prescribing/drugs and therapeutics lectures

Question 1

ACE inhibitors

Answer 1

ACE inhibitors (ramipril, lisinopril, enalapril)

Block ACE to prevent the conversion of AT1 to AT2. AT2 causes vasocon and aldosterone secretion. ACEI reduces afterload, preload, pref dilates efferent glomerular arteriole to reduce interglomerular pressure and slow CKD progression. 	Indications: HTN, CHF, Ischaemic HD, Diabetic nephropathy, CKD with proteinuria. 

Prescription: Ramipril 2.5mg OD PO most common, 1.25 mg in HF or nephropathy. Titrate up to max 10mg per day.

Side effects: bradykinin cough. Hyperkalaemia. Renal failure in renal artery stenosis pts or when with NSAIDS. 

Contraindictations:.
PARK:
Pregnancy/breastfeeding
Aki
Renal artery stenosis
K increase (hyperkalemia)

Question 2

Adrenaline

Answer 2

Adrenaline*

Alpha 1 and 2, beta1 and 2 agonist. Alpha1 – skin, mucosal, abdo viscera vasoconstriction. Beta1 – increases myocardial rate, force and excitability. Beta2 – vasodilate muscle and heart vessels, also bronchodilate and suppress mast cell degran. 	Indications: cardiac arrest as a part of ALS algorithm. Anaphylaxis. Locally to vasoconstrict and reduce bleeding. 

Prescription:
shockable CA- 1mg IV after 3rd shock and every 3-5 min after.

Nonshockable CA – 1mg IV asap and every 3-5min after.

Anaphylaxis – 500microgram IM, repeat after 5 min PRN.

Side effects: hypertension, anxiety, tremor, headache, palpitations, angina, MI, arrhythmia. If combined with a beta blocker may cause widespread vasocon due to unopposed alpha1 vasocon.

Admin:
CA – give whole prefilled syringe of 1:10,000 (1mg in 10ml) then flush.

Anaphylaxis – 0.5ml 1:1000 (1mg in 1ml) IM anterolateral thigh.

Question 3

Amiodarone

Answer 3

Amiodarone

Diverse effects on myocardium. Blockade Na, Ca and K channels, anatagonise alpha and Beta adrenoceptors. 	

Indications: wide range of tachyarrhythmias such as A. Fib, A Flutter, SVT, VT and V Fib. Generally only used when other drugs or electrical cardioversion is inappropriate or ineffective.

Prescription: always requires senior involvement, not to be given by a FY unless for cardiac arrest

– Vfib or pulseless VT immediately after 3rd shock in ALS. 300mg IV then saline flush.

Problems – a generally messy and dangerous drug – hypotension, pneumonitis, AV block, hepatitis, thyroid problems…etc. esp when given chronically.

Question 4

Angiotensin-2 receptor blockers

Answer 4

Angiotensin-2 receptor blockers (candesartan, irbesartan, losartan)

MOA – block action of AT2 on the AT1R. result is reduced TPR, reduced glomerular pressure, reduced aldosterone and thus preload. 

Indications – generally when ACEI are not tolerated. So hypertension, CHF, ischaemic CVD, diabetic nephropathy and CKD. 

Prescription
– PO losartan 12.5mg OD in CHF or 50mg OD in other conditions. Then titrated up depending on response.

Problems – hypotension, hyperkalaemia, renal failure. Avoid in renal artery stenosis, AKI, pregnancy and breastfeeding. Possible angioedema but less likely than ACEI (thought to be something to do with BK metabolism.)

Question 5

Aspirin

Answer 5

Aspirin*

Irreversible inhibitor of COX, prevents thromboxane production and thus platelet aggregation. Platelets have no nucleus so make no new COX and thus the effect lasts for the lifetime of the platelet. 	

Indications- treat acute ACS or ischaemic stroke. Long term prevention of thrombosis. In AF where warfarin and other oral antithrombotics cannot be used. Pain relief.

Prescription
– ACS – 300mg loading dose then 75mg OD PO.

Acute ischaemic stroke – 300mg PO OD for 2 weeks then 75mg. long term in those with risk factors that have had an acute event or have Atrial fib then 75mg PO OD, only secondary prevention as for primary prevention the risk of bleeding outweighs the benefit.

For long term treatment gastroprotection should be considered eg omeprazole 20mg OD. Take after food to minimise gastric irritation.

Problems – not given to children under 16 due to the small risk of Reye’s syndrome which is rare but life threatening and affects the liver and brain. Some people can be allergic to asthma. Avoid in third trimester of pregnancy as inhibition of prostaglandins may cause premature closure of the ductus arteriosus.

Question 6

Bendroflumethiazide

Answer 6

Bendroflumethiazide

others = indapamide

A thiazide diuretic. Inhibits the NA/CL cotransporter in the distal convoluted tubule of the nephron. This prevents the resorption of sodium and osmotic draw of water. The resulting diuresis causes an initial fall in extracellular fluid vol but over time compensation occurs eg RAAS activation to partially reverse this. The long term antihypertensive effect is probably due to vasodilation. (some open potassium channels)	

Indications: an alternative first line treatment for hypertension when CCBs are unsuitable or there are features of heart failure. Also = add on treatment for hypertension when not adequately controlled by a CCB and a ACEI or ARB.

used in chronic mild cardiac failure if renal function is normal

Prescription : bendroflumethiazide 2.5mg OD PO. There is little gained from higher doses. Best to take in the morning so the diuresis is maximal during the day rather than night so as not to disrupt sleep.

They cause a modest diuresis (5% of filtered sodium is lost in the urine). This is because the majority of sodium transport occurs earlier.

Problems – hyponatraemia due to transporter blockade (not usually a problem). Hypokalaemia due to increased delivery of Na to the distal tubule where it can be exchanged for K+, this can cause arrhythmias. Can raise plasma glucose (and thus unmask T2DM), LDL and triglycerides but are still net cardioprotective. Can cause impotence. May precipitate gout attacks due to reduced uric acid excretion. 

Other – the main problem of thiazides is hypokalaemia, one of the main problems of ACEI or ARB is hyperkalaemia, thus prescribing them together causes these effects to cancel out. They also synergistically lower BP as thiazides activate the RAAS and ACEI or ARB block it.

may be ineffective in kidney failure

Question 7

Calcium channel blockers

Answer 7

Calcium channel blockers (amlodipine, diltiazem, nifedipine, verapamil)

Reduce vascular and cardiac (Ca)i. casue vasodilation to lower ABP. Reduce myocardial contractility, suppress AVN conduction and thus slow rate. Reduce rate, contractility and afterload reduce oxygen demand and thus angina.

2 broad classes: dihydropyridines such as amlodipine and nifedipine that are relatively selective for vasculature, and non-dihydropyridines that are cardioselective, verapamil is the most cardioselective. Diltiazem is cardioselective but has some effect on vessels.

Indications: HTN – amlodipine and sometimes nifedipine are 1st or 2nd line. Stable angina – control symptoms. SVT arrhythmias – diltiazem and verapamil to control cardiac rate ie in SVT, A flutter and A fib.

Prescription: amlodipine has a long half life but the others are of only a few hours so modified release variations need to be given.

HTN – amlodipine 5-10mg PO OD.

Angina – diltiazem MR 90mg PO BDS.

SVarr – verapamil 40-120mg PO TDS.

Problems – vasodilation causes ankle swelling, flushing, headache and compensatory tachycardia causes palpitations. Verapamil commonly causes constipation. Cardiac problems can include bradycardia, heart block and cardiac failure. Non-dihydropyridine CCBs shouldn’t be given with beta blockers except under close supervision as they are both negatively inotropic and chronotropic and together can cause heart failure, bradycardia or asystole.

Question 8

Clopidogrel

Answer 8

Clopidogrel* Irreversibly binds the ADP receptors on the surface of platelets to prevent aggregation. Independent of the COX pathway and thus act synergistically with aspirin.

Indications – generally prescribed with aspirin but can be used alone where aspirin is contraindicated.
1 -ACS.
2 - To prevent occlusion of coronary artery stents.
3 – secondary prevention of thrombotic events.
4 – in A Fib where warfarin and novel oral anticogs cant be used.

Prescribing
– loading dose of 300mg PO and maintenance dose 75mg PO OD.

Problems – bleeding and GI upset. It’s a pro-drug so has to be metabolised by CYP450 thus its effect is reduced when given with CYP450 inhibitors such as the PPI omeprazole, so give lansoprazole if worried about gastroprotection.

Question 9

Digoxin

Answer 9

Digoxin

Negatively chronotropic and positively inotropic. In A fib and A flutter its effect is primarily via increasing vagal tone and thus is largely lost during stress and exercise and so is rarely used on its own in AF. In heart failure its effect is via inhibition of the NA/K atpase, Na accumulates and thus so does Ca.

Indications – A fib and A flut. A beta blocker or non-dihdropyridine CCB is usually more effective though.

2 - severe heart failure – third line after ACEI, beta blocker and either spironolactone or ARB.

Prescribing – loading dose of 500 micrograms, then 250-500 micrograms 6 hrs later, then maintenance on 125-250 micrograms PO OD.

Problems – therapeutic doses can cause ST depression (reverse tick sign). Loop and thiazide diuretics can increase risk of digoxin toxicity via causing hypokalaemia. Amiodarone, CCB and spironolactone can increase plasma conc of digoxin. Digoxin is proarrhythmic and has a low therapeutic index. Lots of other problems.

Question 10

Dipyridamole

Answer 10

Dipyridamole

Antiplatelet and vasodilator. Somehow by raising cAMP. 	Indications – secondary prevention of stroke. First line after TIA. Second line after ischaemic stroke (clopidogrel is first line). Given with aspirin. 

2 – to induce tachycardia during a myocardial perfusion scan in the diagnosis of ischaemic heart disease.

Prescription – modified release 200mg PO BDS.

Problems – side effects relate to vasodilation eg headache, flushing, dizziness. Caution in ischaemic heart disease, aortic stenosis, heart failure.

Question 11

Loop diuretics

Answer 11

Loop diuretics (bumetanide, furosemide*)

Act principally on the ascending limb of the loop of henle inhibiting the Na/K/2Cl co transporter. Prevents water being drawn out of the loop by osmosis. Also causes dilation of capacitance veins, this is probably the root of their main benefit in acute heart failure as this effect occurs before the diuresis. 	

Indications -
1 – acute pulmonary oedema to reliev breathlessness with oxygen and nitrates.
2 – relieve fluid overload in chronic heart failure and other oedematous states eg renal disease or liver failure.

Prescription – IV – 40mg furosemide. Also available PO.

also used with thiazide diuretics for resistant heart failure (typically metolazone)

Problems – can be associated with basically any low electrolyte state due to how they work. Acts on a similar transporter in the inner ear that regulates endolymph so can cause tinnitus and hearing loss. Inhibit uric acid excretion and thus can worsen gout. Can affect ay drug excreted by the kidneys eg digoxin. 

compared to thiazides they cause a bigger natriuresis (25% of filtered sodium can be excreted) but which lasts for a shorter duration. they are also effective at low glomerular filtration rates (as occur in chronic renal failure) where thiazide diuretics are ineffective

Question 12

Nicorandil

Answer 12

Nicorandil

Causes venous and arterial dilation due to its actions as a nitrate and by activating K-ATP channels. Efflux of K causes hypopol and inactivation of pd gated Ca, net decrease in Cai. Effect is decreased preload, afterload and dilated coronary vessels.

Indications – stable angina – first line is beta blocker or CCB either together or alone, second line is nicorandil or long acting nitrate.

Prescription – PO only. 5-10mg BD, then 20-30mg BD due to tolerance.

Problems – due to vasodilation eg flushing, headache, also nausea, vomiting, G problems.

Question 13

Nitrates

Answer 13

Nitrates (isosorbide mononitrate, GTN including infusions*)

Converted to NO, increases cGMP synth and reduces Cai in vascular smooth muscle. Venous capacitance vessel dilation, can dilate coronary vessels, dilate systemic arteries to reduce afterload. Most antianginal effects are through reduction of preload.

Indications – short acting agents eg GTN in angina and ACS.

2 – long acting eg isosorbide mononitrate in angina prophylaxis where a beta blocker or CCB would be insufficient.

3 – IV nitrates in treatment of pulmonary oedema, usually with furosemide and oxygen.

Prescription
– stable angina – GTN SL PRN. ACS or heart failure: GTN IV infusion continuous.
Angina prophylaxis – isosorbide mononitrate: BD/TDS or can give modified release tablets or transdermal patches OD.

Problems – vasodilation based effects eg flushing and headaches. Tolerance with sustained use. Can cause cardiovascular collapse in severe aortic stenosis. Don’t use if haemodynamically unstable. Don’t use with PDE inhibitors eg sildenafil as these enhance the hypotensive effect.

Question 14

Spironolactone

Answer 14

Spironolactone

Aldosterone is a mineralocorticoid produced in the adrenal cortex. It acts on the distal tubules of the kidney to increase ENaC activity. This increases reabsorption of Na and whater and increases K excretion. Spironolactone competitively inhibits this.

Indications
1 – ascites and oedema due to liver cirrhosis.
2 – chronic heart failure – usually in addition to a beta blocker and an ACEI or ARB.
3 – primary hyperaldosteronism – whilst awaiting surgery.
4 - Secondary hyperaldosteronism (e.g. chronic liver disease)

Prescription - PO and OD. 100mg in ascites, 25mg in heart failure.

Problems – hyperkalaemia. Gynaecomastia. Care must be taken with other K elevating drugs such as ACEI and ARBs.

Question 15

Statins

Answer 15

Statins
Inhibit HMG CoA reductase an enzyme involved in making cholesterol. Decrease liver production and increase LDL-cholesterol clearance from the blood. Also indirectly reduce triglycerides and slightly increase HDL-cholesterol levels. Slow or reversesthe atherosclerotic process.

Indications
– 1 – primary prevention of CV disease. Used in people over 40 with a 10 year risk of over 20percent.
2 – secondary prevention of CV disease. First line alongside lifestyle changes .
3 – primary hyperlipidaemias : first line.

Prescribing – simvastatin 40mg PO OD, or atorvastatin 10mg PO OD.

Problems – generally safe and well tolerated. Most commonly headache and GI problems. Can also cause muscle pain, myopathy or rarely rhabdomyalysis. Metabolism of statins is reduced by CYP450 inhibitors. Excreted by kidneys so reduce dose in renal disease.

Question 16

Alpha-blockers

Answer 16

Alpha-blockers (alfuzosin, doxazocin, tamsulosin)

Most of the drugs are actually highly selective for alpha1 R eg doxazosin, tamsulosin or alfuzosin. Found mainly on smooth muscle, stim causes contraction, block relax. Blockers cause vasodilation and drop in ABP, and reduced resistance to bladder outflow. 	

Indication –
1 – first line to improve symptoms in benign prostatic hyperplasia.
2 – add on treatment in resistant hypertension.

Prescription
– doxazosin – 1mg OD PO to start.
Tamsulosin – prostate only, less effect on BP, 400micrograms OD PO.

Problems – due to effects on vascular tone – postural hypotension, dizziness, syncope, particularly after the first dose.

Question 17

Beta-blockers

Answer 17

Beta-blockers (atenolol, bisoprolol, metoprolol,

Beta1 are mainly in the heart. Beta2 are mainly in the blood vessels and airways. Block of beta1 reduces force and speed of heart. Prolong refractory period of the AVN. Blockade of this receptor in the kidney reduces renin secretion.

Indications –
1 – ischaemic heart disease. First line. Angina and ACS.
2 – chronic heart failure. First line.
3 – A fib – first line to reduce rate and in paroxysmal A fib to maintain sinus rhythm.
4 – SVT – first line to restore sinus rhythm
5 – hypertension – when ACEI, thiazides and CCBs aren’t effective.

Prescription – varies by drug and indication. Start with a drug that has a short half life in acute scenarios eg ACS as this makes it more responsive to doseage changes.

Problems – fatigue, cold extremities, headache, nausea, slep disturbance, nightmares, impotence. Avoid in asthma due to bronchospasm. CANNOT use with non-dihydropyridine CCBs eg verapamil and diltiazem as this can cause heart filaure, bradycardia and asystole.

Question 18

Anti-muscarinic bronchodilators

Answer 18

Anti-muscarinic bronchodilators (ipratropium bromide, tiotropium)

Competitive inhibitors of ACH. Reduces smooth muscle tone, reduce secretions from glands in resp and GI.

Indications –
COPD – short acting for breathlessness. Long acting to prevent exacerbations.
2 – asthma – short acting for breathlessness with beta agonists. Long acting added to high dose corticosteroids and long acting beta agonsits in step 4 of the treatment protocol.

Prescription – short acting eg ipratropium – stable patients 40micrograms QDS or PRN INH.

Acute attacks = 250-500 micrograms PRN NEBS.

2 – long acting – tiotropium – OD INH.

Problems – dry mouth but otherwise no real side effects when inhaled as lack of systemic absorption.

Question 19

Inhaled steroids

Answer 19

Inhaled steroids (betamethasone, budesonide)

Cytoplasmic receptors, modify gene transcription. Anti-inflammatory. Reduces mucosal inflammation, widens airways, reduces mucus secretion. Improves symptoms and reduces exacerbations in asthma and COPD. 

Indications  – 1 – asthma – step 2 where beta agonists aren’t sufficient.  2 – COPD – prescribed in combination with a long acting beta agonist and or a long acting antimuscarinic. 

Prescription – beclometasone 100micrograms 2 puffs INH BD for asthma. Spacer can improve airway deposition and reduce oral side effects.

Problems – oral candidiasis, hoarse voice. Little systemic absorption except in very high doses.

Question 20

Nicotine replacement therapy

Answer 20

Nicotine replacement therapy

Nervous system NAChR, euphoria and relaxation. Withdrawal causes craving, anxiety, depression and irritability with increased appetite. During abstinence, nicotine replacement therapy prevents withdrawal symptoms.

Varenicline is a partial agonist and reduces withdrawal sympt and the rewarding effects of tobacco nicotine via competition.

Bupropion increases conc of noradrenaline and dopamine via inhibiting reuptake. MOA not fully understood.

Indications – smoking cessation – used alongside non-pharmacological measures to address the psychological and behavioural aspects of dependence.

Prescription – continuous release patch to reduce or prevent craving and/or immediate release preparation such as SL tablets, sprays and gum to control the acute urge. Treatment should start before a cessation attempt to reduce the number smoked per day. If smoking over 10 per day start with high dose patch for 6-8 weeks, then wean to medium/low dose for 2 weeks before stopping.

Varenicline or bupropion should start 1 – 2 weeks before the target quit date. Low starting dos etitrated over first week to optimal treatment doe then continued for 9-12 weeks.

Problems – local irritation. GI upset with oral nicotine. Palpitations, abnormal dreams.
Varenicline – nausea, headache, insomnia, rarely – suicidal ideation.
Bupropion – dry mouth, GI upset, headache, insomnia, depression.
Can precipitate siezures in thoe susceptible. Care in psychiatric disease.
Bupropion – metabolised by CYP450 so careful with other interacting drugs.

Cost - £150 for 12 weeks so pt must have a clear idea of how and when they will quit beforehand.

Question 21

Beta-agonists

Answer 21

Beta-agonists (e.g.salbutamol*) Beta2 R found in the smooth muscle of bronchi, GI tract, uterus and blood vessels. Stimulation causes relaxation. Also stimulates NaK ATPase to shift K from the extracellular to the intraceluar compartment so useful in hyperkalaemia.

Prescription – short acting PRN. Common in adults in 100-200micrograns INH. Long acting – used in a combi inhaler with cortico to ensure use.

Metered dose inhaler = aerosol. Other option is ry powder. A spacer can help with airway deposition.

Indications 

• 1- asthma – short acting to relieve breathlessness. Long acting in step 3 for chronic asthma but ALWAYS to be used in combination with corticosteroids.
  2 – COPD – short acting to relieve breathlessness. Long acting are an option for second line maintenance.
  3 – hyperkalaemia – nebulised salbutamol can be given alongside insulin, glucose and calcium gluconate for the urgent treatment of high serum K+.Problems – due to action in other tissues – tachycardia, palpitations, anxiety or tremor. Promotes glycogenolysis so may increase serum glucose. Long acting agonsits can cause muscle cramps.
  Be careful when prescribing to patients with concurrent cardiovascular disease.
  Long acting agonists are only used in asthma when with a corticosteroid as without it they are associated with increased asthma deaths.

Costs – combi inhalers are expensive – seretide and one other combi inhaler together account for £500million per annum.

Question 22

Atypical antipsychotics

Answer 22

Atypical antipsychotics (quetiapine, olanzapine)

Block post synaptic D2R. there are 3 main DA pathways in the brain that these then target = mesolimbic/mesocortical pathway between the midbrain and the limbic system/frontal cortex.  2 – nigrostriatal from the substancia nigra to the corpus striatum of the basal ganglia.  3 – tuberohypophyseal pathway between the hypothalamus and the pituitary. The main effect of the atypical antipsychotics is believed to be via the mesocoticolimbic pathway.  

Features that distinguish second gen from first gen (the ‘typical antipsychotics) are improved efficacy in ‘treatment resistant’ schizophrenia (particularly clozapine) and against some negative symptoms, and a lower risk of extrapyramidal symptoms. Possibly due to a higher affinity for other receptors esp 5HT and looser binding to D2.

Indications
– 1 – urgent treatment of severe psychomotor agitation leading to dangerous or violent behaviour, or to calm such patients to permit assessment.
2 – schizophrenia – particularly when extrapyramidal side effects have complicated the use of typial (first gen) antipsychotics, or when negative symptoms are prominent.
3 – bipolar disorder – particularly in acute episodes of mania or hypomania.

Prescription – specialist only. Most likely to encounter when the pt is already on them – shouldn’t stop but should check if current presentation could be caused by them or an interaction with the current disease or other drugs being given.

Problems – always check the QT interval as most antipsychotics can lengthen this to sme extent which presents a risk of arrhythmias which may be exacerbated by medications you give eg macrolide antibiotics.  Other – sedation. Extrapyramidal effects (movement abnormalities due to blockade of nigrostriatal pathway. Metabolic disturbance such as weight gain, diabetes and lipid changes are a common problem. QT prolongation.

Question 23

Benzodiazepines

Answer 23

Benzodiazepines (chlordiazepoxide, diazepam, lorazepam, midazolam, temazepam)

Target is the GABAa R. this is a Cl channel. Benzos facilitate and enhance binding of GABA to the R and thus decrease neuron excitability. Result is reduced anxiety, sleepiness, sedation and anticonvulsion. Ethanol acts in a similar manner, thus sudden ethanol removal of ethanol causes withdrawal that can be treated with a benzo that can have its dose titred down to reduce withdrawal symptoms. 	

Indications
– 1 – first line in siezures and status epilepticus.
2 – first line in alcohol withdrawal
3 – common choice for sedation is general anaesthesia is unnessecary or unavailable.
4 – for short term treatment of severe, diasbly or distressing anxiety.
5 – short term treatment of severe, disabling or distressing insomnia.

Prescribing – the effects of the various benzos are similar, the differences are the length of effects.

• Siezures – long acting – lorazepam 4mg IV or diazepam 10mg IV.
• Alcohol withdrawal – oral chlordiazepoxide
• Sedation – short acting to allow raid recovery eg midazolam. Problems – dose dependent drowsiness, sedation and coma. Dependence can develop, abrupt cessation then causing withdrawal. The elderly are more susceptible. Avoid in resp impairment or neuromuscular disease. Most depend on CYP450 for elimination.

Question 24

Co-codamol, co-dydramol

Answer 24

Co-codamol, co-dydramol
Compound preparations of paracetamol and weak opioids codeine and dihydrocodeine.

Indications – the second rung on the WHO pain ladder. Used when NSAIDS are insufficient. 

Prescriptions – all tablets contain 500mg of paracetamol but the dose of opioid varies eg 8/500 or 10/500. If paracetamol has failed consider co-codamol 15/500 2 tabs 6hrly. Only available as PO. Should take doses at regular intervals.

Problems – same as opioid – nausea, constipation, drowsiness, hepatotoxicity etc. take care with hepatic/renal impairment and elderly.

Question 25

Cyclizine

Answer 25

Cyclizine* H1 and Ach R predominate in the medullary vomiting centre and in its communication with the vestibular system. Drugs such as cyclizine block both of these receptors. This makes them useful in treating a wide range of causes of nausea but esp in those associated with motion or vertigo. Indications – prophylaxis and treatment of nausea and vomiting esp in the context of motion sickness and vertigo. Prescription – cyclizine 50mg 8hrly PRN. PO IV or IM. Problems – drowsiness. Cyclizine is the least sedating drug in this class. Anticholinergic effects cause dry throat and mouth. Can cause palpitations transiently after IV. Avoid in patients with prostatic hypertrophy as the anticholinergic effects can cause urinary retention.

Question 26

D2 antaqonists

Answer 26

D2 antaqonists (domperidone, metoclopramide) D2R are the main R in the chemoreceptive trigger zone which senses emetogenic substances in the blood. DA is also important in the gut where it relaxes the stomach sphincters and inhibits gastroduodenal coordination. Thus antagonism of these effects are useful to inhibit nausea due to CTZ stim (eg drugs) or reduced gut motility (eg due to opioids or diabetic gastroparesis). Indications 1 – prophylaxis and treatment of nausea and vomiting in a wide range of conditions esp in the context of reduced gut motility. Prescription – starting dose for both metoclopramide and domperidone is both 10mg TDS. Route of admin is dependent on context eg not PO in a vomiting patient. Problems - diarrhoea is the most common issue. Metoclopramide can cause extrapyramidal movemement disorders. Domperidone does not cross the blood brain barrier so doesn’t cause this, NB the CTZ is largely outside the BBB.

Question 27

Gabapentin

Answer 27

Gabapentin Gabapentin is structurally very close to GABA although appears to act in a largely unrelated manner. Binds with pd gated Ca channels, prevents inflow and thus neurotransmitter release. Pregabalin is believed to act similarly. Indications – 1- focal epilepsy, usually as an addon when other drugs eg carbamazepine are ineffective. 2 – neuropathic pain – pregabalin in particular as second line in diabetic neuropathy and first line in others. 3 – migrane prophylaxis 4 – pregabalin in generalised anxiety disorder. Prescription – PO titrate up dose to balance side effects. Problems – drowsiness dizziness and ataxia, which usually improve after a couple of weeks. Depends on kidneys for excretion so careful in renal impairment.

Question 28

Levodopa (co-careldopa, co- beneldopa)

Answer 28

Levodopa (co-careldopa, co- beneldopa) Levodopa is a dopamine precursor. Used in PD. Indications – 1- early PD> 2 – later PD with dopamine agonists as an optional add on. 3 – econdary parkinsonism (PD with a cause other than idiopathic). Prescription – specialist advice needed. Many prefer DA agonists early in disease. LDOPA is only available in combined preparations with a peripheral dopa-decarboxylase inhibitor – with benserazide (co-beneldopa) or carbidopa (co-careldopa). Be careful with the elderly and those with existing cognitive or psychiatric disease as there is a risk of confusion and hallucination. Also risk of hypotension in CV disease. Problems – nausea, drowsiness, confusion, hallucinations, hypotension. Major problem with LDOPA is wearing off effect where the symptoms get worse towards the end of the dosage interval. This can be overcome with increased doses or increased frequency but this can cause dyskinesias (excessive involuntary movements) at the beginning of the dosage interval – when these occur together this is called the on-off effect.

Question 29

Naloxone

Answer 29

Naloxone Binds opioid receptors where it acts as a competitive antagonist. Little or no effect in the absence of an exogenous opioid. Indications – treatment of opioid toxicity eg resp depression and LOC. Prescription – usually 400-1200micrograms IV, titrated to effect. Can also be given IM or SC or nasal. Should be given in incremental doses every 2-3 mins. Problems – can precipitate an opioid withdrawal reaction in chronic abusers. No other specific issues.

Question 30

NSAIDS

Answer 30

NSAIDS* (diclofenac, ibuprofen) Inhibit COX1 and 2. Indications – PRN for mild to moderate pain. 2 – regular treatment for pain due to inflammation eg RA, osteoarthritis and gout. Prescription - …should be taken with food to minimise GI upset. Problems – GI problems, renal damage, bleeding, hypersensitivity. Interstitial nephritis Nephrotoxicity Renal failure >yrs. - Inhibition of protective action of PG’s on gastric mucosa. PGE2 and PGI2 inhibit gastric acid secretion, increase mucosal blood flow and are ctyoprotective. Bronchospasm, skin rash, Allergic reactions.

Question 31

Ondansetron

Answer 31

Ondansetron A 5HT3 receptor antagonist. High density of 5HT3 Rs in the chemoreceptive trigger zone which is responsible for detecting emetogenic substances in the blood. 5HT is also a key NT released by the gut in response to emetogenic stimuli, it stimulates the vagus nerve which activates the vomiting centre via the solitary tract nucleus. Noteably 5HT is not used in communication between the vestibular system and the vomiting centre. Therefore 5HT3 antagonists are effective against nausea and vomiting due to CTZ stim and visceral stim but not in motion sickness. Indications – prophylaxis and treatment of nausea and vomiting particularly in the context of general anaesthesia and chemo. Prescription – typical is 4-8mg 12hrly PO or IV. A relatively expensive drug. Problems – small risk of prolonged QT.

Question 32

Opioids

Answer 32

Opioids (codeine, dihydrocodeine, fentanyl, morphine*, oxycodone, tramadol) Weak opioids (codeine, dihydrocodiene) – metabolised in the liver to make small amounts of morphine/dihydromorphine which are are stronger U-agonists. 10% of Caucasians have a less active form of CYP450 so may find these ineffective. Tramadol is asynthetic analogue of codeine that’s a bit stronger although it also is thought to act on the 5HT and NA pathways too. Strong opioids – eg morphine and oxycodone – analgesic via U-opioid Rs. Act in the medulla to blunt response to hypoxia and hypercapnia so reduce resp drive and breathlessness. By doiong this they can indirectly reduce sympathetic activity (use in MI). Indications – weak opioids –mild to moderate pain when NSAIDs are ineffective. Second rung of the WHO pain ladder. Strong opioids – rapid relief of acute severe pain. 2 – relief of chronic pain when NSAIDS and weak opioids are ineffective, ie rung 3 of the WHO ladder. 3 – relief of breathlessness in end-of-life care. 4 – to remove breathlessness and anxiety in acute pulmonary oedema (used with oxygen, furosemide and nitrates). Prescription – weak opioids – PO wherever possible. Start codeine/dihydro – 30mg 4hrly, tramadol 50mg 4hrly. Always consider coprescription of a stimulant laxative eg senna. Strong opioids – acute pain morphine 2-10mg IV or on a general ward IM or SC. Chronic pain PO safest, oramorph 5mg PO 4hrly. Once the optimum dose Is found move to a modified release. Give any IV morphine incrementally. Problems – opioid withdrawal is the opposite of the effects of opioids so = anxiety, pain, breathlessness, pupils dilate, skin is cool and dry and piloerect (cold turkey). LOTS of side effects – nauea, constipation, dizziness, neurological and resp depression. Tolerance, dependence, take care in renal or hepatic impairment or elderly. Tramadol lowers the seizure threshold so don’t use in epikeptics or with TCAs or SSRIs which also do so. NEVER give codeine or dihydrocodeine IV as this can cause an anaphylactoid reaction due to histamine release (not true anaphylaxis, different mechanism).

Question 33

Paracetamol

Answer 33

Paracetamol* Poorly understood MOA. Weak COX inhibitor. A weak anti-inflammatory as its action in inflame lesions is inhibited by peroxides. Appears to work centrally as an analgesic. Indications – first line for acute and chronic pain. First rung on the WHO ladder. It can also act as an antipyretic to reduce fever symptoms. Prescription – the usual adult dose is 0.5-1gram every 4-6 hrs. max 4g daily. Problems – at therapeutic doses there are few side effects. Metabolised by CYP450 to NAPQI which is toxic and is conjugated with glutathione before elimination. In overdose the NAPQI causes hepatocellular necrosis.

Question 34

Phenytoin

Answer 34

Phenytoin Incompletely understood MOA. Reduces neuronal activity and inhibits spread of seizure activity. Appears to do this by binding neuronal Na channels and prolonging the refractory state. A similar effect in cardiac purkinje fibres may account for the antiarrhythmic and cardiotoxic effects. Indications – 1 – to control siezures in status epilepticus. 2 – reduce frequency of generalised or focal sizures in epilepsy although drugs with fewer side effects are generally preferred to phenytoin eg valproate. Prescription - status epilepticus – loading dose of 20mg/kg IV followed by 100mg 6-8hrly. 2 – long term phenytoin is usually 150-300mg daily in 1-2doses. Treatment should not be stopped suddenly due to risk of seizure. Problems – dose related neurological effects inc CBM toxicity. Long term use can cause a change in appearance via gum hypertrophy and skin coarsening etc. hypersensitivity. LOW THERAPEUTIC INDEX. A CYP450 inducer. Lots of other side effects.

Question 35

dextrose

Answer 35

an i.v. fluid that contains 5% w/v dextrose. In other words, 5g of dextrose per 100 mL of solution

Question 36

saline

Answer 36

155mEq of Na = 155mmol/L | 155mEq of Cl = 155mmol/L

Question 37

hartmann's

Answer 37

``` One litre of Hartmann's solution contains: 131 mEq of sodium ion = 131 mmol/L. 111 mEq of chloride ion = 111 mmol/L. 29 mEq of lactate = 29 mmol/L. 5 mEq of potassium ion = 5 mmol/L. 4 mEq of calcium ion = 2 mmol/L. 0 mEq of magnesium ion = 0 mmol/L This amounts to an osmolarity of 279 mOsm/L. ```

Question 38

LMWH

Answer 38

inhibit the actions of thrombin and factor Xa. prevent fibrin clot formation. LMWH such as dalteparin and enoxaparin inactivate Xa and thrombin but pref Xa. fondaparinux is synthetic and similar but only affects factor Xa. indications 1 - VTE - first choice prophylaxis. treat DVT and PE. 2 - Acute coronary syndrome - LMWH or fondaparinux are part of the first line therapy Problems - bleeding. injection site reactions. can cause heparin-induced thrombocytopenia. can accumulate in renal impairment. prescription - regular. SC. dose dependent on indication and weight. 1 - VTE prophylaxis - dalteparin 5000 units SC OD. 2 - treatment - higher doses

Question 39

warfarin

Answer 39

warfarin inhibits the natural anticoagulant activity of protein C and S before that of other clotting factors. this means that LMWH needs to be used at the same time initially to provide anticoagulant 'cover'. LMWH is stopped when the INR is in range and stable. Inhibitsvitamin-Kdependent synthesis of clotting factors II, VII, IX, X Also inhibits regulatory factors protein C, protein S, protein Z indications: 1 - DVT, PE 2- AF 3 - heart valve replacement. NOT used to prevent arterial thrombosis e.g. MI or thrombotic stroke as this is driven by platelet aggregation not fibrin. Problems - bleeding, interactions, fetal malformations in the first trimester. low therapeutic index. many antibiotics can cause anticoagulation by killing gut flora that make vitamin K. patients must know about food, alcohol and drug interactions. receive a yellow anticoagulant book to keep records. prescription - taken once daily. 5-10mg on day 1. reduce dose in elderly, low weight, increased bleeding risk. subsequent doses given based on INR. takes several days for full anticoag effect to be realised. traditionally taken at 6pm for consistent INR on the morning bloods. INR = prothrombin time divided by non warfarinised control. warfarin is fairly cheap. NOACs are much more expensive with similar efficacy but better side effect profile and less monitoring. dabigatran, rivaroxiban.

Question 40

insulin

Answer 40

-

Question 41

metformin

Answer 41

-

Question 42

N-acetylcysteine

Answer 42

-

Question 43

movicol

Answer 43

Movicol is a brand-name laxative. Each sachet of this medicine contains macrogol (polyethylene glycol), an iso-osmotic laxative, along with sodium bicarbonate, sodium chloride and potassium chloride. Electrolytes are included to help mitigate the possibility of electrolyte imbalance and dehydration. The contents of the sachets are mixed with water to make a drink. lactulose is also an osmotic laxative holding water in the stool increases its volume and stimulates peristalsis. uses: 1 - constipation and impaction 2 - bowel prep 3 - hepatic encephalopathy - esp lactulose. ``` SE 1 - flatulence 2 - cramps 3 - nausea 4 0dairrhoea ``` practicalities 1 - constipation - lactulose 15ml twice daily, titrating to response. may take a couple of days for it to - to work it requires the PT to drink plenty of water e.g. 6-8 glasses a day.

Question 44

senna

Answer 44

senna is an example of a stimulant laxative. used for constipation or as suppositories for faecal impaction. alternative is glycerol suppositories. - irritants and increase water and electrolyte secretion from colonic mucosa thereby increasing volume and stimulating peristalsis. also have a direct pro peristaltic effect of unknown mechanism. SE - cramping and pain. diarrhoea. practicalities 1-2 tablets of senna PO twice daily. titrate to effect. need to drink enough water as per other laxatives. a reasonable choice in opioid use as will help prevent confusion in the elderly and adherence in general

Question 45

methotrexate

Answer 45

antifolate, antimetabolite, reversibly inhibits dihydrofolate reductase. used in RA, psoriatic arthritis, ank spond, ALL. SE - anaemia, neutropenia, pulmonary fibrosis, hepatitis Competitive inhibition of dihydrofolate reductase. Also has other anti-inflammatory and cytokine modulating effects • Used in RA, psoriatic arthritis, and as a steroid sparing agent in other AI conditions • Low dose used in RA and other AI disease (high doses in haematological malignancies) • Dose: – Weekly dose (7.5 mg-20mg- per week). – Often taken in conjunction with folic acid (5mg, other 6days/week) Usually well tolerated. BUT requires monitoring • SE related to inhibition of cellular replication – Mouth ulcers / nausea – Rx with folic acid – Bone marrow suppression inc. neutropaenia • Others: – Acute cutaneous reactions, hepatitis, pneumonitis (temporary discontinuation) – Chronic use can rarely lead to interstitial pneumonitis and hepatic cirrhosis – Renally excreted so care with CRF or agents that impair GFR • Teratogenic (3 month washout)

Question 46

bumetanide vs furosemide

Answer 46

bumetanide supposedly has a better oral bioavailability

Question 47

what is metolazone

Answer 47

a very potent thiazide diuretic, far more so than bendroflumethiazide

Question 48

erectile dysfunction is a SE of what common drug

Answer 48

beta blockers

Question 49

major problem prescribing a loop and a thiazide

Answer 49

rapid hypokalaemia

Question 50

some causes of gynaecomastia

Answer 50

``` alcohol excess obesity digoxin spironolactone - up to 25% anything with oestrogen in it. ```

Question 51

what is eplerenone

Answer 51

an aldosterone antagonist that is very selective cf spironolactone and thus doesn't cause gynaecomastia. much more expensive though.

Question 52

4 drugs that can cause hyperkalaemia

Answer 52

amiloride losartan ramipril spironolactone

Question 53

what is moxonidine

Answer 53

Moxonidine (INN) /mɒkˈsɒnɪdiːn/ is a new-generation centrally acting antihypertensive drug licensed for the treatment of mild to moderate essential hypertension. It may have a role when thiazides, beta-blockers, ACE inhibitors and calcium channel blockers are not appropriate or have failed to control blood pressure.

Question 54

what is doxazocin

Answer 54

Doxazosin mesylate, a quinazoline compound sold by Pfizer under the brand names Cardura and Carduran, is an α1-selective alpha blocker used to treat high blood pressure and urinary retention associated with benign prostatic hyperplasia (BPH).

Question 55

what is phenoxybenzamine

Answer 55

Phenoxybenzamine (marketed under the trade name Dibenzyline) is a non-selective, irreversible alpha antagonist. It is used in the treatment of hypertension, and specifically that caused by pheochromocytoma. It has a slower onset and a longer lasting effect compared with other alpha blockers. phentolamine is also used for the control of hypertensive emergencies, most notably due to pheochromocytoma. [5]

Question 56

what do you do when cancelling a prescribed drug

Answer 56

cross it out with the infinity sign. print name, date, and bleep

Question 57

Mannitol

Answer 57

(osmotic diuretic, a bit like ethanol; used to treat cerebral oedema)

Question 58

Acetazolamide

Answer 58

carbonic anhydrase inhibitor (only used for altitude sickness)

Question 59

Demeclocyline

Answer 59

Demeclocyline blocks ADH effects used for inappropriate ADH secretion

Question 60

Tolvaptan

Answer 60

ADH receptor blocker (V2 receptors) also used for inappropriate ADH secretion

Question 61

DRUGS CAUSING RENAL IMPAIRMENT

Answer 61

1 ACE inhibitors - efferent arteriole 3 gentamicin amphotericin - tubules. Gentamicin, like other aminoglycosides, causes nephrotoxicity by inhibiting protein synthesis in renal cells. This mechanism specifically causes necrosis of cells in the proximal tubule, resulting in acute tubular necrosis which can lead to acute renal failure. 2 penicillamine - glomeruli. Membranous glomerulonephritis 5 lithium - collecting duct - Lithium enters the principal cells of the collecting duct through epithelial sodium channels in the luminal membrane [9,10]. It then accumulates in these cells and interferes with the ability of ADH to increase water permeability. Several possible mechanisms may be involved Lithium may increase expression of cyclooxygenase-2 and therefore increase urinary prostaglandin E2 excretion by medullary interstitial cells [13]. These prostaglandins then act on principal cells to induce lysosomal degradation of AQP2 water channels and a decline in urine concentrating ability. The predominant form of chronic renal disease associated with lithium therapy is a chronic tubulointerstitial nephropathy 4 NSAIDs - Prostaglandins normally cause vasodilation of the afferent arterioles of the glomeruli, NSAIDS stop this. in rarer cases they can also cause tubule/interstitial damage.

Question 62

USING DRUGS IN KIDNEY FAILURE

Answer 62

1. Avoid nephrotoxic drugs 2. Drugs may be ineffective in kidney failure e.g. thiazide diuretics 3. Sensitivity to a drug may be increased; e.g., opiates, hypnotics, sedatives, antiepileptics 4. Adverse effects more likely in patients with kidney failure; NSAIDs, metformin, K-sparing diuretics, ACE inhibitors, anticoagulants 5. Drug may accumulate so reduce dose or dose frequency; vancomycin, penicillins, cephalosporins, statins, beta blockers, ACE inhibitors, digoxin, sulphonylureas

Question 63

how does carbimazole work in the management of hyperthyroidism

Answer 63

use to treat hyperthyroidism. it inhibits the PERIOXIDASE enzyme in the thyroid follicular cells. this enzyme is responsible for converting iodide to iodine, a crucial step in the production of T4 and T3 as this iodine is then added to thyroglobulin to make T4. another drug that dos the same thing is PROPYTHIOURACIL The aim of the treatment is to render the person euthyroid and maintain them there. these 2 drugs have a delayed onset as you have to wait until the store in the colloid is depleted for the effect to become evident. important SE: carbimazole: - rash - can be hypersensitivity - gi upset - agranulocytosis (important). risk of infection, tell the Pt. - usually treated for 1-2 years on this drug but 50% relapse propythiouracil - higher rate of agranulocytosis so used second line to carbimazole. - additional inhibition of peripheral deiodination as a mechanism. monitoring - tosh can be slow to respond. monitor the T4 and most importantly the patient symptoms.

Question 64

alternative management of hyperthyroidism to euthyroid dose of carbimazole

Answer 64

1 - block and replace - high dose carbimazole to obliterate function and replace with thyroxine. not used that much 2 - radioactive iodine - the definitive solution - destroys the thyroid gland by beta radiation. used in repeated relapse. - decay is over 8 days so can expose those around them and need to admit to hospital for the 8 days. no sex for 6 weeks and don't get pregnant due to theoretical risk to the foetus.

Question 65

drugs that can cause hypothyroidism

Answer 65

amiodarone and lithium are common causes.

Question 66

rx of hypothyroidism

Answer 66

levothyroxine. delayed onset as needs to saturate all the binding site. synthetic analogue. monitor by symptoms and aim for a normal TSH.

Question 67

adrenal axis

Answer 67

CRH to ACTH to mineralocorticoids (aldosterone), glucocorticoids (shares some mineralo effects) and adrenaline

Question 68

causes of too much and too little mineralocorticoids

Answer 68

too much : conn's adenoma adrenal hyperplasia adrenal carcinoma ``` too little : addison's autoimmune infection (TB) tumours ```

Question 69

addison's -what do you need to do when they are unwell e.g. have an infection

Answer 69

they don't have a normal stress response to the infection so you need to double the dose of the steroid. they mustn't stop taking their steroids or this will precipitate an addissonian crisis. the get medic alert bracelets. rx with saline, additional saline as an iv bolus, watch their glucose and find a precipitant.

Question 70

SE of steroids in the long term

Answer 70

1 - metabolic: - weight gain and altered distribution e.g. buffalo hump and moon face. - hyperglycaemia and diabetes 2 - bone loss and osteoporosis 3 - fluid retention due to the mineralocorticoid effects. hypokalaemia and hypertension, 4 - infection 5 - psychosis. 6 - increased gastric acid secretion the result of these side effects means that they will often be on lots of other medications for these side effects.

Question 71

what does a high aldosterone to renin ratio suggest

Answer 71

that the aldosterone is coming predominantly from the adrenal gland rather than being stimulated by the action of renin. e.g. due to conn's, adrenal hyperplasia etc need to do bloods and image adrenals. often treat with surgery and medical management of the high aldosterone is spiro which will manage the blood pressure in this instance.

Question 72

rx of a phaeochromocytoma

Answer 72

surgery is the definitive action but need to medically block the effects of the catecholamines first. ``` 1st = irreversible alpha blockade eg phenoxybenzamine 2nd = beta blockade eg propranolol ``` must not do beta first or you'll get unopposed alpha action causing massive vasoconstriction and refractory hypertension.

Question 73

rx of a prolactinoma

Answer 73

want to mimic the dopamine inhibitory action on prolactin secretion. thus bromocriptine and carbergoline. can also offer transsphenoidal resection if unresponsive or intolerant.

Question 74

rx of acromegaly

Answer 74

give a somatostatin analogue to inhibit GH release. e.g. octreodtide injections. effective for the long term management.

Question 75

1. Carbemazepine (Tegretol®, Tegril®) - use SE issues

Answer 75

``` allergy common (may be serious), teratogenic linear oral dose/serum level relationship usually given for partial seizures and t-c seizures with partial onset ``` hepatic enzyme inducer (beware OCP) reduces post-tetanic potentiation and high frequency discharge of neurons higher therapeutic index than phenytoin

Question 76

2. Sodium Valproate (Epilim®, Epilim Crono®)- use SE issues

Answer 76

drug of choice for primary generalised epilepsy clinical effect ?no relation to serum level teratogenic ``` acute hepatitis (rare), weight gain, tremor at high dosage, hair thinning. inhibits liver enzymes (increases levels of hepatically metabolised drugs) Mechanism ?increased GABA activity/secretion ```

Question 77

3. Lamotrigine (Lamictal®) - use SE issues

Answer 77

monotherapy and adjunctive therapy for all types of seizure blood dyscrasias, behavioural/psychiatric symptoms, gastrointestinal symptoms WARN patients to consult doctor quickly of rash or flu-like symptoms develop common rash-Stevens Johnson Syndrome, TEN

Question 78

Phenytoin (Epanutin®) | -use SE issues

Answer 78

Phenytoin (Epanutin®) t-c seizures side effects++, hirsutism, weight gain, acne overdose-sedation, cerebellar syndome enzyme inducer (eg OCP, other AEDs) variable kinetics (range of T1/2 7-42 hours) (Binds to inactive sodium channels, prolonging inactivation) zero order rate of metabolism Gum hypertrophy in a 17- year old given Phenytoin

Question 79

cyp450 enzyme inducers

Answer 79

BARS CAG barbiturates: phenobarbitone antiepileptics: phenytoin, carbamazepine rifampicin St John's Wort corticosteroids Alcohol - chronic abuse griseofulvin smoking (affects CYP1A2, reason why smokers require more aminophylline) decrease levels of antiepileptic drugs decrease levels of other drugs (eg OCP, Warfarin) Induction is slow

Question 80

cyp450 enzyme inhibitors

Answer 80

AAAA ccrisis ``` Inhibitors of the P450 system include antibiotics: ciprofloxacin, erythromycin amiodarone allopurinol acute alcohol intake ``` ``` cimetidine, omeprazole ca channel blockers, ritonavir - anti hiv isoniazid SSRIs: fluoxetine, sertraline imidazoles: ketoconazole, fluconazole sodium valproate ``` quinupristin Grapefruit juice Inhibition is acute increase levels of other AEDs increase levels of other hepatically metabolised drugs (eg warfarin, oral hypoglycaemics)

Question 81

anti epileptics that bind protein strongly

Answer 81

3. high protein binding valproate, phenytoin displaced by other bound drugs, increasing free levels eg NSAIDS, AEDs

Question 82

body Water Distribution (in health)

Answer 82

Roughly a rule of 1/3rds... - 2/3rds of total body mass in water - 1/3rd of this is in the extra-cellular compartment - 1/3rd of this is in the intra-vascular compartment so about 42 litres in a 70kg male. - 14 extra - 4.5 l intra

Question 83

NICE guidance on fluid maintenance

Answer 83

25-30ml/kg/day water 1mmol/kg/day of K, Na, Cl 50-100g of glucose a day to prevent starvation ketosis for obese people you should adjust to their ideal body weight, people rarely need more than 3 litres a day. consider lower volumes in the elderly, the frail, heart failure, renal impairment. 20-25ml/kg/d Be cautious in: Elderly (consider 20-25ml/kg/day) Obese (target ideal body weight – don’t go over 3L/day)  Heart failure Renal failure (esp. dialysis patients!) Liver failure (reduced albumin, hence oncotic pressure) Can precipitate: Decompensated heart failure Pulmonary/generalised oedema Electrolyte derangement (even in the young/well e.g. hyperchloremic acidosis)

Question 84

Assessing Fluid Requirements

Answer 84

Not the same as a fluid balance! Standard Practice History / Examination Bedside tests / Investigations Think! Treat people as individuals. (note key differences e.g. old vs. young) Normal or altered physiology Co-morbidities Effect of iatrogenic interventions inc. drugs Re-assess post-interventions / on change in clinical state ``` HYPOVOLAEMIA Primary Thirst Cool extremities Increased capillary refill time  Increased RR Tachycardia Hypotension Reduced UO Reduced GCS ``` Other Loss of skin turgor Absence of JVP, patient at 45°  Postural BP drop Fluid balance charts ``` OVERLOAD If the heart and kidneys are functioning normally this should not occur Symptoms/Signs Raised JVP, patient at 45° Generalised oedema Increased weight (need baseline) Ascites Pulmonary oedema Increased RR Crackles Orthopnoea Fluid balance charts ```

Question 85

different gauge cannulae

Answer 85

``` 22G – Blue: 36mls/min 20G – Pink: 61mls/min 18G – Green: 90mls/min 16G – Grey: 200mls/min 14G – Orange/Brown: 300mls/min ```

Question 86

overview of the pain ladder

Answer 86

1 - non opioid 2 - weak opioid and non opioid 3 - strong opioid if acute pain e.g. after surgery and will go away with time then work from the top of the ladder down (e.g. morphine and non opiates). if chronic pain work up the ladder to the level necessary.

Question 87

role of COX1

Answer 87

COX-1 is expressed constitutively in most mammalian cells Responsible for various ‘house-keeping’ /homeostatic functions. Principally: gastric mucosal integrity (PGI2) vasodilation of the afferent arteriole of the glomeruli (PGE2) platelet aggregation (TXA2)

Question 88

overview of COX-2 Selective NSAIDS

Answer 88

Celecoxib and rofecoxib released 1999 Initial studies reported reduced GI side-effects But: Inappropriate end-points Inappropriate comparators (nsNSAID + PPI) Failure to examine lower GI side-effects Lose benefit if also on low-dose aspirin Rofecoxib with in 2004 due to CV toxicity Concern extends to all COX-2 inhibitors

Question 89

name 3 weak opioids

Answer 89

Codeine -Good antitussive potency. Needs conversion to morphine. 20% less analgesic action .Constipation often a problem Low level of euphoria / addiction Dihydrocodeine ``` Tramadol – synthetic codeine analogue Useful drug for moderate pain Relatively safe, little respiratory depression, cardiovascular effect or dependence 10% as potent as Morphine Dual mechanism of action: Opioid agonist Weak noradrenaline / 5HT reuptake inhibitor  ```

Question 90

name 4 strong opioids

Answer 90

Morphine Fentanyl - Highly potent and short acting opiate Used mostly in anaesthesia Often used in PCA Fentanyl patches and lollipops - use in palliative care Pethidine - Similar to morphine (μ-opioid receptor agonist) except tends to cause restlessness not sedation Has additional anti muscarinic effect (dry mouth and blurred vision). Shorter acting – safer during labour As likely as morphine to cause addiction  Oxycodone

Question 91

reason for using methadone in addicts

Answer 91

Synthetic opioid with much longer half life (over 24 hours) Less sedative Produces more gentle abstinence syndrome – used to treat morphine / heroin addiction

Question 92

iron medication

Answer 92

Ferrous sulphate is the classic Orally: 200 mg tds Take with meat and vitamin C. Avoid tea, coffee. GI upset, black stools. Possibility of poisoning in overdose. Alternatives: ferrous fumarate, ferrous gluconate Parenteral: ‘Ferinject’. Ferric carboxymaltose 5% w/v. Dose calculated according to body weight. Usually weekly or less often. Allergy, inconvenience. ‘Facilities for cardiopulmonary resuscitation must be available’

Question 93

folate prescriptions

Answer 93

5 mg, once a day. No side effects.. but... In malabsorption, good to give hydroxycobalamin IM in addition during the acute phase. Ruling out vitamin B12 deficiency is important, as when folic acid therapy is initiated it may aggravate neurological manifestations of underlying vitamin B12 deficiency. In states of severe megaloblastic anaemia where it is essential to initiate therapy immediately, tests for vitamin B12 deficiency should be sent in addition to those for folate deficiency; until test results are available, concomitant therapy with folic acid and vitamin B12 should be given.

Question 94

vitamin B12 replacement

Answer 94

``` Deficiency: ‘Pernicious anaemia’ (PA: autoimmune deficiency of intrinsic factor) Malabsorption Dietary (vegans) Metformin, other drugs. ``` Administration Can be given orally. Parenterally: In PA, hydroxycobalamin 1 mg IM three times a week for 2 weeks then once every three months for life No side effects, really.

Question 95

giving EPO

Answer 95

Made in the kidney: levels fall in renal disease. Normochromic normocytic anaemia. Hb, 8 g/dL minimum. Epo assays not routine (yet) ‘Darbopoietin’ 450 ng/kg once weekly, adjusted according to response. Try to keep Hb between 100-120 g/L. Overtreatment is the main problem.

Question 96

Ruxolitinib - what is it. used in myelofibrosis.

Answer 96

A protein kinase inhibitor: the BNF lists 21 of them. Ruxolitinib inhibits JAK2, ‘Janus kinase 2’, commonly mutated in myelofibrosis. Given orally. No picnic... immunosuppressive (especially TB), can give progressive multifocal leukoencephalopathy. Example of a completely new class of drug. (Some of the others cause arterial hypertension)

Question 97

Warfarin – adverse effects

Answer 97

Contra-indicated in pregnancy (teratogenic) Haemorrhage risk is increased in: HASBLED ``` Hypertension Abnormal renal or liver function Stroke Bleeding Labile INR Elderly (>65) Drugs / alcohol ``` Warfarin necrosis (in patients with protein C deficiency) Osteoporosis? Purpletoesyndrome ``` Interactions: Enzyme Inducers Phenytoin Carbemazepine Rifampicin St John’s Wort ``` ``` Enzyme Inhibitors Omeprazole Anti-fungals Clarithromycin, metronidazole Grapefruit juice ``` Needs regular monitoring with INR

Question 98

Novel Oral Anticoagulants

Answer 98

Riveroxiban: Activated Factor Xa inhibitor (OD) Apixiban: Activated Factor Xa inhibitor (BD) Dabigatran: Direct thrombin inhibitor (BD) Advantages to warfarin: Don’t need monitoring Quicker onset of action Less interaction with other meds Disadvantages Not approved for valvular AF cost lack of exp

Question 99

what is Unfractionated Heparin

Answer 99

Naturally occurring anticoagulant produced by mast cells Doesn’t break down clots! Forms complex between AT, thrombin and heparin causes inactivation of thrombin (needs 18 saccharide units) Increasesactionofantithrombinininactivating factor Xa (needs 1 saccharide unit) IV infusion with regular APTT monitoring Rarely used except in surgical / ITU settings

Question 100

Heparins and LMWH – adverse effects

Answer 100

Bleeding Heparin-induced thrombocytopaenia Fall in platelets 5-10 days after starting heparin – Antibody-mediated Increased thrombus formation Abnormal LFTs • Hyperkalaemia

Question 101

Lymphoma Rx

Answer 101

Cancer of the lymphocytes Lymphadenopathy, malaise, B-symptoms Low grade vs. High grade ``` Chemotherapy: R-CHOP Rituximab Cyclophosphamide Hydroxydaunorubicin (doxorubicin) Oncovin (vincristine) Prednisolone ``` Adverse Effects: Nausea and vomiting, alopecia, neutropenia, haemorrhagic cystitis Co-prescribed with: Anti-emetics, Pegfilgrastim (+/- antibiotics), mesna, allopurinol

Question 102

Leukaemias rx

Answer 102

Lymphoblastic vs. myeloid Bone marrow failure ``` Management Stem cell transplant? Chemotherapy: Cyclophosphamide (alkylating) Doxorubicin (intercalating) Methotrexate (anti-folate) ``` Side effects: Nausea and vomiting, cardiotoxicity, mucusitis, neutropenia

Question 103

Multiple Myeloma Mx

Answer 103

Cancer of plasma cells Paraproteinaemia causes increased viscosity, renal dysfunction Bone marrow failure Bone pain and hypercalcaemia Management Stem cell transplant autologous vs. allogeneic Chemotherapy: Lenalidomide-dexamethasone Melphalan

Question 104

common causes of a sore throat

Answer 104

``` Usually viral (rhino virus, adenovirus RSV, influenza) Sometimes its glandular fever (EB virus) ```

Question 105

what is Co-amoxiclav

Answer 105

(Amoxicillin + clavulinic acid)

Question 106

live attenuated virus vaccinations cannot be used in the immunosuppressed. what are 4 examples of this type of vaccine?

Answer 106

MMR BCG oral polio yellow fever.

Question 107

use of ciclosporin

Answer 107

used as a steroid sparing agent binds the intracellular calcineurin receptor highly selective inhibitory effect on t lymphocytes and IL2 production . major component of antirejection therapy for transplants. also used as second line in autoimmune disease. SE: increase urea and creatinine, HTN, hirsutism, gum hypertrophy and GI disturbance. v little bone marrow suppression narrow therapeutic index interacts with hepatic enzyme inducers and inhibitors.

Question 108

use of tacrolimus

Answer 108

similar mechanism and toxicity to but stronger than cyclosporin. a calcineurin inhibitor. more effective but more toxic and more potent immunosuppressant. causes infections.

Question 109

overview of cytotoxic drugs

Answer 109

used in chemo. cause immunosuppression azathioprine, cyclophosphamide, mycophenalate mofetil (used solely in immunosuppression.) all non specifically inhibit clonal proliferation of b and t cells.

Question 110

CYP 450 metabolised drugs with narrow therapeutic window

Answer 110

Warfarin Theophylline Ciclosporin Estradiol Phenytoin

Question 111

how does azathioprine work

Answer 111

a purine antimetabolite, interferes with DNA synthesis. metabolised by xanthine oxidase so should not be on allopurinol at the same time as this inhibits xanthine ox used in transplants and as a steroid sparing agent in autoimmune disease. mycophenylate mofetil is works in the same way but is only used in transplants. issues - Myelosuppression hepatotoxicity

Question 112

who does cyclophosphamide work

Answer 112

an alkylating agent. cross links dan to prevent replication . used in lymphomas, BMT and autoimmune diseases. good at killing b cells. causes haemorrhagic cystitis, cardiotoxicity, severe pancytopenia.

Question 113

use of thalidomide

Answer 113

appears to be good at inhibiting TNF synthesis. currently used in multiple myeloma and leprosy

Question 114

use of trastuzumab

Answer 114

anti HER2 in breast cancer

Question 115

what is clearance

Answer 115

“Volume of plasma cleared of drug per unit of time.” | ~ Ability of liver + kidneys to dispose of the drug

Question 116

what is first pass metabolism

Answer 116

“Metabolism that a drug goes through prior to reaching the systemic circulation.” This occurs in: 1. Gut wall 2. Liver It is possible to bypass by admistering this by different route of administration

Question 117

difference between 1st order and zero order kinetics and some examples of zero order drugs

Answer 117

• 1st order kinetics - The metabolic process is not limited by the drug concentration so linear degradation occurs. • Rate of elimination may be measure by plasma t1/2 • Most drugs eliminated by 4-5 t1/2 • Zero order kinetics - The metabolic process is limited by drug concentration due to enzyme saturation so non-linear degradation occurs. The most important examples of zero-order kinetics drugs are: • Phenytoin • Alcohol • Salicylates

Question 118

examples of type 1 - 4 drug allergies

Answer 118

Type I - Anaphylaxis • Penicillin, contrast media Type II - Cytotoxic antiboies (→ haemolysis, agranulocytosis, thrombocytopenia) • Haemolysis (methyldopa, penicillin, sulphonamides) • Agranulocytosis (clozapine, carbimazole) • Thrombocytopenia (heparin, quinadine) Type III - Immune complex mediated • Penicillin Type IV - Cell-mediated - uncommon • Topical antibiotic reactions#

Question 119

different clinical phases of drug development

Answer 119

Phase I: Measure of pharmacodynamics, pharmacokinetic and side-effects in healthy people * Phase II: Small pilot studies in ill people and establish dose * IIa: safety and tolerability * IIb: ʻlearning phaseʼ to define dose / dose range to be used in phase III * Phase III: Formalised RCT * Phase IV: Post-marketing surveillence

Question 120

causes of drug interaction can be divided into?

Answer 120

``` pharmacokinetic: A - absorption D - distribution E - elimination M - metabolism ``` pharmacodynamic - synergistic effects e.g. aspirin and warfarin causing bleeding. different target but similar results.

Question 121

Important teratogens - 8

Answer 121

``` Thalidomide Folate antagonists Tetracycline Androgens ACEi Alcohol Androgens Warfarin ```

Question 122

Acute Coronary Syndrome rx

Answer 122

AIRWAY • Secure BREATHING • Oxygen CIRCULATION • IV access and bloods ``` • Drugs: 1. ASPIRIN 300mg [ISIS-II] 2. CLOPIDOGREL 300mg 3. GTN spray (2 puffs, 0.3mg tablet) 4. ATENOLOL 5mg IV [ISIS-I] 5. MORPHINE 5mg + 10mg METOCLOPRAMIDE 6. HEPARIN e.g. enoxaparin 1mg/kg s.c. b.d. ```

Question 123

Treatment post-infarction

Answer 123

“The 4 As” 1. Aspirin 75mg o.d. 2. Atorvastatin 80mg o.d. 3. Atenolol 50-100mg o.d. 4. ACE inhibitor [ISIS-IV]

Question 124

The goals of treating angina are 2-fold

Answer 124

1. Prevent myocardial infarction (aspirin, statin and β-blockers) 2. Control symptoms (β-blocker, nitrates, CCBs and K+ blockers

Question 125

statins in angina - preventing MI

Answer 125

1. Statins e. g. simvastatin, atorvastatin, pravastatin • HMG-CoA reducase inhibitors (rate-limiting step in cholesterol synthesis) → reduced hepatocyte cholesterol and increased LDL receptors. • Actions: ↓ LDL (~40%), ↑ HDL (~15%), ↓ TGs (~30%) + PLEOTROPIC effects * Indications * Total cholesterol > 5 * LDL cholesterol > 3 * Other severe risk factors for CAD Note: if TGs > 3.5 then consider using a fibrate. Those with homozygous familial hypercholesterolaemia will not respond to statins Must monitor transaminases for 8 weeks

Question 126

C.I.s Important S.E.s Interactions for statins

Answer 126

Pregnancy Liver disease SE: Myositis - If CK > 5x normal then stop Hepatotoxicity interactions: CP450 inhibitors Cyclosporin and fibrates both increase risk of myositis

Question 127

C.I.s Important S.E.s Interactions for beta blockers

Answer 127

contraindications: bradycardia/heart block asthma claudication ``` SE: Bronchospasm Cold extremeties Bradycardia Dreams Impotence Diabetes - debatable how much Hyperlipidaemia ``` ``` Interactions Diltiazem/Verapamil Amiodarone Insulin (reduced sensitivity to hyoglycaemia) ```

Question 128

C.I.s Important S.E.s Interactions for nitrates

Answer 128

CI: Valvular stenosis HOCM SE: Headaches Hypotension + tachycardia interactions: Sildenafil tPA (reduced plasma concentration) Heparin (reduced anticoagulant)

Question 129

how do non-dihydropyridine CCBs act on the heart

Answer 129

(negative ionotropy and decreased AV node | conduction). also cause peripheral vasodilation

Question 130

C.I.s Important S.E.s Interactions for CCBs

Answer 130

CI:HOCM ``` SE: Ankle swelling [unresponsive to diuretics] Headaches [short > long-acting] Gum hypertrophy Constipation ``` Interactions Verapamil - β-blockers - ↑ digoxin conc Diltiazem - ↑ digoxin conc - ↑ carbamazepine/phenytoin

Question 131

management of Acute/De-compensated Cardiac Failure

Answer 131

This is a MEDICAL EMERGENCY • Characterised by acute onset breathlessness, pink sputum and severe adrenergic activation. The most important signs are, of course, bibasal crepitations and a gallop rhythm. Treatment should follow these guidelines: AIRWAY • May need support if comatose BREATHING • Sit the patient up • Give oxygen e.g. 10-12L through non-rebreather CIRCULATION • IV access and bloods • Drugs 1. MORPHINE 5mg + metoclopramide 10mg (anxiolytic and vasodilator) 2. FUROSEMIDE 40-80mg (early - vasodilator, late - diuretic) 3. GTN 2 puffs/2 x 0.3mg tablets (vasodilator) Note: BP must be > 90 systolic ``` Most patients should settle. If not then consider… • Specialist help • Further frusemide • Nitrate infusion • IV aminophylinne • Ventilatory support ```

Question 132

management of Hyperkalaemia

Answer 132

1 - treat underlying causes 2- review medications 3- if mild then polystyrene sultanate resin e.g. Calcium resonium 15g/8h PO - binds K in the gut, brings levels down over a few days. can give as enema if vomiting. 4 - if evidence of myocardial excitability (do an ECG) or levels over 6.5mmol/l then get help and treat as an emergency. a - stabilise cardiac membrane with 10ml 10% calcium gluconate over 10 mins b - drive K into cells with 10 units actrapid in 50ml 20% glucose c - if dehydrated give a fluid challenge, smaller vol if impaired d- reassess, refer to renal team early Nebulised salbutamol 2.5mg can help temporarily

Question 133

management of hypokalaemia

Answer 133

if less than 2.5mmol/L need to treat as emergency. NB it will exacerbate digoxin toxicity 1 - if mild, e.g. over 2.5 and no symptoms then give oral K e.g. Sando-K 2tabs/8hr 2 - if severe, less than 2.5 and/or symptomatic give IV K not more than 20mmol/hr, not more concentrated than 40mmol/L. never ever give as a stat bolus.

Question 134

management of hypercalcaemia

Answer 134

• Ca2+ > 3.5 mmol/l +/- symptoms e.g. Confusion, abdominal pain Rx: • 0.9% saline IVI to drive renal loss over 72h • 40mg furosemide IV once rehydrated to further drive loss • Bisphosphonate e.g. Single dose of pamidronate (will reduce over 2-3d) • Prednisolone 60mg o.d. for myeloma/lymphoma

Question 135

Nephro-toxic drugs

Answer 135

* ACE inhibitors (↓ GFR if arterial perfusion is low) * Cyclosporin A (P450 substrate that ↓ GFR and damages tubules) * Getamicin (renal tubular damage) * Lithium (nephrogenic diabetes insipidus) * NSAIDs (↓ GFR, interstitial nephritis, Na+ retention)

Question 136

Drugs that cause peripheral neuropathy

Answer 136

* Amiodarone * Nitrofurantoin * Vincristine + cis-platin * Penicillamine

Question 137

Drugs that cause pulmonary fibrosis

Answer 137

* Amiodarone * Bleomycin * Busulphan

Question 138

Liver Enzyme Inducers (PC BRASS)

Answer 138

``` Phenytoin Carbamezapine Barbituates Rifampicin Alcohol Sulphonyl-ureas Smoking ```

Question 139

Liver Enzyme Inhibitors (CC MOG)

Answer 139

``` Cimetidine Ciprofloxacin Macrolides Omeprazole Grapefruit juice ```

Question 140

4 drugs that can cause drug induced lupus - himp

Answer 140

hydralazine isoniazid minocycline procainamide

Question 141

Porphyrias: acute intermittent porphyria symptoms

Answer 141

``` 5 P's: Pain in abdomen Polyneuropathy Psychologial abnormalities Pink urine Precipitated by drugs (eg barbiturates, oral contraceptives, sulpha drugs) ```

Question 142

what are the porphyria's

Answer 142

The porphyrias are a group of rare diseases in which chemical substances called porphyrins accumulate. The body requires porphyrins to produce heme, which carries oxygen in the blood; but, in the porphyrias, there is a deficiency (inherited or acquired) of the enzymes that transform the various porphyrins into others, leading to abnormally high levels of one or more of these substances. This manifests with either neurological complications or skin problems or occasionally both.

Question 143

Vitamin K dependent cofactors

Answer 143

"Several Tend To Nicely Stop Clots": Factor Seven, Ten, Two, Nine. Protein S, Protein C.

Question 144

Malignant hyperthermia treatment

Answer 144

``` "Some Hot Dude Better Give Iced Fluids Fast!" (Hot dude = hypothermia): Stop triggering agents Hyperventilate/ Hundred percent oxygen Dantrolene (2.5mg/kg) Bicarbonate Glucose and insulin IV Fluids and cooling blanket Fluid output monitoring/ Furosemide/ Fast heart [tachycardia] ```

Question 145

Gynecomastia: common causes

Answer 145

``` GYNECOMASTIA: Genetic Gender disorder (Klinefelter) Young boy (pubertal)* Neonate* Estrogen Cirrhosis/ Cimetidine/ Ca Channel blockers Old age* Marijuana/malignancy Alcoholism Spironolactone thyroid disfunction Isoniazid/ Inhibition of testosterone Antineoplastics (Alkylating Agents)/ Antifungal(ketoconazole) * Asterisk indicates physiologic cause. ```

Question 146

Gynaecomastia-causing drugs

Answer 146

``` DISCOM: Digoxin Isoniazid Spironolactone Cimetidine Oestrogens methyldopa ```

Question 147

Steroids: side effects

Answer 147

``` BECLOMETHASONE: Buffalo hump Easy bruising Cataracts Larger appetite Obesity Moonface Euphoria Thin arms & legs Hypertension/ Hyperglycaemia (diabetes) Avascular necrosis of femoral head Skin thinning/striae/bruising Osteoporosis Negative nitrogen balance Emotional liability ```

Question 148

Nitrofurantoin: major side effects

Answer 148

NitroFurAntoin: Neuropathy (peripheral neuropathy) Fibrosis (pulmonary fibrosis) Anemia (hemolytic anemia)

Question 149

Anticholinergic side effects

Answer 149

``` "Know the ABCD'S of anticholinergic side effects": Anorexia Blurry vision Constipation/ Confusion Dry Mouth Sedation/ Stasis of urine ```

Question 150

SSRIs: side effects

Answer 150

``` SSRI: Serotonin syndrome Stimulate CNS Reproductive disfunctions in male Insomnia ```

Question 151

Tricyclic antidipressents (TCA): side effects

Answer 151

``` TCA'S: Thrombocytopenia Cardiac (arrhymia, MI, stroke) Anticholinergic (tachycardia, urinary retention, etc) Seizures ```

Question 152

Depression: symptoms and signs (DSM-IV criteria)

Answer 152

``` AWESOME: Affect flat Weight change (loss or gain) Energy, loss of Sad feelings/ Suicide thoughts or plans or attempts/ Sexual inhibition/ Sleep change (loss or excess)/ Social withdrawal Others (guilt, loss of pleasure, hopeless) Memory loss Emotional blunting ```

Question 153

nsaids interact with a lot of drugs, what are they,

Answer 153

Oral Anticoagulants - bleeding Anti-Hypertensives - decreases Hypotensive effect Diuretics - decreases Diuretic effect (na+/H2O retention) ACE inhibitors / K+ sparing diuretics - Hyperkalaemia Lithium - most NSAIDS increase Lithium levels Methothrexate - increase mtx levels

Question 154

allopurinol overview

Answer 154

Allopurinol: Competitively binds xanthine oxidase which converts adenine & guanine (purines) to UA. Reduces precipitation in joints and kidneys. * Reduce dose in renal and hepatic failure. * S.E. headaches, dyspepsia, diarrhoea. Gout flare! * Rarely fever, renal failure, allopurinol hypersensitivity (Stevens-Johnson Syndrome and TEN). Note interaction with mercaptopurine and azathioprine • Other uses: prevention of tumour lysis syndrome

Question 155

Bisphosphanates overview

Answer 155

Bisphosphanates- inhibit bone resorbtion (osteoclasts) – Alendronate, etidronate – Reduce vertebral and non vertebral fractures – Daily/ weekly tablets – Can cause • oesphageal ulceration and hypophosphataemia (commonly) • Osteonecrosis of the jaw, atypical femoral fracture (rarely)

Question 156

more specialist drugs used in osteoporosis

Answer 156

Denosumab (anti-RANKL) • SERM’s (selective estrogen receptor modulators e.g. raloxifene) • Strontium • Recombinant PTH (teriparatide) NOTE - HRT is no longer used as increased risk of coronary events and breast cancer

Question 157

DRUG CAUSES OF CONSTIPATION

Answer 157

1. opiates 2. calcium channel blockers (verapamil) 3. anticholinergic drugs (benzhexol, tricyclic antidepressants) 4. iron 5. lithium

Question 158

PHARMACOLOGICAL TREATMENT OF CONSTIPATION

Answer 158

4 classes of drug 1. Bulk forming laxatives e.g. bran, ispaghula husk - softening of faeces 1-3 days 2. Osmotic laxatives e.g. magnesium salts, lactulose - Watery evacuation 1-3 hours 3. Stimulants e.g. senna, - Soft or semi-solid stool 6-8 hrs 4. Stool softeners e.g. arachis oil,

Question 159

DRUGS THAT CAUSE DIARRHOEA

Answer 159

1. laxatives 2. antibiotics 3. SSRI antidepressants 4. orlistat(causesfatmalabsorption; used in obesity)

Question 160

Drugs that cause dyspepsia

Answer 160

* NSAIDs – (Aspirin) * Corticosteroids * Calcium blockers * Bisphosphonates * Nitrates * Theophyllines

Question 161

H2 Rc blockers

Answer 161

* Ranitidine – OTC * Preventing acid secretion mediated by histamine * Symptom relief within a week, 90% ulcers heal within 8 weeks * Need maintenance therapy * S.E; nausea, rash, headache, diarrhoea, constipation

Question 162

Proton Pump Inhibitors

Answer 162

* Irreversible inhibition of H+/K+ATPase * Reduction in gastric acid production * Effective (Cochrane review) * Billion dollar drug * Examples; Omperazole, Lansoprazole * S.E; headaches, abdo pains & diarrhoea (c.diff/infection in cirrhosis)

Question 163

Antispasmotics and drugs altering gut motility

Answer 163

• Motility stimulants – eg metoclopramide and domperidone (DA antagonist) in NUD • Antimuscarinics – eg hyoscine bromide or propantheline bromide in IBS • others – eg mebeverine and peppermint oil in IBS and Diverticular disease

Question 164

D2 Antagonists anti emetics

Answer 164

* Action is on D2 receptors * Block CTZ * Used in neoplastic disease, radiation sickness, drug induced vomiting, general anaesthetics and cytotoxics * Not effective for motion sickness * Examples; Metoclopramide, Domperidone, * S.E; extrapyramidal specially in the young, elevate prolactin levels • Metoclopramide Acts centrally and peripherally Helps also by increase gastric emptying, good for migraine Blocks 5HT also • Domperidone Doesn’t cross BBB and therefore less likely to cause extrapyramidal effects • Prochlorperazine Used in severe vertigo, labyrinthine disorders Similar to chlorpromazine but not neuroleptic effect

Question 165

5-HT3 Antagonist antiemetics

Answer 165

* Gastric prokinetic activity * Very effective but expensive * Used in cytotoxic chemotherapy or radiotherapy * Well tolerated * Examples; Ondansetron, Granisetron * S.E; constipation , rash, flushing, headache, hypersensitivity reaction

Question 166

Antihistamines antiemetics

Answer 166

Centrally acting, on brainstem and vestibular afferents • Good for any cause of N&V mainly in vestibular disorders e.g vertigo, tinnitus, Meniere’s disease, motion sickness • Examples; Cinnarizine, Cyclizine • SE: drowsiness, dry mouth, sometimes blurred vision

Question 167

Anticholinergics antiemetics

Answer 167

• They work on the vomiting centre • Example Hyoscine Bromide • Use Motion sickness, premedication, pallative care • S.E – Drowsiness, blurred vision, difficulty with micturition, dry mouth

Question 168

non standard antiemetics

Answer 168

• Corticosteriods Used to enhance other agents in Chemotherapy • BDZ Work by their anxiolytic and hypnotic actions • Nabilone A synthetic cannabinoid for specialist use mainly in chemotherapy; euphoric effects

Question 169

Forms of acute drug-induced liver disease

Answer 169

Hepatocellular Necrosis - Diclofenac Steatosis - Tetracycline Cholestasis Hepatocanalicular - Augmentin Canalicular - Chlorpromazine, OCP Mixed - Phenytoin

Question 170

patients with any form of cariovascular disease - which should be given aspirin

Answer 170

All patients with ischaemic heart disease should take aspirin if there is no contraindication. However, following recent changes to the guidelines patients who have other forms of cardiovascular disease (e.g. stroke and peripheral arterial disease) should be offered clopidogrel first-line.

Question 171

drug monitoring required for cardiovascular drugs

Answer 171

Statins LFT LFTs at baseline, 3 months and 12 months ACE inhibitors U&E U&E prior to treatment U&E after increasing dose U&E at least annually Amiodarone TFT, LFT TFT, LFT, U&E, CXR prior to treatment TFT, LFT every 6 months The tables below show the monitoring requirements of common drugs. It should be noted these are basic guidelines and do not relate to monitoring effectiveness of treatment (e.g. Checking lipids for patients taking a statin)

Question 172

drug monitoring required for rheumatology drugs

Answer 172

Methotrexate FBC, LFT, U&E The Committee on Safety of Medicines recommend 'FBC and renal and LFTs before starting treatment and repeated weekly until therapy stabilised, thereafter patients should be monitored every 2-3 months' Azathioprine FBC, LFT FBC, LFT before treatment FBC weekly for the first 4 weeks FBC, LFT every 3 months

Question 173

drug monitoring required for neuropsych drugs

Answer 173

Lithium Lithium level, TFT, U&E TFT, U&E prior to treatment Lithium levels weekly until stabilised then every 3 months TFT, U&E every 6 months Sodium valproate LFT LFT, FBC before treatment LFT 'periodically' during first 6 months

Question 174

drug monitoring required for endocrine drugs

Answer 174

Glitazones LFT LFT before treatment LFT 'regularly' during treatment

Question 175

sensitivity specificity PPV NPV - explain

Answer 175

Sensitivity TP / (TP + FN ) Proportion of patients with the condition who have a positive test result Specificity TN / (TN + FP) Proportion of patients without the condition who have a negative test result Positive predictive value TP / (TP + FP) The chance that the patient has the condition if the diagnostic test is positive Negative predictive value TN / (TN + FN) The chance that the patient does not have the condition if the diagnostic test is negative

Question 176

when do you give activated charcoal

Answer 176

within the first hour of ingestion or a little longer in modified release drug overdose e.g. diltiazem.

Question 177

if worried about a poisoning case, where do you refer to?

Answer 177

toxbase run by NPIS - national poisons information service. if you don't know what to do, look it up. the password will be written on the desk of most A and E depts in the country.

Question 178

zopiclone?

Answer 178

Zopiclone (brand names Zimovane and Imovane) is a nonbenzodiazepine hypnotic agent used in the treatment of insomnia. It is a cyclopyrrolone, which increases the normal transmission of the neurotransmitter GABA in the central nervous system, as benzodiazepines do, but in a different way. As zopiclone is sedating, it is marketed as a sleeping pill. It works by causing a depression or tranquilization of the central nervous system. After prolonged use, the body can become accustomed to the effects of zopiclone. When the dose is then reduced or the drug is abruptly stopped, withdrawal symptoms may result.

Question 179

dicobalt edetate

Answer 179

Dicobalt edetate is the coordination compound with the approximate formula Co2(EDTA)(H2O)6. Solutions of this solid have been used in Europe as an antidote to cyanide poisoning

Question 180

benzo overdose associated with

Answer 180

ataxia

Question 181

signs of opiate overdose

Answer 181

reduced GCS, resp depression, resp acidosis, pinpoint pupils

Question 182

management of opiate overdose

Answer 182

naloxone 0.4mg IV/IM/IO first dose up to 2mg total up to 4mg total in severe poisoning. effect in 1-2 mins. short effect of 45 mins and half like of 60-90mins. supportive care due to agitation and pain. look after airway. be careful in people with chronic pain as this will put them in a severely painful state. note that buprenorphine is only partially antagonised methadone has a very long duration of action and ODs require admission and monitoring. young junkie - trying to dose to get a GCS of 10 and not die as complete recovery they will 'bounce off the walls' be careful not to confuse with brainstem infarct in the elderly as it can present in a similar way.

Question 183

benzo overdose effects

Answer 183

ataxic, dysarthric, reduced GCS, drowsy/obtunded conscious level common overdose with something else as well. potentiate the effect of other CNS depressants i.e. alcohol and barbituates.

Question 184

management of benzo overdose

Answer 184

normally supportive only,

Question 185

best prognostic marker regarding paracetamol overdose

Answer 185

prothrombin time as a marker of synthetic function i.e. how well it is working

Question 186

paracetamol toxicity due to

Answer 186

NAPQI n acetyl p benzo quinone imine = toxic metabolite normally bound to gluathione unless overwhelmed . glutathione stores reduced in anorexia nervosa due to malnutrition. also in HIV apparently.

Question 187

examination findings in paracetamol overdose

Answer 187

asymptomatic in first 24 hours RUQ pain wirth nausea and vomiting due to heptatic necrosis in 24-72 hrs then acute liver failure with bleeding jaundice etc

Question 188

managing paracetamol overdose

Answer 188

1 - find out how much and over what period. less than 150mg/kg body weight is NORMALLY fine. - blood levels only relevant over four hours. you can wait. give at about 4 hours at latest staggered overdose is over more than 1 hr. if staggered, treat regardless. check prognostic markers BD psych input if intentional. use the nomogram. the dotted line at the end is due to lack of evidence around efficacy. under 1hr since overdose give activated charcoal. start NAC IV. NB NAC has an anaphylactoid reaction e.g. urticaria. slow down the infusion and give some antihistamines and possibly antiemetic. can give NAC orally but awful nausea and vomiting methionine = gives more glutathione. refer to kings college guidelines and refer for transplant if needed.

Question 189

a high INR is a very common presenting medical problem, almost always to do with warfarin.

Answer 189

1 - prothrombin complex concentrate (octaplex) 50 units/kg up to 3000 units (contains it k dependent clotting factors. authorised by haematology. if not available then FFP 15mls/lkg 2 - stop warfarin - half life is 20-60 hrs, max effect 48hrs post dose. lasts 5 days. 3 - vitamin k PO/IV - effective but takes longer to work. IV takes 24 hrs to reverse warfarin effect. 0.5-1mg for partial reverse 10mg for complete. causes temporary resistance to warfarin. 4 - cryoprecipitate - contains clotting factors 8 and 13 vWF and fibrinogen. used for haemophilia and vWD and hypo fibrinogen states e.g. DIC, post massive infusion resuscitate if need be. give blood if bleeding.

Question 190

what is cryoprecipitate used for

Answer 190

to replace fibrinogen

Question 191

is vitamin K a quick antidote to warfarin

Answer 191

no, takes hours.

Question 192

what antibiotic do you not want to give to someone on warfarin

Answer 192

macrolides.

Question 193

imipramine

Answer 193

a TCA.

Question 194

type of reaction to salicylate overdose

Answer 194

initially alkalotic due to resp centre activation, then acidotic as the salicylate is metabolised to an acid and uncoupling of oxidative phosphorylation to make a metabolic acidosis. also disturbatnce of carbohydrate metabolism. also TINNITUS - pathonemonic. tinitus , vertigo, deafness, hyperventilation, diaphoresis, vomiting (may be blood), coma and convulsions.

Question 195

yellow vision due to what overdose

Answer 195

digoxin overdose.

Question 196

management of salicylate OD

Answer 196

dependent o levels of salicylate less than 500mg/l then I've saline to increase clearance. 500-750 - iv barcarbonate to increase clearance in urine many times even high = haemofiltration.

Question 197

use of IV donepezil

Answer 197

centrally acting reversible acetylcholinesterase inhibitor. Currently, no definitive proof shows the use of donepezil or other similar agents alters the course or progression of Alzheimer's disease (AD). However, 6 to 12-month controlled studies have shown modest benefits in cognition and/or behavior.[3] The UK National Institute for Clinical Excellence (NICE) recommends donepezil as an option in the management of mild to moderate Alzheimer's disease.[4] The person should; however, be reviewed frequently and if there is no significant benefit it should be stopped.

Question 198

use of IV sodium dantrolene

Answer 198

Dantrolene sodium is a postsynaptic muscle relaxant that lessens excitation-contraction coupling in muscle cells. It achieves this by inhibiting Ca2+ ions release from sarcoplasmic reticulum stores by antagonizing ryanodine receptors.[1] It is the primary drug used for the treatment and prevention of malignant hyperthermia, a rare, life-threatening disorder triggered by general anesthesia. It is also used in the management of neuroleptic malignant syndrome, muscle spasticity (e.g. after strokes, in paraplegia, cerebral palsy, or patients with multiple sclerosis), serotonin syndrome, and 2,4-dinitrophenol poisoning.

Question 199

use of IV flumazenil

Answer 199

Flumazenil is a GABAA receptor antagonist primarily available by injection only, and the only GABAA receptor antagonist on the market today. Flumazenil went off patent in 2008 so at present generic formulations of this drug are available. Intravenous flumazenil is primarily used to treat benzodiazepine overdoses and to help reverse anesthesia.

Question 200

TCA overdose presentaiton

Answer 200

antimuscarininc - tachy, hot dry skin, dry mouth, dilated pupils, urinary retention CNS - siezures, resp dep, ataxia, nystagmus, coa cardiac sodium K blockade. prolonged PR, QRS, vent arrhytmias, hypotension serotonin syndrome metabolic acidosis

Question 201

TCA overdose Rx

Answer 201

supportive QRS prolongation/acidosis = sodium bicarbonate, use high conc to make slightly alkalotic. agitation = diazepam

Question 202

what is serotonin syndrome

Answer 202

altered mental status - agitation, confusion delirium, hallucination and coma neuromuscular hyperactivity - shivering, tremor, teeth grinding, myoclonus and hyperreflexia autonomic instability -tachy, fever, hyper/hypotension these 3 above are each present in about 50% severe cases - seizures, hyperthermia, rhabdomyalisis Rx supportive agitation = diazepam hyperthermia - external cooling, dantrolene to relax smooth muscle. rhabdo - Iv sodium bicarbonate to alkalise the urine and increase excretion, haemofiltration chlorpromazine/cyproheptadine - 5ht2a anatagonist of some use

Question 203

what is a raised anion gap acidosis

Answer 203

where acid is added into the system. (Na + K) - (Cl +HCO3) normal = 7-17 causes of raised anion gap acidosis - lactic acidosis - renal failure - ketoacidosis - methanol/ethylene glycol/ formic acid - salicylate poisoning - paracetamol poisoning (lactate) - also iron and isoniazid

Question 204

ethylene overdose pattern and management

Answer 204

= antifreeze/brake fluid brief period looking drunk then metabolic acidosis and the symptoms evolve over 72 hours early - nausea, vomit, seizure, nystagmus, aataxia, ophthalmoplegia, papilloedema, hypotonia, myoclonic jerks, CN palsies 12 - 24 hrs - tachy, hypertension, pulmonary oedema/CCF 24-72 hrs - flank pain, ATN, calcium oxalate crystalluria, hypo K/MG Mx - supportive ethanol/fomepizole - both compete for ETOH dehydrogenase and prevent breakdown of EG into toxic metabolites. - haemodialysis.

Question 205

what is miosis

Answer 205

Miosis (or myosis, from Ancient Greek μύειν, mūein, "to close the eyes") is a term with various definitions, which generally include constriction of the pupil. The opposite condition, mydriasis, is the dilation of the pupil. Anisocoria is the condition of one pupil being more dilated than the other.

Question 206

what is intralipid

Answer 206

a fat emulsion used in TPN, used in the treatment of local anaesthetic overdose.

Question 207

treatment of cocaine overdose

Answer 207

clinically - euphoria - restless, anxiety, paranoia, bruxism - pyretic and diaphoretic, CV effects predominate. - key harms = profound hypertension, version so MI and stroke, aortic dissection, rhabdo - Mx - cool and calm them - iv benzos for cv effects and psych. if concerned re MI use aspirin and clopidogrel, transfer for GTN PCI. - control BP with IV GTN - do not give beta blockers as it leads to effective unopposed alpha version like in phaeochromo.

Question 208

what happens in SIADH

Answer 208

The syndrome of inappropriate antidiuretic hormone secretion (SIADH) involves the excessive secretion of antidiuretic hormone (ADH) from the posterior pituitary gland or another source. ADH controls water reabsorption by the kidneys nephrons, causing the retention of water but not solute. Therefore ADH causes dilution of the blood which decreases the concentrations of solutes such as sodium

Question 209

What causes SIADH?

Answer 209

Brain damage – stroke, subarachnoid haemorrhage, subdural haemorrhage, meningitis/encephalitis/abscess Malignancy – Small-cell lung cancer, also pancreas and prostate Drugs – Carbamazepine, SSRI’s, Amitriptyline, Morphine, sulphylureas Infective – tb, Pneumonia, Lung abscess, Brain abscess Hypothyroidism

Question 210

Signs & Symptoms of SIADH

Answer 210

Symptoms¹ Symptoms vary greatly depending on the timescale of the development of hyponatraemia Therefore mild hyponatraemia may cause significant symptoms if the drop in sodium is acute whereas chronically hyponatraemic patients may have very low serum sodium concentrations and yet be completely asymptomatic. This is thought to be due to cerebral adaptation, where brain cells can adapt their metabolism to cope with abnormal sodium levels, but this can only occur if the change in sodium concentration is gradual. Mild – Nausea / Vomiting / Headache / Anorexia / Lethargy Moderate – Muscle cramps / Weakness / Confusion / Ataxia Severe – Drowsiness / Seizures / Coma Signs¹ These also vary a great deal depending on the rate of serum sodium concentration change Decreased GCS Cognitive impairment (short term memory loss, disorientation, confusion) Focal or generalised seizures Brain stem herniation – severe acute hyponatraemia – coma, respiratory arrest Hypervolaemia –pulmonary oedema, peripheral oedema, raised JVP, Ascites

Question 211

dx and Rx of SIADH

Answer 211

The following features need to be present for a diagnosis of SIADH:³ Hyponatraemia LowPlasma Osmolality Inappropriately elevated urine osmolality (>plasma osmolality) Urine [Na+] >40 mmol/L with normal salt intake Euvolaemia Normal Thyroid & Adrenal Function you need to target your management strategy at the underlying cause for long term correction of sodium metabolism. Management: - correction must be done slowly to avoid precipitating central pontine myelinolysis - fluid restriction - demeclocycline: reduces the responsiveness of the collecting tubule cells to ADH - ADH (vasopressin) receptor antagonists have been developed Fluid restriction This is a common management strategy for increasing serum sodium concentrations, at least temporarily, whilst the underlying cause is sought and treated. Usually the fluid restriction is between 1-1.5 litres per day. It’s largely dependent on patients co-operating with the treatment plan, which some patients can struggle with. Replacing Sodium Another general management strategy for treating hyponatraemia is to replace sodium by giving normal saline 0.9% as a slow infusion. This has to be done with great care, as if the sodium concentration is corrected too rapidly it can result in the devastating complication known as Central Pontine Myelinolysis. This is characterised by permanent damage to the myeline sheath in the brain stem, causing acute paralysis, dysphagia, dysarthria, diplopia and loss of consciousness. As a result, this treatment strategy has to be done with extreme caution, with the recommendation of not correcting serum sodium levels more than 10 mmol/L/24h. Demeclocycline This drug is not first line and only used when fluid restriction alone fails to resolve hyponatraemia. Demeclocycline is a tetracycline antibiotic that reduces the sensitivity of the ADH receptors on the distal tubules of the kidneys. As a result this partially blocks the effects of ADH on the kidneys, essentially creating a partial nephrogenic diabetes insipidus. Vaptans Vaptans are a new class or drugs known as vasopressin receptor antagonists Tolvaptan is a V2 selective vasopressin receptor antagonist that is sometimes used to treat resistant hyponatraemia in SIADH, Heart Failure & Liver Cirrhosis It selectively blocks the effects of ADH (vasopressin) on the kidneys This drug is for specialist use only, given it’s price & the potential for side effects such as liver injury & excessive thirst.

Question 212

use of benzos in cocaine overdose

Answer 212

to cause venodilation

Question 213

CCB OD

Answer 213

profound hypotension give IV calcium, correct glucose.

Question 214

causes of serotonin syndrome

Answer 214

more likely if exposed to 2 or more drugs that increase serotonin 1 - inhabit of breakdown - MAOI - linezolid 2 - inhibition of reuptake - SSRIs - TCAs - synthetic opioids (tramadol, methadone, fentanyl) - cocaine - st johns wort 3 - increase in release - aphetamines - MDMA 4 - receptor agonism - sumatriptan - lithium - LSD

Question 215

MDMA issues and management

Answer 215

``` clinically - picture of catecholamine surge. hyperpyrexia, diaphoresis, hypertensive, techy, mydriasis, cerebral oedema, siezures - comoplicating issues: - dehydration and AKI - hyponatraemia due to sweat and water consumption - rhabdo and DIC - acute hepatitis - MI and CVA ``` Mx - - supportive - cooling and antipyretics, potentially IV dantrolene to relax muscles - benzos for siezures - careful fluid and Na management

Question 216

OD antidotes to - beta blockers

Answer 216

glucagon

Question 217

OD antidotes to - digoxin

Answer 217

digibind

Question 218

OD antidotes to - carbon monoxide

Answer 218

hyperbaric oxygen

Question 219

OD antidotes to - iron

Answer 219

desferrioxamine

Question 220

OD antidotes to - lead

Answer 220

sodium calcium edetate

Question 221

OD antidotes to - organophosphates

Answer 221

atropine/ pralidoxime

Question 222

OD antidotes to - valproate

Answer 222

l-carnitine

Question 223

OD antidotes to - cyanide

Answer 223

dicobalt edetate

Question 224

OD antidotes to - arsenic

Answer 224

dimercaprol

Question 225

what are ticagrelor and prasugrel?

Answer 225

spelling? antiplatelet clopid and pras are irriversible ticagrel is reversible within about 24hours

Question 226

what is the GRACE score

Answer 226

The Global Registry of Acute Coronary Events (GRACE) risk score has been developed for the assessment of the risk of death among patients with acute coronary syndrome. There is a GRACE risk score for the estimation of in-hospital mortality and another for mortality in the period from the time of hospital discharge up to 6 months. tells us how worried we should be and thus the intervention needed. highest is angioplasty.

Question 227

gold standard myo stresstest

Answer 227

myocardial perfusion scan

Question 228

what is ezetimibe

Answer 228

Ezetimibe inhibits the absorption of cholesterol from the small intestine and decreases the amount of cholesterol normally available to liver cells, leading them to absorb more from circulation and thus lowering levels of circulating cholesterol. The exact mechanism is not known, but it appears that ezetimibe blocks the critical mediator of cholesterol absorption, the Niemann-Pick C1-like 1 (NPC1L1) protein on the gastrointestinal tract epithelial cells as well as in hepatocytes; blocks aminopeptidase N, and interrupts a Caveolin 1-Annexin A2 complex involved in traficking cholesterol.