Therapeutics Flashcards
The “5 R’s” of error prevention
- Right patient
- Right time
- Right drug
- Right dose
- Right route
How to take a thorough drug history
WIPE
Go through each drug
=> check box if possible
=> check why and how often they take it
Check for any additional drugs => e.g. inhalers/creams/sprays/drops – people don’t always consider these! => Any HRT and oral contraception? => any OTC drugs? => any herbal medications?
CHECK FOR ALLERGIES
Ask for consent to access care summary records
Type A drug reaction
= augmented response
generally dose-related and usually managed by dose-adjustment
Potential ADRs/side effects of the GI system
Inhibition of saliva Oesophageal erosion Ulcerogenic effects Diarrhoea/infections Constipation Hepatotoxicity
Potential ADRs/side effects of the respiratory system
Bronchospasm
Fibrosis
Anaphylaxis
Potential ADRs/side effects of the CV system
Cardiac arrythmias (e.g. Q-T prolongation) Cardiotoxicity CHF Postural hypotension Hypertension
Potential haematological ADRs/side effects
Neutropenia Thrombocytopenia Bleeding Myelosuppression Aplastic anaemia
Which drug has a risk of causing aplastic anaemia when given orally?
Chloramphenicol
Potential renal ADRs/side effects
Renotoxicity
Fluid retention
Hypo/hyperkalaemia
Which drugs typically cause hypokalaemia?
thiazide / loop diuretics
Which drugs typically cause hyperkalaemia?
ACEis
Potential ADRs/side effects on CNS
Sedation Parkinsonism Depression Addiction Nausea
Potential skin ADRs/side effects
Urticaria
Erythematous eruptions
Toxic Epidermal Necrolysis
Stevens-Johnson Syndrome
Stevens-Johnson Syndrome
severe skin reaction
fever, rash, blisters – can involve mucous membranes too
can be triggered by drugs - e.g. carbamazepine and phenytoin
Patients can have genetic predisposition towards this condition - involving a HLA allele
Toxic Epidermal Necrolysis
severe skin reaction – rare but often fatal
early symptoms are flu-like symptoms. A few days later the skin begins to blister and peel, forming painful raw areas
complications include dehydration, sepsis, pneumonia and multiple organ failure
Risk of TEN with: • antibiotics – sulphonamides, beta-lactams • NSAIDs/corticosteroids • anticonvulsants • anti-retroviral drugs
Penicillin Allergy
in some patients penicillins couple to proteins, forming immunogens and causing a hypersensitivity reaction
Penicillin allergy is a class effect – allergy to one penicillin is allergy to all penicillins
What is important to consider for a patient taking statins?
Any myopathy can rarely progress to rhabdomyolysis, which may result in renal damage.
Mechanisms of drug interaction
Drug absorption altered pH CYP inhibition CYP induction Renal elimination Fluid and electrolyte interactions Pharmacological interactions
What are some important interactions to consider with warfarin?
with NSAIDs - increased risk of bleeding
with antibiotics (esp clarithro/erythromycin) - increased risk of bleeding
What are some important interactions to consider with NSAIDs?
NSAIDs and warfarin - bleeding
NSAIDs and methotrexate - methotrexate toxicity
What are some important interactions to consider with ACEis?
Use with potassium and potassium-sparing diuretics can lead to hyperkalaemia.
What are some important interactions to consider with digoxin?
Use with amiodarone/verapamil can lead to digoxin toxicity
What are some important interactions to consider with oral contraceptives?
Any inducing agent can cause failure of therapy and unwanted pregnancy
What are important interactions to consider with statins?
Macrolides - risk of myopathy
Roughly what percentage of drugs are renally excreted?
What is the significance of this?
~25%
Renal impairment may reduce elimination of these drugs, leading to accumulation/toxicity
What are the two measurements of renal function
Creatinine Clearance (CrCl) estimated GFR (eGFR)
When is eGFR a suitable measurement of renal function?
For most adult patients of normal build.
When should CrCl be used to measure renal function?
DOACs
Patients taking nephrotoxic drugs (e.g. vancomycin, amphotericin B).
Elderly patients (>75 years)
Patients of extreme muscle mass (BMI <18 or >40)
Patients taking medicines which are largely renally excreted and have a narrow therapeutic window (e.g. digoxin)
Which drugs can cross the placenta?
Almost all drugs (except heparin)
Managing epilepsy in pregnancy
Continuation of treatment is preferable – need counselling on risks.
Planned discontinuation of treatment.
Use carbamazepine, with high-dose folic acid supplements to reduce changes of NTDs.
Lamotrigine used first-line in generalised tonic-clonic seizures to avoid teratogenic effects
Anti-epileptic drugs in women of child-bearing age
Many are teratogenic - e.g. phenytoin, Phenobarbital, Valproate.
Phenytoin, carbamazepine, phenobarbital are enzyme inducers and can cause failure of the OCP.
Anti-coagulation in pregnancy
Warfarin is teratogenic - altered bone growth, optic atrophy, mental retardation
Avoid warfarin in trimester 1 (teratogenicity) and 3 (bleeding complications).
Favour LMWHs (e.g. heparin) if anticoagulation required
What should be considered when prescribing in hepatic impairment?
Hepatic clearance Protein binding Sodium retention Effects on coagulation Gastric effects CNS effects Sedation
Dose in 100 % solution
1g per ml
Dose in 10 % solution
100 mg per ml
Dose in 1 % solution
10 mg per ml
Dose in 0.1% solution
1 mg per ml
Dose in 1:1000 Adrenaline
1 mg/ml
Dose in 1:10,000 Adrenaline
100 mcg/ml
Which drugs are prescribed in units?
Insulin
Heparin
Streptokinase
Vasopressin
What are the general goals in treatment of hypertension?
reduction in blood pressure and when this involves drug treatment, this should be with as few side effects as possible
Aim is to • Reduce cardiovascular damage. • Preserve of renal function. • Limit or reverse LVH. • Prevent IHD. • Reduce mortality due to stroke and MIs
What are the NICE treatment targets for treating hypertension?
SBP < 140mmHg (<130mmHg in diabetes)
DBP < 90mmHg (<80mmHg in diabetes).
What is the initial step in treating hypertension?
Lifestyle changes play a central and primary role:
- Alcohol consumption should be reduced
- Weight reduction
- Reduce excess caffeine
- Reducing fat and salt intake, increasing fruit and oily fish in the diet (e.g. Mediterranean diet).
- Increasing exercise
- Smoking cessation
Why is reducing alcohol consumption important in hypertension?
Alcohol increases BP in a significant proportion of patients
How is a diagnosis of hypertension made?
After implementing lifestyle changes, 14 ambulatory measurements are required to confirm hypertension
Criteria for “Pre-hypertensive”
> 120 / >80
Stage 1 Hypertension
> 140 / >90
When is stage 1 hypertension treated?
Treat if <80 years old and one of: • End organ damage • Diabetes • CV disease • High CV risk (>20% in 10 years)
If <40 – refer for 2o hypertension referral
Stage 2 hypertension
> 160 / >100
When should stage 2 hypertension be treated?
All patients
Stage 3 hypertension
> 180 / >120
When should stage 3 hypertension be treated?
All patients
Medical emergency - same day referral!
When is renin released by the kidney?
In response to:
- Decreased renal perfusion pressure
- Sympathetic nerve stimulation (via activation of beta1-adrenoceptors).
- Decreased levels of NaCl
What does renin do?
renin acts on angiotensinogen by cleaving it to form a smaller peptide – angiotensin I.
ACE enzyme then converts AI to AII.
What does angiotensin II do?
Causes potent vasoconstriction
Potentiates release of aldosterone (sodium + water retention)
How do ACEis reduce BP?
prevent the conversion of AI to AII, causing reduced BP via:
Reduced vasoconstriction
Reduced synthesis of aldosterone
Increased levels of bradykinin – a vasodilator
Adverse effects of ACEis
Dry cough in ~10% of patients – due to bradykinin.
May cause hyperkalaemia
=> monitor K+ before and during treatment.
Angioedema – swelling of the eyelids/lips; medical emergency.
=> Increased incidence in black patients.
When should ACEis be avoided and why?
AVOID in renovascular disease.
=> Reduction in perfusion of the kidneys causes renin-dependent hypertension to maintain perfusion via RAAS.
=> ACEis reducing BP can lead to renal underperfusion (kidney damage) and severe hypotension.
AVOID/lower dose in poor renal function
AVOID in pregnancy
In which patients are an ACEi a good idea?
diabetic patients - to prevent diabetic nephropathy
How do AT1 Receptor Antagonists (ATRAs/ARBs) act?
block the action of AII at the AT1 receptor.
These agents have similar consequences as ACEIs but do not give rise to a cough due to no effect on levels of bradykinin
How do calcium channel Inhibitors/Blockers (CCBs) act?
How do dihydropyridines and rate-limiting CCBs differ?
vasodilators, primarily by inhibiting voltage operated Ca2+ channels on vascular smooth muscle, leading to vasodilatation and thereby a reduction in blood pressure
=> The dihydropyridines (e.g. amlodipine) act mainly on vascular smooth muscle.
=> Rate-limiting CCBs (e.g. verapamil) have greater effects on cardiac tissue (particularly the AV node) and will slow the heart down
When are rate-limiting CCBs a better choice?
The body responds to low BP with reflex tachycardia.
RL CCBs will prevent reflex tachycardia
This is a better option in IHD
Which diuretics are typically used in treating hypertension?
Thiazide-Like diuretics - 2nd line treatment
Thiazides also but not so much anymore due to diabetogenic nature
How do thiazide-like diuretics act?
Inhibit Na+/Cl- transport in distal convoluted tubule
=> Promotes sodium (and water) loss and thereby reduces circulating volume
also cause vasodilatation
What is important to remember with thiazide-like diuretics?
They are INEFFECTIVE in moderate renal impairment
=> need to measure eGFR before and during use.
They require secretion in the PCT in order to act in the DCT.
Important side effects of thiazide/thiazide-like diuretics
Hypokalaemia
Postural hypotension
Impaired glucose control – can cause T2DM (particularly Bendroflumethiazide).
Do not use in gout – thiazides compete with uric acid for excretion and worsen gout.
Alpha-blockers in treating hypertension
Drugs of last choice.
competitive receptor antagonists of alpha1-adrenoceptors
Poorly tolerated - widespread side effects due to “wiping out” the SNS.
How do beta-blockers work to lower BP?
Mechanism of action is unclear - thought to be:
=> Reduction in the sympathetic drive to the heart (reducing cardiac output).
=> Reduction in sympathetically-evoked renin release from the kidneys.
When are beta-blockers contraindicated/avoided?
In asthma (caution in COPD) => Potential to block bronchial beta2 receptors and cause bronchospasm
In heart block
key adverse effects of CCBs
Peripheral oedema
Constipation
key adverse effects of thiazide diuretics
Urination Diabetogenic Hypokalaemia Impotence? Postural hypotension
A/C/D steps for treating hypertension - Patient <55 years and non-black
- ACEi/ATRA
- add CCB or diuretic
- ACEi/ATRA + CCB + Diuretic
- Add spironolactone, or beta-blocker, or alpha blocker
A/C/D steps for treating hypertension - Patient >55 years or black
- CCB
- add diuretic or ACEi/ATRA
- CCB + diuretic + ACEi/ATRA
- Add spironolactone, or beta-blocker, or alpha blocker
A/C/D steps for treating hypertension - patient with hypertension and T2DM
- ACEi/ATRA
- add CCB or diuretic
- ACEi/ATRA + CCB + Diuretic
- Add spironolactone, or beta-blocker, or alpha blocker
Why is the A/C/D pathway different for black patients?
People of Afro-Caribbean ethnicity tend to have hypertension which is less renin-dependent, so a CCB is used first line over an ACEi
Statins in hypertension?
Studies show that simvastatin reduces CV risk, even with “normal” cholesterol.
=> statins should be considered for all high risk patients
Hypercholesterolaemia
elevated plasma cholesterol, a risk factor for atherosclerosis
= total cholesterol >6.5 mmol/L
Which drugs can adversely affect lipid profile?
- Beta-blockers
- Thiazides
- Corticosteroids
- Retinoids
- Oral contraceptives
- Anti-HIV drugs.
Lipoproteins
central core of hydrophobic lipid, encased in phospholipid, cholesterol and apolipoproteins
HDL
= High density lipoprotein (“good cholesterol”)
LDL
= Low density lipoprotein (“bad cholesterol”)
What is the ideal total cholesterol?
< 5.0 mmol/L
What is the significant issue with raised cholesterol?
High LDL and/or low HDL
What can be a clinical sign of hypercholesterolaemia/dyslipidaemia?
Xanthomata and xanthelasma
what is a QRISK score?
How is it calculated?
assesses the risk of a patient’s chance of CV event in the next 10 years
uses the patient’s:
- Age, ethnicity, BMI, smoking status, diabetes
- Cholesterol:HDL ratio
- Systolic BP
process of atherogenesis
- Damage to endothelium – smoking, hypertension, turbulent flow, diabetes.
- Inflammation – monocytes/macrophages infiltrate and accumulate, generate reactive oxygen species which can cause oxidative damage.
=> LDL binds to LDL-receptors, oxidised LDL can damage the receptor and prevent cholesterol uptake. - Fatty Streaks form – foam cells beneath the endothelium, rich in cholesterol as it deposits beneath the endothelium (~20/30 years).
- Plaque formation – calcified, cholesterol rich plaque beneath the endothelium (~40 years).
=> Begins to cause narrowing of the artery.
How much does a coronary artery need to be narrowed to get symptoms of angina?
when the artery is narrowed by >70%
what can happen if an atheromatous plaque becomes unstable and ruptures?
Myocardial infarction - in the coronary circulation
Stroke - in the cerebral circulation
Management of dyslipidaemia
Modify risk factors:
- Smoking cessation
- Treat HTN / DM
- Exercise
- Drug-induced?
Low-cholesterol diet (but only ~25-30% of cholesterol comes from the diet).
Cholesterol-lowering drugs.
HMG-coenzyme A reductase
enzyme which catalyses the 1st committed step in cholesterol synthesis.
Many steps down the line, cholesterol is formed.
Statins
HMG-CoA Reductase inhibitors, hepatoselective
inhibit cholesterol synthesis, thereby reducing plasma cholesterol
Reduction in hepatic cholesterol synthesis leads to an upregulation of hepatic LDL receptors, promoting LDL uptake from the plasma (i.e. a 2nd cholesterol lowering effect)
effects of statins
Reduction in LDL cholesterol (increased HDL)
Reduction in mortality
Improve endothelial function
Reduced CV risk in all high-risk CV patients (even with low/normal cholesterols).
NICE Guidance for statins
Primary Prevention – patients with >10% risk of CVD, asses via QRISK3.
=> 20mg atorvastatin (low intensity)
Secondary Prevention – patients with CVD
=> 80mg atorvastatin (high intensity)
when should statins be taken?
Should be taken at night to offset the nocturnal increase in cholesterol synthesis (except atorvastatin).
adverse effects of statins
Muscle pain
=> Very rarely leading to rhabdomyolysis (Simvastatin > atorvastatin)
Increased risk of diabetes but expert view is that this is outweighed by CV benefits.
Nocebo effect
Simvastatin - interactions
Contraindicated with macrolides
=> CYP450 inhibitors cause raise in plasma concentration of statin.
=> Increased risk of muscle damage
Interaction with amlodipine, verapamil, diltiazem
Interacts with psoralens (grapefruit juice) which inhibit CYP450
Cholesterol-lowering drugs - Ezetemibe
prevents cholesterol absorption from the GI tract.
For use on top of a statin, if the statin isn’t fully controlling cholesterol levels
Cholesterol-lowering drugs - Alirocumab
monoclonal antibody inhibiting PCSK9.
=> PCSK9 binds to LDL receptor and leads to its degradation.
=> Alirocumab increases the number of hepatic LDL receptors and lowers LDL.
Used in addition to max. dose statins.
SC administration every 2 weeks
Cholesterol-lowering drugs - fibrates
activate PPAR-alpha, alters lipoprotein metabolism
Used with statins when triglycerides and cholesterol are raised.
Reduce IHD but not mortality, so not routinely recommended.
Adverse effects – rhabdomyolysis
What antiplatelet drugs are there?
Low-dose aspirin
Dipyridamole
Clopidogrel
Abciximab
How does aspirin have anti-platelet activity?
an irreversible inhibitor of cyclo-oxygenase
Prevents production of prostaglandins, thromboxane (TXA2) and prostacyclin (PGI2).
HOWEVER, endothelial cells have a nucleus and can produce more mRNA for COX, and therefore allow the production of PGI2 to occur within a couple of hours.
Platelets lack a nucleus so cannot produce more COX and therefore aspirin will inhibit TXA2 production for the platelet lifespan of 7 days.
Use of low-dose aspirin
Used to prevent MI in patients who have previously had an MI
=> Recommended for secondary but not primary prevention.
Reduces incidence of stroke
Dipyridamole
Phosphodiesterase inhibitor – prevents the breakdown of cAMP and cGMP.
Raised levels of cAMP and cGMP have inhibitory effects on platelet aggregation. Also inhibits adenosine uptake.
Used to prevent thrombosis.
Used in conjunction with aspirin – evidence of synergy.
Clopidogrel
ADP from aggregating platelets leads to expression of glycoprotein IIb/IIIa on the surface of the platelets. GP IIb/IIIa binds fibrinogen (and vWF) which leads to cross-linking of platelets.
Clopidogrel inhibits the ADP-induced expression of glycoproteins.
For patients who cannot take aspirin, clopidogrel is similarly effective/safe.
=> But may be used alongside aspirin for greater antiplatelet effects
Abciximab
Monoclonal antibody against GP IIb/IIIa.
Given to patients undergoing angioplasty to prevent thrombosis.
Only use once
Fibrinolysis
= A natural endogenous process in the body, activated in parallel with the clotting system.
Plasmin digests the fibrin of the clot (and also some of the clotting factors).
thrombolytics/fibrinolytics/“clot busters”
Drugs which interact with fibrinolysis
e.g. alteplase
activate the conversion of plasminogen to plasmin to digest the fibrin of a clot
the earlier these drugs are given and reperfusion is achieved, the more effective they are
what is the primary use of thrombolytic drugs?
thromboembolic stroke
can also be used for PE
(was previously the primary treatment for MI, but now angioplasty is the gold-standard)
What are the goals of treatment in chronic heart failure?
- Identify / treat any cause (e.g. valvular disease, IHD)
- Reduce cardiac workload
- Increase cardiac output
- Counteract neurohormonal maladaptation
- Relieve symptoms
- Prolong quality life – reduce hospitalisation.
Pharmacological management of CHF
Pharmacological management is stage-dependent
All patients with LV systolic dysfunction should receive an ACE inhibitor and a Beta-blocker initially
All patients with oedema should receive a diuretic
ACEIs in chronic heart failure
now 1st line as have been shown to prolong life
Reduce arterial and venous vasoconstriction (reduce after- and pre-load)
Reduce salt/water retention, hence reduce circulating volume
Inhibits RAAS, prevents cardiac remodelling?
ATRAs in chronic heart failure
if ACEI is not tolerated (cough)
or in addition to ACEI as add on therapy.
beta-blockers in chronic heart failure
first line with ACEis for stable, moderate heart failure
Beta1 selective agents only (e.g. bisoprolol)
At a low dose – reduce disease progression, symptoms and mortality
=> Reduce sympathetic stimulation, heart rate and O2 consumption
=> Antiarrhythmic – will control rate in atrial fibrillation
=> Oppose the neurohormonal activation which leads to myocyte dysfunction.
What should you do if a patient is on atenolol but is then diagnosed with CHF?
swap atenolol to bisprolol
what is important counselling for prescribing a beta blocker for a patient with CHF
Symptoms may get worse at first, before improving in the long-term
Diuretics in chronic heart failure
Very important for symptomatic relief.
Usually loop or sometimes thiazide diuretics.
- Reduce circulating volume.
- Reduces preload on the heart.
- Relieve pulmonary and peripheral oedema.
Actions of digoxin
- +ve inotrope (increases the force of contraction)
* Also impairs AV conduction and increases vagal activity - causing heart block and bradycardia
Dose of digoxin
Dose is titrated up to reach a HR >60
Digoxin toxicity
= major problem due to the narrow therapeutic window.
=> Anorexia, nausea, visual disturbances, diarrhoea
Digoxin in heart failure
usually reserved for failure with AF or when ACEI + diuretic fails
What should be monitored in CHF patients?
Renal function
Potassium levels
IHD - how do nitrates help?
e.g. GTN
Main action is to cause venodilatation via release of NO
=> leads to a decrease in preload and a reduction in cardiac work
Can cause coronary vasodilatation to some extent, however, if the artery is narrowed by stenosis then the impact is limited.
Plays an important role for managing acute attack.
Tolerance to nitrates
Prolonged exposure to nitrates can reduce effectiveness.
Aim is to have a “nitrate free period” (potentially overnight)
IHD - beta blockers
First choice drugs for prevention.
Negative inotropic and chronotropic effects
=> Reducing cardiac work and preventing symptoms.
Coronary flow only occurs during diastole, then by slowing the heart the diastolic period will be increased, as will the time for coronary blood flow.
Anti-arrhythmic effects and reduce the risk of MI.
Why are the anti-arrhythmic effects of beta-blockers useful in IHD?
Ischaemic tissue from IHD is prone to generating arrythmias.
IHD - CCBs
Act by inhibiting voltage operated calcium channels on vascular smooth muscle, reducing contractility.
=> Cause vasodilatation and improve coronary blood flow, thereby preventing symptoms.
Rate-limiting agents are favoured in IHD if the patient has good contractility, as they reduce cardiac work (DHPs tend to cause reflex tachycardia)
What are some rate-limiting CCBs?
Verapamil, diltiazem
What are some non-rate limiting CCBs?
The dihydropyridines - amlodipine, nifedipine
Drug choice in IHD
Stable angina - GTN for relief
For prevention
=> beta blocker +/- nitrate
=> or CCB +/- nitrate (if beta-blocker contraindicated)
If refractory - add:
- CCB (DHP)
- beta-blocker
- Nicorandil
what is a combination of drugs to AVOID when prescribing in IHD?
a beta-blocker and rate-limiting CCB !!!!
Substantial risk of asystole, potentially fatal.
IHD - Nicorandil
= a potassium channel activator
Causes vasodilatation of vascular smooth muscle
IHD - Ivabradine
Inhibits the If channels (pacemaker Na+/K+ currents in the SA node).
Reduces heart rate.
Found to be equally as effective as atenolol, but without the beta-blocker side effects
what are the injectable anticoagulants?
Unfractionated heparin
Low Molecular Weight Heparins (e.g. enoxaparin, tinzaparin)
Why is enoxaparin favoured out of the injectable anticoagulants?
actions are very predictable and it can be prescribed as a fixed dose.
How do the heparins act?
Act by activating antithrombin III (a natural protein in the plasma).
Antithrombin inactivates some clotting factors and thrombin by complexing with the serine proteases of the factors
what are the heparins used for?
- Prevent thrombosis (venous, unstable angina)
- Prevent blood clotting on collection
- Provide anticoagulation whilst warfarin takes effect (takes about 3 days)
A major use if preventing DVT/PE in hospitalised patients
which heparins require anticoagulation monitoring and how?
Unfractionated heparins are monitored via APTT – activated partial thromboplastin time
LMWH do not require coagulation monitoring
what can occur after >5 days of heparins
can cause an immune response that involves the killing of platelets – can lead to thrombocytopaenia.
How does warfarin work?
Vitamin K is an essential for production of prothrombin and Factors VII, IX and X (Vitamin K important for post-ribosomal carboxylation of glutamic acid residues of these proteins).
Warfarin blocks Vitamin K reductase, needed for Vit K to act as a cofactor (Vitamin K Epoxide Reductase Complex, VKORC).
How long does it take for warfarin to take effect and why?
Coagulation factors exist in the circulation for ~3 days, so it takes about 3 days for warfarin to take effect.
what are the indications for warfarin?
to prevent unwanted thrombosis:
- in patients with replaced heart valves
- Atrial Fibrillation
- PE
- DVT
why is warfarin difficult to use?
- Has a narrow therapeutic window
2. Many drug interactions – activity can be potentiated/reduced.
What is Prothrombin Time ?
= the time for coagulation following the addition of thromboplastin.
Prolonged by abnormalities of Factors VII, X, V, II, or I
Prolonged by liver disease (as the liver produces coagulation factors)
Prolonged by warfarin
International Normalised Ratio (INR)
measures normal prothrombin time against the patient’s
normal = ~1
target range varies depending on indication for use
(2.5 for most indications, but 3.5 for mechanical heart valve)
what can over-anticoagulation lead to?
gastric/cerebral bleeding
haemoptysis
blood in faeces/urine
easy bruising
Reversing warfarin
Warfarin can be reversed with vitamin K injections if:
- Patient is bleeding
- Patient has a very high INR (>8)
- Warfarin overdose
counselling for warfarin
Patient must take at the same time every day (6pm)
If they miss a dose, then they should NOT take two doses together and they should inform their doctor at the next blood test
Inform HCPs that they take warfarin - interactions, bleeding, etc.
Females - advised not to become pregnant whilst taking warfarin
Dietary advice
Patients should report any signs of bleeding
when is there a need for anticoagulation in pregnancy and how should this be achieved?
Pregnancy hormones produce a hypercoagulable state in the mother to prevents post-partum haemorrhage.
=> Risk of thrombosis – thrombophilia, decreased venous return due to the gravid uterus and immobility during labour.
Mothers with artificial heart valves…
- Warfarin is teratogenic – altered bone growth, optic atrophy, mental retardation.
- Avoid warfarin in trimester 1 and 3.
- Favour LMWHs
DOACs
Dabigatran – an oral thrombin inhibitor
Apixiban and Rivaroxaban: oral inhibitors of activated factor X
Just as effective as warfarin
Less interactions
Do not require INR monitoring
Less reversible
what is the recommended alcohol intake?
0 – 14 units per week (men and women)
Provided the amount is not drunk in one or two bouts and that there are 2-3 alcohol free days a week
what should be done if a drug is causing liver injury as an adverse reaction?
stop the drug entirely to prevent further damage
what AST:ALT ratio is associated with alcoholic liver disease?
AST:ALT of more than 2:1
Lifestyle changes in managing dyspepsia
Avoidance of causative drugs
Avoidance of causative foods
GORD – propping up bed, removing belts!
What are the goals of treatment in dyspepsia?
Symptomatic relief
Mucosal protection
Eradication of H. pylori (if indicated)
Prevent development of gastric carcinomas
what factors increase acid secretion in a gastric parietal cell?
Histamine via H2 receptors
Gastrin
Acetylcholine via mAChRs on parietal cells
what factors decrease acid secretion in a gastric parietal cell?
Prostaglandins (E2 and I2) via stimulating production of mucous and bicarbonate ions.
Antacids
Raise the pH of the stomach with an acid-base titration
Widely available (OTC)
Provide rapid relief but not cure
what can be an issue with the antacid magnesium hydroxide?
can cause diarrhoea
Alginates
May be combined with antacids, provide rapid relief.
Alginic acid forms a viscous foam when combined with saliva.
The foam floats on the gastric contents forming a raft, which protects the oesophagus during reflux.
Histamine H2 antagonists
Block the H2 receptor on parietal cells, which are coupled via adenylyl cyclase to increase cAMP which activates the proton pump
Reduce gastric secretion, provide symptomatic relief.
Best given at night, when the histamine system is most active
Low doses are available OTC, High doses are available by prescription
PPIs
activated by acidic pH due to their pKa
Act via irreversible inhibition of the proton pump (H+/K+-ATPase).
=> Very effective and inhibit H+ secretion by >90%
What is there a risk of when taking PPIs?
May lead to achlorhydria and increased risk of Campylobacter infection (food poisoning)
Rebound acid hypersecretion
Following cessation of H2RAs or PPIs
Increase in acid release
=> Potentially due to increased expression of proton pumps??
Causes an increase in dyspepsia symptoms
Avoid prolonged usage of these drugs
H. pylori triple therapy
Two from:
- Clarithromycin
- Amoxicillin – avoided in patients with penicillin allergy
- Metronidazole – the only antibiotic that you cannot drink alcohol with.
Plus PPI and/or H2 antagonist.
Triple Therapy will be taken for 1 week, and then the PPI alone
minimising GI damage when taking NSAIDs/steroids
“take with/after food” (probably ineffective but does no harm)
Paracetamol instead?
Prophylaxis with a PPI (H2 antagonists are less or ineffective, except Famotidine)
Give NSAID in combination with misoprostol
=> Stable PGE1 analogue, which acts on prostanoid receptors to inhibit gastric H+ secretion.
What is important to remember when prescribing misoprostol?
Causes uterine contractions – not used in females of child-bearing age because of the risk of abortion.
What is nausea?
= an unpleasant sensation that immediately precedes vomiting
A cold sweat, pallor, salivation, self-absorption, loss of gastric tone, duodenal contractions, and reflux of intestinal contents into the stomach
what is emesis?
= a protective and coordinated involuntary reflex involving powerful sustained contraction of the abdominal, chest wall and diaphragm muscles to increase intra-gastric pressure, and opening of the oesophageal sphincter, glottis and jaws.
what can trigger emesis?
Toxins – bacterial poisons, alcohol, drugs (especially anticancer agents, opioids, digoxin, SSRIs, levodopa, erythromycin, etc.)
Motion sickness
Smells
Migraine
Pregnancy
anti-emetics: H1-receptor Antagonists
e.g. cyclizine
Act on vestibular nuclei
Effective in motion sickness
Can also have anti-muscarinic actions
Cyclizine – used in pregnancy.
anti-emetics: anti-muscarinic agents
e.g. hyoscine.
Effective in motion sickness and irritation of the stomach
Anti-muscarinic side effects – dry mouth, urinary retention, blurred vision, constipation.
anti-emetics: Dopamine-receptor Antagonists
e.g. metoclopramide.
Acts in Chemoreceptor Trigger Zone
has unwanted CNS effects (e.g. drug-induced parkinsonism)
Effective against anticancer drug-induced emesis
anti-emetics: 5-HT3-antagonists
e.g. ondansetron
Blocks 5-HT at 5-HT3- receptors in the gut and CNS.
Particularly effective against anti-cancer drugs.
Post-operative N&V.
anti-emetics: steroids
e.g. dexamethasone
Shown to have some anti-emetic properties
What is the main method of managing diarrhoea?
= Oral Rehydration Therapy (ORT)
A solution of electrolytes to replace the electrolytes lost in diarrhoea
Must be isotonic to work correctly.
Glucose in the solution allows greater transport of Na+ via a symporter, and water follows the Na+.
The role of antibiotics in diarrhoea
Most simple infections are viral, and antibiotics are of little value.
If microbiology identifies a causative bacterium, then appropriate antibiotics may be used.
Probiotics in diarrhoea
May be some benefit in preventing antibiotic-associated diarrhoea and C. diff-associated diarrhoea.
Potentially also infective diarrhoea.
Anti-motility agents in diarrhoea
If symptomatic relief is required, then anti-motility agents are an option.
=> opioids, anti-muscarinics
However, they do not shorten the length of the infection
Antimotility agents: opioids
e.g. Loperamide (Imodium)
Loperamide does not penetrate the BBB and has efficient enterohepatic cycling, so is retained largely in the gut
Act by reducing tone and peristaltic movements of GI muscle by inhibiting the pre-synaptic release of acetylcholine - via activation of µ-opioid receptors
Reduced motility leads to increased transit time
=> promotes water absorption
=> symptomatic relief
Antimotility agents: anti-muscarinics
- Dicycloverine – antimuscarinic agent.
* Tricyclic antidepressants – also constipating as a side effect through antagonism of muscarinic receptors
What is the approach to managing constipation?
Best approach to management is a balanced diet, high in fibre.
If dietary treatment fails, laxatives can be used
Osmotic Laxatives
- e.g. lactulose – disaccharide of galactose and fructose; enters the colon unchanged and is converted by bacteria to lactic and acetic acid (increases osmolality of stool)
- e.g. Macrogols (polyethylene glycol)
The increase in osmolality causes water to be retained, which raises the fluid volume.
Laxatives - magnesium
Has an osmotic effect;
Mg2+ also releases CCK which increases GI motility
Laxatives - Bulking Agents
e.g. ispaghula, methylcellulose.
Increase the bulk in the lower GI tract
stimulant laxatives
Senna extracts – enter colon metabolised to anthracene derivatives, which stimulates GI activity.
Dantron – irritant
Laxatives - Prucalopride
New, highly selective 5-HT4 agonist which increases GI motility
Last choice – used when all other agents have failed
IBS - management
Lactulose or loperamide for symptoms?
Antispasmodic agents - e.g. mebeverine
Amitriptyline (TCA)
=> Low doses widely used + effective (higher doses used for depression, lower doses for neuropathic pain and IBS).
=> provide some pain relief
IBD - 5-Aminosalicylates (5-ASA):
e.g. sulphasalazine, mesalazine (both metabolised to yield 5-ASA)
= the mainstay for ulcerative colitis, use is less clear for Crohn’s.
5-ASA acts by inhibiting leukotriene and prostanoid formation, scavenging free radicals, decreasing neutrophil chemotaxis
What is there a risk of with mesalazine?
Can cause blood disorders by affecting the bone marrow.
Patient should report any sore throats, fevers, easy bruising/bleeding
IBD - corticosteroids
Used to induce remission in IBD.
• Prednisolone
=> glucocorticoid with anti-inflammatory, immunosuppressive actions
=> lots of side effects
• Budesonide
=> poorly absorbed so far less systemic side effects.
=> Specifically for distal ileal, ileocaecal or right sided colonic disease.
IBD - Immunosuppressants
azathioprine
methotrexate (Effective in Crohn’s but not UC)
infliximab
what is there a risk of when taking azathioprine?
Risk of pancreatitis
Risk of myelosuppresion - bruising/bleeding and infections
what is a the basis of pharmacological management of T1DM ?
replace insulin in an attempt to return blood glucose to normal and preventing diabetic complications.
Types of insulin regimens
different regimens suit different individuals’ needs
include:
- Twice daily regimens
- Multiple dosing regimens
- Single daily regimens
Twice daily insulin regimen
= most commonly used
2 daily injections,
one 30 minutes before breakfast and one before the evening meal of short- and longer-acting insulins in combination
two thirds of the insulin given as the morning dose.
Multiple dosing insulin regimen
= “basal-bolus regimen”
a single dose of medium-acting insulin is given at bedtime and doses of short acting insulin are given 30 minutes before each meal.
allows more flexibility with the timing of meals.
Single daily insulin regimen
involve 1 daily injection before breakfast or at bedtime of intermediate-acting insulin, with or without a short-acting insulin
rarely used - generally for patients with T2D who are unable to control their blood glucose with antidiabetic drugs
when is a patient’s insulin requirement increased?
stress, infection, accidental or surgical trauma, puberty (effects of growth hormone) during the latter two trimesters of pregnancy
when is a patient’s insulin requirement reduced?
coeliac disease,
renal or hepatic impairment
endocrine disorders - e.g. untreated Addison’s disease.
Insulin pumps
may be used which allow continuous subcutaneous administration.
=> provide a continuous infusion, which may be increased at mealtimes.
particularly useful in difficult to control diabetes.
IV insulin
reliable route of administration
used in hospital in an acute setting, to hyperglycaemia under control
Subcutaneous insulin administration
what is there a risk of developing with this route?
= most conventional route
uses a disposable syringe, in which the different insulins may be mixed to achieve the desired combination
at a site of repeated injections, there may be LIPOHYPERTROPHY, leading to unpredictable insulin absorption
=> patients should rotate the sites used
T2DM - diet/lifestyle modifications
In mild or initial disease: dietary/lifestyle modification
- reduce the amount of simple carbohydrates in the diet
- limit the intake of mono and disaccharides,
- increase non-starch polysaccharides
- reduce the intake of fat
- low GI foods
- weight loss in obese
- increased exercise
when are anti diabetic drugs started in T2DM?
after 3 months, if lifestyle changes have been implemented but insufficient
anti-diabetic drugs - Sulphonyureas
e.g. glibenclamide, gliclazide, tolbutamide
SUs increase insulin secretion by inhibiting ATP-sensitive potassium (KATP) channels
associated with:
- Weight gain (and increased insulin resistance) so are often avoided in obesity.
- Hypoglycaemia – especially in the elderly, with long-acting agents, or after missing meals.
anti-diabetic drugs - Biguanides
= metformin
Its action is less clear – may activate AMP-kinase
It is the drug of choice for obese patients – does not cause weight gain
Does not cause hypoglycaemia
Should not be used in renal impairment.
anti-diabetic drugs - Glitazones
e.g. Pioglitazone
Activate nuclear PPAR-gamma receptors, which alters gene expression and results in insulin-like effects.
“Insulin sensitisers” which work by enhancing glucose utilization in tissues, and so reduce insulin resistance
Effects include:
=> reduced hepatic glucose output
=> increased glucose transporters (GLUT) in skeletal muscle with increased peripheral glucose utilization
=> Increased fatty acid uptake into adipose cells
anti-diabetic drugs - DPP-4 Inhibitors
Incretins (e.g. Glucagon-like peptide) regulate the endocrine pancreas
Dipeptidyl peptidase-4 inhibitors (e.g. sitagliptin) inhibit the breakdown of incretins and enhance their activity.
Guidelines for T2DM control
3 months of diet control
Inadequate control?
Normal renal function => metformin
Renal impaired => SU/ pioglitazone/DDP-4 inhibitor
Poor control => dual, and then triple therapy
(+ HTN control throughout)
Depression - SSRIs
e.g. citalopram, fluoxetine, paroxetine, sertraline
Selectively inhibit the neuronal reuptake of 5-HT, thus enhancing synaptic concentrations of 5-HT and down-regulating presynaptic 5-HT receptors.
SSRIs are better tolerated than TCAs and are safer in overdose which means that SSRIs are first choice for depression.
Some SSRIs are also licensed for the treatment of anxiety disorders, panic and obsessive-compulsive disorder.
Depression - TCAs mechanism of action
e.g. amitriptyline, nortriptylline
Inhibit the neuronal uptake of noradrenaline and 5-HT, leading to augmented concentrations in the synaptic cleft.
The increase in catecholamines may lead to down-regulation of presynaptic alpha2¬¬-adrenoceptors and 5-HT receptors and postsynaptic beta-adrenoceptors.
Exhibit binding at a range of receptors including muscarinic receptors, histamine, alpha1-adrenoceptors and 5-HT receptors
Problems associated with TCAs
sedating
QT interval prolongation
dangerous in overdose
Antimuscarinic side effects limit tolerability of TCAs. These include:
- dry mouth
- blurred vision
- constipation
- urinary retention
why might sedation caused by TCAs be useful?
can be useful if the patient is also suffering from sleep disturbances
other uses of TCAs, outside of depression
amitryptilline (at a low dose) has some uses in:
- managing neuropathic pain,
- prophylaxis of migraine
- irritable bowel syndrome
in which patients are TCAs not suitable?
Pts with ischaemic heart disease,
Pts aged >70 years
those who are thought to be at high risk of attempting suicide.
Depression - NARIs
Noradrenaline reuptake inhibitors
e.g Reboxetine
- Selectively inhibits noradrenaline reuptake .
- Useful for patients who cannot take TCAs but are resistant to the effects of SSRIs.
Depression - SNRIs
Serotonin-Noradrenaline Reuptake Inhibitors
e.g. Venlafaxine
• Inhibits serotonin and noradrenaline reuptake but fails to bind to additional receptors
=> fewer side-effects (lack of sedative and antimuscarinic side-effects but does cause gastrointestinal side-effects).
• Associated with causing hypertension
Depression - NaSSAs
Noradrenergic and Specific Serotonergic Antidepressants
Mirtazapine
• Exhibits alpha2-adrenocepter antagonist activity, inhibiting negative feedback by these presynaptic receptors and thus producing an increase in noradrenaline and 5-HT transmission.
• Sedation in early treatment but antimuscarinic side-effects are limited.
Depression - SRMs
Serotonin Receptor Modulators
e.g. Nefazodone and trazodone
• Inhibition of serotonin reuptake and the selective inhibition of postsynaptic serotonin receptors.
Depression - MAOIs
Monoamine Oxidase Inhibitors
- inhibit the monoamine oxidases, which increases the concentration of these neurotransmitters
- Most act irreversibly – effects may persist for 2-3 weeks after the cessation of treatment.
- Can interact with food => “Cheese reaction”
- Moclobemide, a selective reversible inhibitor of MAO-A (RIMA), reduces interactions with food since tyramine is metabolised by MAO-B.
Why are MAOIs rarely used now?
MAOIs also prevent the breakdown of the indirectly acting sympathomimetic amine, tyramine (from diet)
=> causes the release of catecholamines and leads to a hypertension.
Tyramine is present in certain foods such as cheese
=> this response is known as the “cheese reaction”.
Management of mild depression
“watchful waiting” – patient is reassessed after 2 weeks
initial treatment with antidepressants not recommended
1st line pharmacological management of depression
SSRI (e.g. fluoxetine) = 1st line
BUT a sedating TCA might be preferred if sleep is impaired (unless risk of suicide)
How long do anti-depressants usually take to work?
~2 weeks
management of depression if not managed by SSRI
If initial treatment fails, swap to an alternative SSRI or another class of antidepressant
how long should antidepressant therapy be continued?
Treatment should be continued for at least 6 months after remission
(2 years if 2 recent depressed episodes)
reduce dose gradually to prevent withdrawal.
“Manic depression” - 1st line management
Lithium remains the first line agent for both acute treatment and prophylaxis of bipolar disorder
Lithium should be avoided in renal impairment.
Narrow therapeutic window – range of interactions and requires therapeutic drug monitoring
“Manic depression” - 2nd line management
Anticonvulsants - e.g. carbamazepine and valproate
=> prophylactic mood stabilisers in bipolar disorder
Neuroleptics (antipsychotics) - e.g. haloperidol and chlorpromazine
=> control psychotic symptoms (particularly during manic phase)
Management of anxiety
Beta-blockers reduce physical symptoms
Benzodiazepines reduce anxiety and aggression, and induce sleep
Why should the treatment period with benzodiazepines be limited?
Issues with tolerance and dependence
=>
Treatment should be limited to 2- 4 weeks
what are the two main systems controlling bronchial calibre (and one lesser system)?
- Parasympathetic ANS
- Sympathetic ANS
(3. Sensory local reflex arc)
Parasympathetic control of bronchial calibre
vagus nerve => release acetylcholine
Acts upon muscarinic M3 ACh receptors in the bronchial smooth muscle
Causes bronchoconstriction and increased mucous secretion.
Sympathetic control of bronchial calibre
Circulating adrenaline acting on beta2-adrenoceptors on bronchial smooth muscle.
Causes bronchodilation and inhibition of mucous secretion.
Sympathetic nerve fibres releasing noradrenaline will also stimulate adrenoceptors
Local reflex arc in the airways
sensory nerves sense stimuli => cause a local reflex arc => release transmitters for local effects on the airways
E.g. a cough reflex in response to dust
Asthma attack - Spasmogens
act rapidly to cause constriction of the airways, leading to bronchospasm = EARLY PHASE
Spasmogens include – histamine, Prostaglandin D2, Leukotrienes (C4 & D4).
Asthma attack - Chemotaxins
released to attract WBCs (especially eosinophils and mononuclear cells) to the airways, causing an inflammatory LATE PHASE response a few hours later.
Chemotaxins include – leukotriene B4, platelet activating factors (PAFs)
How does salbutamol work?
Selective agonist for beta2-adrenoceptors on smooth muscle => causes relaxation and in turn an increase in FEV1.
Given by inhalation; localising the action and providing a rapid effect.
What might prolonged use of salbutamol lead to?
may lead to receptor down-regulation – the beta2-adrenoceptors become less responsive
Long-acting beta agonists (LABA)
e.g. salmeterol
given for long term prevention and control (e.g. overnight), as it stays bound to the receptors for a lot longer than a SABA
Asthma - Xanthines
e.g. aminophylline, theophylline
adenosine receptor antagonist/phosphodiesterase inhibitor
cause bronchodilator, but not as good as beta-adrenoceptor agonists (therefore only 2nd line use).
Oral (or IV aminophylline in emergency)
Asthma - Muscarinic M-receptor antagonists
e.g. ipratropium/tiotropium
Block parasympathetic bronchoconstriction (M3 ACh-receptor)
Given by inhalation to prevent antimuscarinic side effects.
Limited/little value in asthma, however, have a major role in COPD.
Asthma - steroids
Preventative, they do not reverse an attack.
Takes 2-3 days to have an effect.
Anti-inflammatory by activation of intracellular receptors, leading to altered gene transcription (decrease cytokine production) and production of lipocortin/annexin A1.
Usually given as an inhaler but if the exacerbation is severe, there may be a course of oral steroids.
Side effects of inhaled steroids
Throat infections, hoarseness (inhalation)
=> counsel patient to wash mouth out after use.
Asthma - Leukotriene receptor antagonists (LTRAs)
e.g. Montelukast
Increased role as add on therapy.
Has both preventative and bronchodilator uses.
Antagonises the actions of LTs by blocking their receptors
Also useful against symptoms of hayfever and eczema.
Stepped management of asthma
- Short acting beta2-agonist AND Regular inhaled steroid.
- Trial of LABA (or LTRA/xanthine if this fails).
- Increase dose of inhaled steroid.
- Add oral steroid.
If salbutamol is used >2x per week - step up
COPD - management
Lifestyle advice – STOP SMOKING to reduce further damage to the airways
Pharmacological Management:
=> Bronchodilators – beta2-agonist and tiotropium.
=> Inhaled steroids?
(However only ~15% of patients will benefit)
=> Antibiotics for infectious exacerbations
=> Oxygen therapy
Contraindications in asthma
NSAIDs
Beta-blockers
What is the goal of treatment of cancer pain?
symptom management
What is the goal of treatment of pain in palliative care?
symptom management
What is the goal of treatment of pain in post-surgical pain?
- Patient comfort and satisfaction
- Earlier mobilization
- Reduce hospital stay
- Reduce costs
- Minimise stress response/neuroendocrine effects
- Minimise adverse effects on respiratory, cardiovascular, GI/urinary and MSK systems
WHO Pain ladder - step 1
Simple analgesics (e.g. NSAIDs, paracetamol)
WHO Pain ladder - step 2
Opioids suitable for use in mild-to-moderate pain (e.g. codeine, tramadol) and simple analgesics
WHO pain ladder - step 3
Opioids suitable for use in severe pain (e.g. morphine) and simple analgesics
Adverse effects of NSAIDs
GI – erosion and ulceration
Renal – reduce renal blood flow, acute renal failure, sodium/potassium/water retention.
Airway – bronchospasm
Haematological – reduce platelet aggregation (aspirin = irreversible, NSAIDs = reversible).
?CV risk
Prescribing NSAIDs
The aim is to use the lowest effective dose and for the shortest period of time necessary to control symptoms.
Regular review is required.
Consider co-prescription of a PPI to reduce risk of adverse GI effects
what are some weak opioids?
Codeine
Dihydrocodeine
Dextropropoxyphene
Tramadol (PO)
what are some strong opioids?
Morphine Diamorphine Oxycodone Buprenorphine Fentanyl
Use of weak opioids
most effective when used in combination with paracetamol
What is important to remember about the metabolism of codeine?
Codeine is metabolised to morphine via CYP450 2D6
Pharmacogenetics - some patients are unable to convert it (more common in some ethnicities in particular, e.g. Chinese population)
Use of strong opioids
Used in acute pain, persistent non-cancer pain and palliative care
Adverse effects of opioids
- Nausea & vomiting - manage with anti-emetics
- Constipation - manage with laxatives
- Sedation
- Respiratory depression – overdose
- Hypotension
- Urinary retention
Initiating morphine
Pain assessment, including current analgesia.
Determine opioid requirement
=> Use short acting preparation, regularly, plus PRN doses
Convert total daily dose to modified release formulation
=> Taken every 12 or 24 hours
How can you convert to an alternative opioid?
Determine 24-hour requirement
Use conversion factor for alternative opiate to determine new 24-hour requirement
Convert to appropriate dosage regimen
Opioid equivalences – found in palliative care section of the BNF
Patient Controlled Analgesia (PCA)
Morphine IV is the drug of choice
=> 1 mg bolus, 5-minute lock-out = typical settings
Tramadol, oxycodone or fentanyl if morphine allergy
Advantages of PCA for pain relief
Rapid analgesia once pain at steady state Ready prepared Patient satisfaction No dose delay Patient acceptability No peaks or troughs
Disadvantages if PCA for pain relief
Expensive
Requires IV access
Training
Monitoring
Epidural Opioids
especially used in maternity, lower limb, spine or abdominal surgery
Mixture of local anaesthetic and opioid usually (fentanyl commonly)
Adverse effects - hypotension, ‘wrong route’, infection
what is a syringe Driver?
what are the indications for its use?
Continuous subcutaneous infusion - important use in terminal care
Diamorphine is opioid of choice due to excellent aqueous solubility - can mix in other drugs
Indications:
- Unable to take medicines by mouth (e.g. N&V, dysphagia)
- Bowel obstruction
- Patient does not wish to take regular medication by mouth
monitoring of opioid therapy
- Pulse
- BP
- Respiration rate – respiratory depression is a sign of opioid toxicity.
- Oxygen saturation
- Pain intensity
- Sedation score
- Opioid usage
- Opioid side effects
Use of Naloxone
= Opioid-receptor Antagonist
- Used to manage opioid overdose
- Higher affinity for opioid receptor than agonist – rapid effects
- Short half-life when given IV – may need repeat doses
- May induce pain
- Titrate gradually until effect is achieved
Neuropathic pain - clinical presentation
Symptoms: • Burning • Electric shock • Pins and needles • Scalding • Shooting • Stabbing
Signs:
• Continuous vs. evoked
• Hyperalgesia
• Allodynia
Pharmacological treatments for neuropathic pain
Tricyclic antidepressants
Anticonvulsants - Carbamazepine, Gabapentin, Pregabalin
Opioids
Local anaesthetics
Capsaicin
Causes of neuropathic pain
Can be:
- damage to a peripheral nerve
- a change in pain processing, leading to hypersensitivity
what is the aim of management in treating hyperthyroidism?
what are the options for achieving this?
achieving euthyroidism
- antithyroid drugs (thionamides)
- radioactive iodine to irradiate and destroy part of the thyroid gland
- partial thyroidectomy.
What are the anti-thyroid Drugs?
How do they work?
Carbimazole and propylthiouracil
Decrease the production of thyroid hormones by inhibiting the iodination of thyroglobulin and this occurs via inhibition of thyroperoxidase
Why do anti-thyroid drugs take a few weeks to work?
due to the long half-lives of thyroid hormones
What can be a side effect of therapy with anti-thyroid drugs?
May cause agranulocytosis leading to leucopenia
=> If patients report with sore throats, mouth ulcers, bruising or non-specific illness, a full blood count should be carried out
the drug should be withdrawn if there is leucopenia
symptomatic relief in hyperthyroidism
beta-blockers reduce the actions of catecholamines at beta-adrenoceptors
Symptomatic relief from Tremor, Anxiety, Palpitations
(diltiazem may control tachycardia in patients who cannot receive a beta-blocker)
Regimen options for treating hyperthyroidism
- High-dose carbamizole for 1-2 months achieve euthyroidism (+beta-blocker), then maintenance dose for ~18 months
- BLOCK AND REPLACE: High does carbamizole to suppress all thyroid activity (+ beta blocker), then carbimazole + levothyroxine
Treatment of hypothyroidism
Restoring thyroid hormone levels is achieved by administration of levothyroxine (thyroxine).
=> The dose required is the one that leads to correct TSH levels
Levothyroxine in young patients
Starting dose is 50-100 mg per day
May be increased after 6 weeks by 25-50 mg and thereafter until maintenance levels are achieved
Levothyroxine in older patients/ patients with IHD
why is this done in patients with IHD?
Starting dose used is 25 mg
Increased every 3-4 weeks by 25mg, until normalisation of TSH levels
because thyroxine may lead to the worsening or uncovering of angina
What is the goal of management of epilepsy?
to control seizures with the lowest possible dose and with the fewest side-effects
mono therapy is preferred, and the treatment is built up slowly
what treatment will occur when a patient has a first seizure or isolated seizure?
likely go untreated as it may be an isolated event and so it may be preferable to avoid long term medication.
What other pathologies can cause seizures and should be ruled out before a diagnosis of epilepsy?
Cerebral tumours (including metastasis) Cerebrovascular accident Alcohol withdrawal Hyper/hypoglycaemia Syphilis Drugs (e.g antidepressants) may reduce seizure threshold
treatment of generalised epileptic seizures
1st choice: valproate or carbamazepine
(lamotrigine in females of childbearing age)
2nd choice: levetiracetam
treatment of absence seizures
1st choice: ethosuximde
2nd choice: valproate/lamotrigine
AEDs: Valproate
Potentiates GABA, causes Na-channel blockade
Side effects include: Sedation, weight gain, tremor
associated with causing birth defects (a reason to avoid in females of childbearing age)
associated with causing liver damage (hence liver function is monitored)
AEDs: Carbamazepine
Use-dependent blockade of Na-channels
Side effects include: Rashes, Dizziness, Double vision
Induces metabolism of itself and many other drugs
Many interactions: induction leads to accelerated metabolism of interacting drugs
Associated with causing birth defects
AEDs: Phenytoin
Less commonly used
Many side effects:
- increased gum growth
- nystagmus a toxic effect
Associate with causing birth defects
Zero order kinetics => disproportionate increases in plasma concentration on increasing dose
i.e. a small increase in the dose or a drug interaction can quickly shift the plasma concentration above the therapeutic window
AEDs: Lamotrigine
Use-dependent blockade of Na-channels, reduces release of glutamate
Not particularly sedating
Withdraw if the patient develops a rash/flu-like illness due to the risk of bone marrow toxicity
Monitoring AED therapy
FBC should be monitored for haematological effects
=> many cause leucopaenia
=> lamotrigine - aplastic anaemia
=> valproate - thrombocytopenia
LFTs/INR should be monitored for liver function
Skin - rashes, severe skin reactions
what should be done if an AED is causing severe leucopenia in a patient?
withdraw the drug, under the cover of another drug
AEDs in pregnancy
carbamazepine, valproate and phenytoin are teratogenic
=> Especially causing neural tube defect
=> carbamazepine considered the safest of these
To prevent NTD – 5mg folic acid daily in 1st trimester, with counseling & screening
Neonatal bleeding tendency may occur with carbamazepine, and phenytoin (due to enzyme induction) and so vitamin K1 is given for 3rd trimester
Newer agents (e.g. lamotrigine for generalised seizures) may be considered 1st line in women of childbearing age
AEDs - failure of treatment
Review drug - use the maximum dose?
Swap with another antiepileptic drug
Further failure – add a second drug
what is status epilepticus?
= continuous seizure for 30 mins or 2 fits without recovery between them
How is status epileptics managed?
diazepam/lorazepam/clonazepam or a slow IV of phenytoin
if this fails, a general anaesthetic such as propofol
AEDs - interactions
ENZYME INDUCTION with phenytoin, carbamazepine and phenobarbitone
This leads to many interactions – e.g. failure of oral contraceptives
=> Patient use additional barrier methods or a high dose pill
Epilepsy/AEDs and driving
Driving is permitted if seizure free for 1 year
(Or if attacks occur while asleep over a 3-year period)
BUT some drugs may cause drowsiness – avoid driving if affected (see BNF)
Withdrawal of AEDs
Might be considered if the patient is seizure free for 2-4 years
Withdraw drug gradually, as withdrawal can precipitate epilepsy
Stop driving during withdrawal
