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Intro. To Cardiovascular Pharmacology

Intro. To Cardiovascular Pharmacology. Vasoactive Peptides & Inhibitors Dec. 2008. Introduction. Cardiovascular Reflex Regulation Overall coordination and integration of the CVS is accomplished primarily by the ANS. Major aspects of CV regulation: BP = CO x TPR

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Intro. To Cardiovascular Pharmacology

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  1. Intro. To Cardiovascular Pharmacology Vasoactive Peptides & Inhibitors Dec. 2008

  2. Introduction • Cardiovascular Reflex Regulation • Overall coordination and integration of the CVS is accomplished primarily by the ANS. • Major aspects of CV regulation: BP = CO x TPR • Short-term: intrinsic mechanisms (preload, afterload), reflex activation of ANS • Long-term: trophic or structural changes (e.g. hypertrophy)

  3. Introduction • Determinants of Cardiac Output: CO = HR X SV • Determinants of Stroke Volume: • Contractility: force with which muscle contracts at given resting fiber length. • Preload: load present before contraction, reflects venous filling pressure (end-diastolic pressure). • Afterload: resistance against which heart pumps blood during systole, determined by aortic pressure (MAP).

  4. Introduction

  5. Objectives • Discuss the biosynthesis and pharmacologic actions of the following peptides: • Angiotensins • Plasma Kinins • Natriuretic Peptides • Endothelins • Describe therapeutic uses of drugs that inhibit or modify their actions.

  6. Introduction • Vasoactive Peptides • can function as neurotransmitters or local and systemic hormones. • are important in regulation of normal CV function and may contribute to several CV disorders. • include vasoconstrictors and vasodilators. • act via specific receptors to produce second messengers. • have complex interactions with other hormones.

  7. Biosynthesis of Angiotensins { Liver Low BP Low NaCl NE/Epi Kidney Renin + -

  8. Regulation of Renin Secretion • Intrarenal baroreceptor senses changes in perfusion pressure in afferent arterioles. • Macula densa chemoreceptor senses changes in NaCl conc. • Beta1-adrenergic receptor mediates sympathetic nerve activity. • Angiotensin receptor mediates negative feedback.

  9. Biosynthesis of Angiotensins Other enzymes Ang converting enzyme (ACE) Peptidases Biologic activity: Ang II>Ang III>Ang I

  10. Other Enzymes and Peptides • ACE is involved in degradation of other peptides such as bradykinin (discussed later). • Several other enzymes (e.g. chymase) can convert Ang I to Ang II, bypassing ACE. • Ang II may be converted to Ang (1-7) by a homolog of ACE (ACE2). These 2 peptides may counterbalance each other.

  11. Angiotensin II Receptors • AT1 (major one) - mediate most effects of Ang II via activation of phospholipases,protein kinases, etc. • AT2(fetal and some adult tissues)- modulate effects of Ang II during growth and development via activation of phosphatases. • These 2 receptors may have complementary or opposite functions, and pathologic stimuli may lead to upregulation of one or the other.

  12. Actions of Ang II on AT1 Receptors • CVS: • Blood vessels: vasoconstriction (increases PVR and BP) • Heart: weak positive chronotropic and inotropic effects, minor reflex effects • Vascular and myocardial hypertrophy • Adrenal Cortex: • Aldosterone secretion (sodium retention)

  13. Actions of Ang II on AT1 Receptors • Kidney: • Constriction of renal arterioles (reduces renal blood flow and increases glomerular hydrostatic pressure) • Contraction of mesangial cells (decreases permeability) • Promotion of sodium reabsorption • Inhibition of renin secretion (- feedback)

  14. Actions of Ang II on AT1 Receptors • ANS: • Facilitation of catecholamine release from adrenal medulla and peripheral nerve terminals • CNS: • Increased sympathetic activity (incr. BP) • Stimulation of thirst and drinking • Increased ADH and ACTH secretion

  15. Additional Actions of Ang Peptides • Actions of Ang II on AT2 Receptors • CVS: Vasodilation, inhibition of cellular proliferation, etc. • Actions of Ang (1-7) • CVS: Vasodilation, inhibition of cellular proliferation, etc. • Note that these actions tend to oppose those of Ang II on AT1 receptors.

  16. Pathologic Roles of Ang II • Hypertension • Heart failure • Ventricular remodeling and hypertrophy • Chronic renal disease • Other CV disorders: atherosclerosis, vascular inflammation, thrombosis

  17. Sites of Action of Drugs ThatInhibit the RAS

  18. Inhibition of the RAS • Inhibitors of renin secretion • Beta1-adrenergic receptor blockers • Other drugs: NSAIDs, central agents • Inhibitors of renin activity • Ang convertingenzyme (ACE) inhibitors • Ang receptor blockers (ARBs)

  19. Renin Inhibitors • MOA: Suppress plasma renin activity and reduce levels of Ang I and Ang II. • Specific inhibitors (angiotensinogen analogs) include aliskiren, which is orally active.

  20. Actions of ACE Inhibitors • MOA: Inhibit conversion of Ang I to Ang II and decrease Ang II levels. • Have NO effects on generation of Ang II by alternative pathways. • Increase PRA and Ang I levels by removal of feedback inhibition. • Decrease aldosterone secretion, which may increase potassium retention.

  21. Effects of ACE Inhibition • Effects on CVS • Decrease PVR and BP • Improve arterial compliance • No effect on HR • Decrease afterload, preload • Reduce vascular/ventricular hypertrophy

  22. Effects of ACE Inhibition • Other effects • Improve renal perfusion and lower intraglomerular capillary pressure. • Improve insulin sensitivity and glucose metabolism; may prevent development of type 2 diabetes.

  23. Differences Between ACE Inhibitors DrugGroupProdrug Captopril SH No Enalapril* COOH Yes Lisinopril COOH No Fosinopril PO3 Yes Ramipril COOH Yes *Enalapril is converted to enalaprilat by an esterase.

  24. Clinical Use of ACE Inhibitors • Therapeutic Uses • Hypertension • Heart failure • Post-MI LV dysfunction • Chronic renal failure • Reduction of CV events in high-risk pts. • Contraindications • Pregnancy (fetopathic effects) • Bilateral renal artery stenosis

  25. ACE Inhibitors • Precautions • Hypotension (patients with high PRA) • Hyperkalemia (patients taking K supplements or K-sparing diuretics) • Renal function impairment (patients dependent on Ang II to maintain GFR) • Drug interactions: NSAIDs may impair their hypotensive effects

  26. The RAS is activated in conditions causing hypoperfusion, resulting in constriction of efferent afterioles. Treatment with an ACE inhibitor dilates efferent arterioles and lowers the driving force for glomerular filtration.

  27. ACE Inhibitors • Adverse Effects • Common: cough, rash, taste changes, etc. • Rare: angioedema, proteinuria, neutropenia, glycosuria, hepatotoxicity

  28. Case • A 72-year-old man presents to the office for routine follow-up. He is being treated for hypertension and heart failure with enalapril and a diuretic. His BP is well controlled and he has no symptoms of heart failure. He does complain that he has been coughing frequently in the past few months. History and examination reveal no other cause of a chronic cough. What should you do?

  29. Ang II Receptor Blockers • Selective AT1 receptor antagonists • Agents: Losartan, valsartan, etc. • May have pharmacokinetic differences (e.g. some are prodrugs). • Therapeutic uses, contraindications, and precautions are similar to those for ACE inhibitors. • Fewer adverse effects than ACE inhibitors (e.g. no cough).

  30. Summary: Effects of RAS Inhibitors • Despite their different MOAs, RAS inhibitors have similar therapeutic effects, contra-indications, and precautions. • Only ACE inhibitors increase bradykinin levels.

  31. The Kallikrein-Kinin System

  32. Plasma Kinins • Receptor Subtypes • B1:induced during chronic inflammation • B2:constitutive - acute inflammation and other physiologic actions • Signal Transduction • Activation of phospholipases • Formation of other autacoids (PGs, NO)

  33. Actions of Kinins • CVS: produce vasodilation, increase vascular permeability, and contract large vessels • Nonvascular smooth muscle: produce contraction (slow onset) • Kidney: ion transport • Sensory nerves: pain • Pathologic roles: inflammation, etc. • May be responsible for some side effects of ACE inhibitors (e.g. cough and angioedema).

  34. Natriuretic Peptides • Atrial natriuretic peptide (ANP) • Stored as inactive precursor; released in response to myocyte stretch, other factors. • Brain natriuretic peptide (BNP) • Released by increased ventricular volume and pressure (marker for LV dysfunction). • C-type natriuretic peptide (CNP) • Released by increased shear stress in blood vessels.

  35. Natriuretic Peptides • Receptor Subtypes: ANPA,B,C • Signal Transduction • Stimulation of guanylate cyclase increases cGMP levels.

  36. Actions of Natriuretic Peptides Plasma volume expansion Vasodilation Natriuresis Diuresis ANP BNP Renin/Ang/Aldosterone SNS activation Growth factors

  37. Natriuretic Peptides • Pathologic Roles • Elevated levels of ANP and BNP are found in patients with heart failure, etc. (adaptive response). • Therapeutic Agents • NP analogs: BNP (nesiritide) for acute HF

  38. Endothelins • Synthesized by endothelin converting enzymes (ECEs) • Three peptides: ET-1, ET-2, ET-3 • Receptor Subtypes: ETA, B • Signal Transduction: Phospholipases

  39. Actions of Endothelins • CVS: • Blood vessels: transient vasodilation (ETB) followed by vasoconstriction (ETA) • Heart: positive inotropism and chronotropism • Vascular and myocardial hypertrophy • Nonvascular smooth muscle: • Contraction (e.g. bronchoconstriction)

  40. Endothelins • Pathologic Roles • Some CV, renal, and pulmonary disorders • ET receptor antagonists (ERAs) • Agents: Bosentan (nonselective), ambrisentan (ETA selective) • Therapeutic use: pulmonary hypertension • Adverse effects mainly due to vasodilation • Contraindicated in pregnancy (teratogenic)

  41. Summary: Key Points • Know the physiologic & pathologic roles of the following peptides and whether they are mainly vasoconstrictors or vasodilators: • Angiotensin II • Bradykinin • Natriuretic Peptides (ANP, BNP) • Endothelin • Know the characteristics and uses of drugs that affect peptide synthesis or receptors.

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