Flashcards in Pharmacology Deck (81):
Where are motor neurone cell bodies located?
- Inner spinal cord
- Surface of brain
Are motor neurones myelinated?
Are motor neurone branches supplying individual muscle fibres myelinated?
What does each branch of a motor neurone divide into? What is the function of this?
- Forms a chemical synapse at NMJ
- Releases ACh
Where do synaptic vesicles move to in the terminal bouton to release ACh?
What part of the muscle fibre receives the incoming ACh?
What happens to the sarcolemma in the end-plate?
Thrown into folds:
- Nicotinic ACh receptors at junctional folds
Describe briefly an overview of synaptic transmission
1. Choline + AcetylCoA = ACh
2. ACh storage
3. ACh release upon Calcium influx
4. Receptor activation
5. ACh inactivation by acetylcholinesterase
6. Re-uptake of choline and acetylCoA
How is choline transported into the pre-synaptic nerve?
Via choline transporter:
- Symported with sodium
Where dose the AcetylCoA come from for ACh formation?
Where is ACh synthesised and what enzyme catalyses it?
What happens when an action potential arrives at the pre-synapse?
2. Opening of voltage-gated calcium channels
3. Calcium influx
What happens after calcium influx?
ACh-containing vesicles exocytose into cleft at active zones
What is the structure of the nicotinic ACh receptor?
Pentamer of glycoprotein subunits:
- [(Alpha1)2, Beta1, Delta, Epsilon]
What is the epsilon subunit in embryonic muscle nicotinic ACh receptors?
A Gamma subunit
What does the nicotinic ACh receptor surround?
Central, cation sensitive pore:
- Five M2 helices
What is the conformation of the pore in:
1. Absence of ACh
2. The binding of one ACh
3. The binding of two ACh
4. The binding of three ACh
4. Not possible
Which one of the following values is the rough true value for the permeability ratio of the nicotinic ACh pore to potassium and sodium (PK+/PNa+):
They have roughly the same permeability
What ions move in/out of the pore in the sarcolemma?
At resting potential, which effect is the greatest; the sodium driving force or the potassium driving force and what does this result in?
Sodium driving force since sodium in > potassium out:
- Depolarisation -> End Plate Potention (e.p.p.)
How do we describe the amount of ACh contained in a vesicle?
What do we call the electrical response on the sarcolemma upon exposure to one quantum of ACh?
What dose the term 'Electrotonic repsonse' mean?
Many m.e.p.p. sum to produce the e.p.p
What does the End Plate Potential need to be greater than to trigger an 'all-or-nothing' AP to be generated?
What happens when threshold is reached?
Voltage-activated sodium channels open up along the sarcolemma resulting in contraction along the muscle
Why do we need sodium channels along the length of the muscle fibre?
To allow AP propagation
What feature of the sarcolemma does the AP enter that is in close proximity to the sarcoplasmic reticulum?
Transverse (T) Tubules
What does the AP trigger when it gets close to the SR?
When calcium is released from inside the SR into the cell what happens?
It interacts with troponin on myofibrils -> Contraction
What does acetylcholinesterase hydrolyse ACh into?
Choline and acetate
True or false; Acetylcholinesterase is so efficient that some ACh is hydrolysed even before it binds to receptors?
What is the alternate name for Neuromyotonia?
What are the symptoms of neuromyotonia?
Myotonia - Slow relaxation
What is the pathogenesis of the acquired form of neuromyotonia?
1. Autoantibodies against voltage-gates K+ channels in motor neurone
2. Cell cannot be brought back to resting potential
How is neuromyotonia treated?
> Block Na+ channels
> May potentiate GABA
This syndrome is a rare cause of muscle weakness in the limbs that is associated with small cell lung cancer.
Lambert-Eaton Myasthenic Syndrome (LEMS)
What is the origin of LEMS?
1. AutoAbs against voltage-gated calcium channels in motor neurone terminal
2. Reduced calcium entry during depolarisation
3. Reduced ACh release
How is LEMS treated?
Potassium channel blockers:
(Both increase [ACh} in cleft)
A patient presents with muscle weakness especially during exercise. They have also noticed that their eyelid is drooping and they have difficulty moving their eyes.
What is the pathogenesis of Myasthenia Gravis?
1. AutoAbs against nicotinic ACh receptors in endplate
2. Reduced number of functional channels
3. Reduced amplitude of e.p.p.
How can myasthenia gravis be treated?
- Edrophonium (For diagnosis)
What type of toxin is botulinum toxin?
How does the botulinum toxin work?
1. Enzymatically modifies vesicle docking proteins
2. Prevents ACh exocytosis
3. Irreversibly inhibits ACh release
True or false; Anticholinesterases are highly effective in treating botulinum toxicity?
When can botulinum toxin be used clinically?
- Dystonia treatment (squint)
- Reduces wrinkling
How do vecuronium and atracurium work? Where are they used and why?
1. Competitive antagonists of nicotinic ACh receptors
2. Reduce e.p.p. to below threshold
- In surgery
- Induce reversible muscle paralysis
True or false; Paracetamol has a lot of anti-inflammatory action?
What NSAID reduces the risk of peptic ulcers and how?
- Targets cyclooxygenase-2 (COX-2 Inhibitor)
> Responsible for pain
- No COX-1 action -> Reduced peptic ulcer risk
If prescribing an NSAID for pain relief in arthritis what must you co-prescribe?
What NSAID should be avoided in the patient has cardiovascular (IHD/CHF/PAD/CVA/Uncontrolled Hypertension) risk factors?
(And high dose [>2400mg daily] Ibuprofen)
What two NSAIDs are 'safest' to prescribe?
What is step 1 of the WHO analgesia ladder?
What is step 2 of the WHO analgesia ladder?
What is step 3 of the WHO analgesia ladder?
What are the indications to prescribe a DMARD?
1. Active inflammation were benefit > risk
2. Almost all new-onset RA -> Start within 3 months
3. If steroid dose needs reduced
What is methotrexate?
A folate antagonist
What are the side effects of methotrexate?
Hepatitis + cirrhosis
- Stop in M and F >= 3 months before pregnancy
What are the side effects of sulfasalazine?
What is a very rare side effect of hydroxychloroquine (HCQ)?
What are the side effects of sodium aurothiomalate (gold) and penicillamine?
Bone marrow suppression
Give some examples of anti-TNFs and their administration route
True or false; DMARD and Anti-TNF co-prescription increases their efficacies? Explain why
Steroids -> Immunosuppress -> Prevent Abs against Anti-TNFs
What is the 1st line treatment for RA?
Methotrexate + One other DMARD + Short-term steroids
What do you do if the 1st line treatment for RA fails?
Try a different combination of two DMARDs (usually still including methotrexate)
What is the 2nd line treatment for RA? (Assuming two DMARDs gives inadequate response)
Methotrexate + Anti-TNF (usually Certolizumab in Tayside)
When can an Anti-TNF be prescribed?
1. If >= 2 standard DMARDs fail to control disease
2. If a patients DAS28 score is >5.1, on two occasions, three months apart. This includes:
- Counting tender joints
- Counting swollen joints
- Check CRP
- Ask patient to rate severity (0-100)
What is the 3rd line treatment for RA?
Methotrexate + Tocilizumab (Tayside)/Rituximab
How does rituximab work?
Monoclonal Ab against CD20/B cells
What are side effects of Anti-TNFs?
Major infection risk:
- TB reactivation -> Anti-TNF breaks down granulomas
- Pulmonary fibrosis
How does tocilizumab work?
What other biologic therapies are available and how do they work?
- CTLA-4 Ig
- Blocks full T cell activation
- Inhibits IL-12 + IL-23
For each of the following drugs, state what conditions they can be used to treat:
1. RA, PA, AS
2. RA, CTDs
(PA = Psoriatic Arthritis)
(AS = Ankylosing Spondylitis)
(CTDs = Connective Tissue Disorders)
What are the treatment options for acute gout?
1st - NSAIDs
2nd - Colchicine (Diarrhoea and vomiting)
3rd - Steroids
How can we lower urate and prevent gout?
Xanthine oxidase inhibitors:
What are side effects of allopurinol?
Marrow aplasia (rare)
When is febuxostat used instead of allopurinol?
- If allopurinol isn't tolerated
- If a patient has renal impairment (GFR
What can febuxostat worsen?
Give some examples of uricosurics
What are common indications for steroids?
Which of the following is not a metabolic effect of steroids:
- Salt and water retention
- Increased lipolysis
- Increased gluconeogenesis
- Increased hepatic glycogen deposition
- Increased protein breakdown
- Increased calcium absorption
Increased calcium absorption
(Steroids can reduce calcium absorption hence long term use being associated with oestoporosis)