Pharmacology Flashcards
What are the functions of non-steroidal anti-inflammatory drugs (NSAIDs)?
Anti-inflammatory.
Analgesic.
Give examples of NSAIDs?
Ibuprofen.
Naproxen.
Diclofenac.
Indometacin.
Etodolac.
Celecoxib (Cox 2 inhibitor).
What are the indications in rheumatology for prescribing NSAIDs?
Inflammatory arthritis.
Mechanical musculoskeletal pain.
Pleuritic/pericardial pain.
What are the adverse effects of NSAIDs?
Dyspepsia.
Oesophagitis.
Gastritis.
Peptic ulcer.
Small/large bower ulceration.
Renal impairment.
Increased cardiovascular events.
Fluid retention.
Wheeze.
Rash.
When do you aim to start patients with inflammatory arthritis on DMARDs?
Within 3 months of symptom onset.
How long does it take for a DMARD to take effect?
Slow-acting.
Takes about 6 weeks to work.
What effect do DMARDs give?
Pure anti-inflammatory with NO direct analgesic effect.
Reduce rate of damage to joints.
Improve standard lab tests of inflammation e.g. ESR, CRP.
What are the commonly used DMARDs?
Methotrexate.
Sulphasalazine.
Leflunomide.
Hydroxychloroquine.
How can methotrexate be administered?
Orally, subcutaneously.
What conditions can methotrexate be used to treat?
Rheumatoid arthritis.
Psoriatic arthritis.
Connective tissue disease.
Vasculitis.
Can methotrexate be used in pregnancy?
No it is teratogenic and must be stopped for 3 months before trying to conceive in both male and female patients.
What are the adverse effects of methotrexate?
Leukopenia/thrombocytopenia.
Hepatitis/cirrhosis - alcohol intake must be limited.
Pneumonitis.
Rash/mouth ulcers.
Nausea/diarrhoea.
Needs monitoring of FBC and LFTs.
Can leflunomide be used in pregnancy?
No, it is teratogenic.
Tend to be avoided in female patients of child-bearing age as it has a very long half-life and requires a washout.
What are the adverse effect of sulfasalazine?
Nausea.
Rash/mouth ulcers.
Neutropenia.
Hepatitis.
Reversible oligozoospermia.
Monitoring of FBC and LFTs.
What are the side effects of leflunomide?
Leukopenia/thrombocytopenia.
Hepatitis/cirrhosis - alcohol intake must be limited.
Pneumonitis.
Rash/mouth ulcers.
Nausea/diarrhoea.
Needs monitoring of FBC and LFTs.
Which DMARD can be used in pregnancy?
Sulphasalazine.
What are the effects of hydroxychloroquine?
No effect on joint damage.
Which conditions would you prescribe hydroxychloroquine to?
Used in connective tissue diseases such as SLE (helps skin, joints and general malaise), Sjogren’s and rheumatoid arthritis.
Given to all patients with SLE.
What are biologic therapies?
Drugs designed to target specific aspects of the immune system found to be implicated in inflammatory conditions.
What are the current targets of biologic therapies?
Tumour necrosis factor (TNF).
CD20 B cells.
IL-6.
IL-17, 12 and 23.
Which drug is more effective, DMARDs or biologics?
Biologics are found to be 1.5 times more effective than DMARDs, but not all patients need them.
What conditions is anti-TNF therapy given to?
Rheumatoid arthritis.
Psoriatic arthritis.
Ankylosing spondylitis.
Give examples of anti-TNF therapies?
Etanercept.
Adalimumab.
Certolizumab.
Infliximab.
Golimumab.
Biosimilars: Benepali.
When would you put a patient on biologic therapy?
Somebody must have a DAS28 score >5.1 whilst on 2 DMARDs.
What are the main adverse effects of anti-TNF therapy?
Risk of infection - reactivation of latent TB.
Risk of malignancy - skin cancer.
Contraindicated in certain situations - pulmonary fibrosis, heart failure.
What medications are given to treat an acute episode of gout?
Colchicine (diarrhoea common side effect).
NSAIDs.
Steroids (either oral or IM).
What treatments are given as prophylaxis in gout?
Allopurinol.
Febuxostat.
Uricosurics - not normally used anymore.
What is allopurinol?
Xanthine oxidase inhibitor.
How is allopurinol prescribed?
Needs to be increased gradually in steps to make sure uric acid levels are below a threshold of 360micromol/L because rapid reduction in uric acid level may result in exacerbation of gout.
Interacts with azathioprine -> irreversible bone marrow suppression.
If a patient is on allopurinol prophylactically and has an acute flare, do you stop the allopurinol?
No.
What are the side effects of allopurinol?
Rash (vasculitis) - commoner in elderly and in renal impairment (use lower doses).
Azathioprine interaction.
Marrow aplasia - rare.
What is febuxostat?
Xanthin oxidase inhibitor.
Which patients would you consider giving febuxostat to?
Those who cannot tolerate allopurinol.
Those with renal impairment.
Caution in patients with ischaemic heart disease.
What are the indications of corticosteroids in rheumatology?
Connective tissue disease.
Polymyalgia rheumatica/giant cell arteritis.
Vasculitis.
Rheumatoid arthritis.
What are the adverse effects of corticosteroids?
Weight gain - centripetal obesity (only an issue in high dose over a prolonged time period).
Muscle wasting.
Skin atrophy.
Osteoporosis.
Diabetes.
Hypertension.
Cataract.
Glaucoma.
Fluid retention.
Adrenal suppression.
Immunosuppression.
Avascular necrosis of the femoral head.
How can the toxicity of corticosteroids be reduced?
Use the lowest possible dose for as short a time as possible.
Consider steroid-sparing agents.
Osteoporosis prophylaxis.
Watch for cardiovascular risk factors.
What innervates skeletal muscle?
Motorneurons with myelinated axons.
What neurotransmitter and receptor do the motorneurons that innervate skeletal muscle release and act upno?
Acetylcholine.
Nicotinic acetylcholine receptors.
What are the key features found at a skeletal neuromuscular junction?
Terminal bouton (and surrounding Schwann cell).
Synaptic vesicles.
Synaptic cleft.
Endplate region of the muscle cell membrane (sarcolemma) thrown into a series of junctional folds.
Synaptic vesicles containing ACh.
Nicotinic ACh receptors located at regions of the junctional folds.
What process occurs at each of the numbered points?
How does choline get into the synaptic terminal?
Choline is transported into the terminal by the choline transporter (symport with Na+).
Where is acetylcholine synthesised and how it this done?
Acetylcholine is synthesised in the cytosol from choline and acetyl coenzyme A (acetyl CoA – supplied by mitochondria) by the enzyme choline acetyltransferase (ChAT, or CAT).
How does acetylcholine get from the cytosol of the synaptic terminal into vesicles?
Vesicular acetylcholine transporter.
How is acetylcholine released into the synaptic cleft?
Arrival of the action potential at the terminal causes depolarization and the opening of voltage-activated Ca2+ channels, allowing Ca2+ entry to the terminal.
Ca2+ causes vesicles ‘docked’ at active zones to fuse with the presynaptic membrane (exocytosis) – ACh diffuses into the synaptic cleft to activate post-synaptic nicotinic ACh receptors in the endplate region.
How is endplate potential generated?
ACh binds to NAChR on the muscle endplate.
Channel opens -> Na+ influx & K+ efflux.
Driving force for Na+ is greater than that for K+ causing a depolarisation known as endplate potential.
How does an action potential in skeletal muscle bring about contraction?
Action potential propagates over the surface membrane (sarcolemma) of skeletal muscle fibre and enters transverse (T) tubules (invaginations of the sarcolemma that dip deeply into the muscle cell).
T-tubules are in close apposition to the sarcoplasmic reticulum (SR, Ca2+ store).
Action potential arriving at the T-tubule triggers release of Ca2+ from the SR which in turn causes contraction by interacting with troponin associated with the myofibrils.
What breaks down excess acetylcholine in the synaptic cleft and what does it break it into?
Acetylcholinesterase.
Choline and acetate.
What part of synaptic transmission goes wrong in Neuromyotonia?
Antibodies are formed against the voltage-activated K+ channels in motorneurons -> disrupt function resulting in hyperexcitability.
What part of synaptic transmission goes wrong in Lambert-Eaton Myasthenic Syndrome?
Antibodies form against the voltage-activated Ca2+ channels in the motor neuron terminal -> reduced Ca2+ entry in response to depolarisation -> reduced vascular release of ACh.
Reduced Ca2+ conductance presynaptically -> decreased release of ACh -> muscle weakness.
What part of synaptic transmission goes wrong in Myasthenia Gravis?
Antibodies form against nicotinic ACh receptors in the endplate -> reduction in the number of functional channels -> reduction in amplitude of endplate potentials.
Reduced numbers of nAChRs ->muscle weakness.
What part of synaptic transmission goes wrong when botulinum toxin enters the body?
Enters presynaptic nerve terminal to irreversibly, enzymatically modify proteins involved in the docking of vesicles containing ACh -> preventing exocytosis.
Failure of ACh release -> paralysis.
What part of synaptic transmission goes wrong when curare-like compounds enter the body?
Interfere with the postsynaptic action of ACh by acting as competitive antagonists of the nAChR -> reduced amplitude of the endplate potential to below threshold for muscle fibre action potential generation.
