Drugs - Renal Flashcards
What is the 1st choice of treatment in acute, uncomplicated lower UTIs?
Nitrofurantoin
What are some alternatives to nitrofurantoin in the treatment of lower UTIs?
Trimethoprim, Amoxicillin and Cephalexin
Why is nitrofurantoin so effective in UTIs?
Nitrofurantoin requires concentration in the urine by renal excretion for therapeutic effect, it is not effective against clinical infections elsewhere in the body.
Spectrum of activity of nitrofurantoin?
Active against most organisms that cause uncomplicated UTIs including E. coli (gram-negative) and Staph. saprophyticus (gram-positive)
Mechanism of nitrofurantoin?
- Metabolised in bacterial cells by nitrofuran reductase
- Its active metabolite damages bacterial DNA and causes cell death (bactericidal)
Which type of bacteria are resistant to nitrofurantoin?
Bacteria with lower nitrofuran reductase activity are resistant to nitrofurantoin (relatively rare for E. coli to acquire nitrofurantoin resistance)
Main side effect of nitrofurantoin?
GI upset - N&V, diarrhoea
How can nitrofurantoin affect the urine?
Nitrofurantoin specifically can turn urine dark yellow or brown.
What side effect can nitrofurantoin cause in neonates?
Haemolytic anaemia
Main contraindications of nitrofurantoin?
- Pregnancy towards term (avoid in 3rd trimester)
- Babies in first 3 months of life (due to risk of haemolytic anaemia)
- Renal impairment (as excreted via kidneys)
Is nitrofurantoin contraindicated in severe renal or hepatic impairment?
Renal
Length of Abx treatment for nitrofurantoin?
- 3-day course typically sufficient for uncomplicated UTIs in women and 7 days of treatment in men or those with more complicated infection
- Prevention of recurrent UTIs – single nightly dose
How can side effect of GI upset be reduced with nitrofurantoin?
Take with food or milk to minimise GI upset
Nitrofurantoin should not be prescribed for pyelonephritis or other complicated UTIs. Why? What should be prescribed instead?
As tissue concentrations of nitrofurantoin are very low.
These should be treated with an IV broad spectrum antibiotic e.g. broad spectrum penicillin with B-lactamase inhibitor, a cephalosporin, or a quinolone, with or without an aminoglycoside.
What trimester of pregnancy should nitrofurantoin be avoided in?
3rd
Indications for trimethoprim?
- Acute lower UTIs
- Prophylaxis of recurrent UTIs
- Acne, RTIs and prostatitis
What is co-trimoxazole also known as?
septrin
What is co-trimoxazole made up of?
Trimethoprim + sulfamethoxazole
What is co-trimoxazole indicated in?
used for treatment and prevention of pneumocystis pneumonia in immunosuppression (e.g. HIV infection)
What is the purpose of combining trimethoprim with sulfamethoxazole?
- Trimethoprim is ought to have broad spectrum but this is increasingly limited by resistance
- Combination with a sulfonamide extends the spectrum to include activity against the fungus Pneumocystis jirovecii
- Trimethoprim inhibits bacterial folate synthesis, slowing bacterial growth (bacteriostasis)
- Sulfamethoxazole, a sulfonamide, also inhibits bacterial folate synthesis but at a different step in the pathway → given together for more complete inhibition of folate synthesis
What class of Abx is sulfamethoxazole?
Sulfonamide
Mechanism of trimethoprim?
Inhibits bacterial folate synthesis, slowing bacterial growth (bacteriostasis).
Most common Abx that causes hyperkalaemia?
Trimethoprim (trimethoprim-sulfamethoxazole)
Side effects of trimethoprim?
- GI upset – N&V, sore mouth
- Skin rash (3-7%)
- Severe hypersensitivity – anaphylaxis, drug fever, erythema multiforme (rarely occurs with trimethoprim but more commonly with sulfonamides)
- Folate antagonist so can impair haematopoiesis – can cause haematological disorders e.g. megaloblastic anaemia
- Hyperkalaemia
Which trimester of pregnancy should trimethoprim be avoided?
1st trimester of pregnancy (folate antagonist)
Contraindications of trimethoprim?
- 1st trimester of pregnancy (folate antagonist)
- Folate deficiency (more susceptible to adverse haematological effects)
- Renal impairment (dose reduction) – as excreted mainly unchanged in urine
- Neonates, elderly & HIV infection are particularly susceptible to adverse effects
How is trimethoprim excreted?
Renally
What are the 4 main interactions of trimethoprim?
- Potassium-elevating drugs (ACEi, ARBs, aldosterone antagonists)
- Folate antagonists (e.g. methotrexate)
- Drugs that increase folate metabolism (e.g. phenytoin)
- Warfarin
How does trimethoprim interact with potassium-elevating drugs?
predisposes to hyperkalaemia
How does trimethoprim interact with methotrexate?
Both folate antagonists → increases risk of adverse haematological effects
How does trimethoprim interact with phenytoin?
Phenytoin increases folate metabolism and trimethoprim is a folate antagonist → increases risk of adverse haematological effects
How does trimethoprim interact with warfarin?
Trimethoprim can enhance the anticoagulant effect of warfarin by killing the normal gut flora that synthesise vitamin K
How does trimethoprim affect creatinine?
Trimethoprim competitively inhibits creatinine secretion by the renal tubules. This commonly leads to a small reversible rise in serum creatinine concentration during treatment, without reduction in GFR.
Why is trimethoprim less effective for UTIs in patients with renal impairment?
as the increased serum concentration of creatinine competes with trimethoprim for secretion into urinary tract
What class of drug is Doxaz_osin, Tamsulosin_ and Alfuz_osin_?
Alpha blockers
Indications for alpha blockers (tamsulosin)?
- 1st line in BPH when lifestyle changes are not enough
- Add on treatment to resistant hypertension
What class of drug can be added to alpha blockers in the context of BPH in selected cases?
5a-reductase inhibitors (e.g. Finasteride)
Mechanism of alpha blockers (doxazosin, tamsulosin)?
- Most are highly selective for the a1-adrenoceptor (found mainly in smooth muscle including blood vessels and urinary tract - bladder neck and prostate in particular).
- Stimulation of receptors induces contraction, so blockage induces relaxation
Effect → a1-blockers causes vasodilatation, decrease in BP, and reduced resistance to bladder outflow.
Side effects of alpha blockers?
- Postural hypotension (especially after first dose)
- Dizziness
- Syncope
What is the main contraindication to alpha blockers?
Existing postural hypotension
Main interaction of alpha blockers?
Antihypertensives (e.g. ACEi, ARBs) → result in additive BP lowering effect
Which alpha blocker is licensed for BPH and hypertension?
Doxazocin
Which alpha blocker is licensed for BPH only?
Tamsulosin
What can be done to avoid additive BP lowering effect when combining alpha blockers and antihypertensives?
May be helpful to omit doses of existing antihypertensives on day a-blocker is started
What class of drug is finasteride?
5a-reductase inhibitor
Main indication for finasteride?
BPH → Usually 2nd line after a-blockers
Mechanism of finasteride (5a-reductase inhibitor)?
Reduce the size of the prostate gland by inhibiting 5a-reductase (intracellular enzyme) which converts testosterone to its more active metabolite dihydrotestosterone
Dihydrotestosterone stimulates prostatic growth → inhibition of this reduces prostatic enlargement and improves urinary flow.
Why is an alpha blocker preferred for initial therapy in BPH over 5a-reductase inhibitors?
Can take months for effect of 5a-reductase inhibitors to become evident clinically
What are the side effects of 5a-reductase inhibitors largely due to?
Antiandrogen effects
What is the purpose of dihydrotestosterone?
Stimulates prostatic growth
What is the active metabolite of testosterone?
dihydrotestosterone
Which enzyme converts testosterone to its more active metabolite dihydrotestosterone?
5a-reductase (an intracellular enzyme)
Give some side effects of finasteride relating to its anti-androgen action
- Impotence
- Reduced libido
- Gynaecomastia (can affect adherence)
- Hair growth – advantage in male pattern baldness
- Breast cancer
What is the main contraindication for 5a-reductase inhibitors (finasteride)?
Pregnancy
- Cannot take drugs
- Cannot be exposed to drugs e.g. handling broken or damaged tablets or through semen during unprotected sex with man taking them
Why is finasteride contraindicated in pregnancy?
can cause abnormal development of external genitalia
What is it important to advise patients taking finasteride if they have a partner?
Importance of condom during sex if woman pregnant/could become pregnant, shouldn’t handle tablets
Suspected adverse effects of medicine be reported to who?
Medicines and Healthcare Products Regulatory Agency (MHRA)
What class of drug is sildenafil?
Phosphodiesterase (PDE) (type 5) inhibitor
What is the major indication for sildenafil?
Erectile dysfunction
What is another (less common) indication for sildenafil?
Primary pulmonary hypertension
Give the mechanism as to how sildenafil results in the treatment of erectile dysfunction
During an erection, there is nitric oxide release which causes stimulation of cGMP production which causes arterial smooth muscle relaxation, vasodilatation and penile engorgement.
PDE inhibitors prevent the breakdown of cGMP by PDE-5 enzymes.
Which enzyme is responsible for the breakdown of cGMP?
PDE (phosphodiesterase enzyme)
What is required for sildenafil to cause an erection?
Sexual stimulation
Where is PDE type 5 predominantly found?
Found predominantly in the smooth muscle of the corpus cavernosum of the penis and arteries of the lung
Which type of PDE is sildenafil selective for?
PDE type 5
Side effects of sildenafil?
- Side effects mainly related to vasodilation:
- Flushing
- Headache
- Dizziness
- Nasal congestion
- Hypotension
- Tachycardia
- Palpitations
- Small risk of vascular events (e.g. MI, stroke)
- Priapism
What is priapism?
Erection fails to subside for prolonged period despite absence of stimulation → urgent medical review
4 main contraindications for sildenafil?
- Stroke
- ACS
- CVS disease
- Severe hepatic or renal impairment (metabolism & excretion reduced)
3 main interactions of sildenafil (PDE inhibitor)?
- Drugs that increase nitric oxide concentration e.g. nitrates, nicorandil
- Other vasodilatory drugs e.g. alpha-blockers, CCBs
- Cytochrome P450 inhibitors
Why should sildenafil not be prescribed in people taking any drug that increases nitric oxide concentration (nitrates***, ***nicorandil)?
This can cause marked arterial vasodilatation and CVS collapse due to combined effects on cGMP
Why should sildenafil be prescribed with caution in people taking other vasodilatory drugs? (e.g. a-blockers, CCBs)
increased risk of hypotension
Why should sildenafil be prescribed with caution in people taking drugs that are cytochrome P450 inhibitors? (e.g. amiodarone, diltiazem, fluconazole)
Adverse effects increased by cytochrome P450 inhibitors
When should sildenafil be taken?
Take an hour before sex
What class of drugs are oxybutin, tolterodine and solifenacin?
Antimuscarinics (genitourinary uses)
Main indication of antimuscarinics in genitourinary medicine?
To reduce urinary frequency, urgency and urge incontinence in overactive bladder where bladder training is ineffective.
Mechanism of antimuscarinics (oxybutynin, solifenacin) in overactive bladder?
- Antimuscarinics help in overactive bladder through antagonism of the M3 receptor (main muscarinic receptor subtype in the bladder)
- Contraction of the smooth muscle of the bladder is under parasympathetic control
- Blocking muscarinic receptors promotes bladder relaxation, increasing bladder capacity – in patients with overactive bladder, this may reduce urinary frequency, urgency and urge incontinence
Antimuscarinics help in overactive bladder through antagonism of which receptor?
M3 receptor
What is the main muscarinic receptor subtype found in the bladder?
M3
Why solifenacin less likely to cause side effects than other antimuscarinics used in overactive bladder?
Solifenacin is more selective for the M3 receptor which may reduce side effects
Is contraction of the smooth muscle of the bladder under para or sympathetic control?
Parasympathetic
Side effects of oxybutynin/solifenacin/tolterodine? (antimuscarinics)
- Classic antimuscarinic side effects:
- ‘Can’t see’ – blurred vision
- ‘Can’t spit’ – dry mouth
- ‘Can’t pee’ – urinary retention (ensure no urinary obstruction)
- ‘Can’t shit’ – constipation
- Tachycardia
Contraindications for antimuscarinics for overactive bladder?
- UTIs
- Acute-closure glaucoma
- Urinary retention (blockage etc)
- Arrythmias
Why should antimuscarinics be used with caution in the elderly and those with dementia?
More prone to neurological side effects (e.g. confusion, drowsiness) which can be problematic
Main interaction of antimuscarinics?
Adverse effects more pronounced when combined with other drugs that have antimuscarinic effects e.g. tricyclic antidepressants
What class of drugs are goserelin and leuprolide?
GnRH analogues/agonists
Main indication of GnRH agonists?
Prostate cancer (hormonal treatment)
Mechanism of GnRH analogues in the management of prostate cancer?
Prolonged activation of GnRH receptors leads to lower amount of testosterone made by the testicles (suppressed gonadotrophin secretion).
How can GnRH initially affect testosterone levels? How can this be managed?
Can cause initial transient increase in testosterone before falling to low levels – this can be treated with anti-androgens/androgen antagonists
Side effects of GnRH agonists in the management of prostate cancer?
- Reduced libido
- Impotence (erectile dysfunction)
- Gynaecomastia
- Weight gain
- Osteoporosis
- Anaemia
- Infertility
What class of drugs are flutamide and bicalutamide examples of?
Androgen receptor antagonists/anti-androgens
Indications for flutamide?
Prostate cancer:
- a) Can be added to treatment if orchiectomy or a GnRH agonist is no longer working by itself
- b) Can be given for a few weeks when a GnRH agonist is first started to help prevent a tumour flare (due to transient increase in testosterone)
- c) Can be combined with orchiectomy or GnRH agonist as 1st line hormone therapy
A 69 y/o woman has persistent hyperkalaemia despite treatment with IV fluids, insulin and glucose. She was admitted 2 days earlier with diarrhoea and vomiting which has caused an AKI. Preparations are being made for urgent haemodialysis. What other medication may be considered to control hyperkalaemia while waiting for haemodialysis?
- Calcium gluconate
- Calcium polystyrene sulfonate (Calcium Resonium)
- Gliclazide
- Ipratropium bromide
- Salbutamol
Salbutamol (nebulised)
Why is nebulised salbutamol indicated in the treatment of hyperkalaemia?
Like insulin, B2-agonists stimulate Na+/K+ ATPase pumps on cell surface membranes, promoting a shift of K+ from the extracellular to intracellular compartment → this makes nebulised salbutamol a useful adjunct in the treatment of hyperkalaemia
However, its potassium lowering effect is relatively short-lived
Which drug is used in the management of hyperkalaemia where there are hyperkalaemia associated ECG changes?
Calcium gluconate
A 73 y/o woman is advised to take oxybutynin to improve her symptoms of urinary urgency and urge incontinence. What best describes the mechanism by which oxybutynin should improve her symptoms?
- Agonism at the B2-adrenoceptor
- Antagonism at the a1-adrenoceptor
- Antagonism at the muscarinic M3 receptor
- Antagonism at the nicotinic ACh receptor
- Inhibition of 5a-reductase
Antagonism at the muscarinic M3 receptor
- A 48 y/o is found to be hyperkalaemic. One month ago he was admitted to hospital with a non-ST-elevation MI, for which he underwent PCI. His medications are aspirin, clopidogrel, atorvastatin, bisoprolol and ramipril. What drug is most likely to cause hyperkalaemia?
- Aspirin
- Atorvastatin
- Bisoprolol
- Clopidogrel
- Ramipril
Ramipril → ACEi commonly cause an increase in serum potassium concentration
A 92 y.o woman, who lives in a residential home for people with dementia, is found confused and wandering. Her caregivers think that this was precipitated by a medicine for ‘overactive bladder’ which was started last week. What drug is most likely to have caused her confusion?
- Finasteride
- Furosemide
- Solifenacin
- Tamsulosin
- Trimethoprim
Solifenacin
Solifenacin is an antimuscarinic drug used to treat urinary urgency and urge incontinence
Side effects – dry mouth, blurred vision, constipation and confusion (elderly are particularly vulnerable to side effects).
What class of drug is finasteride?
5a-reductase inhibitor
What class of drug is tamsulosin?
alpha blocker
A 61 y/o man with BPH is advised to take tamsulosin to improve urinary flow. What side effects is most likely to occur when starting this drug?
- Bronchospasm
- Postural hypotension
- Erectile dysfunction
- Gynaecomastia
- Prostate cancer
Postural hypotension
- Tamsulosin is an a-blocker that blocks the a1-adrenoceptors in the smooth muscle of the prostate gland, increasing urinary flow and relieving obstructive symptoms
- a1-adrenoceptors are also found in the smooth muscle of blood vessels → can cause hypotension, particularly postural hypotension
An 82 y/o man with COPD is breathless and has recurrent exacerbations. His PMH includes a history of urinary retention 2ary to BPH. What treatment should be used with caution in this patient?
- Salbutamol
- Salmeterol
- Seretide
- Symbicort
- Tiotropium
Tiotropium
- Tiotropium is a long acting antimuscarinic bronchodilator
- Side effects include urinary retention in those susceptible
A 33 y/o man with severe renal impairment requires antibiotic treatment for sepsis. What antibiotic can be generally used without dosage reduction in severe renal impairment?
- Benzylpenicillin
- Co-amoxiclav
- Gentamicin
- Metronidazole
- Vancomycin
Metronidazole
- Metronidazole is metabolised and eliminated by the liver
- Dose reduction is required in severe hepatic impairment rather than renal impairment
A 67 y/o man presents to the GP to discuss his medication. For several years he has been taking sildenafil for erectile dysfunction. He has previously found this to be an effective and tolerable treatment but says it has recently been causing headaches. He has a PMH of COPD. In addition, he was recently found to have AF. His treatment has been adjusted frequently over the past weeks. His regular treatment now comprises digoxin, simvastatin, tiotropium, and warfarin. Examination is normal other than for an irregular pulse at a rate of 80—90 bpm. What drug is most likely to interact with sildenafil to provoke side effects?
- Digoxin
- Diltiazem
- Simvastatin
- Tiotropium
- Warfarin
Diltiazem
- Diltiazem is a CCB that inhibits CYP3A4 activity → i.e. is a cytochrome P450 inhibitor
- This increases risk of adverse effects of sildenafil
A 60 y/o man is advised to take sildenafil as required for erectile dysfunction. His medical problems include HTN and COPD. His DH includes doxazosin, indapamide, ramipril, and salbutamol and tiotropium inhalers. What drug should he avoid taking at the same time of day as sildenafil?
- Doxazosin
- Indapamide
- Ramipril
- Salbutamol
- Tiotropium
Doxazosin
- Sildenafil is a PDE inhibitor that causes vascular smooth muscle relaxation and vasodilatation
- Doxazosin is an alpha blocker which has a vasodilatory effect
- Concomitant use may cause hypotension and collapse
Why does trimethoprim lead to hyperkalaemia?
Trimethoprim has the potential to induce hyperkalemia by interfering with urinary potassium excretion.
