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Hypertension

  • BP > 140 / 90
  • few recognisable, treatable causes; but 30-35% of Australians have this disease
  • multifactorial
  • 90 % “essential” (of unknown etiology); but there is a strong genetic link (so ask if parents/grandparents had it)
  • remainder - secondary hypertension (endocrine/renal: e.g. Cushing's disease (cortisol), primary hyper-aldosteronism - quite common, tumour of adrenal medulla - diagnosis: urinary catecholamines, aortic coarctation, renal artery stenosis). Exclude these causes before going into treatment
  • diagnosis is important
  • Target: 120/80; risk is a continuum, want to go down the risk as far as you can go - people do better if they're down lower at BP
  • Right cuff, right conditions, more than one measurement

Ambulatory blood pressure monitoring

  • Indications
    • Possible white coat hypertension
    • Variable blood pressure
    • Evaluation of efficacy of treatment over 24 h
    • Evaluation of drug resistant hypertension
    • Nocturnal hypertension

Non-drug treatment of Hypertension

  • Weight loss 5-10 mm/10 kg weight loss
  • Limit alcohol - 2-4 mm Hg
  • DASH diet DASH diet - 6 mm Hg
  • Physical activity 30 min/day - 4-9 mm Hg
  • Reduce sodium to <100meq/d - 2-8 H mmg

BUT Drugs consistently better than lifestyle in head to head comparisons

  • note: blood pressure is on component of risk, also includes: cholesterol, glucose intolerance, cigarette smoke, ECG-LVH (end-organ damage)

Target BP

See slide

Antihypertensive agents

Either target CO or TPR. >1/2 patients will not be controlled on a single drug, and will require multiple treatments with additive effects

  • diuretics
  • beta adrenoceptor antagonists
  • alpha adrenoceptor antagonists, Ca channel blockers
  • drugs acting on RAS system
  • centrally acting agents

Diuretics

  • Increase rate of urine flow
  • most increase Na+ excretion
  • Several groups of diuretics exist, with different mechanisms / sites of action - determines potency

Loop diuretics

  • inhibit Na+, Cl- reabsorption in thick ascending limb, loop of Henle via Na+/ 2Cl-/ K+via Na / 2Cl / K cotransporter
    • Sodium stays in the lumen, and water follows by osmosis
  • eg frusemide, bumetanide
  • ARx:
    • hypokalemia metabolic alkalosis
    • allergic reaction
    • hearing loss
    • drug interactions

NB: more opportunity to absorb sodium earlier in the nephron because there's more Na in the filtrate to be sucked out the earlier you are in the nephron

Thiazides

  • inhibit Na+, Cl-reabsorption in early DistConT via Na+/Cl-cotransporter
  • eg chlorothiazide
  • ARx:
    • hypokalemia, hyponatremia
    • hyperlipidemia
    • hyperglycemia
    • uric acid retention
    • allergic reaction
  • No longer first line in anyone under 65 because of the risk of diabetes
  • Less potent than loop diuretic because it acts slightly further on in the nephron

K sparing diuretics

  • Amiloride, spironolactone
  • Spironolactone: aldosterone antagonist (aldo synthesises Na/K transporter)
  • Amiloride can be combined with a thiazide in the one tablet - amiloride might raise K, while thiazide might lower K
    • Amiloride inhibits the Na/K transporter directly
  • Mild effect - acts towards end of nephron
  • Adverse effects - hyperkalemia (avoid sole therapy) hyponatremia

Beta adrenoceptor antagonists

No longer first line

  • Mechanism of action:
    • reduce cardiac output - rate, contractility
    • reduce renin release - volume/tone
  • Drugs vary in their:
    • selectivity selectivity - Beta 1 vs Beta 2 adrenoceptor adrenoceptor b1> b2 preferred
      • human heart b1(b1 :b2 = 75:25)
      • kidney b1
      • bronchi, peripheral vessels, metabolic (b2)
    • intrinsic sympathomimetic activity
    • lipid solubility - determines whether it will cross into the brain and cause adverse effects e.g. dreams
  • Nonselective (b1 and b2)
    • Propranolol
    • Timolol
  • Beta 1 Selective
    • Atenolol
    • Metoprolol
  • No longer 1st line in uncomplicated hypertension
  • Adverse effects related to beta related to beta adrenoceptor blockade:
    • cold hands, feet, bronchospasm
    • increased triglycerides
    • dreams, insomnia dreams, insomnia
    • fatigue

Alpha/Beta adrenoceptor antagonists

  • carvedilol (includes both alpha 1 blocking and beta 1 blocking)
    • having a beta blocker as well blocks the possibility of compensatory hypertension in alpha 1 blockade
  • blocks effect:
    • a1= vasodilatation
    • b1= blocks reflex tachy , cardia, renin release
    • b2
  • also labetolol

Alpha adrenoceptor antagonists

  • Prazosin, terazosin terazosin - a1 selective
    • Stops contraction when NA binds to blood vessel (affects resting tone)
  • Mechanism of action:
    • arterial, venodilation -
    • due to blockade of postsynaptic a1 receptors
  • Adverse effects:
    • postural hypotension - 1st dose effect (not good in the elderly; should take it at night because of 1st dose)
    • weakness, drowsiness

Calcium channel blockers

  • Calcium - pivotal role as intracellular 2nd messenger: calcium is critical for muscle cell contraction
  • Transient increases in [Ca++] can be initiated by:
    • increased release from intracellular storage sites release from intracellular storage sites
    • increased Ca++ permeability of plasma membrane - opening of channels (receptor- or voltage-operated channels)
  • Many cells have voltage sensitive Ca++ (VOCC)
  • ALL L type Ca channel blockers relax arterial smooth muscle --> increase the lumen, reduce the pressure
  • ARx
    • Dihydropyridines (more vascular selective):
      • Oedema, flushing
      • Headache
      • Reflex increase in sympathetic activity
    • Diltiazem, Verapamil (vascular and cardio selective):
      • bradyarrhythmia (in other contexts, verapamil is used to block conduction in the heart)

Enalapril & other ACEI

  • block the conversion of AI to AII
  • therefore decreased vascular tone (TPR), BP, decrease aldoserone production (volume effects)
  • Adverse effects:
    • severe hypotension (kidney's rely on Ang to control renal efferent arterial tone), acute renal failure, hyperkalemia (due to blocking Aldo), cough, loss of taste, rash, fetal malformation (Ang necessary for fetal development -- can't be used after first trimester), can't be used in impaired renal function
    • block Ang1 --> Ang2 stops bradykinin (endogenous vasodilator) being broken down --> prolong bradykinin --> adverse effects
      • produces cough (bradykinin irritates lung; cough in 25%)
  • ACE present in:
    • lungs
    • heart, kidney, vessels

Drugs affecting RENIN ANGIOTENSIN System

  • AII Antagonists
  • AII receptors widely distributed:
    • vascular smooth muscle, adrenal cortex, kidney, brain
  • 2 types of AII receptor identified - AT1 & AT2
  • MOST known actions of AII mediated by AT1

Losartan, Irbesartan

NB: Agonist for both AT1 and AT2 receptors is Ang2

  • Selective for AT1 receptors receptors - which causes the cardiovascular effects
  • Inhibit cardiovascular effects of AII
  • similar efficacy to ACEI; combining the two drugs may be useful
  • Adverse effects:
    • Similar to ACEI BUT no cough
    • hyperkalemia
    • Headache dizziness
    • AVOID in renal impairment, pregnancy

Renin inhibitor

  • Aliskirin
  • Inhibits renin, lowers Ang II & aldo levels
  • Similar efficacy as Ang II receptor blockers
  • Suggestion of additional benefits
  • No difference in adverse events vs Ang II blockers?
  • More data needed

Centrally acting antihypertensives

Baroreceptors signal to the nucleus tractus solitarius, relay to RVLM, sympathetic output through the spinal cord to affect the heart, blood vessels and kidney. The drugs act in the medulla, in the cardiovascular centre, and are agonist molecules (hijack the system that normally respond to pressure changes)

  • Act by decreasing sympathetic outflow from brain centres, and decreasing vascular tone --> reduce BP
  • alpha methyldopa - converted to alpha methyl NA (an agonist of the alpha 2 receptor)
  • clonidine - alpha2 agonist, and imidazoline agonist
  • Both act at brainstem alpha 2 receptors (agonists)
  • ARx:
    • both:
      • Sedation, sleep disturbance, dreams,
      • depression
      • dry mouth
    • alpha methyldopa- Hepatotoxicity, Hemolytic anemia BUT can be used in pregnancy
    • Clonidine - withdrawal syndrome (rebound increase in BP)

BPtreatment112.PNG

^ Heart foundation guidelines


Treatment of Hypertension- overview

  • benefits are unequivocal
  • lifestyle measures may be useful
  • diverse group of drugs
  • AIM is to NORMALISE BP
  • Adverse effects may preclude use
  • 50% of patients will not respond adequately to monotherapy -- need to add drugs
  • Combination therapy used

Which drug should I choose

  • No significant differences in outcome - total major CV events- between ACEI, Calcium antagonists, diuretics or beta blockers
  • Larger reduction in BP produces larger reduction in risk
  • MESSAGE: lower BP as far as you can, the further you safely lower it, the better. Choose the best drug for the individual given the side effect profile/comorbidities - but the particular drug doesn't really matter

Combination therapy - Guiding Principles

  • Use drugs from different groups
  • Aim for at least additive effects (combine mechanisms) - eg
    • ACEI or ARA & Ca channel blocker
    • ACEI or ARA & thiazide diuretic
    • ACEI or ARA & beta blocker
    • beta blocker & Ca channel blocker (Dihydropyradine only (see above))
    • thiazide diuretic & Ca channel blocker
  • Avoid : ACEI & K sparing diuretic; beta blocker & verapamil or diltiazem

Table

Study the table in the slides

==Take Home Message==

  • Hypertension is common cause of morbidity, but too few patients are adequately treated
  • A reduction in cardiovascular disease mortality and morbidity can be achieved through improved treatment and control of hypertension
  • A choice of drugs is available for hypertension; Systematic trial and error may be necessary

Case

  • Longstanding history of hypertensive, doesn't smoke or drink, BMI 32, 160-170/92-96 sitting, pulse 72, arteriolar narrowing in eyes, everything else normal
  • Currently on atenolol, hydrochlorothiazide and esinopril and ibuprofen
  • on 3 antihypertensives
    • a BB, a thiazide diuretic and an ACEI
  • Questions to ask
    • Compliance
    • Other cause of hypertension (see secondary causes above)
    • Weight loss if possible
    • Interfering substances
    • White coat hypertension? Monitor at home
  • Recommendation: take her off ibuprofen and monitor
    • Look at creatinine (3 agents)
    • If still hypertensive, add a different agent from a different class
    • If still hypertensive, contact a specialist