic in selected circumstances.
Glucocorticoids (↓ Prostaglandin synthesis) (Myriad of musculoskeletal conditions)
Antidepressants (↑ serotonin and norepinephrine in synapses) (Chronic pain syndrome)
Anticonvulsants (GABA mimetics) (Neuropathic pain)
- Glucocorticoids:
Mechanism of Action: Glucocorticoids, such as prednisone or dexamethasone, have anti-inflammatory effects by inhibiting the synthesis of prostaglandins and other inflammatory mediators.
Primary Use: Glucocorticoids are used to manage a myriad of musculoskeletal conditions, autoimmune disorders, and inflammatory conditions.
Analgesic Role: In conditions associated with inflammation, such as rheumatoid arthritis or certain types of joint inflammation, glucocorticoids can contribute to pain relief by reducing inflammation.
- Antidepressants:
Mechanism of Action: Antidepressants, such as tricyclic antidepressants (TCAs) or selective serotonin and norepinephrine reuptake inhibitors (SNRIs), increase the levels of serotonin and norepinephrine in synapses, modulating pain perception.
Primary Use: Antidepressants are primarily prescribed for the treatment of depression, anxiety, and other mood disorders.
Analgesic Role: In lower doses than those used for mood disorders, certain antidepressants can be effective in managing chronic pain syndromes, such as neuropathic pain.
Anticonvulsants:
Mechanism of Action: Anticonvulsants, such as gabapentin or pregabalin, have GABA-mimetic effects and modulate the excitability of neurons, particularly in the context of neuropathic pain.
Primary Use: Anticonvulsants are used to control seizures in epilepsy and to manage certain psychiatric disorders.
Analgesic Role: They are also effective in treating neuropathic pain conditions, such as diabetic neuropathy or post-herpetic neuralgia.
Describe the ANALGESIC LADDER.
Step 1: Non-Opioid Analgesics (mild pain):
Examples: Acetaminophen (paracetamol), nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen or aspirin.
Purpose: Non-opioid analgesics are recommended for the initial management of mild pain. They act by reducing inflammation and blocking pain signals. Acetaminophen is commonly used for its analgesic and antipyretic properties, while NSAIDs also have anti-inflammatory effects.
Step 2: Weak Opioids (moderate pain):
Examples: Codeine, tramadol.
Purpose: If pain persists or becomes more severe, weak opioids may be added to the treatment regimen.
These opioids have a lower potency compared to strong opioids, and they are often combined with non-opioid analgesics for synergistic effects. Codeine is frequently used in combination with acetaminophen or NSAIDs.
Step 3: Strong Opioids (severe pain):
Examples: Morphine, oxycodone, hydromorphone, fentanyl.
Purpose: In cases of severe or persistent pain, strong opioids are introduced.
These medications provide potent analgesia and are effective in managing moderate to severe pain.
The choice of opioid, its formulation, and the route of administration depend on the individual patient’s needs and the nature of the pain.
