T1 L16-L17: How anti-hypertensives work

• What is hypertension?

  Persistently higher than normal blood pressure

  measured using ABPM or HBPM
• When will hypertension need to be treated?

  if mean BP>150/95mmHg
• What is the blood pressure formula?

  Blood Pressure = Cardiac Output x Total Peripheral Resistance
• What is the cardiac output formula?

  Cardiac Output = Stroke Volume x Heart Rate
• What is stroke volume regulated by?

  ventricles
• What is heart rate regulated by?

  SA node
• What is total peripheral resistance?

  a measure of the degree of constriction of the arterioles
• How is the sympathetic regulation of BP when there is a decrease in cardiac output?

  decreased cardiac output → decreased aortic blood flow → activate SNS:

  • alpha-1 receptors in venules → increase preload → increase force of contraction
  • noradrenaline:
  • alpha-1 receptors → increase arterio-constriction → increase afterload
  • beta 1 receptors → increase force of contraction
• How does the extrinsic regulation of blood pressure work in the beta-1 receptors in heart?

  beta-1 receptors are G protein coupled receptor (GPCR) → stimulate Adenylate cyclase (AC) → increase cyclic AMP → increase protein kinase A → more calcium enters into heart muscle → increase action potential in cardiomyocytes → increase frequency of heart beat / force of contraction
• How is TPR regulated in arterioles perfusing skin and GI tract?

  NE bind to alpha receptors → decreased cAMP → contraction → less blood flow
• How is TPR regulated in arterioles perfusing skeletal muscle and heart?

  adrenaline → B2 receptor in muscle → produce cAMP → phosphorylate myosin light chain kinase → inhibit contraction → dilate blood vessel & increase blood flow

  
• How does Renin-Angiotensin-Aldosterone System (RAAS) work to regulate blood pressure?

  decreased renal perfusion → kidney secretes RENIN → converts Angiotensinogen (from liver) → Angiotensin I → ACE (from lungs) converts Angiotensin I → Angiotensin II

  Effects of Angiotensin II:

  • increase sympathetic activity
  • increase tubular reabsorption of Na+ and Cl-; excretion of K+ → water retention
  • stimulates adrenal gland → secrete aldosterone: has above effects
  • increase arteriolar vasoconstriction; increase BP
  • stimulate pituitary gland → secrete ADH: water reabsorption
• What are the overall effects of RAAS?

  water and salt retention

  effective circulating volume increases

  renal perfusion increases (juxtaglomerular apparatus)

  
• How is TPR regulated through Angiotensin II?

  Increases in Ang II → increase IP3 → increase intracellular [Ca2+]

  Causes constriction of arterioles and increase in total peripheral resistance and in BP
• How is preload regulated by RAAS?

  AT1-R (type 1 angiotensin II receptor) → venule constriction

  RAAS also facilitates Na+ and H2O retention

  
• How does aldosterone increase water retention?

  activates cytoplasmic receptors → bind to nucleus to increase expression of Na+ channels →aid Na+ and water retention

  
• What factors is choice of anti-hypertensive drug treatment dependent on?

  • Age (<55 years old ACE inhibitor/angiotensin receptor blocker (ARB); >55 years old or all Black African/Americans calcium channel blocker)
  • Race (ACE inhibitors/beta blockers may be less efficacious in black African/Amercians).
  • Co-existing diseases
• What are the Classes of Anti-Hypertensives?

  • ACE inhibitors and Angiotensin receptor blockers
  • Calcium channel antagonists
  • Diuretics
  • Beta Blockers
  • Vasodilators
• What are the Side Effects and Contraindications of anti-hypertensives?

  • Dry cough with ACE inhibitors
  • 1st Dose Hypotension
  • Renal impairment: Do NOT give give to patients with bilateral renal artery stenosis.
  • May cause Hyperkalaemia
• Why can ACE inhibiters cause dry cough as a side effect?

  ACE inhibitor → inhibits Kinase II → can't break down bradykinin → bradykinin levels increase → stimulate sensory neurons in airways → drive cough
• What is the action of ACE inhibitors?

  inhibit ACE activity so stop RAAS

  inhibit Kinase II (vasoconstricator)
• What group of patients should you never give ACE inhibitors to and why?

  patients with bilateral renal artery stenosis
• What test to see if a patient has kidney problems?

  monitor blood creatinine
• Are ACE inhibitors good for diabetics?

  yes

  as no adverse effect on serum glucose or lipids
• What is an example of an ACE inhibitor and how are they named generally?

  Ramipril

  ends with PRIL
• What is an example of ARBs (angiotensin receptor agonists) and how are they named generally?

  Losartan

  ends with ARTAN
• How do ARBs work to reduce blood pressure and why are they good?

  block action of Ang II on AT1-R

  no cough side effects
• How do aldosterone antagonists work and what is an example?

  Block aldosterone action on nephron

  can be used as an add-on for resistant hypertension

  but FRONTLINE for hypertension in patients with primary aldosteronism (too much aldosterone produced - endocrine problem)

  Example: Spironolactone

  
• How do calcium channel agonists work and what are some examples?

  Target L-type Ca2+ channels

  classes:

  • dihydropyridines (amloDIPINE): in smooth muscle of arterioles
  • (less used for hypertension) Phenylalkylamines (verapamil) & Benzothiazepines (diltiazem): in heart → decrease frequency and force of contraction
• On which mechanism do Calcium Channel Agonists act on?

  smooth muscle contraction in arterioles

  
• What are the side effects and contraindicators of Calcium Channel Agonists?

  • Peripheral oedema
  • Flushing and headaches
  • Combinations of Ca2+ channel antagonists not recommended
  • Grapefruit juice enhances action (CYP3A4)
• Why can Calcium Channel Agonists cause peripheral oedema as a side effect?

  Preferential dilation of precapillary arteriole and impairment of the function of the pre-capillary sphincter increases hydrostatic pressure across the capillary and reduces fluid reabsorption

  
• How do Thiazide and Thiazide-like Diuretics work?

  inhibit sodium reabsorption and hence inhibit water reabsorption

  BUT chronically reduce total peripheral resistance

  eg bendroflumeTHIAZIDE

  newer: indapamide (thiazide-like diuretic)

  
• What are the Side Effects and Contraindications of Thiazide and Thiazide-like Diuretics?

  • chronically reduce total peripheral resistance
  • Hypokalaemia
  • Increase in urate
  • Increase in glucose
  • Increase in blood lipids
• What group of patients do thiazide-like diuretics need to be used with caution and why?


  patients with diabetes

  close K+ channel, less calcium release, less insulin

  
• How do beta blockers work to reduce blood pressure and what is an example?

  block action of catecholamines on beta 1 receptors on heart

  selective B1 antagonists, eg bisoprOLOL
• What are the side effects and contraindications of beta blockers?

  • fatigue
  • vaso/brochoconstriction: Smooth muscle cell in the airways or peripheral arterioles perfusing skeletal muscle
  • Hypoglycaemia
• How can beta blockers cause hypoglycaemia as a side effect?

  Low blood glucose → activates the release of adrenaline → mobilises glucose release from liver→ tremor, palpitations, sweats

  Blocked by Beta Blockers

  Combinations of beta blockers and thiazides contraindicated in diabetics
• How do vasodilators work to reduce blood pressure?

  alpha 1-antagonists

  noradrenaline → alpha 1 → IP3 → calcium → constriction

  eg doxAZOSIN

  Other vasodilators such asminoxidil open K+ channels
• What type of drug is Doxazosin and what specifically is it used for?

  vasodilator (alpha 1-antagonist)

  Used to treat hypertension in patients with benign prostatic hypertrophy