CV+renal (anki)

• Blood pressure is a modifiable risk factor in atherosclerosis and CVD
• Therapeutic Drug Class/es used in Tx of Angina

  Beta blockers + Calcium channel blockers
• Therapeutic Drug Class/es used in Tx of Blood clots:

  Anti-coagulants
• Therapeutic Drug Class/es used in Tx of Heart Failure:

  ACE inhibitors, Diuretics, Digitalis drugs
• Therapeutic Drug Class/es used in Tx of Heart Rhythm disorders (arrhythmias):

  Anti-arrhythmics, Anti-coagulants, Beta blockers, Calcium channel blockers, Digitalis drugs
• Therapeutic Drug Class/es used in Tx of Hypertension:

  ACE inhibitors, Beta blockers, Angiotensin receptor blockers, Calcium channel blockers, Diuretics
• Therapeutic Drug Class/es used in Tx of Dyslipidaemia:

  Statins, fibrates, ezetimibe and thiazalidinedamines, bile acid sequestreants, nicotinic acid
• In Normals and hypertensive patients, blood pressure is regulated at 4 sites.

  1. Resistance in arterioles (from the heart)

  2. Capacity in venules (to the heart)

  3. Pump (heart)

  4. Kidney: regulates the volume of intravascular fluid
• load pressure in hypertensive patents is regulated by the same mechanisms as in normals, but renal blood volume-pressure control system is set at ‘high’.
• Define: Primary (essential) hypertension Most prevalent: high blood pressure with unknown etiology Variety of underlying mechanisms incl. genetic factors; not a single, specific cause.
• Define: Secondary Hypertension Associated with a specific disorder (e.g. chronic renal disease, Cushing syndrome: too much glucocorticosteroids increase cortisol levels: enhances ephinephrine-mediated vasoconstriction) ~ 5% of high blood pressure patients Much more common in children
• Define: Congestive heart failure Heart unable to supply blood at a rate sufficient to meet body demands
• Both Hypertension and heart failure are linked to the Renin- Angiotensin System (RAS), which regulates Blood volume, Electrolyte balance, Arterial blood pressure
• Describe 3 management options of Primary Hypertension

  1. Reduce blood volume (less venous pressure, cardiac output) e.g. Ca-channel blockers
  2. Reduce systemic vascular resistance e.g. Beta blockers, Ca-channel blockers
  3. Reduce cardiac output: depressing heart rate, stroke volume. e.g. diuretics, ACE inhib, ARBs
• Describe treatment for Secondary hypertension:

  Controlling or removing the underlying disease or pathology, in most cases in combination with antihypertensive drugs.
• Describe MOA of Beta Blockers block binding of norepinephrine (NE) and epinephrine to b-adrenoreceptors (b1) in cardiac nodal tissue
• MOA of Calcium Channel Blockers

  CCB block calcium entry and cause:

  1. vascular smooth muscle relaxation (vasodilation),
  2. decreased myocardial force generation (negative inotropy)
  3. decreased heart rate (negative chronotropy)
• Describe MOA of Loop Diuretics in Hypertension:

  • Diuretics decrease blood volume through increased urine output by the kidney.
  • Loop diuretics inhibit Na-K-Cl cotransporter in the thick ascending limb (reabsorbs 25% of Na-load), leads to less water reabsorption: diuresis (increased water loss) and natriuresis (increased sodium loss).
• Describe MOA of Thiazide Diuretics in Hypertension

  • Diuretics (and Thiazides) decrease blood volume through increased urine output by the kidney.
  • Thiazide diuretics inhibit NaCl transporter in the distal tubule, which only re-absorbs about 5% of filtered sodium. This is sufficient for therapeutic purposes.
• Renin-Angiotensin-Aldosterone system (RAAS) regulates blood volume, electrolyte balance & arterial blood pressure
• In vascular endothelium Bradykinin stimulates: production of Arachidonic Acid metabolites, production of NO, production of Endothelium-derived hyperpolarizing factor

  Result: Promotes vasodilation
• ACE regulates balance between vasodilation and natriuretic properties of bradykinin; and vasoconstrictive, salt-retentive properties of Angiotensin II
• Most vasoconstrictive effects of Angiotensin II are mediated by the Angiotensin AT1R receptor
• Angiotensin II binds to AT1R on smooth muscle cells, what affect does this have? This stimulates smooth muscle cell migration, contraction and growth
• Describe the Development of the 1st ACE inhibitors

  1965: 1st ACE inhibitor from venom of South American pit viper

  1980: hypothetical model of the active site of ACE based on:

  • the knowledge of substrate binding specificity
  • ACE is similar and closely related to carboxypeptidase A
  • also a Zinc-metalloproteinase like ACE
  • active site has been clarified by X-ray crystallographic studies
• How does Angiotensin II act at the cellular levels to induce smooth muscle cell survival, growth and hypertrophy? (3 pathways)

  1. p38/MAPK, Akt

  2. Ras/MAPK

  3. MAPK, JNK/STAT
• How does Angiotensin II act at the cellular levels to induce Smooth muscle cell contraction? (3 pathways)

  1. Phosholipase C > Incr interaction of myosin/actin
  2. D Phospholipase A2 PKC > Vasoconstriction/-dilation
  3. Erk > contration, cell growth
• Give example/s of Sulfhydryl-containing ACE Inhibitors Captopril
• Give example/s of Dicarboxylate-containing ACE Inhibitors Enalapril
• Give example/s of Phosphonate-containing ACE Inhibitors Fosinopril
• Describe Benefitial effects of ACE inhibitors

  • Acute and long term: Lower blood pressure
  • Lower peripheral vascular resistance without causing a compensatory increase in heart rate. This is a great advantage over other vasodilators, such as Calcium channel blockers.
  • No adverse metabolic effects
  • Reduced cardiovascular mortality
  • Regression of left ventricular hypertrophy
• General structure and requirements of ACE inhibitors:

  1. N-Ring must contain carboxylic acid to mimic C-terminal -COOH of ACE substrates
  2. Large hydrophobic heterocyclic rings in the N-ring increase potency and alter pharmacokinetic parameters
  3. Carboxylate or phosphinate binding to Zinc mimics peptide hydrolysis transition state of Angiotensin
  4. Esterification of carboxylate or phosphinate produces an orally bioavalable drug
  5. Optimal ACE inhibition when stereochemistry of ACE is similar to L-amino acid
• Common side effects of ACE inhibitors:

  • Nausea
  • Vomiting
  • Diarrhea
  • Skin Rash (Captopril - due to thiol group)
  • Cough (most common)
  • Liver toxicity
  • First dose hypotension (extension of desired physiological effect)
  • Increases Renin – rapid return of hypertension
  • Hyperkalaemia (due to decrease in aldosterone secretion)
  • Angiooedema (swelling)
• Describe synthesis of Peptidic Angiotensin Receptor Blockers:

  Series of peptide angiotensin II receptor antagonists obtained by simple replacement of various amino acid residues of angiotensin II, particularly amino acids 1, 5, and 8
• Evidence-Based Medicine:

  • EBM is ‘the conscientious, explicit, and judicious use of current best evidence in making decisions about the care of individual patients’
  • EBM is the integration of best research evidence with clinical expertise and patient values”
• Define Statistically significant

  Probability that your outcome occurred due to chance
• Define Clinically significant

  Does the difference in effect translate to a meaningful difference in outcome?
• Define Relative risk. How is it calculated? RR - the ratio of the probability of the outcome occurring in the exposed group compared to the non-exposed group
• Describe how to calculate Relative risk RR:

  incidence in exposed / incidence in non-exposed
• Relative risk results and their meaning:

  • RR > 1.0 = Exposed group more likely to have outcome
  • RR ≈ 1.0 = Exposed and unexposed equally likely to have outcome
  • RR < 1.0 = Exposed group less likely to have outcome

  
  

  • If RR = 2.0, then those who are exposed have twice the risk of having the outcome
  • If RR = 0.5, those who are exposed have half the risk of having the outcome