HTN/Dilators (Cardiovascular Part III)

Question 1

Nitric Oxide pharmacokinetics/background

Answer 1

endogenous, gas messenger 
lipophilic, highly reactive
formed from L-arginine
1/2 life - few seconds
elimination - oxidation to form NOx, nitrosylation of hemoglobin

Question 2

3 types of Nitric Oxide Synthase enzymes

Answer 2

nNOS - neuronal, iNOS- induceable (macrophage), eNOS (endothelium)

Question 3

Protective biological roles of Nitric Oxide

Answer 3

neurotransmitter, immune cytotoxicity, inhibit platelet aggregation, cytoprotection, vasodilator smooth muscle relaxant, decrease cell adhesion, proliferation

Question 4

Pathogenic biological roles of Nitric Oxide

Answer 4

inflammatory tissue injury, shock, hypotension, cell proliferation, neuronal injury

Question 5

Nitric Oxide mediated vasodilation MOA

Answer 5

ACh stimulates formation of NO by increasing Ca++ influx and activating NOS, that converts L-arginine to NO that will go to the VSMC and increase cGMP causing relaxation/vasodilation of the smooth muscle

Question 6

What are the organic nitrates?

Answer 6

nitroglycerin
isosorbide dinitrate
isosorbide mononitrate

Question 7

mechanism of action of sodium nitroprusside

Answer 7

release NO spontaneously which increases cGMP and leads to vascular smooth muscle relaxation and dilation

Question 8

mechanism of action of organic nitrates

Answer 8

go through metabolism to release NO, need thiols to convert to NO which will then increase cGMP and cause relaxation and dilation of VSMC

Question 9

metabolism of sodium nitroprusside

Answer 9

spontaneous breakdown to NO and cyanide, the cyanide combines with sulfur groups to form thiocyanate and undergoes renal excretion

if builds up or have impaired renal function = cyanide toxicity

Question 10

sodium nitroprusside pharmacokinetics

Answer 10

onset <2 mins
duration 1-10mins
half life 2 mins but half life of thiocyanate about 2-7 days
renal excretion but some as exhaled air or feces

Question 11

sodium nitroprusside effects on cardiovascular

Answer 11

decrease arterial/venous pressure, decrease PVR, decrease afterload, slight increase in HR

Question 12

sodium nitroprusside effects on renal, cns, and blood

Answer 12

renal: vasodilation w/o significant change in GFR
CNS: increase cerebral blood flow and intracranial pressure
blood: inhibits platelet aggregation

Question 13

sodium nitroprusside uses

Answer 13

hypertensive crisis, controlled hypotension during surgery, congestive HF, acute MI

Question 14

why does sodium nitroprusside have a limited use in acute MI treatment?

Answer 14

d/t coronary steal which alters blood flow resulting in diversion of blood away from the ischemic areas

Question 15

sodium nitroprusside adverse effects

Answer 15

profound hypotension, cyanide toxicity, methemoglobinemia, thiocyanate accumulation, increased serum creatinine, HA, increased intracranial pressure, restlessness, flushing, dizziness, palpitation, nausea

Question 16

s/s of cyanide toxicity

Answer 16

tissue anoxia, venous hyperoxemia, lactic acidosis, confusion, death

Question 17

explain methemoglobinemia

Answer 17

some iron in hemoglobin is oxidized to ferric state with impaired oxygen affinity so there is a reduced o2 delivery to the tissues

Question 18

what do we use to reverse methemoglobinemia?

Answer 18

methylene blue

Question 19

what are drug interactions with sodium nitroprusside?

Answer 19

negative inotropes, general anesthetics, circulatory depressants, PDE-5 inhibitors (sildenafil), soluble guanylate cyclase stimulators (riociguat)

Question 20

pearls about sodium nitroprusside

Answer 20

light and temperature sensitive (store at 20-25 degrees C, wrap aluminum around container)
deterioration = bluish color (normally brown tint)
diluted in D5%

Question 21

primary action of nitroglycerin

Answer 21

venous capacitance vessel dilation (decreased preload, myocardial o2 demand)
mildly dilates arteriolar resistance vessels (modest decreased afterload)
large coronary artery dilation (increased supply)

Question 22

nitroglycerin cardiovascular and pulmonary effects

Answer 22

decrease VR, decrease LVEDP/RVEDP, decrease CO, increase coronary blood flow to ischemic areas, bronchial dilation, inhibits HPV

Question 23

what is something we need to be mindful of with nitroglycerin?

Answer 23

can build tolerance, after about 8 hours = diminishing effectiveness

Question 24

clinical uses of nitroglycerin

Answer 24

angina (acute and prevention), hypertension, controlled hypotension during surgery, ACS, acute MI, heart failure

Question 25

nitroglycerin adverse effects

Answer 25

throbbing HA, increased ICP, orthostatic hypotension, dizziness, syncope, reflex tachycardia, flushing, vasodilation, venous pooling, decreased CO, methemoglobinemia (rare)

Question 26

nitroglycerin pharmacokinetics

Answer 26

large first pass effect after oral admin metabolized in the liver IV - immediate onset, 3-5 min duration Spray or Sublingual - 1-3min onset, >25min duration Oral ER- 60 min onset, 4-8hr duration Topical - 15-30min onset, 7 hour duration Transdermal- 30 min onset, 10-12hr duration

Question 27

drug interactions with nitroglycerin

Answer 27

antihypertensives (additive effect), PDE-5 inhibitors (ABSOLUTE CONTRAINDICATION- profound potentiation/hypotension), guanylate cyclase stimulating drugs

Question 28

what are isosorbide mononitrate and dinitrate used for?

Answer 28

prophylaxis angina pectoris, heart failure in Black patients in combo w/ hydralazine

Question 29

what do phosphodiesterase enzymes do?

Answer 29

regulate intracellular levels of 2nd messengers cAMP and cGMP

Question 30

what do PDE 5 Inhibitors do? (MOA)

Answer 30

blocks cGMP from breaking down to inactive GMP so it increases cGMP which leads to vasodilation/relaxation

Question 31

MOA of PDE 3 inhibitors?

Answer 31

increase cAMP by preventing cAMP converting to AMP

Question 32

Milrinone (PDE 3 inhibitor) pharmacokinetics and adverse effects

Answer 32

onset 5-15mins half life 3-6 hours majority not metabolized, >80% excreted renally unchanged adverse effects: arrhythmias, hypotension

Question 33

Milrinone effects and clinical uses

Answer 33

increase contractility, vasodilation, little chronotropic activity clinical uses: acute HF or severe chronic HF, cardiogenic shock, heart transplant bridge or post op

Question 34

Describe the renin angiotensin aldosterone system :-)

Answer 34

decreased BP is sensed and renin is released where it meets up with angiotensinogen and converts it to angiotensin I where that is converted into angiotensin II by angiotensin converting enzyme, angiotensin II will increase blood pressure and stimulate aldosterone release which will cause salt and water retention to also increase blood pressure

Question 35

If you block aldosterone what electrolyte abnormality would we be concerned about?

Answer 35

potassium

Question 36

What are AT1 receptors?

Answer 36

GPCRs/ang II receptors | lead to vasoconstriction, decrease renal blood flow and GFR, increase aldosterone, remodeling

Question 37

What drugs can inhibit the RAAS?

Answer 37

renin inhibitors, beta-1 adrenergic antagonists, angII antagonists (ARBs), ACE inhibitors, aldosterone antagonists

Question 38

how do ACE inhibitors work in terms of angiotensin?

Answer 38

block conversion of angI to angII (so decreased angII) leading to vasodilation, decreased remodeling, decreased aldosterone, decreased sympathetic output, and increased natiuresis

Question 39

Another mechanism of ACE inhibitors

Answer 39

blocks bradykinin from breaking down (increased bradykinin) can lead to vasodilation, cough, angioedema

Question 40

Bradykinin

Answer 40

endogenous peptide 1/2 life: 17 sec stimulates NO and prostacyclin formation, vasodilation and increased capillary permeability

Question 41

What are ACE inhibitors first line therapy for ?

Answer 41

HTN, CHF, mitral regurgitation, more effective in patients with diabetes and delay progression of renal disease

Question 42

clinical effects of ACE inhibitors

Answer 42

decrease BP, PVR, preload, afterload, workload, improves/prevents hypertrophy *does not result in reflex tachycardia

Question 43

ACE inhibitors pharmacokinetics

Answer 43

many are prodrugs and usually renally eliminated, usually used in combo with diuretics, interacts with K+ sparing diuretics and supplements, longer duration of action

Question 44

what do we worry about with ACE inhibitors? and common adverse effects

Answer 44

hypotension! (long duration of action) | hyperkalemia, renal dysfunction, dry cough, angioedema, fetal malformations

Question 45

why are ACE inhibitors contraindicated in patients with renal artery stenosis?

Answer 45

may develop renal failure d/t efferent arteriole vasoconstriction

Question 46

angiotensin blockers (ARBs) MOA

Answer 46

competitive antagonist at AT1 receptors, blocks effects of angII , does not block the breakdown of bradykinin similar uses as ace inhibitors

Question 47

angiotensin blockers pharmacokinetics

Answer 47

avoid in sever renal and hepatic dysfunction, highly protein bound, some metabolized through CYP system

Question 48

Spironolactone (aldosterone antagonist) MOA and uses

Answer 48

competitive antagonist at mineralocorticoid receptors and prevent nuclear translocation and blocks transcription of genes coding for Na+ channels increase Na and H2O excretion, diuresis, increase K+ reabsorption (HTN, HF, K+ sparing diuresis, hyperaldosteronism, acne, hirsutiusm)

Question 49

hydralazine (direct vasodilator) MOA, effects and uses

Answer 49

release of NO and inhibit Ca++ release from SR vasodilates arterioles, minimal venous effect decreased SVR and DBP, increase HR, SV, CO used in HTN and HF

Question 50

hydralazine pharmacokinetics and adverse effects

Answer 50

extensive first pass, half life 1.5-3 hrs A/E: HA, nausea, palpitations, sweating, flushing, reflex tachycardia, Na+ and H2O retention, angina dont give in CAD and mitral valve disease

Question 51

Why is hydralazine given with a beta blocker and/or diuretic

Answer 51

because it can cause reflex tachycardia (beta blocker will prevent that) and Na+ and H2O retention (which the diuretic will prevent)

Question 52

minoxidil (direct vasodilator) MOA, effects, uses

Answer 52

directly relaxes the arteriolar smooth muscle, little effect on venous, increases efflux of K+ = hyperpolarization and vasodilation dilates arterioles not veins use in HTN usually in combo with diuretic and beta blocker

Question 53

minoxidil pharmacokinetics and adverse effects

Answer 53

peak 2-3 hours, half life 4 hours | A/E: tachycardia, increased workload, palpitations, angina, Na/H2O retention, edema, weight gain, hypertrichosis

Question 54

drugs commonly used for controlled hypotension

Answer 54

sodium nitroprusside (0.3-0.5 mcg/kg/min; dont exceed 2) nitroglycerin (125-500 mcg/kg/min) nicardipine (5 mcg/kg/min) dexmeditomidine (0.2-0.7 mcg/kg/hr)