Cardiovascukar therapeutics

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  • Created by: z
  • Created on: 18-03-16 17:59

Hypertension

  • stages:
    • stage 1 HTN: BP>140/90 mmHg 
    • stage 2 HTN: > 160/100mmHg
    • severe HTN: >180 systole or >110 diastole
    • WCH (white coat HTN)/masked HTN (opposite)
  • causes: inceased volume or constriction
  • Rx:
    • step 1 
      • under 55 yr = A (ace inhibitor or angiotensin II R blocker)
      • > 55 or black = C (CCB)
    • step 2 = A + C
    • step 3 = A + C + D (thiazide like diuretic)
    • step 4/resistant HTN = A + C + D + further diuretic pr alpha/beta blocker, seek expert advice
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RAA system drugs

  • ACEi
    • e.g. ramipril, perindopril, lisinopril, enalapril
    • s/e: dry cough (bradykinin). first dose hypotension, reversible AKI, hyperkalaemia
      • rare: angioedema
    • must check U&Es after titration
    • CI: pregnancy, bloodfeeding, renal artery stenosis
    • also use in: CKD, CCF, post-MI
  • ARBs
    • e.g. losartan, candesartan, valsartan
    • s/e: no cough, else same as ACEi
    • CI: same as ACEi > check U&Es
    • also used in: CKD, CCF
  • direct renin inhibitors
    • e.g. aliskiren
    • limited clinical use
    • s/e diarrhoea, AKI, svere allergic reactions
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Beta-adrenergic receptor antagonists

  • cardioselective (B1): bisoprolol, metoprolol, atenolol, nebivolol
  • non-selective: propanolol
  • w/ weak alpha blocking: carvedilol, labetalol
  • B-ad Rs and GPCR- stim adenylate cyclase and cAMP r[prod
    • B1: incr cardiac rate and force
    • B2: vasodilation, bronchodilation, smooth m relaxation. hepatic glycogenolysis, tremor
  • thus action of beta blockers:
    • reduce CO (HR and SV)
    • inhibit renin release
    • s/efatiwgue, bradyC, bronchoconstriction, cold extremities, ED, depression, hypoglycaemia
  • clinical uses: CCF, IHD, arrythmias, anxiety, migraine prophylaxis, oesophageal varices, glaucoma, thyrotoxicosis,essential tremor
  • CI:
    • absolute: asthma
    • relative: peripheral vascular disease, acute HF
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Alpha-adrenoceptor antagonists

  • alpha-1 blockers e.g. doxazosin, terazosin
  • action: vasodilation (block alpha-med constriction)
  • s/e/ postural hypotension
  • use in BPH
  • only use as add on Rx for HTN (step 4)
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CCBs

  • block Ca+ entry through L-typw CCs
  • action: vasodilation
  • 2 types:
    • dihydropyridines- act preferntially on vascular smooth m.
      • e.g. amlodipine, nifedipine, felodipine
      • 1st line for afro-caribbean pt and >55yros
      • s/e: ankle swelling, GORD, flushing, gingival hyperplasia
      • also use for Raynaud's, angina
    • non-dihydropyridines: act on heart and blood vessels
      • e.g. verapamil (esp heart), diltiazem (intermediate)
      • rate limiting CCBs
      • short elimination hal flifes- use modifed release versions
      • s/e: worsening FF, herat block, constipation (verapamil)
      • also use for: arrythmias, angina, migraine, cluster headaches
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Diuretics

  • thiazide;thiazide-like
    • bendroflumethiazide, hydrochlorothiazide; indapamide, chlortalidone
    • black NA-Cl channels in DCT > Na and water loss
    • depend on being excreted into renal tubule, thus less use w/ incr renal impairment
    • s/e: gout, impotemce, electrolyte disturbance, glucose tolerance (DM prob), hypercalcaemia
  • loop diuretics
    • furosemide, bumetanide
    • block NAKCl pump in asc loop > incr Na and H2O
    • also short lived antiHTN effect > then reflex stimulation of RAAS
    • s/e: electrolyte disturbance, polyuria, dehydration
    • also used in: CFC, nephrotic syndrome, ascites
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Potassium sparing diuretics

  • aldosterone antagonists
    • work by blocking aldosterone mediated Na/H2O reabsorption and K excretion in CDs
    • e.g. spironolactone (competitive Ald antagonist), eplerenone (mineralCCD R antag)
    • action: reduce Na and H2O reabs and K excretion
    • also use in: HF, ascites, hyperaldosteronism, Conn's
    • s/e: hyperK, gynaecomastia, erectile dysfunction
  • others:
    • amiloride. triamterene
    • act on Cd too, block eputhelial Na channels and block K excretion
    • weak duiretic activity
    • use in combo w/ furosemide
      • e.g. co-amilofruse 5/40mg
    • s/e: hyperK
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Other HTN drugs

  • direct vasodilators
    • hydralazine
      • s/e: lupus-like syndrome (monitor ANA), reflex tachycarida and tachyphylaxis
    • minoxidil 
      • K-ATP channel activator
      • s/e: hypertrichosis
  • central-acting (NB avoid abrupt discobt b/c of reflex HTN)
    • moxonidine 
      • I1 recepto agonist
    • methyldopa
      • pre-synaptic alpha2 agonist
      • s/e: depression, parkinsonism, monitor FBC, LFT, DCT
    • clonidine 
      • both
      • also used in ADHD
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postural/orthostatic HTN

  • >20mmHg systolic drop / >10mmHg diastolic drop
  • causes: adrenal insufficiency, autonomic failure (DM, Parkinson's, multiple system atrophy, parogressive supranuclear palsy), drugs, dopa decarboxylase deficiecy (rare)
  • Rx
    • non-pharm (main)
      • stand slwoly, drink water, small meals, compression stockings, stop drugs, counter-manouevres, sleeping head up tilt
    • pharm:
      • midodrine, droxydopa 
      • fludrocortisone
      • desmopressin, atomeoxetine, pyridostigmine, octreocide
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Heart failure

  • 'CO insufficeint to adequately perfuse the organs'
    • reduced renal flow > RAAS activation > Na retention > water retention > oedema
    • drugs that inhibit these changes improve survival
  • 2 types of HF
    • diastolic: HF w/ preserved LV EF
    • systolic: HF w/ reduced LV ejection fraction
      • Rx > cautiously
        • ACEi or ARBs
          • reduce preload and afterload
          • decr symp, slow progression, prolong life
        • B-blockers: reduce sympath overact; incr survival but can worsen HF in acute setting
          • bisoprolol, carvedilol, nebivolol only; ivabradine if BB not tolerated
        • aldosterone antagonist
        • duiretics: reduce preload b/c reduce ECV- no incr in survival
        • digoxin:useful if HF caused by AF
        • hydralaxine w/ isosorbide dinitrate
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Cardiac arrythmias

  • atrial tachyarrythmias
    • narrow complex
      • SVT
      • AF/flutter
  • anti-arrythmic drugs
    • class I: block voltage-gated Na channels
      • Ib: fast dissociation - liocaine, mexiletine, phenytoin
      • Ic: slow dissociation - flecaininde, propafennone
      • Ia: intermediate dissociation: - disopyramide, procainamide
    • class II: B blockers (block AVN conduction)
    • class III: prolong cardiac action
      • amiodarone, sotalol
    • class IV: CCBs
      • varapamil, diltiazem
    • others: digoxin, adenosin
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Flecainide

  • VW class Ib
  • slows conduction in the atria, His, purkinje, accessory pathways, ventricles
  • lengthens PR and QRS intervals
  • effective gegen atrial arryth and tachyc involv accessory pathways - WPW syndromes
  • exacerbate pre-exisying conduction disordersmain use: cardioversion in recent onset AF, maintenance of SR after DC cardioversion, PAF, prophylaxis, or AVRT in WPW
  • CI: prev MI, LV dysfunctino, structural heart disease
  • specialist use only
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Amiodarone

  • prolongs AP duration and effective refractory period
  • class I, III and IV activity
  • meat by liver to desethylamiodarone 9acitve)
  • long half life- > 30 days
  • depresses SA nose may provoke torsades de pointes (ventricular tachycardia w/ "twisting of QRS complexes"
  • s/e:
    • lungs- fibrosis
    • liver - hepatitis
    • thyroid dysfucntion
    • neuro- tremors, ataxia,
    • skin - photosensitivoty
    • eyes - conreal microdeposits, optic neuritis
    • testes -ochitis
  • dronadreon: fewer s/e
    • CI in class IV HF or recent decompensation
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Adenosine

  • adenosine
    • A1 adeonsine R agonist
    • hyperpolarisation
    • transient AV block
    • chest tightness, flushing, impending doom
    • shortlived- seconds
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Supraventricular tachycardia

  • Rx
    • place defib pads
    • vagal manoeuvres
    • carotid sinus massage
    • large bor canal, proximal vein
    • adenosine 6mg IV, 12 mg
    • if ineffective: verapamil 5-10,g IV (slow injection)
    • DC cardioversion if haemodynamically compromised
  • prophylaxis
    • disopyramide, digoxin, verapamil, Bblockers, sotalol
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Digoxin

  • cardiac glycoside
  • inhib Na/K ATPase in cardiac myocytes > incr intracell Na > inhib Na/Ca exchange > incr intracell Ca > positive inotropic effect
    • enhanced vagal inhib of SAN automaticity and AVN conduction
  • loading dose in urgent situ
  • t1/2 ~36hrs
    • NB prolonged ig renal impairment
    • NB more effect if low K as it D competes w/ K to bind to Na/K ATPase (e.g. if on duiretics)
  • narrow therapeutic index - monitor plasma conc
  • s/e: hypo/hyperK, arrythmias, N+V, diarrhoea, fatigue, confusion, xanthopsia
  • serologically may find digoxin specific antibody fragments (Fab)
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Atrial fibrillation

  • paroxysmal
  • persistent
  • permanent
  • Rx
    • pharma
      • rate control: BB, diltiazem (non-DHP CCB), verapamil, digoxin
      • rhythm control: amiodarone, flecainide
      • anticoag: warfarin, NOACs (rivaroxaban, apixaban, dabigatran)
    • non-pharma
      • DC cardioversion
      • catheter ablation
      • left atrial appendage closure
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Anticoagulants

  • vitamin K antagonists
    • warfarin, acenocoumarin, phenindione
      • warfarin
        • inhib II, Vii, IX, X
        • anticoag takes days to develop
        • AF aim: INR 2-3
        • antidote: vit K, FFP, prothrombin complex concentrate (Beriplex)
        • interactions: 
          • incr: wranberry juice, ciprofloxacin, clarithromycin, metronidazole
          • decr: dietary vit K, rifampicin, carbamazepine
  • novel oral anticoag (NOACs)
    • no need for INR monitoring; decr dose if renal prob; good for AF, not for mech heart valve 
    • direct thrombin (IIa) inhibitors
      • dabigatran
    • factor Xa inhibitors
      • rivaroxaban, apixaban
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Ischaemic heart disease

  • primary prevention
    • smoking cessation: nicotine replacement Rx, varenicline (nic R partial agonist), buproprion (NorA reuptake inhib; lowers seizure threshold)
    • obesity: orlistat (lipase inhib), GLP1 agonists (liraglutide), surgery
    • BP
    • dysliidaemia: statins (HMG CoA reductase inhibitors), ezetimibe, fibrates, bile sequestrant resins (e.g. colestryramine), nicotinic acids
    • thromobophilia
    • DM
    • alcohol
    • diet
  • risk predictors: Framingham, QRISK2, JBS3 risk calculator
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Dyslipidaemia Rx

  • measure HDL, LDL, triglycerides
  • think familial disorder if FH and total chol > 9mmpl/L
  • statins:
    • HMG CoA reductase inhibitors; upreg LDL Rs
    • e.g. atorvastatin, simvastatin, pravastatin, rosustatin
    • reduce total chol by upto 40%
    • pleiotropic effects: anti-inflam ,atheroma plaque stabilisation, neutrophil function
    • s/e: myalgia, muositis, raised LFTs, rhabdomyolysis (rare)
  • ezetimibe
    • blocks NPC1L1 transport protein in enterocytes in duodenum > inhib absorp of chol
    • augments statin effects, also useful if statin CI
    • lowers chol but no iproved CV outcomes
    • s/e: GI symptoms
  • fibrates
    • e.g bezafibrate, fenofibrate, gemfibrozil
    • s/e: GI, rash, pruritis, rhambdomyolysis (esp w/ statin)
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Angina pectoris

  • pharmacotherapy stratergies:
    • slow HR > reduce metabolic demand of myocytes
    • improve blood supply (coronary vasodilation)
    • reduce preload (venodilation)
    • reduce afterload (lower systemic BP)
  • GTN spray for acute attacks
  • prevention
  • stable angina:
    • rate limiting drugs: BB, verapamil, diltiazem
    • ivabradine - inhibs pacemaker If current; use w/ BB if HR>60bpm; incr AF risk
    • nitrates
      • reduce preload and afterload and incr bklood supply; s/e: headache, OHypoTN; don't use w/ PDE5 inhibs (e.g. sildenafil)
    • DHP CCBs: amlodipine
    • nicorandil - K channel activator and NO donor; A+V dilation; s/e headache, dizziness
    • ranolazine - inhib late Na current > decr intracell Ca > reduced force of contraction
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ACS

  • Rx
    • asprirn 300mg loading dose
    • oxygen to maintain SpO2 94-98%
    • morphine IV 5-10mg
    • metaclopramide IV 10 mg
    • clopidogrel 300mg loading dose
    • LMWH e.g. enoxaparin 1mk/kg BD
    • GTN spray/tablet/IV
  • STEMI
    • PCI
    • thrombolysis (if PCI not available)
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Thrombolysis

  • plasminogen activators (cleave plasminogen to release plasmin > digests fibrin and CFs)
    • streptokinase
      • but ab deveop after 1st use > allergic reactions
      • IV infusion
    • recombinant tissue plasminogen activator (tPA)
      • e.g. alteplase, tenecteplase, reteplase
      • IV
      • also use for massive PE
  • s/e: bleeding, stroker 0.5-1%
  • CI: recent trauma/surgery/stroke/CPR, prev haem stroke, uncontolled HTN, bleeding disorders, pregancy
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Heparins

  • activate antithrombin III
  • unfractioned heparin:
    • IV bolus/infusion
    • immediate action, short t1/2
    • dose moniroed by APTT (norm: 1.5-2.5)
    • antidote: protamine sulfate
    • can cause hep-induced thrombocytopenia (HIT)
  • LMWH
    • subcut
    • enoxaparin, tinziparin, dalteparin
    • longer t1/2
    • do not prolong APTT
    • reduce dose in remal impairment
    • use for: PE, DVT (Rx and prophylaxis)
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Antiplatelet drugs I

  • aspirin
    • irrevers inhib COX-1 > reduces TXA2 synth (TXA2 stim platlet activation and aggregation)
    • TXA2 synth recovers 7-10 days
    • use for aCS, IHD, stroke
    • s/e upper GI bleed
  • clopidogrel
    • adenosine P2Y inhibitor- inhibs ADP induced platelt aggregation
    • prodrug - requires metabolisation by P450 enzymes
    • interaction w/ omeprazole
    • prasugrel: more effectiv efor ACS, but higher stroke risk
  • ticagrelor
    • inhib ADP induced platelet aggregation
    • does not reuqire haptic activation
    • s/e bleeding, SOB
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Antiplatelet drugs II

  • dipyridamole
    • inhib platelet activation: inhib PDE, blocks adeonsine uptake, inhibs TXA synth
    • not used for IHD
    • s/e dizziness, headache, GI disturbance
    • does NOT incr risks of bleeding
  • Gp IIb/IIIa inhibitors
    • inhib platelet aggregation and thrombus formation
    • IV infusion
    • used during PCI 
    • adjunct to aspirin and heparin
    • abciximab -  immunogenicity means may nly use once
    • eptifibate, tirofan 
  • bivalirudin
    • hirudin analogue > direct thrombin inhibitor
    • quick onset, short t1/2
    • w/ aspirin and clopidogrel for pt undergoing PCI for ACS
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