066
Pages 1626-1650
Notes & Notes for MRCP
By Dr. Yousif Abdallah Hamad
Acetylsalicylic acid (ASA, aspirin)
Overview • Aspirin works by blocking the action of both cyclooxygenase-1 and 2. • Cyclooxygenase is responsible for prostaglandin, prostacyclin and thromboxane synthesis. • Cyclo-oxygenase is an enzyme that converts arachidonic acid to thromboxane A2 (TXA2), a strong platelet agonist • Because the platelet has no protein synthetic apparatus the effects of aspirin are irreversible and last for the life of the platelet (8-10 days) • ↑ bleeding time (PT and PTT unchanged) • The blocking of thromboxane A2 formation in platelets reduces the ability of platelets to aggregate which has lead to the widespread use of low-dose aspirin in cardiovascular disease. • Until recent guidelines changed all patients with established cardiovascular disease took aspirin if there was no contraindication. Following the 2010 technology appraisal of clopidogrel this is no longer the case. Mechanism of action • ASA covalently attaches an acetyl group to COX. • Irreversible COX-1 inhibition → inhibition of thromboxane (TXA2) synthesis in platelets → inhibition of platelet aggregation (antithrombotic effect) • Onset of antiplatelet action: within minutes • Duration of antiplatelet action: 7–10 days • Irreversible COX-1 and COX-2 inhibition → inhibition of prostacyclin and prostaglandin synthesis → antipyretic, anti-inflammatory, and analgesic effect Effects • Low dose (below 300 mg/day): inhibition of platelet aggregation • Intermediate dose (300-2400 mg/day): antipyretic and analgesic effect • High dose (2400-4000 mg/day): anti-inflammatory effect
What do the current guidelines recommend? • first-line for patients with ischaemic heart disease • Current NICE guidelines advise that people with acute upper gastrointestinal bleeding who take aspirin for secondary prevention of vascular events and in whom haemostasis has been achieved continue on low dose aspirin. • the U.S. Preventive Services Task Force (USPSTF), recommended that, for some people, aspirin can be used to help reduce their risk of cardiovascular disease and colorectal cancer. Potentiates • oral hypoglycaemics • warfarin • steroids
Reye syndrome
Notes & Notes for MRCP
By Dr. Yousif Abdallah Hamad
Chapter 13
Pharmacology
• Definition: a rare type of hepatic encephalopathy that is associated with aspirin use for viral illness in children < 19 years • Aetiology: aspirin use in individuals < 19 years of age with a febrile illness • Pathophysiology accumulation of salicylate metabolites in the liver → mitochondrial injury and reversible inhibition of enzymes required for fatty acid oxidation; acute encephalopathy Hyperammonemia → cerebral edema → ↑ ICP • Features Preceding viral infection (e.g., influenza, varicella or viral gastroenteritis) Acute encephalopathy Severe vomiting coma Liver failure Fatty degeneration Hepatomegaly • Diagnostics: clinical diagnosis; further testing to rule out other causes (diagnosis of exclusion) ↑ AST and ALT Hyperammonemia Hypoglycemia Liver biopsy: microvesicular hepatic steatosis • Prevention Aspirin should be avoided in individuals < 19 years of age Exception: children with Kawasaki disease • Prognosis →Mortality rate: ∼ 20%
In hypersensitive patients aspirin can cause: • Angioedema • Bronchospasm, and • Urticaria (skin rashes).
ASA can be continued normally if patient is going for dental procedure
Aspirin is not considered to be safe in breast-feeding due to the risk of causing Reye's syndrome in the baby.
Notes & Notes for MRCP
By Dr. Yousif Abdallah Hamad
Salicylate overdose
The mixed respiratory alkalosis and metabolic acidosis in a sweaty, confused patient point
towards salicylate overdose.
The development of pulmonary edema suggests severe poisoning and is an indication for
hemodialysis.
Tinnitus is characteristic and salicylate toxicity may produce deafness.
Overview
• A key concept for the exam is to understand that salicylate overdose leads to a mixed
respiratory alkalosis and metabolic acidosis.
Early stimulation of the respiratory centre leads to a respiratory alkalosis
later the direct acid effects of salicylates (combined with acute renal failure) may lead
to an acidosis.
• The metabolic acidosis can increase the transfer of salicylates across the blood-brain
barrier, thereby increasing CNS toxicity
Features
• Early features:
hyperventilation (centrally stimulates respiration) respiratory alkalosis
the most prominent feature of the early period after aspirin overdose
tinnitus: typically occurs at plasma salicylate concentrations above 400-500 mg/l
vertigo
lethargy
sweating, pyrexia
salicylates cause the uncoupling of oxidative phosphorylation leading to
decreased adenosine triphosphate production, increased oxygen
consumption and increased carbon dioxide and heat production
peripheral vasodilatation and bounding pulse
nausea/vomiting → dehydration
• Later features:
metabolic acidosis
by uncoupling oxidative phosphorylation, leading to a build- up of organic
acids in the blood.
hyperglycaemia and hypoglycaemia
Hypoglycaemia is commonly seen in children but not in adults
seizures
coma
Although decreased consciousness is seen in aspirin overdose, it is seen late,
and is associated with severe metabolic acidosis and hypokalaemia.
Early presentation with coma will suggest that another drug has been
taken in addition to aspirin.
Treatment
•
No specific antidote
•
The management is supportive, with measures to prevent further absorption from the
gastrointestinal tract and enhance excretion.
•
General (ABC, charcoal) Multi-dose activated charcoal may be indicated
Notes & Notes for MRCP
By Dr. Yousif Abdallah Hamad
Chapter 13
Pharmacology
activated charcoal should be repeated as bezoars may form, resulting in delayed
absorption of salicylate. This should continue until salicylate levels have peaked.
•
Urinary alkalinization
alkalinisation of the urine should be considered in patients with a plasma level > 300
mg/L.
urine and serum alkalinization through intravenous sodium bicarbonate
( 1.25% or 8.4% )
By alkalinizing the urine, charged salicylic acid will become protein bound and
secreted through the proximal tubule, which minimizes the diffusion of uncharged
salicylate back into the renal epithelium.
The ionisation of a weak acid, such as salicylic acid, is increased in an
alkaline environment.
The administration of an intravenous infusion of sodium bicarbonate aiming
for a urinary pH of 7.5-8 will increase the excretion of the acid 10-fold.
Alkalinization of the serum further promotes diffusion of salicylate out of the brain.
•
Haemodialysis
Indications for haemodialysis in salicylate overdose
serum concentration > 700mg/L
metabolic acidosis resistant to treatment
acute renal failure
pulmonary oedema
neurological impairment (coma, hallucinations or seizures)
Clopidogrel Most (PPIs) ↓ Clopidogrel effect but lansoprazole is OK
• Clopidogrel is an antiplatelet agent used in the management of cardiovascular disease.
• Clopidogrel belongs to a class of drugs known as thienopyridines which have a similar
mechanism of action. Other examples include:
prasugrel
ticagrelor
ticlopidine
Mechanism (Inhibition of the platelet ADP receptor)
•
antagonist of the P2Y12 adenosine diphosphate (ADP) receptor, inhibiting the activation of
platelets
Indications
• clopidogrel is used in addition to aspirin in patients with an acute coronary syndrome. The
dose is 300 mg.
• NICE now recommend clopidogrel first-line following an ischaemic stroke and for peripheral
arterial disease.
• Recent Royal College of Physician (RCP) guidelines support the use of clopidogrel in TIAs.
However the older NICE guidelines still recommend aspirin + dipyridamole
Interactions
•
concurrent use of proton pump inhibitors (PPIs) may make clopidogrel less effective (MHRA
July 2009)
•
this advice was updated by the MHRA in April 2010, evidence seems inconsistent but
omeprazole and esomeprazole still cause for concern. Other PPIs such as lansoprazole
should be OK
Notes & Notes for MRCP
By Dr. Yousif Abdallah Hamad
Clopidogrel
• action → antagonist of the P2Y12 adenosine diphosphate (ADP) receptor, inhibiting the
activation of platelets
• other members of the same class (thienopyridines):
prasugrel
ticagrelor
ticlopidine
• Indications → 1st line for : ACS , an ischaemic stroke , TIA and peripheral arterial disease.
• Interaction → most (PPIs) ↓ Clopidogrel effect but lansoprazole is OK
Prasugrel
• a third-generation thienopyridine antiplatelet agent
• ADP receptor inhibitors
• advantages compared with clopidogrel
faster onset of action,
greater potency in the inhibition of adenosine-induced platelet aggregation,
more consistent antiplatelet response
• Prasugrel is contra-indicated in patients with prior transient ischaemic attack or
stroke.
In the TRITON-TIMI 38 trial, patients in this group had a higher rate of stroke when
taking Prasugrel compared with those taking Clopidogrel.
IIb/IIIa inhibitors (eg: Abciximab)
• Other members of this drug group
abciximab
eptifibatide
tirofiban
• Action
monoclonal antibody antagonizes IIb/IIIa glycoprotein receptor on activated
platelets
• prevents platelet aggregation
• Abciximab is a humanised monoclonal antibody
Phosphodiesterase III (PDE) inhibitors (dipyridamole & cilostazol )
Notes & Notes for MRCP
By Dr. Yousif Abdallah Hamad
Chapter 13
Pharmacology
Mechanism of action • inhibits phosphodiesterase → increase platelet cAMP (due to decreased breakdown of cAMP) → reduce intracellular calcium levels → inhibition of platelet aggregation. • direct arterial vasodilation inhibits cellular uptake of adenosine → more available to act on coronary vessels → vasodilation • inhibition of thromboxane synthase
Indications
• Dipyridamole is an antiplatelet mainly used in combination with aspirin after an ischaemic
stroke or transient ischaemic attack
• Cilostazol is currently licensed for the management of patients with intermittent
claudication without rest pain and with no signs of tissue necrosis.
It is a first-line medication for the treatment of claudication caused by peripheral
artery disease (PAD).
Trials show an improvement in time to initial pain on walking and maximal walking
distance when compared to placebo.
metabolised by cytochrome P450 3A4.
Contraindications
• known bleeding tendencies (e.g. active peptic ulcer disease, previous haemorrhagic stroke
in the last 6 months).
• Asthmatics (may provoke bronchospasm)
Angiotensin-converting enzyme (ACE) inhibitors
Mechanism of action
•
Inhibit the conversion angiotensin I to angiotensin II
Indications
• hypertension
first-line treatment in younger patients with hypertension and are also extensively
used to treat
less effective in treating hypertensive Afro-Caribbean patients.
• diabetic nephropathy
• heart failure.
• secondary prevention of IHD.
Side-effects
•
Cough:
occurs in around 15% of patients
may occur up to a year after starting treatment.
Thought to be due to increased bradykinin levels
The enzyme ACE is also responsible for the metabolism of bradykinin in mast cells
and ACEi leads to its bradykinin accumulation
This phenomenon is not seen in subjects taking angiotensin receptor blockers such
as losartan.
•
Angioedema:
may occur up to a year after starting treatment
ACE inhibitors are the most common cause of drug-induced angioedema
Notes & Notes for MRCP
By Dr. Yousif Abdallah Hamad
(swelling of his lips and tongue )
•
Hyperkalaemia
•
ACEi dilate the efferent arteriole of the glomerulus, ↓GFR ↑ creatinine and BUN.
•
1st-dose hypotension: more common in patients taking diuretics
Cautions and contraindications
•
Pregnancy and breastfeeding – avoid ( ACEi & ARB renal dysgenesis in the fetus)
Exposure to ACE inhibitors in the first trimester showed a significant increase in major (in
particular, cardiovascular) congenital malformation.
•
Renovascular disease - significant renal impairment may occur in patients who have
undiagnosed bilateral renal artery stenosis
•
Aortic stenosis - may result in hypotension
•
Patients receiving high-dose diuretic therapy (more than 80 mg of furosemide a day) -
signficantly increases the risk of hypotension
•
Hereditary of idiopathic angioedema
•
The co-administration of a potassium-sparing diuretic and an ACE inhibitor, may result in
profound hyperkalaemia. Thus patients on both these drugs should have their potassium
monitored closely.
Monitoring
•
Urea and electrolytes should be checked before treatment is initiated and after increasing
dose
Monitoring of renal function and potassium is important after commencement of an
ACE inhibitor.
The optimum period to check this is one to two weeks after commencing
the medication.
•
A rise in the creatinine and potassium may be expected after starting ACE inhibitors.
Acceptable increases are an increase in serum creatinine, up to 50% from
baseline or up to 265μmol/l (whichever is smaller) and an increase in
potassium up to 5.5 mmol/l.
NICE guidelines state that when initiating ACE inhibitor therapy a 25% reduction in
the eGFR or 30% increase in the serum creatinine is tolerable and should not
lead to changes in dosing.
ACE inhibitors should also be stopped or dose adjusted if is there is a rise in the
serum potassium level to greater than 6 mmol/l.
Other causes of a deterioration in renal function should be excluded first before
stopping the ACE inhibitor.
e.g: patient taking trimethoprim
This drug competes with creatinine for excretion in the nephron
↑ serum creatinine.
the appropriate option would be to re-check the blood tests in one
to two weeks once trimethoprim has been discontinued to see
whether the level of renal dysfunction is sustained or improves.
Usage of ACEi & ARB as combination (NICE January 2015)
• Do not combine an ACE inhibitor with an ARB to treat hypertension.
• no significant benefits of ACEi & ARB combination were seen in people who did not have
heart failure and there was an increased risk of hyperkalaemia, hypotension, and impaired
renal function.
• The NICE guideline on chronic heart failure recommends that, after seeking specialist
advice, the addition of an ARB licensed for heart failure is an option that could be
considered for people who remain symptomatic despite optimal therapy with an ACE
Notes & Notes for MRCP
By Dr. Yousif Abdallah Hamad
Chapter 13
Pharmacology
inhibitor and a beta-blocker
Candesartan and valsartan are the only ARBs licensed as add-on therapy to ACE
inhibitors in this situation.
Other options are adding an aldosterone antagonist licensed for heart failure or
hydralazine in combination with nitrate.
direct renin inhibitors
•
Aliskiren (branded as Rasilez) Direct renin inhibitor
•
Action: by inhibiting renin blocks the conversion of angiotensinogen to angiotensin I
•
indication: only current role would seem to be in patients who are intolerant of more
established antihypertensive drugs
•
no trials have looked at mortality data yet. Trials have only investigated fall in blood
pressure. Initial trials suggest aliskiren reduces blood pressure to a similar extent as
angiotensin converting enzyme (ACE) inhibitors or angiotensin-II receptor antagonists
•
adverse effects were uncommon in trials although diarrhoea was occasionally seen
Other notes
• Enalapril is a prodrug for enalaprat, the active agent
• irbesartan : the dose response is linear, as such dose can be titrated more easily
from a base of 75 mg to a maximum of 300 mg.
Adrenoceptor antagonists Doxazosin is an α-1 adrenoceptor antagonist used in the treatment of hypertension and benign prostatic hypertrophy
Alpha antagonists
•
alpha-1: doxazosin
cause orthostatic hypotension
•
alpha-1a: tamsulosin - acts mainly on urogenital tract
•
alpha-2: yohimbine
•
non-selective: phenoxybenzamine (previously used in peripheral arterial disease)
Phenoxybenzamine presurgical management of hypertension in
phaeochromocytoma.
Beta antagonists
•
beta-1: atenolol
•
non-selective: propranolol
Carvedilol and labetalol are mixed alpha and beta antagonists
Beta-blockers
Notes & Notes for MRCP
By Dr. Yousif Abdallah Hamad
Indications
•
angina
•
post-myocardial infarction
•
Heart failure: there is now strong evidence that certain beta-blockers improve both
symptoms and mortality. Especially Bisoprolol
•
arrhythmias: beta-blockers have now replaced digoxin as the rate-control drug of choice in
atrial fibrillation
•
hypertension: the role of beta-blockers has diminished in recent years due to a lack of
evidence in terms of reducing stroke and myocardial infarction.
•
thyrotoxicosis
•
migraine prophylaxis
•
anxiety
Beta- blocker in heart failure
• NICE recommends β blockers in all HF patients.
• In chronic obstructive pulmonary disease (COPD) patients with HF, cardioselective β
blockers appear safer at lower doses than higher doses or non-selective β blockers.
• Bisoprolol 5 mgs is too high an initial starting dose, a low dose can always be titrated up
later, if tolerated. ( starting dose Bisoprolol 1.25 mg od )
• Carvedilol though effective treatment for heart failure is not selective and therefore carries a
greater risk of causing bronchospasm.
• Atenolol though cardioselective has no clinical evidence for prognostic benefit in heart
failure.
• The patient should be closely monitored for deterioration in lung function postadministration.
Examples
• Atenolol
Atenolol is a water soluble beta-blocker,
taken once daily
not associated with drowsiness/sleep disturbance like the lipid-soluble beta-blockers.
• Propranolol
one of the first beta-blockers to be developed.
Lipid soluble therefore crosses the blood-brain barrier
• Nebivolol
has a vasodilatory action in addition to β-blocking effects
associated with a lower incidence of erectile dysfunction compared with other βblocking agents
• Bisoprolol → the most cardio-selective beta-blocker
• Metoprolol
The most lipid-soluble and therefore has the largest volume of distribution
↑lipid solubility → greater penetration across the blood-brain barrier (and also into
other tissues), and therefore a greater incidence of night terrors
Maximal gastrointestinal absorption of drugs occurs when there is intermediate lipid
and water solubility, so that drugs with greater lipid solubility, although allowing
greater tissue penetration, may be more poorly absorbed
Metoprolol though selective is shorter acting.
• Oxprenolol → has an intrinsic sympathomimetic properties.
Notes & Notes for MRCP
By Dr. Yousif Abdallah Hamad
Chapter 13
Pharmacology
Carvedilol
Bisoprolol
Not β1- selective
Highly β1- selective
Vasodilatation due to α-1- blockade
No α-1- blocking activity
Lipids effects
Positive lipid effect ↑↑HDL & ↓↓LDL
Negative lipid effect ↑↑ cholesterol , TG, VLDL
Lipid profile almost not affected
Oral bioavailability of digoxin increased
No interaction with other CV drugs known
Sensitive to liver enzyme induction
Not sensitive to liver enzyme induction
Extensive metabolism in the liver (CYP2D6)(dose
adjustment in liver impairment)
No dose adjustment required
Side-effects
•
bronchospasm
•
cold peripheries
•
β-Blockers cause a rise in peripheral vascular resistance due to the unopposed αadrenoceptor effects (vasoconstriction)
•
Fatigue
fatigue is a frequent side effect
typically is felt two hours and beyond after taking the drug.
•
sleep disturbances, including nightmares
•
β-blockers associated with increased dreams/possible night terrors
Contraindications
•
uncontrolled heart failure
•
asthma
•
sick sinus syndrome
•
concurrent verapamil use: may precipitate severe bradycardia
•
There is a theoretical risk of intrauterine growth retardation with the use of atenolol in
pregnancy although the studies which showed this effect were done with very large doses
of atenolol.
Beta-blocker overdose
Features
•
bradycardia
•
hypotension
•
heart failure
•
syncope
Management
•
if bradycardic then atropine
•
in resistant cases glucagon may be used
•
Glucagon acts by bypassing the blocked β-receptor, thus activating adenyl cyclase
formation of cyclic AMP from ATP. Cyclic AMP in turn exerts a direct stimulant action on the
heart.
•
The action of glucagon, essential for reversing the effect of beta-blocker overdose
Promotes the formation of cyclic AMP.
Doses of glucagon used are much higher than those conventionally used for
reversing hypoglycaemia in diabetes, with a bolus of 3-10 mg being required, then 25 mg/hr by infusion.
• Haemodialysis is not effective in beta-blocker overdose
Calcium channel blockers
• Voltage-gated calcium channels are present in:
- myocardial cells,
- cells of the conduction system and
- cells of the vascular smooth muscle.
(they have no effect on veins).
• The various types of calcium channel blockers have varying effects on these three areas and it is therefore important to differentiate their uses and actions.
Examples
Indications & notes
Verapamil
• Angina, hypertension, arrhythmias
• Highly negatively inotropic
• Should not be given with beta-blockers as
may cause heart block
Diltiazem
• Angina, hypertension
• Less negatively inotropic than verapamil
but caution should still be exercised when
patients have heart failure or are taking
beta-blockers
Nifedipine,
amlodipine,
felodipine
(dihydropyridines)
• Hypertension, angina, Raynaud's
• Affects the peripheral vascular smooth
muscle more than the myocardium and
therefore do not result in worsening of
heart failure
• What is the conventional cardiac micro-anatomical structure targeted by calciumchannel blockers?
L-type calcium channels
all conventional calcium-channel blockers work on L-type calcium channels
The L-type channels are found on a tubular network of invaginations of
sarcolemma of muscle fibres called T (transverse) tubules.
T tubules contain 2 main types of calcium channels:
L-type calcium channels (where calcium channel blocker do interact)
T (transient) type calcium channels (conventional calcium channel
blockers have no effect here).
Notes & Notes for MRCP
By Dr. Yousif Abdallah Hamad
Side-effects and
cautions
• Heart failure,
• constipation,
• hypotension,
• bradycardia, flushing
• Hypotension,
• bradycardia,
• heart failure,
• ankle swelling
• Flushing,
• headache,
• ankle swelling
Notes & Notes for MRCP
By Dr. Yousif Abdallah Hamad
Chapter 13
Pharmacology
Centrally acting antihypertensives
Methyldopa not utilised in a patient with abnormal LFTs Examples of centrally acting antihypertensives include: • methyldopa: used in the management of hypertension during pregnancy • moxonidine: used in the management of essential hypertension when conventional antihypertensives have failed to control blood pressure • clonidine: the antihypertensive effect is mediated through stimulating alpha-2 adrenoceptors in the vasomotor centre
Bosentan
•
Bosentan is a competitive antagonist of both endothelin-A (ETa) and endothelin-B (ETb)
receptors, leading to falls in both pulmonary and systemic vascular resistances without an increase
in heart rate
•
effective in patients with pulmonary arterial hypertension
•
It is excreted in bile following metabolism by the cytochrome P450 enzymes and this is a potential
source of interaction with drugs metabolised by the same isoenzyme
•
Common unwanted effects include
flushing
hypotension
dyspepsia
fatigue
Haemoglobin concentrations can fall by up to 1 g/dl during bosentan treatment
Hepatotoxicity:
The most serious unwanted effect is dose-dependent hepatotoxicity, and it is
therefore contraindicated in patients with moderate to severe liver disease
Generally, hepatotoxicity occurs within the first 3-4 months of treatment
teratogenic and therefore contraindicated in pregnancy
Notes & Notes for MRCP
By Dr. Yousif Abdallah Hamad
Nitroglycerin • Nitroglycerin products are both venous capacitance dilators and coronary and systemic artery dilators • Administration of nitroglycerin results in: dilation of systemic veins decreased myocardial wall tension decreased oxygen demand vasodilation of large and medium-sized coronary arteries increased coronary blood flow to the subendocardium reduced afterload reduced preload increased ventricular compliance • Nitrates may cause haemolytic anaemia
Nicorandil
Action
•
acts through the opening of potassium channels .
•
Nicorandil is an activator of ATP-dependent potassium channels
•
Effect relaxation of smooth muscle in veins venodilatation ↓ ventricular filling pressures +
dilatation of the coronary arterioles
•
It relaxes vascular smooth muscle through membrane hyperpolarisation via increased
transmembrane potassium conductance and, like nitrates, through an increase in intracellular cyclic
guanosine monophosphate (GMP).
Indication
•
now second-line treatment for angina
•
Use nicorandil for treatment of stable angina only in patients whose angina is inadequately
controlled by first line anti-anginal therapies, or who have a contraindication or intolerance to first
line anti-anginal therapies such as beta-blockers or calcium antagonists
Side effects
•
Headache
The most common unwanted effect (- 35% of patients),
appears to be dose-dependent
resolves with continued treatment
•
Ulcerations
oral ulceration, flushing and gastrointestinal disturbances
(ulceration of the upper and lower gastrointestinal tract and may present with life
threatening bleeding)
Nicorandil can cause serious skin, mucosal, and eye ulceration, including gastrointestinal
ulcers which may progress to perforation, haemorrhage, fistula, or abscess
Contraindication
•
Use with phosphodiesterase inhibitors such as sildenafil is contraindicated since they can
potentiate the hypotensive effects of nicorandil
Notes & Notes for MRCP
By Dr. Yousif Abdallah Hamad
Chapter 13
Pharmacology
Digoxin and digoxin toxicity The half-life of digoxin is around 36-48 hours. This results in a delay before steady plasma levels are seen, it may take a week to start its action
• Digoxin is a cardiac glycoside now mainly used for rate control in the management of atrial
fibrillation.
• As it has positive inotropic properties it is sometimes used for improving symptoms (but not
mortality) in patients with heart failure.
• digoxin is highly water-soluble
• Digoxin has a high volume of distribution and long half-life (36-48 h), which means that
loading doses are required to allow the drug to reach a steady-state concentration more
quickly.
If initiated on a maintenance dose (without loading), it will take several days to reach
a steady state.
• Digoxin is almost exclusively renally cleared; as a result, renal impairment will significantly
alter the half-life of this medication.
Mechanism of action
•
decreases conduction through the atrioventricular node which slows the ventricular rate in
atrial fibrillation and flutter
•
Increases the force of cardiac muscle contraction due to inhibition of the Na+/K+ATPase
pump which is located in the sarcolemmal membrane.
•
Also stimulates vagus nerve
What is the pharmacokinetic reason that drives the practice of loading with digoxin?
Volume of distribution.
• The volume of distribution for Digoxin is very large (510 litres). This means that
administered doses are rapidly distributed to body tissues.
• The initial distribution lasts for some 6-8hrs, which drives the typical loading regimen for
Digoxin of two larger doses (500mcg) some 6-12hrs apart.
• Without loading Digoxin typically takes a few days to reach therapeutic effect.
Digoxin can worsen hyperkalaemia
• Translocation of potassium from the cells into the extracellular space can occur from
digoxin overdose due to its dose-dependent Na-K-ATPase pump inhibition.
Notes & Notes for MRCP
By Dr. Yousif Abdallah Hamad
Digoxin toxicity
• Plasma concentration alone does not determine whether a patient has developed digoxin
toxicity.
• The BNF advises that the likelihood of toxicity increases progressively from 1.5 to 3 mcg/l.
Samples taken after 6 h will be more accurate in estimating the body’s digoxin
• the mechanism of action leading to tachy-arrhythmias in digoxin toxicity Inhibition
of the sodium pump
Features
•
generally unwell, lethargy, anorexia,
The earliest features of digitalis toxicity include: Nausea, vomiting, anorexia.
•
cholinergic effects : nausea, vomiting, diarrhea
•
confusion,
•
yellow-green vision
•
arrhythmias (e.g. AV block, bradycardia)
(Digoxin toxicity can result in any abnormal cardiac rhythm except type-ll
second-degree atrioventricular (AV) block)
Precipitating factors
•
classically: hypokalaemia
(hyperkalaemia may also worsen digoxin toxicity, although this is very small print)
•
increasing age
•
renal failure
•
myocardial ischaemia
•
hypomagnesaemia,
•
hypercalcaemia,
•
hypernatraemia,
•
acidosis
•
hypoalbuminaemia
•
hypothermia
•
hypothyroidism
•
amyloidosis
Notes & Notes for MRCP
By Dr. Yousif Abdallah Hamad
Chapter 13
Pharmacology
• drugs: amiodarone, quinidine, verapamil, diltiazem, spironolactone (competes for secretion in distal convoluted tubule therefore reduce excretion), ciclosporin. Also drugs which cause hypokalaemia e.g. thiazides and loop diuretics Bumetanide is a loop diuretic and may cause hypokalaemia as a side effect. The potassium loss caused by bumetanide increases the toxicity of digoxin.
Management
Antidote "KLAM"
•
slowly normalize K+
•
Lidocaine
•
digoxin Antibodies (anti-dig Fab
fragments)
•
Mg2+
Phenytoin may be used as an alternative to lidocaine (both are class IB agents) if immune therapy is unsuccessful or unavailable in the treatment of tachyarrhythmias secondary to digoxin toxicity.
•
Treatment of digoxin toxicity should be guided by the patient’s signs and symptoms and the
specific toxic effects and not necessarily by digoxin levels alone.
•
Activated charcoal if presented within 1 h of an overdose
The first-line treatment for acute ingestion is repeated dosing of activated charcoal to
reduce absorption and interrupt enterohepatic circulation.
•
Binding resins (eg, cholestyramine)
may bind enterohepatically-recycled digoxin.
may be more appropriately used for treatment of chronic toxicity in patients with
renal insufficiency.
•
correct arrhythmias
•
severe sinus bradycardia (hemodynamically unstable bradyarrhythmic patients) Atropine
•
ventricular tachycardia responds best to digoxin immune therapy, but phenytoin and
lidocaine are useful if immune therapy is ineffective or unavailable.
These drugs depress the enhanced ventricular automaticity without significantly
slowing AV conduction
•
Magnesium sulfate, 2 g IV over 5 minutes, has been shown to terminate dysrhythmias in
digoxin-toxic patients with and without overt cardiac disease.
Magnesium is contraindicated in the setting of bradycardia or AV block and should
be used cautiously in patients with renal failure.
•
Premature ventricular contractions (PVCs), bigeminy, or trigeminy may require only
observation unless the patient is hemodynamically unstable, in which case lidocaine may
be effective.
•
Digibind
Its brand name of Digoxin immune fab or Digoxin-specific antibody is an
antidote for overdose of digoxin
Action: bind to the digoxin unable to bind to its action sites
is an immunoglobulin fragment that binds with digoxin.
first-line treatment for significant dysrhythmias from digitalis toxicity
Indications for digoxin-specific antibodies include:
Hemodynamically unstable arrhythmia
Tachyarrhythmias with hypotension
bradycardia with hypotension that do not respond to atropine
Notes & Notes for MRCP
By Dr. Yousif Abdallah Hamad
treatment.
End organ damage
digoxin level > 4ng/ml if chronic ingestion
digoxin level > 10 ng/ml if acute ingestion (taken 6 h after the last dose)
Hyperkalaemia (if not respond to insulin-dextrose infusions): potassium > 5
mEq/L and symptomatic
SE Serum sickness
• If digoxin-specific antibodies not available lidocaine or phenytoin
•
Digoxin toxicity related ventricular tachycardia:
Phenytoin and lidocaine are useful for ventricular tachycardia if immune
therapy is ineffective or unavailable
Phenytoin is thought to suppress the pro-arrhythmic properties of digoxin
without diminishing its inotropic effects.
lidocaine is useful for chemical cardioversion of digoxin toxicity related
ventricular tachycardia. This is because it can reduce ventricular
automaticity without significantly slowing AV conduction.
Calcium channel blockers are contraindicated because they may increase digoxin
levels.
Amiodarone is shown to increase digoxin levels and as such can worsen the risk of
rhythm disturbance further.
VT in digoxin toxicity is resistant to electrical cardioversion, which may actually
precipitate VF and asystole.
Bretylium is contraindicated in the treatment of digoxin induced arrhythmias as it can
actually precipitate ventricular tachycardia.
Quinidine worsens AV and SA conductivity and reduces digoxin tissue binding and is
therefore also contraindicated.
•
conventional dialysis is ineffective
•
monitor potassium
Electrolytes
In acute toxicity, hyperkalemia is common
Although calcium is often used to ameliorate cardiac toxicity from
hyperkalemia, it is not recommended in patients with digoxin toxicity
because it can delay after-depolarization and may precipitate
ventricular tachycardia or fibrillation. This is based on the fact that
intracellular calcium levels are already high in this setting.
potassium level > 5 mEq/L digoxin Fab fragments
Chronic toxicity is often accompanied by hypokalemia and
hypomagnesemia
Concomitant hypomagnesemia may result in refractory hypokalemia
Correction of electrolyte imbalances may reverse dysrhythmias.
Which measurement would be most useful when monitoring patient for digoxin efficacy? Pulse rate Measuring drug plasma concentration will tell you whether digoxin is at therapeutic concentrations in the blood, but not whether it is having a therapeutic effect.
Chapter 13
Pharmacology
Diuretics
Class
Compound
Action
Side effects
Loop Diuretics
Furosemide
Bumetanide
ethacrynic acid
Thiazides
hydrochlorothiazide,
indapamide
K+ sparing
agents
spironolactone
Aldosterone receptor antagonist
Hyperkalemia
amiloride, triamterene Osmotic Diuretics mannitol Inhibit water reabsorption throughout the tubules, but mostly in the proximal tubule
Loop diuretics
Action
• Furosemide and bumetanide are loop diuretics that act by inhibiting the Na-K-Cl
cotransporter (NKCC) in the thick ascending limb of the loop of Henle, reducing the
absorption of NaCl.
• There are two variants of NKCC; loop diuretics act on NKCC2, which is more prevalent in
the kidneys.
Indications
•
heart failure: both acute (usually intravenously) and chronic (usually orally)
•
resistant hypertension, particularly in patients with renal impairment
Adverse effects
•
hypotension
•
hypocalcaemia
•
hyponatraemia
•
renal impairment (from dehydration + direct toxic
effect)
•
hypokalaemia
•
hypochloraemic alkalosis
•
hyperglycaemia (less common than with thiazides)
•
ototoxicity
•
gout
• Loop diuretics induces ototoxicity by affecting Na+/K+/2Cl- cotransporters present
in the inner ear.
• Explanation of respond to i.v furosemide but not oral in heart failure Increased
bioavailability
In right heart failure The patient has a lot of gut oedema which would reduce
the absorption of oral furosemide. Intravenous furosemide would have a much better
bioavailability and thus therapeutic effect.
Protein binding of drugs may be reduced in elderly patients, this may be due to
malnutrition.
• Explanation of not responding to furosemide in chronic kidney disease (CKD)
Tubular secretion of furosemide is reduced in CKD
Organic acids accumulate in renal failure and compete for tubular secretion with
furosemide. This competition can be overcome by using a larger dose of the drug.
Notes & Notes for MRCP
By Dr. Yousif Abdallah Hamad
inhibit NKCC2 in the thick ascending loop of Henle
Deafness
inhibit NaCl co-transporter in
early distal tubule
hyponatraemia,
hypokalaemia,
hypercalcaemia
inhibit Na channel in late distal tubule Hyperkalemia
Pulmonary edema
Notes & Notes for MRCP
By Dr. Yousif Abdallah Hamad
A 76-year-old lady taking perindopril 2 mg, bisoprolol 1.25 mg and had recently had her dose of
furosemide increased from 40 mg to 80 mg. C/O dizziness, particularly when standing upright after
being seated. There were no clinical signs of cardiac failure. Serum urea: 13.3 mmol/L. Serum
creatinine: 221 µmol/L. What is the next step in her management?
Stop the furosemide temporarily and restart at a lower dose within a few days
This lady is developing postural hypotension after the recent increase in
furosemide dose.
She has moderate renal impairment.
Stopping either her beta-blocker or ACE inhibitor is not the best option for
treatment at this stage.
Bendroflumethiazide
the target of action of thiazide diuretics NaCl co-transporter
the target of action of loop diuretics NKCC2
•
Bendroflumethiazide (bendrofluazide) is a thiazide diuretic which works by inhibiting sodium
absorption at the beginning of the distal convoluted tubule (DCT).
•
The NaCl co-transporter:
the target of thiazide diuretics
it contributes to the reabsorption of about 10% of the filtered load of sodium.
Mutations causing loss of function of the NaCl co-transporter cause Gitelman's
syndrome, the commonest monogenic cause of hypokalaemia in adults.
•
Potassium is lost as a result of more sodium reaching the collecting ducts.
•
Bendroflumethiazide has a role in the treatment of mild heart failure although loop diuretics
are better for reducing overload.
•
The main use of bendroflumethiazide was in the management of hypertension but recent
NICE guidelines now recommend other thiazide-like diuretics such as indapamide and
chlortalidone.
Bendroflumethiazide - mechanism of Hypokalemia: • ↑ sodium reaching the collecting ducts • Activation of the renin-angiotensin-aldosterone
Which loop diuretic is known to cause sulfa-drug allergy?
Furosemide
Which loop diuretic is used for diuresis in patients allergic to sulfa drugs?
Ethacrynic Acid
Notes & Notes for MRCP
By Dr. Yousif Abdallah Hamad
Chapter 13
Pharmacology
Common adverse effects
•
dehydration
•
postural hypotension
•
hyponatraemia, hypokalaemia,
Hypomagnesaemia, hypercalcaemia
•
gout
•
impaired glucose tolerance
•
impotence
Rare adverse effects
•
thrombocytopaenia
•
agranulocytosis
•
photosensitivity rash
•
pancreatitis
•
hypochloraemic alkalosis
Amiloride
• The potassium-sparing diuretic amiloride inhibits sodium channels in the distal segment
of the distal convoluted tubule
• Amiloride inhibits the action of aldosterone on the distal convoluted tubule producing
potassium reabsorption.
• In treating a patient with congestive heart failure who develops hypokalaemia, the
best choice is to add a small dose of amiloride to his furosemide therapy
Triamterene
• Triamterene, a potassium sparing diuretic similar to amiloride.
• occasionally prescribed with thiazide or loop diuretics, to prevent hypokalaemia.
• It inhibits the movement of sodium through channels towards the end of the distal tubule
and collecting ducts, preventing the passage of sodium from the urinary space into the
tubular cells. This action causes hyperpolarisation of the apical plasma membrane,
preventing the secretion of potassium into the collecting ducts.
• Hyperkalaemia is common (>5%), and is unaffected by concurrent potassium depleting
diuretics.
• In mild hyperkalaemia, (eg: K = 5.9 mmol/l) with no evidence of cardiac toxicity. The
management involves stopping the triamterene, and repeating the U&E in one week.
Spironolactone
• Spironolactone is an aldosterone antagonist
• acts in the cortical distal convoluted tubule and collecting duct.
Indications
•
ascites: patients with cirrhosis develop a secondary hyperaldosteronism. Relatively large
doses such as 100 or 200mg are often used
•
hypertension: used in some patients as a NICE 'step 4' treatment
•
heart failure (see RALES study below)
•
nephrotic syndrome
•
Conn's syndrome
•
Spironolactone is a diuretic with anti-androgen effects. This makes it a useful agent in
the treatment of hormonal acne and hirsutism.
It blocks the androgen receptor and 5α-reductase enzyme that is responsible for the
synthesis of dihydrotestosterone (DHT) and can be used to treat hirsutism.
Adverse effects
•
hyperkalaemia
•
gynaecomastia
Spironolactone and eplerenone are both aldosterone receptor antagonists that have
shown survival benefit in patients with NYHA III/IV systolic heart failure.
Notes & Notes for MRCP
By Dr. Yousif Abdallah Hamad
Eplerenone has a lower antiandrogenic effect compared to spironolactone and may, therefore, be preferable if patient develops erectile dysfunction and bilateral gynecomastia. RALES • NYHA III + IV, patients already taking ACE inhibitor • low dose spironolactone reduces all-cause mortality
Eplerenone Indications • Eplerenone is a spironolactone-like agent indicated as an add-on to standard therapy after a myocardial infarction, and heart failure Side-effects • Common side-effects: hyperkalaemia, dizziness, hypotension, diarrhoea, nausea and prerenal renal dysfunction • Uncommon side-effects : eosinophilia, dehydration, hypercholesterolemia and hypertriglyceridaemia Cautions • The drug is metabolised via the CYP3A4 system, so that inducers or inhibitors of the 3A4 enzyme subtype may precipitate drug interactions
Diuretic abuse • Diuretic abuse is not uncommon amongst athletes and jockeys as a means of weight loss. • The patient has a hypokalaemic alkalosis, and urine potassium excretion is high despite the hypokalaemia.
Respiratory drugs
_______________Theophylline
• Theophylline, like caffeine, is one of the naturally occurring methylxanthines.
• The main use of theophyllines in clinical medicine is as a bronchodilator in the management
of asthma and COPD
Action
• The exact mechanism of action has yet to be discovered.
• One theory suggests theophyllines may be a non-specific inhibitor of phosphodiesterase
resulting in an increase in cAMP.
• antagonism of adenosine and prostaglandin inhibition
It blocks the adenosine receptor
Blockade of the receptors by theophylline results in:
relaxation of smooth muscles, especially bronchial muscles
constriction of cerebral blood vessels
stimulation of the cardiac pacemaker
stimulation of gastric secretions
• Theophylline also releases calcium ions from the sarcoplasmic reticulum in skeletal and
cardiac muscle, thus enhancing their contractility, including diaphragmatic contractility
• plasma theophylline concentration of between 10 and 20 mg/l is required for satisfactory
bronchodilatation.
Side effect
• At therapeutic doses, the side-effect of Aminophylline Jitteriness
Notes & Notes for MRCP
By Dr. Yousif Abdallah Hamad
Chapter 13
Pharmacology
• adverse effects can occur within the range 10-20 mg/l and both the frequency
• severity increase at concentrations above 20 mg/l
Factors increasing the plasma theophylline concentration:
• heart failure
• cirrhosis
• viral infections
• increased age (the elderly)
• Diet:
Obesity
High carbohydrate intake
High methylxanthine intake (for example, tea, coffee)
• drugs that inhibit its metabolism
Commonly prescribed drugs that can increase serum theophylline levels include:
clarithromycin, erythromycin
ciprofloxacin,
cimetidine,
oral contraceptives
allopurinol.
Fluvoxamine
Consideration should be given to reducing theophylline dose when these drugs are
prescribed.
• cessation of enzyme-inducing drugs.
Factors decreasing the plasma theophylline concentration: (increasing theophylline
clearance):
• Diet:
Low carbohydrate
High protein intake
• Social:
chronic alcoholism without cirrhosis
smoking
Smoking cessation sudden increase in theophylline level
Regular tobacco use up-regulates hepatic enzyme activity; cessation
will be associated with a decrease of hepatic enzyme activity, such that
theophylline concentrations may increase.
• Drugs: drugs that induce liver metabolism: eg:
Rifampicin
Carbamazepine.
Theophylline poisoning • Theophylline has a narrow therapeutic window and needs close monitoring of its serum level to avoid toxicity • Symptoms of toxicity may be delayed following the ingestion of sustained-release preparations for up to 48 h • Theophylline toxicity occurs with concomitant use of clarithromycin due to inhibition of cytochrome P450 (CYP1A2 and CYP3A4) by clarithromycin. • Features of mild to moderate theophylline toxicity include nausea, vomiting, epigastric, tremor, tachycardia, restlessness and hallucinations. Severe toxicity can cause convulsions, arrhythmias and metabolic acidosis. • Studies have shown an approximate 20% increase in both peak and trough theophylline levels with concomitant use of clarithromycin and it is recommended that theophylline levels should be monitored prior, during and on cessation of clarithromycin and dosage
Notes & Notes for MRCP
By Dr. Yousif Abdallah Hamad
adjustment of theophylline made accordingly. • Features mild to moderate theophylline toxicity nausea, vomiting, epigastric, tremor, tachycardia, restlessness and hallucinations. Severe toxicity: convulsions, arrhythmias metabolic acidosis, hypokalaemia and hyperglycaemia • Management activated charcoal charcoal haemoperfusion is preferable to haemodialysis In cases of severe theophylline toxicity, charcoal haemoperfusion can be used
Antimuscarinic agent • Muscarinic antagonists (antimuscarinic agents) are a group of anticholinergic drugs that competitively inhibit postganglionic muscarinic receptors. • Which organ systems are most affected by an antimuscarinic agent depends on the specific characteristics of the agent, particularly its lipophilicity. Lipophilic agents (i.e., atropine or benztropine) are able to cross the bloodbrain barrier and therefore affect the central nervous system (CNS) in addition to other organ systems. Less lipophilic agents (i.e., ipratropium or butylscopolamine) are administered if the CNS does not need to be targeted, specifically for respiratory (e.g., asthma), gastrointestinal (e.g., irritable bowel syndrome), or genitourinary applications (e.g., urinary incontinence).
Notes & Notes for MRCP
By Dr. Yousif Abdallah Hamad
Chapter 13
Pharmacology
Action • Muscarinic antagonists (the majority of anticholinergic drugs) inhibit the effect of acetylcholine on muscarinic receptors, Effects of muscarinic antagonists Muscarinic receptors Organ/Tissue Effects M1, M4, M5 Central nervous system • Influences neurologic function (e.g., cognitive impairment) M2 Heart • ↑ Heart rate • Increases AV-node conduction → arrhythmias M3 Smooth muscle • Gastrointestinal tract ↓ Intestinal peristalsis , ↓ Salivary and gastric secretions • Urinary tract ↓ Bladder contraction (decreases detrusor muscle tone, increases the internal urethral sphincter tone) • Airway Bronchodilation ↓ Bronchial secretions • Eye Mydriasis → narrowing of the iridocorneal angle Impaired accommodation • Blood vessels: minimal effect on vascular tone and blood pressure Exocrine glands • ↓ Secretions (sweat) Antimuscarinic side effects "Blind as a bat (mydriasis), mad as a hatter (delirium), red as a beet (flushing), hot as a hare (hyperthermia), dry as a bone (decreased secretions and dry skin), the bowel and bladder lose their tone (urinary retention and paralytic ileus), and the heart runs alone (tachycardia).”
Side effect
Contraindications
Impaired
secretion by
exocrine
glands
•
Dry mouth and sore throat
•
↓ Respiratory tract secretions
•
Hyperthermia und warm, dry skin
Cardiovascular
system
•
Tachycardia
•
Tachyarrhythmias
Decreased
smooth muscle
tone
•
Gastroesophageal reflux
•
Obstipation or ileus
•
Impaired micturition/urinary retention
•
Vasodilatation and flush
Eye
•
Mydriasis and photophobia
•
Blurred vision
CNS
•
Excitement, agitation, and hallucinations with
the use
of lipophilic parasympatholytics (e.g., atropi
ne), especially in elderly patients
•
Confusion, disorientation
•
Coma, seizure, and rarely death
Notes & Notes for MRCP
By Dr. Yousif Abdallah Hamad
• Acute asthma • Respiratory distress • Heart failure • Myocardial infarction • Hyperthyroidism • Hiatal hernia associated with reflux esophagitis • Ulcerative colitis • Paralytic ileus • Obstructive disease of the gastrointestinal tract (e.g., achalasia, pylori c stenosis or duodenal stenosis) • Obstructive uropathy (e.g., benign prostatic hyperplasia, urinary retention) • Narrowangle glaucoma • Myasthenia gravis
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