Pain 😪 Flashcards
What is the process of neurotransmission in the Central Nervous System?
Using a provided diagram, describe the neurotransmission process in the Central Nervous System, focusing on the events at the synapse. Begin with the arrival of an action potential at the presynaptic neuron and trace the sequence of events that lead to the transmission of a neural message to the postsynaptic neuron. Highlight the critical molecular and cellular events involved in this process and discuss the role of neurotransmitters, receptors, and other relevant components. Support your explanation with a clear and labelled illustration of the synaptic transmission process.
1) Arrival of action potential: An action potential reaches the axon terminal of the presynaptic neuron. This depolarisation causes voltage-gated calcium (Ca**) channels in the membrane to open.
2) Calcium influx: Calcium ions (Ca?) enter the presynaptic terminal from the extracellular space due to the concentration gradient. The increased intracellular Ca” concentration acts as a signal to initiate the next steps.
3) Neurotransmitter release: The influx of Ca”* triggers synaptic vesicles containing neurotransmitters (e.g., glutamate, GABA dopamine) to move toward the presynaptic membrane. Vesicles fuse with the presynaptic membrane via a process called exocytosis, releasing neurotransmitters into the synaptic cleft.
The neurotransmitters diffuse across the synaptic cleft and bind to specific receptors on the postsynaptic membrane (e.g., ligand-gated ion channels or G-protein-coupled receptors).
4) Postsynaptic response and termination of signal:
Depending on the type of receptor and neurotransmitter: Excitatory neurotransmitters (e.g., glutamate) cause an influx of positive ions (e.g., Na), leading to depolarization and the generation of an excitatory postsynaptic potential (EPSP).
Inhibitory neurotransmitters (e.g., GABA) cause an influx of negative ions (e.g., CI) or efflux of K, leading to hyperpolarization and the generation of an inhibitory postsynaptic potential (IPSP). If the summation of EPSs reaches the threshold, an action potential is initiated in the postsynaptic neuron.
The signal is terminated by: Reuptake: Neurotransmitters are taken back into the presynaptic terminal via transporter proteins.
Enzymatic Degradation: Enzymes (e.g., acetylcholinesterase) break down neurotransmitters in the synaptic cleft.
Diffusion: Neurotransmitters diffuse away from the synaptic cleft.
What is the relationship between neurotransmission and pain pathways (ascending and descending pathways), including nociceptive and neuropathic pain, in the development and perpetuation of chronic pain?
Ascending Pathways
Nociceptive Pain: This type of pain results from actual or potential tissue damage. Nociceptors detect harmful stimuli and send signals via A-delta and C fibers to the spinal cord. These signals are then relayed to the brain through pathways like the spinothalamic tract. Look at 4 stages of nociception
Neuropathic Pain: This pain arises from damage to the nervous system itself, such as nerve injury or diseases like multiple sclerosis. It involves abnormal processing of pain signals both at the peripheral and central levels.
Descending Pathways
Pain Modulation: Descending pathways from the brain to the spinal cord modulate pain signals. Neurotransmitters like serotonin, norepinephrine, and endogenous opioids play a significant role in this modulation, either inhibiting or facilitating pain.
Central Sensitization: Chronic pain can lead to central sensitization, where the central nervous system becomes hypersensitive. This results in an exaggerated response to pain stimuli and can perpetuate pain even in the absence of an ongoing injury.
Neurotransmitters
Glutamate: Involved in excitatory neurotransmission, it plays a key role in transmitting pain signals.
Substance P: Associated with transmitting pain and inflammatory signals.
Serotonin and Norepinephrine: Key players in descending pain modulation, influencing pain inhibition and facilitation.
Chronic Pain Development
Chronic pain can develop due to a combination of peripheral and central sensitization, leading to a persistent state of pain hypersensitivity. This can be influenced by various factors, including genetic predisposition, psychological stress, and environmental factors.
Understanding these mechanisms helps in developing targeted treatments for chronic pain management, aiming to disrupt the maladaptive changes in pain pathways.
Chronic pain, persistent stage
Include receptor names and pathways
What is the general structure of a neuron?
Dendrite: the input region, receives input from other neurons (excitatory - generate an electrical impulse - or inhibitory - keep the neuron from firing)
Cell body: nucleus, stores DNA abs rough ER, which builds protein abs mitochondria. It maintains the nerve cell and is involved in the growth and development of the nerve cell.
Axon: main conduction unit, carries info in the form of electrical signal known as the action potential. It transmits electrical signals to other neurons, muscles or glands.
Axon terminals: the output region, release of neurotransmitter.
What is the role of neurotransmission in the development and maintenance of chronic pain?
Provide a detailed overview of the pain pathways, including key neurotransmitters, receptors, and brain regions. Additionally, discuss how changes in neural plasticity may contribute to the transition from acute to chronic pain.
How do analgesics affect neurotransmission in the Central Nervous System?
Briefly describe how the drugs below affect neurotransmission in the CNS
Amitriptyline
Inhibits reuptake of neurotransmitters such as norepinephrine and serotonin, increasing their levels in the synaptic cleft and enhancing neurotransmission
modulates serotonin receptors and alpha-adrenergic receptors (antidepressant and analgesic effects)
affects sodium ion channels (reduce neuronal excitability and help alleviate pain)
anticholinergic properties: blocking the action of acetylcholine (reduce muscle spasms and other pain-related symptoms)
Pregabalin
By binding to these alpha-2-delta subunits of voltage-gated calcium channels, pregabalin inhibits the influx of calcium ions into neurons. This reduces the release of several neurotransmitters involved in pain signaling, such as glutamate, substance P, and noradrenaline
The decreased calcium influx leads to a reduction in the synaptic release of these neurotransmitters, which helps in alleviating pain and anxiety
Fentanyl
Binds to mu-opioid receptors (MORs) in the brain and spinal cord - by activating MORs, fentanyl triggers the release of dopamine in the brain’s reward centers, leading to feelings of euphoria and relaxation.
Fentanyl inhibits the transmission of pain signals by reducing the release of neurotransmitters e.g. substance P and glutamate
Nonsteroidal anti-inflammatory drugs (NSAIDs)
Inhibits the cyclooxygenase enzyme (COX-1 and COX-2) which prevents the formation of prostaglandins.This decreases the sensitisation and amplification of the pain signal.
Act on the descending pain control system (structures e.g. periaqueductal gray matter (PAG), rostral ventromedial medulla (RVM)) and these areas send inhibitory signals to the spinal cord to modulate pain.
Interact with endogenous opioids and cannabinoids in the CNS, enhancing the inhibitory effects on pain transmission.
Paracetamol
inhibits COX-2 and peroxidases to prevent formation of prostaglandins. Produces analgesic effect by preventing sensitisation to noxious stimuli
Metabolite (AM404) is a TRPV1 agonist → Inhibits uptake of endocannabinoids (free radical scavenger). leads to increased levels of AEA in the synaptic cleft → enhance pain relief by activating cannabinoid receptors (CB1 and CB2), which play a role in modulating pain perception
Why is it recommended not to use an electric blanket or sit under direct sunshine when wearing these patches
Increased vasoldilation
The recommendation to avoid using an electric blanket or sitting in direct sunlight while wearing fentanyl patches is based on the risk of increased skin temperature, which can significantly impact the patch’s performance:
Accelerated Drug Release: Fentanyl patches are designed to release the drug at a controlled and constant rate over approximately 72 hours. Elevated skin temperature can enhance skin permeability, accelerating the release and absorption of fentanyl into the bloodstream, potentially leading to unintended overdose and dangerously high fentanyl concentrations.
Altered Pharmacokinetics: Localized heating of the skin can disrupt the drug’s pharmacokinetics, compromising both the safety and the effectiveness of the patch.
Skin Irritation and Adhesion Issues: Excessive heat can cause skin irritation and weaken the patch’s adhesion to the skin. This may result in uneven drug delivery and reduce the patch’s therapeutic effectiveness.
Explain how Fentanyl reaches systemic circulation once leaving the patch at a constant rate of delivery.
Fentanyl, when delivered via a transdermal patch, enters systemic circulation through transdermal absorption, providing a controlled and continuous release of the active pharmaceutical ingredient (API) into the bloodstream through the following steps:
Application: The patch should be applied to clean, dry, and hairless skin, such as the upper arm or chest. The adhesive layer ensures the patch remains securely attached to the skin.
Skin Penetration: Fentanyl, uniformly distributed within the adhesive layer, passes through the outermost skin layer (stratum corneum) into the underlying tissues via passive diffusion, driven by a concentration gradient. This process is facilitated by fentanyl’s lipophilic nature.
Systemic Absorption: After reaching the dermis, fentanyl diffuses through the capillary walls into the bloodstream, bypassing the intestinal and hepatic first-pass metabolism.
Distribution: Once in the bloodstream, fentanyl is distributed to tissues and organs, including the central nervous system, where it binds to mu-opioid receptors, producing potent analgesic effects for chronic pain management.
Controlled Release: The matrix design of the patch ensures a constant drug release rate over a typical duration of 72 hours. This steady release helps maintain consistent drug levels, providing sustained pain relief while minimizing fluctuations.
Pregabalin effect on neurotransmission
Bind to presynaptic alpha2-delta subunits of voltage-gated calcium channels in the CNS.
This inhibits the influx of calcium ions and the release of excitatory neurotransmitters such as glutamate, substance P, and CGRP (Calcitonin Gene-Related Peptide) on the primary afferent neuron
This prevents the activation of the receptor on the secondary afferent neuron and the propagation of pain signals to the brain.
Among the designs presented above, which one was discontinued for the transdermal delivery of Fentanyl, and what were the two main reasons for its discontinuation?
The reservoir transdermal patch was recalled and subsequently removed from the market after extensive testing. It was replaced by the matrix-type fentanyl patch due to several health and safety concerns:
Dosing Errors: Reservoir patches were associated with a higher risk of dosing errors, leading to either overdose or subtherapeutic dosing. Both scenarios carry severe health consequences, including the potential for fatalities. Narrow therapeutic index. Dose doubling : Damaging the patch (e.g., cutting it) can lead to the rapid release of the entire drug reservoir, effectively “doubling” or significantly increasing the intended dose.
This risk was one of the reasons reservoir patches for Fentanyl were discontinued.
Variability in Drug Delivery: Minor changes in body temperature or skin conditions could significantly affect drug absorption from reservoir patches, resulting in unpredictable and potentially unsafe variations in drug delivery.
Risk of Misuse and Overdose: The design of reservoir patches allowed for tampering, as the fentanyl could be easily separated from the drug reservoir. This facilitated misuse, such as extracting and injecting or ingesting the concentrated fentanyl gel, leading to rapid and dangerous doses.
The matrix-type fentanyl patch addresses these issues by incorporating the drug directly into the adhesive layer, preventing unauthorized extraction and minimizing the risk of misuse. This design enhances patient safety and reduces the likelihood of adverse events.
Matrix drug delivery system patch: Why do you think this design is more suitable for delivering Fentanyl?
Consistent Drug Distribution: The adhesive matrix ensures fentanyl is evenly distributed across the patch, enabling uniform delivery of the drug to the skin throughout its surface.
Controlled and Sustained Release: This design allows for a steady release of fentanyl over a prolonged period, typically 72 hours, maintaining stable therapeutic drug levels in the bloodstream and reducing the risk of dose dumping, which can lead to safety concerns.
Drug Stability: The patch provides a stable environment for fentanyl, preventing degradation and ensuring reliable drug release.
Simplified Manufacturing: The matrix design requires fewer components compared to reservoir patches, making it easier to manufacture.
Patient Comfort and Safety: Its thin and flexible design ensures comfort and ease of use, with minimal risk of overdose or subtherapeutic dosing, both of which pose significant health risks, including fatalities.
Misuse Prevention: By integrating fentanyl within the adhesive layer, the design prevents unauthorized extraction or tampering, enhancing patient safety and reducing the likelihood of misuse or adverse events.
In the original study from which the pharmacokinetic and pharmacodynamic parameters were taken, it was noticed that there was a slight time delay between the maximum plasma concentration of the drug and the maximum reduction in pain score. What would explain such a time delay?
Time is required for: the drug to move from the bloodstream to target tissues / conversion into active metabolites / to bind to receptors
The therapeutic effect of a drug may not align with its peak plasma concentration due to factors like receptor interaction and downstream signaling delays.
Drug distribution to target receptors is influenced by tissue perfusion, lipophilicity, and active transport mechanisms, causing a time lag.
Receptor binding and signaling kinetics can delay the onset of the physiological response.
Indirect effects, such as modulation of secondary messengers or neurotransmitters, may introduce additional delays.
Adaptive body responses, including receptor desensitization, feedback mechanisms, and counter-regulatory effects, can affect the timing of drug action.
Individual differences in genetics, metabolism, and health contribute to variability in drug response timing.
Prodrugs require time for metabolic activation, leading to delays between plasma concentration peaks and therapeutic effects.
LG had a baseline pain score 9, measured using the Lickert Pain score. The relationship between pain score and concentration of a drug that she was taking was best described by the following model:
Where E is the measured pain score, E0 is the baseline pain score, C is drug concentration in µg/L, and Emax is the maximum reduction in pain score (from baseline), which was 8. The C50 was 0.1µg/L.
Using the information provided, determine the plasma concentration that would produce a 30% reduction in pain score from baseline for LG.
E = E0 - Emax x C/( C + C50)
0.3 x 9 = 2.7
9 - 2.7 = 6.3 (E)
6.3 = 9 - (8 x C / C + 0.1)
9 - 6.3 =( 8 x C )/ (C + 0.1)
2.7 = 8C /( C + 0.1)
2.7 x (C + 0.1) = 8C
2.7C + 0.27 = 8C
0.27 = 8C - 2.7C
0.27 = 5.3C
C = 0.27 / 5.3
= 0.051mcg/L
Type of headache: medication overuse
- Diagnostic criteria
Headache occurring on 15 or more days per month in a person with a pre-existing primary headache disorder, which develops as a consequence of regular overuse of one or more drugs that can be taken for acute and/or symptomatic treatment of headache, for more than 3 months.
[chronic]
If:
Ergotamines, triptans, opioids, or combination analgesics are taken on 10 days or more per month.
Simple analgesics such as paracetamol, nonsteroidal anti-inflammatory drugs (NSAIDs), or aspirin (either alone or in any combination) are taken on 15 days or more per month.
Risk of developing MOH
Highest with opioids and triptans
Intermediate with paracetamol and aspirin
Lowest with non-steroidal anti-inflammatory drugs such as ibuprofen
- Management
It usually, but not always, resolves after the overused medication is stopped.
Advise on how to:
Withdraw from overused medication
To stop taking all overused acute headache medications for at least 1 month.
To stop drugs such as triptans, ergotamines, and simple analgesics abruptly.
To keep a headache diary to measure the frequency, duration, and severity of headache and medication use during withdrawal.
Headache type: giant cell (temporal) arteritis
- Diagnostic criteria
GP for temporal arteritis, they’ll ask about symptoms and examine temples.
After having some blood tests then referred to specialist
Carry out further tests to diagnose temporal arteritis.
Tests
an ultrasound scan of your temples
a biopsy under local anaesthetic – where a small piece of the temporal artery is removed and checked for signs of temporal arteritis
If problems with vision - have a same-day appointment with an ophthalmologist
- Management
High-dose corticosteroid therapy, such as prednisolone, is essential for managing GCA. For patients without vision loss, the initial dose is 40–60 mg daily, while those with vision loss or double vision require 60–100 mg daily and immediate ophthalmological assessment.
A healthy lifestyle with a balanced diet and adequate vitamin D is also recommended. Early intervention with effective glucocorticoid doses is crucial for preventing complications.
Headache type: migraine
Migraines, with or without aura, involve moderate to severe throbbing pain, typically unilateral, lasting 4–72 hours in adults or 1–72 hours in adolescents. Symptoms include photophobia, phonophobia, nausea, and aggravation by routine activities. Auras are reversible, lasting up to 60 minutes, with visual, sensory, or speech disturbances. Episodic migraines occur on fewer than 15 days per month; chronic migraines occur on 15+ days for over three months. Refer for atypical auras like motor weakness, double vision, or altered consciousness.
Acute Migraine Management
Use pain relief medications like Paracetamol or NSAIDs (e.g., Ibuprofen) alone or alternated every 4 hours, with a maximum of 8 tablets per day. If OTC treatments fail, prescribe triptans (e.g., Sumatriptan, Naratriptan) or NSAIDs like Naproxen. Limit acute medications to no more than two days per week to prevent medication overuse headaches (MOH). Combination therapies (oral triptan + NSAID or Paracetamol) can be considered, along with anti-emetics for
Headache type: trigeminal neuralgia
characterised by sharp, electric shock-like pain along the trigeminal nerve, usually affecting one side of the face (rarely bilateral).
The pain is typically localised to the jaw, lips, and gums, with sudden, brief episodes lasting seconds to minutes. It is triggered by activities such as touching the face and may be followed by periods of remission
Start with 100 mg of carbamazepine twice a day and titrate in increments of 100 mg. variables including mild facial contact, food, conversation, or exposure to cold air: 200 mg every two weeks until pain subsides · After pain subsides, lower the dosage to the lowest maintenance level · People may find that keeping a daily pain journal helps them understand and cope with their pain.
Headache type: tension
Tension-type headaches are characterised by mild to moderate, bilateral, pressing or tightening pain, lasting from 30 minutes to several days. Episodic tension-type headaches occur on fewer than 15 days per month, while chronic tension-type headaches occur on 15 or more days per month for at least 3 months. Mild sensitivity to light or sound may occur.
For acute treatment of tension-type headaches, consider aspirin, paracetamol, or an NSAID (e.g., ibuprofen), taking into account the patient’s preferences and comorbidities. Avoid aspirin in those under 16 due to the risk of Reye’s syndrome and do not use opioids. For prophylaxis, consider up to 10 sessions of acupuncture over 5-8 weeks, or a low dose of amitriptyline (10-75 mg) for chronic cases. Encourage stress management through activities like yoga, a regular sleep schedule, hydration, and avoidance of triggers. Cold or warm compresses may also help. Limit painkiller use to avoid overuse headaches.
Headache type: cluster
Intense, stabbing or burning pain on one side of the head, usually around or behind the eye
The excruciating pain that peaks quickly
Pain lasts 15 minutes to 3 hours, often within 30 minutes to 2 hours
Occurs multiple times daily during cluster periods
Follows cyclical pattern: clusters lasting weeks to months, followed by remission
Associated with autonomic symptoms:
-Redness and watering of the affected eye
-Nasal congestion or runny nose
-Drooping or swollen eyelid
Restlessness or agitation during attacks
Sweating on the affected side of the face
No aura or warning signs
Triggers: alcohol, specific foods, changes in sleep patterns
Cluster headache management involves high-flow oxygen therapy (100% at 12-15 L/min) for acute attacks, and subcutaneous or intranasal sumatriptan (6mg SC, max 12mg/day; 10-20mg intranasal, max 40mg/day).
Preventive treatments include verapamil and corticosteroids.
Lifestyle advice includes avoiding alcohol during cluster periods, maintaining a regular sleep schedule, and exercising regularly.
Describe your management plan with justifications for your action.
Diagnosis:
Medication overuse headache due to prolonged use of Co-codamol 30/500mg at max dose for 5 months (contrary to “when required” prescription).
Headaches occurring on 15 or more days, twice in the last 2 months- this meets the criteria for medication overuse headache.
Management:
Immediate Action:
Discontinue Co-codamol use entirely for 1 month (without titrating down).
Education:
Explain medication overuse as the cause of headaches.
Advise patient that pain may worsen before improving.
Referral to GP:
Assess underlying causes, including residual pain from traffic injury.
Review adequacy of primary headache treatments.
Evaluate need for alternative prescriptions.
Describe how both LHRH agonists (e.g., Goserelin) and anti-androgens (e.g., Enzalutamide) treat prostate cancer.
Prostate cancer depend on the hormone testosterone for their growth and survival.
LHRH agonists: luteinizing hormone-releasing hormone
Mimic the natural LHRH hormone produced by the hypothalamus.
Activate LHRH receptors, initially cause luteinizing hormone (LH) and follicle stimulating hormone (FSH) production by pituitary cells in the brain to increase, causing a surge in testosterone levels.
But after further treatment, pituitary cells lose their LHRH receptors and shut down LH and FSH production.
Anti-androgens:
Compete with testosterone(similar chemical structure to testosterone) for its bonding site on the AR
→ trigger ARs to pair up
→ paired-up Ars reach the nucleus but can’t work properly or activate target genes
1st generations - Flutamide, Bicalutamide
Lower affinity to ARs
Only suppress ARs when they are present normal levels
Can block testosterone production by the testes but can’t prevent testosterone production by the adrenal glands
2nd generations - Enzalutamide, Apalutamide, Abiraterone
Far greater affinity to ARs
Prevents ARs from entering the nucleus
Prevents paired-up ARs from activating genes
Abiraterone block CYP17A which is necessary for manufacture of testostrone anywhere in the body
LHRH Agonists (e.g., Goserelin)
Mechanism of Action:
Target: Luteinizing Hormone-Releasing Hormone (LHRH) receptors in the anterior pituitary gland.
Action:
Initially stimulate LHRH receptors, causing a transient surge in luteinizing hormone (LH) and follicle-stimulating hormone (FSH).
This leads to an initial increase in testosterone production (known as a testosterone flare).
Prolonged activation desensitizes and downregulates LHRH receptors, leading to suppression of LH and FSH secretion.
Decreased LH levels result in reduced testosterone production by the testes, effectively inducing chemical castration.
Effect on Prostate Cancer:
Prostate cancer cells are typically androgen-dependent; reduced testosterone levels slow tumor growth and progression.
Anti-Androgens (e.g., Enzalutamide)
Mechanism of Action:
Target: Androgen Receptors (ARs) in prostate cancer cells.
Action:
Competitively inhibit androgen binding to androgen receptors.
Prevent androgen-receptor complex translocation to the nucleus.
Block androgen-receptor mediated transcription of genes required for prostate cancer cell survival and proliferation.
Effect on Prostate Cancer:
Directly antagonizes androgen signaling pathways, impairing cancer cell growth and promoting apoptosis in androgen-sensitive cancer cells.
Can also be used to manage the testosterone flare caused by LHRH agonists.
Combined Use:
LHRH agonists and anti-androgens are often used together to maximize androgen suppression and block androgen receptor signaling.
This combination is particularly useful in managing the initial testosterone flare associated with LHRH agonists and in achieving a more comprehensive inhibition of androgen-driven tumor growth.
This dual approach forms the foundation of androgen deprivation therapy (ADT) for prostate cancer treatment.
After Docetaxel chemotherapy, the patient receives metoclopramide to go home with to treat delayed nausea and vomiting. Describe the mechanism of action of metoclopramide and explain some cautions and contraindications.
(Hint: identify the model of action, preparations, doses, side effects, cautions and detail cautions about serious adverse effects).
Available preparations
· Tablet
· Oral solution
· Solution for injection ampoules
Mechanism of action of Metoclopramide
· Acting as a dopamine receptor antagonist, particularly at the D2 subtype of dopamine receptors. By blocking these receptors in the chemoreceptor trigger zone (CTZ) of the central nervous system, it reduces the sensitivity of the CTZ to stimuli that trigger nausea and vomiting therefore, inhibits the emetic ‘vomiting’ reflex
· Stimulating the release of Acetylcholine (ACh) and enhances its action by sensitising tissues to its effects leading to increased motility and coordination in the GIT
· Directly stimulating muscarinic receptors, specifically M1 and M2 receptors in the GI smooth muscle and increases the responsiveness of the muscles to Acetylcholine (ACh)
· Increasing the tone of the lower oesophageal sphincter leading to preventing reflux of gastric contents into the oesophagus
Common side effects of Metoclopramide
· Asthenia ‘abnormal physical weakness and lack of energy’
· Depression
· Diarrhoea
· Nausea
· Drowsiness or sedation
· Hypotension
· Menstrual cycle irregularities
· Extrapyramidal symptoms (EPS) ‘movement disorders’ represented in tremors, restlessness, involuntary movement and muscle stiffness. The risk gets higher with higher doses intake and prolonged use
· Parkinsonism including tremors, bradykinesia ‘slowness of movement’ and rigidity
· Acute dystonic reactions involving facial and skeletal muscle spasms and oculogyric crises, which are all more common in the young girls, young women and elderly
Less common but potentially serious side effects of Metoclopramide
· Allergic reactions ‘anaphylaxis’ including symptoms of skin rash, itching, swelling, severe dizziness and breathing difficulties
· Tardive dyskinesia represented in irreversible movement disorder associated with prolonged treatment duration and characterised by repetitive, involuntary movements of the face, tongue or other body parts
· Neuroleptic malignant syndrome (NMS) represented in hyperthermia ‘high fever’, muscle rigidity, altered mental status and autonomic dysregulation
· Hyperprolactinemia represented in increase prolactin levels leading to symptoms, such as breast enlargement ‘gynecomastia’ and breast tenderness
· Cardiac effects represented in tachycardia and hypotension
· Seizures manifesting as convulsions or involuntary movements which have been reported in some of the patients
Cautions of Metoclopramide administration
· Asthma
· Atopic allergy
· Bradycardia
· Cardiac conduction disturbances
· Severe hepatic impairment leading to increased risk of drug accumulation and toxicity
· Moderate to severe renal impairment ‘end-stage renal failure’
· Children and young adults
· Elderly
· May mask underlying disorders, such as cerebral irritation
· Pre-existing Parkinson’s disease
· Uncorrected electrolyte imbalance
· Breastfeeding
Contraindications of Metoclopramide administration
· Hypersensitivity to Metoclopramide or any of its components
· 3 - 4 days after GI surgery
· Epilepsy
· GI haemorrhage
· GI obstruction
· GI perforation
· Phaeochromocytoma
Before the next cycle of Docetaxel, the Pharmacist Independent Prescriber reviews the patient in the clinic. They prescribe Akynzeo (netupitant/palonosetron) for the patient to try and prevent further sickness for the next cycle. Describe the mechanism of action of the agents in Akynzeo. How does palonosetron differ from other 5-HT3 receptor antagonists?
(Hint: identify the model of action, preparations, doses, side effects, cautions and detail cautions about serious adverse effects).
Available preparation
· Capsule
Mechanism of action of Akynzeo ®
· Akynzeo ® is a combination medication which contains 2 active ingredients, Netupitant and Palonosetron which both act synergistically in the prevention of nausea and vomiting responses associated with chemotherapy including both acute phase (0 – 24 hours after chemotherapy) and delayed phase (24 – 120 hours after chemotherapy)
· Netupitant acts as neurokinin-1 (NK1) receptor antagonist, which are found in the CNS particularly in the brainstem and the area postrema, which is a region associated with vomiting reflex. By blocking these receptors, it causes the inhibition of binding of substance P, which triggers nausea and vomiting therefore, inhibits the emetic ‘vomiting’ reflex during delayed phase of chemotherapy
· Palonosetron acts as a selective antagonist of serotonin type 3 (5-HT3) receptors, which are found in the CNS particularly in the chemoreceptor trigger zone (CTZ) and the vagal nerve terminals in the GIT. It does not interact significantly with other serotonin receptor subtypes. By blocking 5-HT3 receptors, it causes the inhibition of binding of serotonin, which triggers nausea and vomiting therefore, inhibits the emetic ‘vomiting’ reflex during acute phase of chemotherapy
Common side effects of Akynzeo ®
· Constipation
· Headaches
· Dizziness or light-headedness
· Transient elevation in liver enzymes
· Asthenia ‘abnormal physical weakness and lack of energy’
Less common but potentially serious side effects of Akynzeo ®
· Allergic reactions ‘anaphylaxis’ including symptoms of skin rash, itching, swelling, severe dizziness and breathing difficulties
· QT interval prolongation which could potentially lead to a serious cardiac arrhythmia known as Torsades de Pointes (TdP), which is a polymorphic ventricular tachycardia characterised by a gradual change in amplitude and twisting of the QRS complexes around the isoelectric baseline
· Serotonin syndrome, particularly when used in combination with other serotonergic medications. Symptoms may include confusion, hallucinations, rapid heartbeat, fever and muscle coordination difficulties
Cautions of Akynzeo ® administration
· Moderate to severe hepatic impairment affecting enzymes activity leading to reduced drug metabolism and clearance
· Moderate to severe renal impairment
· Susceptibility to QT interval prolongation
· Electrolyte disturbances
· Elderly > 75 years old
Contraindications of Akynzeo ® administration
· Hypersensitivity to Akynzeo ® or any of its components
· Pregnancy and breastfeeding
· Intake of Apomorphine for managing Parkinson’s disease. The combination between both drugs can potentially lead to severe hypotension and loss of consciousness
· Intake of potent CYP450 3A4 inhibitors, such as certain antifungal medications including Ketoconazole, antibiotics including Erythromycin and Clarithromycin, antiretrovirals including Ritonavir, Indinavir and Atazanavir and CCB as Verapamil. The combination between both drugs can potentially lead to elevated Netupitant serum concentrations leading to drug toxicity due to inhibition of CYP450 3A4, which is primarily responsible for Netupitant metabolism
· Congenital prolonged QT interval syndrome
The patient is currently on MST (Morphine Sulphate M/R Tablets) - 10mg BD orally for his back pain. After a detailed drug history, we found out he is also using regular Morphine Sulphate 10mg/5mL Liquid – 10mg QDS orally.
(1) What is the total amount of morphine he is on per day?
Tablets: 20mg
Liquid: 40mg
Total: 60mg
Can you name an acute oncological emergency associated with severe back pain for patients who have prostate cancer?
Metastatic spinal cord compression (MSCC)
MSCC is due to a pathological vertebral body collapse or direct tumour growth causing compression of the spinal cord.
