Drug Class Individual Examples or Molecular mechanism and resultant effect Main Clinical use(s) Common or important unwanted

e(s) Common or important unwanted Any cautions or contra- monitoring Any significant drug
common ending effects indications requirements interactions
Alpha adrenoceptor -osin Competitive reversible antagonist of alpha1 -Resistant hypertension. -Postural hypotension Postural hypotension? - -
antagonists adrenoceptor; prevents noradrenaline-mediated -secondary hypertension -dizziness Heart failure?
-(phaeochromocytoma) -fainting
constriction of smooth muscle; vasodilator urinary retention in prostate -headache
hyperplasia - nasal congestion
-urinary incontinence
Beta adrenoceptor -lol The stimulation of Beta1 adrenoreceptor by -Uncomplicated HT (less -bradycardia -asthma -Gradual - Be weary with other
antagonists (beta (nor)adrenaline -> increase cAMP -> contraction of common now) -heart block -bradycardia & heart block withdrawal drugs which slow the
-arrythmias -B2 antagonism (poor tissue perfusion,
blockers) heart muscle is blocked by Beta1 adrenoreceptor -angina pectoris bronchospasm) -acute HF heart rate (CCB)
antagonists. -post MI -diarrhoea, nausea -type 1 diabetes
-(stable) HF -AV metabolic effects (hypoglycaemia, -claudication
dyslipidaemia)
Organic nitrates Glyceryl trinitrate Requires an SH group. Nitrates bind to receptor in -Acute effort angina -Headache - Caution defibrillating with - -other vasodilators
vascular smooth muscle, NO group stimulates -Angina @ rest (Prinz metal) -Flushing nitrate patches particularly nifedipine
- acute HF -Hypotension with syncope
cGMP-> increase PKG-> decrease Ca2+ in cell -Tachycardia -Alcohol
Phosphate released from myosin and it relaxes.
Isosorbide mononitrate - Angina Prophylaxis (all vasodilators cause the above
-Acute HF symptom)
Calcium channel Depolarised L-type Ca Blocks Calcium channels-> decrease in calmodulin -Hypertension -Vasodilator associated symptoms -Aortic stenosis - -
modulators Channels; Non rate- -> ↓ in MLCK -> ↓ in cross bridges -> vasodilation in -All types of angina (used less so -peripheral oedema -Severe Myocardial
that rate limiting CCB) -HF (rare in patients with poor LVF)
limiting: -dipine smooth muscle Depression
Hyperpolarised L-type Blocks Ca channels -> ↓ in calmodulin -> ↓ in MLCK -Supraventricular Arrythmias -Vasodilator associated symptoms but Verapamil->Sick sinus syndrome, - -Can increase the effects
Ca channels; Rate- -> ↓ in crossbridge -> cardiac muscle relaxes -> -All types of angina cause bradycardia instead and less impaired cardiac conduction of digoxin
-Hypertension (less so than non- marked oedema Diltiazem ->Myocardial
limiting: inotropic effect rate limiting) -Constipation in the elderly Verapamil ->
depression & Impaired cardiac
verapamil, diltiazem -Verapamil-> steal effect Combinations with large
conduction
-Diltiazem-> heart block doses of beta blockers
ACE Inhibitors -pril Block the ACE preventing angiotensin 1 being -Hypertension -Dry cough -taste disturbance -Renovascular disease - Start with a -diuretics
converted to angiotensin 2-> ↓ in Ang2 -> ↓ in -Post MI -Rarely angioedema -teratogenicity -Watch for rising K+ small dose in -Other hypotensive
-High risk IHD patients -Acute renal failure
aldosterone from kidney. Bradykinin metabolism -HF -First dose hypotension Do not give if pregnancy is HF patients agents
is also inhibited -> ↓ sympathetic activation, -Diabetic nephropathy -hyperkalaemia planned NSAIDS
vasodilation. -Progressive renal insufficiency -skin rash -Severe aortic stenosis
Angiotensin -sartan Antagonise the effects of Ang2 at the AT1 -Hypertension when intolerant -1st dose hypotension -Similar to ACEI + -Start with a -diuretics
receptor receptors. Metabolism of bradykinin is not to ACEI -Acute renal Failure -bilateral renal artery stenosis low dose -Other hypotensive agents
-rest are similar to ACEI -hyperkalaemia -atherosclerosis in the elderly
antagonists (ARB’s) prevented -rarely angio-oedema -NSAIDS
PCT: Osmotic Mannitol Freely permeable, affects osmotic gradient -Increased intracranial pressure -hypotension, fluid, and electrolyte -renal impairment -Electrolytes -Aminoglycosides
diuretics reducing amount of H2O reabsorption (cerebral oedema) imbalance -Hepatic impairment should be -other diuretics
PCT: CAI diuretics Acetazolamide Inhibitions of carbonic hydrase in PCT-> loss of -Glaucoma -Metabolic acidosis -3rd trimester pregnancy Monitored, -diabetic drugs
acid base balance decrease Na+ & HCO3- -Acute altitude sickness -Hypokalaemia -Symptomatic especially -anticonvulsants
-Epilepsy -Renal stone formation
reabsorption-> weak diuretic as DCT compensates -Glaucoma -Haemorrhage hyperuricaemia (gout) with long -digoxin
Thiazide & thiazide- -thiazide Acts early in DCT. Inhibits Na+/Cl- co-transporter. Most -HT in elderly & black African -Urate retention (gout) -Addison’s disease Term use -same as Loop diuretics but
Na+ already reabsorbed. ↑ Ca2+ reabsorption due to -2nd/3rd line below CCB for HT but - Hyponatremia, Hypokalaemia milder +
like diuretics indapamide considered 1st/2nd if oedema is
- Arrythmias and high
Na+ gradient across basolateral membrane. -↑cholesterol & hyperglycaemia -Lithium
present. Osteoporosis? -Hypercalcaemia -Hyponatraemia doses.
Loop diuretics Furosemide (-ide) Secreted into PCT cells via OAT. Na+/K+/2Cl- co- -Pulmonary Oedema -Hypo… volaemia, kalaemia, -Thiazide diuretics (both are
transporter inhibited in ascending limb. ↓ Medullary -Chronic HF magnesaemia, natraemia, strong)
-Resistant Hypertension hypocalcaemia -aminoglycoside antibiotics
interstitial osmolarity -> ↓H2O reabsorption @ CD.
-Nephrotic syndrome -Hyperuricaemia (gout) -ACEI & other vasodilators
↑Ca2+ + Mg2+ secreted as no p.d created -Acute hypercalcaemia -Oto & renal toxicity (high dose) -NSAIDS (diuresis impaired)
-Allergic skin & kidney reactions
Potassium-sparing Aldosterone dependent: Aldosterone receptors blocked leading to deactivation of -4th agent in resistive HT -Hyperkalaemia , hyponatraemia -ACEI
diuretics Spironolactone silent Na+ channels. ↑Na+ secretion. ↓ K+ & H+ -Conn’s syndrome -Metabolic acidosis -Drugs known to cause
secretion. Late DCT -Secondary Hyperaldosteronism Gynaecomastia, testicular atrophy & hyperkalaemia
-HF (blocks aldosterone) menstrual irregularities
Aldosterone- Late DCT. Block Na+ channels. ↓ p.d across principal -loop or thiazide induced hypoK+ -Hyperkalaemia, hyponatraemia -Lithium
independent: amiloride cell. ↓ K+ & H+ excretion. ↑ Na+ excretion. -Metabolic acidosis -Hyperkalaemia causing
drugs
Cardiovascular drugs
 Anti-platelet, anti-coagulant and lipid lowering drugs

Drug Individual Molecular mechanism and resultant effect Main Clinical use(s) Common or important Any cautions or contra- monitoring requirements Any significant drug
Class Examples or unwanted effects indications interactions
common ending
Anticoag Warfarin -Inhibitor of Vit K epoxide reductase, preventing the -Prophylaxis of DVT/PE -Haemorrhage -Pregnancy -Check baseline PT -↓ effect: Alcohol,
ulants -Prophylaxis of atrial fibrillation -Alopecia -Active bleeding -Loading dose 1-3 days rifampicin, anti-
(Vit K antagonist) regeneration of reduced Vit K, needed for clotting synthesis. epileptics, rifampicin
(more -Prophylaxis of valve emboli when -Fall in Hb -Recent peptic ulcer -Aim for INR maintenance dose & monitor INR
Delayed onset of drug due to stored reserves. Clotting -Severe HT regularly. (anti-biotic)
importa factors precursors II, VII, IX, X (1972) can’t be reduced to prosthetic valves are being fitted -GI upset -↑ effect: Most
nt in -Teratogen -Bacterial Endocarditis -If major bleed give; Vit K (slow IV/ oral),
clotting factor -> VIIa, IXa, Xa & Thrombin (IIa) can’t be -Haemophilia prothrombin complex or FFP. INR<8 & NO bleed antibiotics, NSAID’s,
venous formed -> ↓ clotting ability. -Skin/ soft tissue necrosis anti-platelets & other
-Recent surgery withdraw. INR>8 & bleed withdraw and may need
thrombo anti-coagulant’s
reversible agent.
sis)
UFH -Binds to and activates ATII. UFH-ATII inactivates thrombin -Prophylaxis & treatment of DVT/PE -Haemorrhage -Bacterial Endocarditis -Routinely monitor platelet count & measure -NSAIF’s
IIa & Xa. LMWH does not act long enough to inactivate -Extracorporeal circuits (haemodialysis) -↓ aldosterone secretion -Major trauma heparin platelet antibodies. -Anti-platelets
-Less useful but still used in acute (hyperkalaemia) -anaesthesia -UFH given as bolous then infusion adjusted by
thrombin (IIa), main effect is Xa. UFH acts faster but for -Thrombocytopenia APTT->aim for 1.5-2.5x control.
coronary syndrome & peripheral arterial -Haemophilia
shorter time whereas LMWH has a slower onset but lasts -Hypersensitivity Reactions - -LMWH does not affect APTT, can measure factor
occlusions. -Peptic Ulcer-Cautioned in
longer. Rarely osteoporosis & using Xa activity if needed though rarely done.
alopecia the elderly
LMWH: - 1% patient’s immune- -Protamine sulfate binds to drug making it
Enoxaparin sodium mediated HIT ineffective and acting as an antidote.
NOACS/DOACS: -Direct inhibition of Thrombin (IIa) which affects the -treatment & prophylaxis of -GI upset -Similar to warfarin & -INR not reliable/required -Other coagulants
dabigatran coagulation cascade -> ↓ coagulation. Shorter duration of DVT/PE -Abdominal pain heparin but with a -Before treatment: U&E, LFT, FBP & -NSAID’s
(Antithrombin -Dyspepsia reduced risk of coagulation profile -P-gp1 or enzyme
inhibitor)
action compared to warfarin & heparin. -Prophylaxis of stroke in
-Haemorrhage haemorrhage. -During treatment: @3 months adherence, Inhibitors or inducers
NOACS/DOACS: -Direct inhibition effect of Xa which affects the coagulation Non-valvular atrial fibrillation -Thrombocytopenia AV effects, efficacy. @ 6months: U&E, LFT &
xaban (Xa inhibitor) cascade -> ↓coagulation. Shorter duration of action. FBP.
Anti- Aspirin (COX-1 Selectively & irreversibly inhibits COX-1 -> ↓ TXA2 -> ↓ platelet -Secondary prevention: Ischaemic -GI irritation/ bleeding -Lack of response in some - -Ibuprofen (can make
platelet inhibitor) aggregation -> ↑ bleeding time. ↑ vasodilation as TXA2 is a stroke/TIA, angina pectoris, ACS, post - hypersensitivity reactions patients it less effective)
agents vasoconstrictor. @ higher doses COX-2 can be inhibited -> ↓ PGI2. MI, following stents/bypass, peripheral -Reye’s syndrome in some -Irreversible platelet -In conjunction
PGI2 inhibits aggregation & causes vasodilation so inhibiting this inhibition
(more arterial disease, in atrial fibrillation if kids
has unwanted effects for what aspirin aims to do. Platelets have no -Patients allergic to NSAID’s
importa nuclei and so can’t generate new COX-1. Anti-aggregatory effect of warfarin contraindicated.
-Anaemia
nt in drug is irreversible for 7-10 days. Daily generation of new platelets -Primary prevention: CVD (less common
-Haemophilia
arterial is 10-14% per day- recovery of platelet function by 4-5 days after now)
-Von Willibrand
thrombo drug cessation. Aspirin selectivity COX-1>COX-2.
sis) Thienopyridines ADP binds to purinergic P2Y12 receptors on platelets unmasking -Secondary prevention in patients -GI bleeding & irritation -Irreversible inhibition of - -Proton pump
-grel glycoprotein receptors (GPIIb/IIIa) that become exposed to fibrinogen intolerant to aspirin. -Dyspepsia P2Y12 ->bleeding risk for 7- inhibitors-> influence
enhancing platelet aggregation. Thienopyridines are a pro-drug. 15% -With aspirin for 3 months after ACS & -Hypersensitivity reactions 8 days enzymes that
undergoes a 2-step oxidation by CYP2C19 enzymes in the liver. Active coronary artery surgical procedures. -genetic variation in liver metabolise it
metabolite selectively and irreversibly inhibits ADP-> ↓ platelet enzymes to activate it
aggregation.
Ticagrelor & Cyclopentyl-triazolo-pyrimidine that does not bind to ADP binding -ACS patients undergoing PCI with -haemorrhage -chest pain -More potent than - -CYP3A inhibitors as
site but a separate site on P2Y12 receptor reversibly inhibiting it & thrombosis -dyspnoea -HBP or LBP clopidogrel with ↑ ticagrelor is
cangrelor bleeding risk.
preventing G-protein signalling. Rapid onset and offset. P2Y12 - Used when something stronger than -nausea -cough metabolised by this.
signalling blocked-> fibrinogen not unmasked & so ↓aggregation. clopidogrel is needed. -diarrhoea -back pain -anti-fungal
- lipid controlling drugs
Dipyridamole TXA2 synthase inhibitor, may also enhance prostacyclin -Given with oral anti-coagulants for -GI bleeding -Aortic stenosis - -riociguat
synthesis, Phosphodiesterase inhibitor [↑cAMP] & inhibits thromboembolism prevention in patients -Dizziness -Coagulation disorders -Other anti-platelets
with prosthetic heart valves. -myalgia -hypotension
reuptake & metabolism of adenosine. Collectively these
mechanisms ↓ platelet adhesion + aggregation & ↑ vasodilation. -Given with aspirin for 2⁰ prevention of -chest pain
ischaemic stroke, TIA -Hypersensitivity reactions
Lipid- -statin HMG-CoA reductase inhibition-> ↓ cholesterol synthesis -> up- -High cholesterol -> used to lower LDL. -Myalgia/ myositis/ -pregnant - Before starting check… lipid profile, - Other statins
lowering regulation of LDL receptors -> movement of LDL into cells -> ↓ rhabdomyolysis -history of liver liver functioning, CK -Possibly other
agents circulating LDL. -GI disturbance abnormalities /muscle pain cardiovascular drugs
-Liver enzyme abnormality -heavy drinkers
ezetimibe Reduces LDL being absorbed across the GI-wall. -High cholesterol -> used to lower LDL. -GI disturbance - -statins & fibrates
-Headache
-ocumab Monoclonal antibodies against PCSK-9 (PCSK-9 inhibitors)-> -High cholesterol -> used to lower LDL. -Nasopharyngitis -Pregnant - -Statins
(Evolocumab & ↑ recycling of LDL receptors -> ↑ absorption of LDL into liver cells. -Back pain -Hepatic or renal
Alirocumab) Taken fortnightly or monthly but expensive. Store in fridge @ 2-8 ⁰C. -Flu-like symptoms impairment
Fenofibrate Activate the nuclear transcription factor PPARαespecially in liver -High cholesterol -> used to lower LDL. -GI upset -Gall bladder disease -Monitor hepatic traminases every 3 months -Statins
muscle. Increased transcription for lipoprotein lipase, apo-A1 & apo- -Myalgia -Pacreatitis for the first 12 months of treatment.
A5 -> ↓ VLDL -> ↓ triglycerides. -hypothyroidism
 Respiratory drugs

Drug Class Individual Examples or Molecular mechanism and resultant effect Main Clinical use(s) Common or important unwanted Any cautions or contra- monitoring Any significant drug
common ending effects indications requirements interactions
Beta2 adrenoceptor SABA: Activation of β2 adrenoreceptors -> ↑ cAMP -> activation of -Acute Symptomatic relief for -Tremor -Loss of responsiveness to -Inhaler -linezolid risk of increased BP
agonists Salbutamol PKA -> phosphorylation of MLKC & Ca2+-dependent K+ channels asthma & COPD. -tachycardia @ high dose (selectivity of treatment with excessive use. technique - risk of glaucoma with
-> bronchodilation. Short acting eliminated within (3-4 hours). βreceptor is dose dependent)
levalbuterol tartrate ipratropium
-Hypokalaemia
LABA: Activation of β2 adrenoreceptors ->C cAMP -> activation of -Management of chronic -Muscle cramps -Tachycardia -Loss of responsiveness to -Inhaler
Salmeterol PKA -> phosphorylation of MLKC & Ca2+-dependent K+ channels asthmatic - Throat irritation -Tremor treatment with excessive use. technique
-> bronchodilation. Longer acting eliminated within (12 hours) -prophylaxis of exercise or -pulmonary oedema (with parenteral
Impatronium Glyccoride allergen induced bronchospasm. use)
-Moderate/ severe asthma -Hypokalaemia
Muscarinic SAMA: ipratropium -Block muscarinic receptors, antagonise bronchospasm & -irritant induced asthma -No tremor or arrythmias -GI & urinary disruptions for -Inhaler -Avoid if known
antagonists bromide ↓ mucus secretion. Inhaled; bronchodilation maximal -COPD with episodes of -Cause dry mouth oral ipratropium. technique hypersensitivity to atropine
effect 30-60 mins after use. For a duration of 3-6 hours. bronchospasm -GI upset -Glaucoma & its derivatives
-reversible airway obstruction -Throat complaints -Cystic Fibrosis - β2 agonists- risk of
-sever/life threatening acute -Eye & vision disorders -Avoid spraying near eyes glaucoma
asthma.
-Acecdotal

LAMA: -Block muscarinic receptors, antagonise bronchospasm & -Maintenance treatment for -GI upset -Bronchospasm -Arrhythmias previous 12 -Inhaler -Other antimuscarinic drugs -
tiotropium ↓ mucus secretion. Longer acting bronchodilation. COPD - Taste disturbance -Insomnia months technique > ↓ absorption of levodopa
-Severe asthma add on to -Risk of infection -dysphagia -HF previous 12 months
corticosteroids -MI in previous 6 months.
Inhaled Budesonide Bind to nuclear receptors -> Long acting. GRE ejected from -Prophylactic of asthma -Oropharyngeal candidiasis – - Care should be taken in -Inhaler -Antidiabetic drugs
corticosteroids Beclomethasone corticosteroid binding globulin & binds to cytosolic receptor (budesonide) suppressed mucosa immunity leading patients with untreated technique -Antiretroviral drugs
which exposes a DNA binding domain. This allows the steroid- -Asthma maintenance & COPD to bacterial growth (wash mouth after quiescent TB, or other -Potassium level -P450 inhibiting drugs
receptor complex to associate with glucocorticoid response (beclomethasone in dual use to prevent) untreated infections monitoring may -Cobicistat
elements present in promoter region of target genes. mRNA therapies) -Throat irritation be needed with -Azole antifungals
strands produced -> anti-inflammatory proteins are produced
-Wheeze the use of
-> anti-inflammatory immunosuppressive response -> ↓
beclomethasone
phospholipase A2 & COX-2. ↑ β2 responsiveness
Leukotriene -lukast Antagonise Leukotriene (LTD4) receptors resulting in a -Exercise induced asthma -Abdominal pain -Avoid unless essential in -Predicted to ↑ exposure:
receptor Montelukast & combination of broncho-dilatory & anti-inflammatory -Allergen (Concomitant -Headache Churg-Strauss syndrome pregnancy & breast feeding Clopidogrel, Fibrates,
antagonists Zafirlukast effects. Less effective than corticosteroids – but they rhinitis) induced asthma -URTI - Leflunomide, opicapone,
have an additive effect when given with corticosteroids. -GI upset
(Generally well tolerated drugs). Given orally as tablets. -Less effective in severe - diarrhoea -Predicted to ↓ exposure:
asthmatic patients receiving -Nausea Antiepileptic drugs,
high doses of other drugs. -Headache Enzalutamide, Mitotane,
-Skin reactions Rifampicin

Xanthine’s Theophylline -Inhibit phosphodiesterase (cAMP/ cGMP), block -Difficult to control asthma -Nausea -Hyperuricaemia -Bad P450 liver metabolism (old Narrow -Serum theophylline levels ↑
adenosine receptors, prevent diaphragmatic fatigue. Oral -stable COPD (not effective in -arrythmias -Urinary disorder age, smoking, alcohol, other therapeutic by: OCP, Erythromycin,
slow-release formulas (not used as much any more due acute obstructive -Convulsions - GI discomfort medications) window -need to CCB, cimetidine
to narrow therapeutic window and long list of adverse exacerbations) -Anxiety -Vomiting -Heart arrythmias or disease monitor drug
-dizziness -Epilepsy levels -Serum theophylline levels ↓
effects) by: Phenytoin,
-Headache -Hyperthyroidism
-Palpitations -Peptic Ulcer Carbamazepine & rifampicin
-Seizure -Hypertension
-Skin reactions -Fever
Anti-arythmetics

Drug Individual Examples or Molecular mechanism and resultant effect Main Clinical use(s) Common or important unwanted Any cautions or contra- monitoring Any significant drug
Class common ending effects indications requirements interactions
- Inhibits Na+/K+ channels. ->Increase in intracellular level of Na+. - -Atrial fibrillation Arrhythmias Eosinophilia Hypercalcaemia Heart Block -plasma-digoxin [ ]
> Increased Na+ decreases the Na+/Ca2+ exchanger decreasing Cerebral impairment Nausea Hypokalaemia Myocarditis assay
Digoxin -Atrial flutter Hypomagnesaemia 2nd degree AV block -Electrolytes See BNF
Anti- release of Ca2+ from cells. -> Increase in Ca2+ in cells slowing down Diarrhoea Skin reactions
arithmetic’
-Heart failure (for sinus rhythm patients) Dizziness Visual disorders Hypoxia WPW syndrome -Renal function
the conduction velocity through the AV node. Vent tachycardia Ventricular fib.
s Gynaecomastia
Hydrazaline Elevates cGMP leading to a relaxation of the -Older antihypertensive Tachycardia Flushing -Systemic lupus erythematous
-Pregnancy Palpitations Headache -IHD
smooth muscle (arterioles>veins) Fluid retention Drug-induced lupus Cerebrovascular Disease
Other hypertensives
-Severe hypertension
-Symptomatic bradycardia due to acute
Atropine Anti-muscarinic receptor blocker overdosage of Beta-blockers
Constipation
-Ant. Uveitis Dizziness
-Cycloplegia Dry mouth
-GI symptom relief caused by smooth
Dillator related symptoms
 muscle spasm.

Amiodarone (specialist Increases the refractory period in cardiac tissues -Heart arrythmias
drug) by blocking K+ channels
Can also block Na+ channels and Ca2+ channels.
-AF -Elderly Other anti-hypertensive
Ivabradine Blocks the IF currents (Na+ channels), in phase 4 -Angina in patients with normal -AV block
-Arrythmias -Hypotension
of the Pacemaker AP, having an inotropic effect sinus rhythm. -Dizziness -Hepatic imp. -Renal imp.
-Mild to severe Chronic HF -Headache
Hypertension management:

ACUTE HF management:

 IV loop diuretics e.g. furosemide or bumetanide

 Possible additional treatments…
o Oxygen (, i.e. keep oxygen saturations at 94-98%)
o vasodilators (Nitrates)
 Treat cardiomyogenic shock if it occurs

CHRONIC HF management:

 Loop diuretics to manage oedema (NOTE: they don’t improve long term mortality)
 The first-line treatment for all patients is both an ACE-inhibitor and a beta-blocker (improve mortality in chronic HF)
o ACE-I & β-blockers have no effect on mortality in heart failure with preserved ejection fraction, HFpEF (diastolic failure)
 Second-line treatment is an aldosterone antagonist – Monitor K+

WARFARIN inducers and inhibitors

 Warfarin is metabolised by CYP450

 CYP450 inducers decrease Warfarin levels in the blood (increase clot risk/ lower INR)
o St. John’s Wart
o Anti-epileptics (e.g carbamazepine, phenytoin, phenobarbital)
o Rifampin
o Smoking

 CYP450 inhibitors increase Warfarin levels in the blood (increase Haemorrhage risk/ high INR)
o Valproic acid
o Anti-fungal ( Fluconazole, Miconazole)
o Amiodarone (Heart Arrythmias)