Hypertension

• HYPERTENSION is...

  1. increased diastolic pressure (pressure when heart is filling) (minimum pressure)
  2. increased systolic pressure (pressure while heart is contracting) (maximum pressure)
  3. increased pulse pressure (differneces between the two)

  *STAGE 1 HYPERTENSION ~ 90-100 mmHg

  *STAGE 2 HYPERTENSION ~ 100-120 mmHg

  *STAGE 3 HYPERTENSION ~ >120 mmHg

  • 60% hypertensive patients 'adequately' controlled
  • 10% at optimal blood pressure
  • estimated 70 million untreated hypertensive patients in the world's top 7 economies
• HYPERTENSION IS CLASSIFIED by aetiology:

  1. primary (essential or idiopathic) hypertension- cause unknown
  2. secondary hypertension- identified cause
• PRIMARY HYPERTENSION

  • lifestyle contributors

  1. obesity
  2. insulin resistance
  3. high alcohol intake
  4. high sodium; low potassium uptake
  5. age

  • genetic factors:

  1. up to 65% ( twin studies)
  2. around 10 genes identified that after salt/ water balance
  3. other genes may affect obesity, alcohol use etc
  4. epigenetic: maternal diet
• CONSEQUENCES OF HYPERTENSION

  • High sustained arterial BP increases mortality from:

  1. coronary artery disease (myocardial infarction)
  2. stroke (cerebral haemorrhage, thrombosis and thromboembolism)
  3. heart failure
• TREATMENT

  • Life style modification

  1. lose weight
  2. limit alcohol intake
  3. increase aerobic activity
  4. reduce sodium intake
  5. maintain K+, Ca2+, Mg2+ intake
  6. stop smoking
  7. reduce dietary fat and cholesterol
• ANTIHYPERTENSION DRUGS: BASIC PRINCIPLES

  • Basic pressure control by drugs:

  BLOOD PRESSURE = CARDIAC OUTPUT X PERIPHERAL RESISTANCE

  • interferes with control mechanisms
  • calcium channel blockers or ACE inhibitor or ATII antagonist or thiazide-like diuretic sound be primary treatment (may need beta blockers)

  
• CALCIUM CHANNEL BLOCKERS

  • the L-type is found in cardiac and vascular smooth muscle

  1. ideal target for modulating blood pressure

  
• NORADRENALINE AND VASCULAR TONE

  
• CONSEQUENCES OF DEPOLARISATION

  1. Reduce the opening of the L-type calcium channels
  2. target organs: vasculature (and heart)
  3. vessels: inhibit Ca2+ entry
  4. heart: reduced contractility and S-V conduction
  5. side-effects: headache. constipation

  
• PHYSIOLOGICAL CONTROL OF BLOOD PRESSURE

  
• PHYSIOLOGICAL CONTROL OF RENIN SECRETION

  • secreted by cells of juxtaglomerular apparatus

  1. Adrenaline
  2. Prostacyclins
  3. decreased Na+ in distal tubule
  4. decreased in blood pressure in kidney
  5. actions of other hormones
• TISSUE DISTRIBUTIONS OF RENN, AT AND ACF

  • Renin-discrete (juxtaglomerular apparatus)

  1. global control- secreted into circulation

  • angiotensionogen- produced in liver- secreted into circulation
  • ACE- found in many tissues

  1. several subtypes
  2. local production of angiotensins
• Drugs that act on RAAS:

  • renin inhibitors
  • ACE inhibitors
  • angiotensin receptors
  • angiotensin II antagonists
• RENIN INHIBITORS

  • approved in 2007
  • post-market surveillance:

  1. kidney problems
  2. stroke
  3. hypotension
• ACE INHIBITORS

  • prototypical examples- captopril, lisinopril
  • unwanted effects- initial dose hypotension cough (bradykinin)
• ANGIOTENSIN RECEPTORS

  • G-protein coupled receptors (multiple subtypes)
  • angiotensin II type 1 receptor (AT1 receptor)

  1. AT1- vascular effects/ aldosterone release

  • angiotensin II type 2 receptor (AT2 receptor)

  1. AT2- growth and development
• CLINICAL USES

  • Other clinical uses of ACEIs and ARBs:

  1. can be used un heart failure
  2. useful after a heart attack
  3. some studies indicate centrally active ACEIs and ARBs may be useful in Alzheimer's disease
• DIURETICS

  • they increase urine output
  • intravascular salt and water depletion

  1. short term effect
  2. renal failure

  • also used to treat oedema

  1. pulmonary oedema due to heart failure
  2. side effects of other therapy

  • longer term effects due to arterial dilation

  1. reduced Ca2+ entry due to increased Na+

  • three main classes: loop, thiazide, potassium sparing
• LOOP DIURETICS

  • consequences: water cannot be absorbed from the descending limb
  • main example: flurosemide, bumetanide
  • act by inhibiting Na+/ K+/ 2Cl- cotransporter in ascending limb of the loop of hence
  • Clinical uses: heart failure; pulmonary oedema; renal failure (all involve salt and water overload)
  • hypertension with renal failure

  1. also get vascular effects

  • most powerful diuretics

  
• THIAZIDE DIURETICS

  1. increased NaCl passed to more distal segments
  2. less difference is osmolarity between urine and plasma
  3. lesser ability to reabsorb water in more distal portions

  • EXAMPLES: bendroflumethiazide; Clortalidone
  • act by inhibiting Na+/Cl- cotransport in distal convoluted tubule
  • CLINICAL USES:

  1. oedema due to heart failure
  2. hypertension (lower doses)- initial effects due to diuretics, later effects --> vascular effect

  
• HYPOKALAEMIA (low potassium levels)

  • MAJOR problem with loop diuretics, thiazides
  • increased NaCl passed on to collecting duct increases transport across PRINCIPAL cells
  • increases lumen -ve potential, leading to K+ loss
  • increased volume or urine: increased flushing of K+
• POTASSIUM SPARING DIURETICS

  • Mechanism: decrease trans-principal cell Na+ movement, decrease -ve lumen potential
  • EXAMPLE: spironolactone, amiloride
  • weak diuretic action on their own
  • usually in combination with other diuretics
  • spironolactone used in hyperaldosteronism

  1. cirrhosis (failure to metabolise ALD)
  2. cohn's syndrome (adrenal tumour)

  
• SPIRONOLACTONE

  • Aldosterone antagonist
  • Aldosterone increases sodium absorption by:

  1. increasing number Na+/ K+ ATPase (genomic)
  2. stimulating ENac Na+ channels via protein mediator

  
• AMILORIDE

  • Blocks ENac sodium channels in lumens membrane

  
• ADRENOCEPTOR ANTAGONISTS IN HYPERTENSION

  PERIPHERAL FUNCTIONS OF ADRENERGIC RECEPTORS

  
• DOXAZOSIN

  • Dilats arterioles and veins by blocking α1-adrenoceptors
  • used where other therapy has proved ineffective or unacceptable
  • unwanted effects include:

  1. postural hypotension (fades)
  2. urinary incontinence
  3. retrograde ejaculation

  *2 and 3: relaxation of bladder neck
• ANTAGONISTS AT β-ADRENOCEPTORS

  PROPRANOLOL

  • competitive antagonist
  • non-selective β-adrenoceptor antagonist
  • very lipid soluble

  ATENOLOL, BISOPROLOL

  • competitive antagonists
  • β1 selectivity: Bisoprolol > Atenolol > Propranolol
  • uses of β-arenoceptor antagonists:

  1. decrease cardiac output
  2. decrease renin release
  3. decrease sympathetic tone
• β-ADRENOCEPTOR ANTAGONISTS: UNWANTED EFFECTS

  • bronchoconstriction:

  1. bronchial asthma
  2. bronchitis
  3. emphysema

  • cold extremities

  1. Raynaud's phenomenon and claudication

  • precipitation of cardiac failure/ heart block

  1. patients with heart disease
  2. carvedilol, bisoprolol, nebivolol

  • glucose control

  1. patients with diabetes
  2. reduced insulin sensitivity
  3. masks hypoglycaemia warning signs

  • vivid dreams

  1. propranolol- worse than atenolol
• BETA BLOCKERS

  • Drugs with a high potency at β-1 and low potency at β-2 adrenoceptors are known as cardioselective beta-blockers
  • drugs which do nit distinguish between β1 and β2 are known as non-selective
• INDICATORS = what the drug should be used for
• Cautions = conditions or factors that increase the risk associated with the drug
• CONTRA-INDICATORS = conditions or factors that suggest a drug should not be prescribed
• BASIC MECHANISM IN ASTHMA