Vasodilators 2 Flashcards
Vascular Relaxation Mechanisms
Cyclic GMP (nitrates/nitrites) -increasing cGMP facilitates dephosphorylation of myosin light chain proteins, prevents myosin-actin interactions Intracellular Ca (Ca channel blockers and Na channel blockers) -reduction of Intracellular Ca reduces MLC kinase efficacy; reduces myosin-actin interactions Cell Membrane Potential (direct vasodilators) -increases K permeability; hyperpolarization Cyclic AMP (Beta2 Agonists) -increasing cAMP increases rate of MLC kinase inactivation reduces myosin-actin interactions
CV Responses of Ca Channel Blockers
- arterial dilation
- depressed myocardial contraction
- reduction in SA node pacemaker rate and slowing of intra-cardiac electrical conduction
- intrinsic natriuretic/diuretic effect
Major CV Effects of Ca Channel Blockers
Coronary Vasodilation: Verapamil, Diltiazem, Nifedipine
Cardiac Contractility Suppression: Verapamil, somewhat diltiazem
SA Node automaticity Suppression: Verapamil and diltiazem
AV Node Conduction Suppression: verapamil and diltiazem
Clinical Uses of Ca Channel Blockers
- HTN
- Angina Pectoris
- Peripheral Vasospasm
- Supraventricular Cardiac Arrhythmias
- Raynaud’s Phenomenon
Side Effects of Ca Channel Blockers
Flushing
HA
Peripheral Dependent Edema (nifedipine)
Myocardial Depression (Verapamil, Diltiazem)
Constipation (Verapamil)
Reflex Tachycardia (Nifedipine)
Gingival Hyperplasia (Nifedipine>Verapamil)
Ca Channel Blocker Precautionary Uses and Contraindications
Pregnancy: dihydropyridines shouldn’t be used in early pregnancy (limb bud defects) and may prolong labor
Ischemic Heart Disease (angina, MI): dihydropyridines cause reflex Tachycardia
Imparied Myocardial Function: Verapamil, Diltiazem
Impaired Cardiac Conductance (heart block): V, D
Verapamil
- Arterial Vasodilation, Negative Inotropic and Chronotropic Effects, Natriuretic Effect
- Tx for HTN
- Management of Suprventricular Arrhythmias
- Prevention and Termination of Paroxysmal Supraventricular Tachycardia
- Monotherapy for Angina Pectoris
- Combination with B-blockers NOT RECOMMENDED
- Caution: greater hypotension in elderly
- Limiting Factors for use are myocardial depression and constipation
Diltiazem
- Arterial Vasodilation, Less Cardio-depressant effects than verapamil, natriuretic effect
- Treatment for HTN
- Tx of Atrial Flutter and Fibrillation
- Treatment for Paroxysmal Supraventricular Tachycardia
- Monotherapy for Angina Pectoris
- May be used in combo with B-blockers
- Limiting Factors for use are myocardial depression, acute MI and CHF
Nifedipine
- Arteriolar Vasodilation, Minimal Cardio-depressant effect, natriuretic effect
- Reflex Tachycardia and increase in contractility
- attenuated with slow-release formulations - Treatment for HTN
- not well-tolerated as monotherapy
- Used in combo with B-blocker, ACE inhibitors, Diuretics
- Limiting Factors for use are precipitation/worsening of angina pectoris, MI, Pregnancy
- Caution: greater hypotension in elderly
- Peripheral Edema
- Don’t use in early pregnancy (limb bud defects)
Summary of Ca Channel Blockers (Major Clinical uses and KEY adverse effects)
MAJOR Clinical uses:
- HTN (D,V,N)
- Angina Pectoris (D,V,N)
- Vasospasm (N)
- Atrial Arrhythmias (D,V)
Adverse Effects
- HA (D,N,V)
- Flushing (D,N,V)
- Dizziness (N)
- Nausea (N)
- Dependent Edema (N)
- Constipation (V)
- Bradycardia (D,V)
- Heart Block (D,V)
- Reflex Tachycardia (N)
- Limb Bud Defects (N)
Hydralazine
Class: Direct Acting Vasodilator (MOA unknown)
-effective orally
Combo Tx with isosorbide dinitrate for HF in African Americans
Side effects and Precautions:
- presentation of lupus-like Syndrome in some patients (slow-acetylators)
- Reflex Tachycardia
- Contraindicated in CAD and Rheumatic Valve Disease
Minoxidil
Class: Activates Vascular ATP-Sensitive K channels
-dilates arterioles (prodrug)
Uses: severe refractory HTN, Hair Growth
Diazoxide
Class: Activates Vascular ATP-Sensitive K channels
-dilates arterioles (given IV, highly bound to plasma proteins)
Uses: HTN emergencies
Side Effects of K Channel Openers
- Hypertrichosis (minoxidil)
- Reflex Tachycardia
- Salt and Water Retention
- Hyperglycemia (diazoxide)
- Subendocardial Necrosis (by reflex released catecholamines) (diazoxide)
- Left Ventricular Hypertrophy and Pericardial Effusion (minoxidil)
- Gynecomastia (minoxidil)
Contraindications and Precautions of K Channel Openers
- HTN caused by pheochromocytoma
- Ischemic Heart or Cerebral Disease
- Treatment of compensatory hypertension (as with aortic coarctation or AV shunt)
Summary of “Direct” Vasodilators (clinical uses and Key adverse effects)
Major Clinical Uses:
- refractory HTN (M)
- HTN Crisis (diazoxide)
- HTN: Pregnancy (H, D)
Adverse Effects
- Reflex Tachycardia (M,D,H)
- hypotension (D)
- Edema (D, H)
- Hyperglycemia (D)
- Hypertrichosis (M)
- Gynecomastia (M)
- Lupus Syndrome (H)
Ranolazine
Class: Na Channel Blockers
Use: chronic Angina
-for patients symptomatic on other anti-anginal therapy: 4th line Tc)
-Doesn’t lower BP or HR
-For diabetic patients (Small reductions in HbA1c)
MOA: blocks Na coming into cell during ischemia, regulate the amount of Na coming into the cell, reducing amount of Ca coming in
Side Effects:
-potential for QTc Prolongation
Contraindications:
- Hepatic Impairment
- QTc Prolongation
- Patients takings drugs known to prolong QTc or inhibit P450 (CYP3A)
Drug-Drug Interactions:
- Drugs that inhibit CYP3A
- Verapamil
- Digoxin
Mechanism of Nitrovasodilators
- forms NO directly
- NO activates guanylyl cyclase to promote cGMP formation in VSM
- Activation of MLC phosphatase which dephosphorylates MLC leading to VSM relaxation
Pharmacokinetics and Dynamics of Nitrovasodilators
- low oral availability (exception is isosorbide mononitrate)
- Nitroglycerin has several routes of administration (sublingual preferred, rapid onset of action)
- polymorphism is mitochondria aldehyde dehydrogenase contributes to efficacy variability to nitroglycerin; loss of nitro efficacy evident with the Lyse504 allele
Nitroglycerin
Actions:
- rapid NO donor
- stimulates intracellular cGMP production
- dilates veins at lower concentration and arteries at slightly higher concentrations
- decrease preload and afterload variables
- decreases myocardial oxygen demand and increases coronary blood supply
indications/uses:
- acute angina
- angina prophylaxis
- IV for CV surgery to lower BP
Contraindications:
- hypersensitivity
- hypotension (IV use)
Adverse Effects:
- HA
- postural Hypotension
- syncope
- Reflex tachycardia
- various GI disturbances
- methemoglobinemia
Nitroprusside
Actions:
- NO donor
- non-selective vasodilator
- decrease preload
- decreases afterload
- rapid onset and reversal
Indications/Uses:
-HTN crisis
Contraindications:
- HTN Associated with aortic coarctation or AV shunt
- cerebral ischemia
- certain genetic disorders
Adverse Effects
- excessive hypotension
- rebound HTN upon withdrawal
- Reflex Tachycardia
- methemoglobinemia
- cyanide toxicity
Nitrovasodilators (clinical uses and contraindications)
***Rarely used alone: add on therapy with Ca channel blockers and/or Beta blockers is better (timolol, propranolol, metoprolol)
Clinical Uses:
- Angina
- HTN crisis
Contraindications:
-Hypotension
Adverse Effects:
- hypotension (NG,NP)
- HA (NG)
- Methemoglobinemia (NG, NP)
- Cyanid Toxicity (NP)
