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Angeli - N929 Pharmacology > Exam 2: CV Drugs 3 - VASODILATORS > Flashcards

Exam 2: CV Drugs 3 - VASODILATORS Flashcards

1
Q

Nitrovasodilator Drugs - NO background

A
  • Endogenous, gas messenger
  • Lipophilic, highly reactive & labile free radical
  • Formation – from L-arginine (aa)
  • Elimination – oxidation to form NOx (NO2 or NO3); nitrosylation of hemoglobin
  • t ½ ~ few seconds
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2
Q

EDRF

A
  • EDRF is identified as NO
    • Endothelium Mediated Vascular Smooth Muscle Relaxation
    • EDRF: Endothelium-derived relaxing factor
    • NO Release accounts for the biological activity of endothelium-derived relaxing factor
    • Endothelium-derived relaxing factor produced and released from artery and vein is NO
    • EDRF → ↑ cGMP, which acts on smooth muscle
    • cGMP = relaxes smooth muscle, vasodilation
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3
Q

NO formation picture

A
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4
Q

NOS: Nitric Oxide synthase enzyme

What are the 3 types? Occur in various tissues)

A
  • nNOS – neuronal, found in neurons first
  • iNOS – inducible, found in macrophages
  • eNOS – endothelium ** one that we’re concerned with most
  • NO: Nitric Oxide
  • NO formed in the body on the spot
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5
Q

NO: Multiple Biological Roles

A
  • Protective (bolded) & Pathogenic (regular)
    • Nt
    • Inhibit Plt aggregation
    • Cytoprotection
    • Vasodilator smooth muscle relaxant***
    • ↓ cell adhesion, proliferation
    • Inflammatory tissue injury
    • Shock – hypotension
    • Cell proliferation
    • Neuronal injury, NMDA
    • Immune cytotoxicity
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6
Q

Nitric oxide mediated vasodilation

A
  • ACh activates muscarinic receptors
  • Ca++ influx that activates NOS
  • Resultant NO will activate GC – guanylyl cyclase – forms cGMP → relaxation occurs
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7
Q

Nitrovasodilator (NO-donor) Drugs

A
  • Organic nitrates
    • Nitroglycerin
    • Isosorbide dinitrate
    • Isosorbide mononitrate
  • Sodium nitroprusside
  • Amyl nitrite (not really used therapeutically)
  • Nitric oxide gas – used in neonates, pHTN
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8
Q

Organic nitrates & sodium nitroprusside

A
  • Mechanism of action:
  • NO release resulting in activation of GC in vascular sm muscle, formation of cGMP, vascular smooth muscle relaxation and vasodilation
  • Organic nitrates – require metabolism to release NO
  • Organic nitrates have to go thru a metabolism step – with nitrosothiol needed – eventually releases NO
  • This is how NTG has a tolerance effect – need a break where they’re off of it. As opposed to SNP that doesn’t need this, spontaneous release of NO.
  • Organic nitrates like NTG
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9
Q

Sodium nitroprusside: mechanism of action

A
  • Structure – complex of 1 iron, 5 cyanide and 1 NO group
  • Spontaneous breakdown to NO & cyanide
  • Direct acting peripheral vasodilator
  • Relaxation of arterial & venous smooth muscle
  • Metabolism
    • Cyanide combines with sulfur groups to form thiocyanate (eg, thiosulfate, cysteine, etc.); undergoes renal excretion
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10
Q

Sodium nitroprusside: PK

A
  • Onset < 2 minutes
  • Duration 1-10 minutes
  • Half-life ~ 2 minutes
  • Half-life thiocyanate ~2-7 days
    • increased with impaired renal fxn
  • Renal excretion as metabolites (mostly thiocyanate); some exhaled air, feces
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11
Q

Sodium Nitroprusside clinical effects

A
  • Cardiovascular
    • ↓ arterial/venous pressure
    • ↓ peripheral vascular resistance
    • ↓ afterload
      • In HF or acute MI – CO may increase due to ↓ afterload
    • Slight incr HR
    • Lacks significant effects on nonvascular smooth muscle and cardiac muscle
  • Renal • vasodilation without significant change in GFR
  • CNS • ↑ cerebral blood flow and intracranial pressure
  • Blood
  • NO - Inhibits platelet aggregation
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12
Q

Sodium Nitroprusside Clinical Uses

A
  • Hypertensive crisis
  • BP reduction to prevent/limit target organ damage
  • Controlled hypotension during surgery • During anesthesia, to reduce bleeding when indicated
  • Congestive heart failure • Acute, decompensated
  • Acute myocardial infarction
    • To improve cardiac output in LV failure & low CO post-MI
    • Limited use due to coronary steal- altered blood flow results in diversion of blood away from ischemic areas
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13
Q

Sodium Nitroprusside: Adverse Effects

A
  • Profound hypotension- possible impaired organ perfusion
  • Cyanide toxicity
    • often dose/duration related, but may occur at recommended doses
    • Tissue anoxia
    • Venous hyperoxemia – tissues cannot extract oxygen
    • Lactic acidosis
    • Confusion, death
  • Methemoglobinemia
    • Some iron in hemoglobin is oxidized to ferric (+3) state with impaired oxygen affinity; reduced O2 delivery to tissues (hypoxia); metHb >10% symptomatic
    • Measured by how much Hbg is affected by this
    • Should be considered as a differential diagnosis in patients with impaired oxygenation despite adequate cardiac output and arterial oxygenation
    • Reversal agent - Methylene blue
  • Thiocyanate accumulation
    • ↑ risk with prolonged infusion; renal impairment
    • Neurotoxicity, including… tinnitus, miosis, hyperreflexia
    • Hypothyroidism – due to impaired iodine uptake
  • Renal • Incr serum creatinine (transient)
  • Others include… • Incr intracranial pressure; GI (nausea); headache; restlessness; flushing; dizziness; palpitation
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14
Q

Sodium Nitroprusside Drug Interactions

A
  • Hypotensive drugs including…
    • Negative inotropes
    • General anesthetics
    • Circulatory depressants
  • Phosphodiesterase Type 5 inhibitors (eg., sildenafil, tadalafil – for ED) - also causes hypotension
  • Soluble guanylate cyclase stimulators (eg., riociguat) – (role of cGMP in vasodilation) – also hypotension
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15
Q

Sodium Nitroprusside Stability & Administration

A
  • Stability
    • Unstable
    • Light & temperature sensitive
      • Protect from light and store at 20–25°C
      • deterioration results in change to bluish color
      • wrap the container with aluminum foil or other opaque material
  • Administration
    • IV infusion via infusion pump
    • Diluted in 5% dextrose
    • Shortest infusion duration possible to avoid toxicity; if reduction in BP not obtained within 10 minutes @ max infusion rate, discontinue (cyanide toxicity)
    • Solution has faint brownish tint; if discolored (eg., blue, green, red) discard
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16
Q

Organic Nitrates

A
  • nitroglycerin (glyceryl trinitrate)
  • isosorbide dinitrate
  • isosorbide mononitrate
  • amyl nitrite (rarely used)
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17
Q

Nitroglycerin mechanism of action

A
  • GC: guanylyl cyclase enzyme
  • NO: nitric oxide
  • NO release through cellular metabolism – glutathione-dependent pathway
  • Requires thiols
  • NO released—stimulates GC and formation of cGMP
  • Vascular smooth muscle relaxation and peripheral vasodilation
  • Primary action: venous capacitance vessels
  • mildly dilate arteriolar resistance vessels
  • dilation of large coronary arteries
  • Administered IV, SL, translingual spray, transdermal, ointment
  • These require that metabolism step, compared to SNP
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18
Q

NTG - effects on venous capacitance vessels, arteriolar resistance and myocardial arteries

A
  • Venous capacitance vessels
    • Decreased preload
    • Decreased myocardial O2 demand
  • Arteriolar resistance vessels (mild)
    • Modest decreased afterload
    • Decreased myocardial O2 demand
  • Myocardial arteries
    • Increased myocardial O2 supply
    • ↓ MVO2 is how NTG is good for MI’s, used to think that the dilation of the large epicardial arteries was the primary mechanism
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19
Q

NTG effects on CV, other, pulm

A
  • Cardiovascular
    • ↓ VR; decrease L and R ventricular end diastolic pressure
    • decrease Cardiac Output
    • No change in SVR
    • Increase in coronary blood flow to ischemic subendocardial areas (opposite of SNP)
    • Sodium Nitroprusside = Steal
  • Other
    • Smooth muscle relaxation in bronchi, GI tract –small effects, but it’s still a possibility
    • Inhibits platelet aggregation
  • Pulmonary
    • bronchial dilation
    • Inhibits Hypoxic pulmonary vasoconstriction
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20
Q

NTG tolerance, cautions, clinical uses

A
  • Tolerance – after 8-10 h, results in diminishing effectiveness
    • Nitrosothoil
    • Need to take the patch off for some time to get back that effect – double check this
  • Cautions – volume depletion, hypotension, bradycardia or tachycardia, constrictive pericarditis, aortic/mitral stenosis, inferior wall MI and Rt ventricular involvement
  • Clinical uses
    • Angina
      • Acute angina pectoris (sublingual) & prevention (longr-acting oral, transdermal, ointment, etc.)
        • → Venodilation decreases venous return to the heart which reduces RVEDP and LVEDP
        • → Reduces myocardial oxygen requirements
    • Hypertension
      • Perioperative hypertension
      • Hypertensive emergencies
      • Postoperative hypertension (eg., following coronary bypass surgery)
    • Controlled hypotension during surgery
    • Non-ST-Segment-Elevation
    • Acute Coronary Syndrome
    • Acute Myocardial Infarction – limits damage
    • Heart Failure, Low-output syndromes
      • decreases preload; relieves pulmonary edema
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21
Q

NTG adverse effects

A
  • CNS
    • Throbbing headache
    • Increased ICP
  • Cardiovascular
    • Orthostatic hypotension, dizziness, syncope
    • Reflex tachycardia (baroreceptor)
    • Flushing
    • Vasodilation, venous pooling, decreased cardiac output
  • Hematologic
    • Methemoglobinemia (rare)
  • Tolerance
    • limitation of the use of nitrates
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22
Q

NTG PK

A
  • Large first-pass effect (90%) following oral admin – why we give it SL or IV
  • Metabolism
    • Liver– denitrated by glutathione-organic nitrate reductase to glyceryl dinitrate and then mononitrate
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23
Q

NTG onset & duration for each route

A
  • IV
    • onset: immediate
    • DOA: 3-5 min
  • SL
    • onset: 1-3 min
    • DOA: >25 min
  • translingual spray
    • onset: 1-3 min
    • DOA: >25 min
  • PO, extended release
    • onset: 60 min
    • DOA: 4-8 hrs
  • Topical
    • onset: 15-30 min
    • DOA: 7 hrs
  • Transdermal
    • onset: 30 min
    • DOA: 10-12 hrs
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24
Q

Isosorbide Dinitrate onset & duration for each route

A
  • SL
    • onset: 2-5 min
    • DOA: 1-2 hrs
  • PO
    • onset: 60 min
    • DOA: up to 8 hrs
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25
Q

Isosorbide Mononitrate onset & duration for each route

A
  • PO
    • onset: 30-45 min
    • DOA: >6 hrs
  • PO, extended release
    • onset: 30-45 min also
    • DOA: >12-24 hrs
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26
Q

NTG Drug Interactions

A
  • Antihypertensive drugs –additive effects
  • Selective PDE-5 inhibitor drugs (avanafil, tadalafil, vardenafil, sildenafil)
    • Absolute contraindication
    • Profound potentiation
    • Possible life-threatening hypotension and/or hemodynamic compromise
    • Accumulation of cGMP by inhibiting its breakdown
  • Guanylate cyclase stimulating drugs (riociguat) – increase the production of cGMP
  • Other –see text
  • Anything that causes ↑ cGMP will be contraindicated
  • cGMP = vasodilation/relaxation
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27
Q

Other organic nitrates - Isosorbide mononitrate, dinitrate

PO use and metabolism

A
  • Oral nitrate forms – used for the prophylaxis of angina pectoris
    • Additional- heart failure in Black patients in combination with hydralazine (direct-acting vasodilator)
  • Orally - Well absorbed from the GI tract duration of action 6 hours
  • Metabolism
    • Dinitrate metabolized to mononitrate form (t1/2=5 hrs) – active metabolite
    • Mononitrate metabolized (by denitration) to isosorbide to sorbitol - inactive
    • Regular and extended-release forms
    • Need appropriate dosing intervals, to allow for nitrate-free period, to avoid tolerance
    • Disease concerns: similar to NTG
    • Avoid concomitant use with PDE5 inhibitor drugs
    • Toxicity similar to NTG
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28
Q

Phosphodiesterase Inhibitor Drugs: Phosphodiesterase enzymes

A
  • Family of enzymes that breakdown cyclic nucleotides
  • Regulate intracellular levels of 2nd messengers cAMP & cGMP
  • 11 major subfamilies (eg., PDE-3, PDE-4, PDE-5, etc); differ in localization, potential therapeutic targets
  • Inhibitors – boost levels of cyclic nucleotides by preventing breakdown
  • Older, non-selective drugs that inhibit PDE: caffeine, theophylline

Boost both cAMP and cGMP

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29
Q

PDE3:

brand, distribution, substrate, fn, inhibitor clinical use

A
  • PDE3 breaks down cAMP. So by inhibiting it you have MORE cAMP - more inotropy/chronotropy/vasodilation
  • drug
    • amrinone
    • milrinone
  • distribution
    • broad
    • includes heart and VSMC
  • substrate
    • cAMP
    • cGMP
  • fn
    • cardiac contractility, plt aggregation
  • inhbiitor clinical use
    • inotrope + peripheral vasodilator
    • limited for acute HF
  • cliastazol is used for intermittent claudication
30
Q

PDE4:

brand, distribution, substrate, fn, inhibitor clinical use

A
  • drug
    • roflumilast
  • distribution
    • broad
    • includes CV, neural, immune/inflammatory
  • substrate - cAMP
  • fn
    • immune, inflammatory
  • inhibitor clinical use
    • COPD - decreases inflammation & remodeling
31
Q

PDE5:

brand, distribution, substrate, fn, inhibitor clinical use

A
  • remember that PDE5 breaks down cGMP, so by inhibiting this enzyme, you have MORE cGMP
  • drug
    • sildenafil
    • tadalafil
    • vardanafil
  • distribution
    • broad
    • VSMC, esp erectile tissue, retina, & lung
  • substrate - cGMP (relaxer!)
  • fn
    • VSMC relaxation (esp erectile tissue, lung)
  • inhibitor clinical use
    • ED
    • pHTN
32
Q

What does cAMP enhance/do?

A
  • Ca++-channel activation
    • ↑ cytosolic Ca++
    • actin-myosin-troponin interaction
    • positive inotropy and chronotropy
  • cAMP-dependent protein kinase
    • ↑ phosphorylated phospholamban
    • augmented Ca++ uptake by SR
    • vasodilation

PDE3 inhbitors prevent the breakdown of cAMP

“I went to cAMP when I was 3 (PDE3), no one knows why”

33
Q

PDE3 inhibitor - Milrinone

clinical uses, PK

A
  • Clinical Uses
    • Acute heart failure or severe chronic HF
    • cardiogenic shock (off-label)
    • heart transplant bridge or post-op (off-label)
  • PK
    • Onset (IV) 5-15 minutes
    • Half-life ~3-6 hrs
    • Parenteral only
    • Majority not metabolized; >80% excreted renally unchanged
  • Note: amrinone another PDE3 inhibitor was withdrawn from market in US
34
Q

PDE3 inhibitor - Milrinone

Effects, Adverse Effects

A
  • Effects
    • Inotropic, ↑ cardiac contractility
    • Vasodilation
    • Little chronotropic activity
  • Adverse effects
    • Arrhythmias
    • Hypotension
35
Q

RAAS: Renin info

A
  • Is an enzyme, not named like most are named -ase
  • Secreted by the JG Apparatus
  • Vasoconstriction and sodium retention
  • Goal - maintain tissue perfusion through increase extracellular fluid volume
  • RAAS is synergistic with SNS by increasing the release of noradrenaline from the sympathetic nerve terminals
  • SNS: sympathetic nervous system
  • ACE think -ase – enzyme that converts ANGI to ANG II
36
Q

RAAS - key components

A
  • Regulates tissue perfusion, blood pressure, electrolytes & fluid
  • Remember the B1 action of renin in the kidney!! SO metop would block this
  • Remember that ACE = kininase II !
    • Also breaks down bradykinin, which causes vasodilation
    • Prevents vasodilation → increases vasoconstriction
    • ACE located in membrane of endothelial cells
37
Q

Info on:

Renin

ANG I

ACE

ANG II

Aldosterone

A
  • Renin
    • formed/secreted from JG cells
    • rel stimulated by decrease BP or Na+, B1 rec activation
    • protease - cleaves angiotensinogen to form…
  • Angiotensin I
    • inert
  • ACE (kininase II)
    • broad protease action - forms ANG II from ANG I
    • metabolism of BKN to inactive form
    • located in the membrane of EC cells (??)
  • ANG II
    • vasoconstriction (AT1 receptor)
    • aldosterone secretion (AT1 receptor)
    • other: increases ADH, increases proximal tubule Na+ reabsorption
  • Aldosterone
    • steroid; adrenal cortex
    • regulates gene expression, increases Na+ reabsorption
    • H2O retention, K+ excreted (??? what)
38
Q

ANG II receptors

A
  • GPCR
  • subtypes: AT1 R, AT2 R
  • Current antagonist drugs block AT1 R
  • AT1R
    • reg of BP
    • reg of body fluid balance
    • vasoconstriction
    • inflammation
    • plt aggregation/adhesion
    • ROS production
    • proliferative
    • hypertrophy
    • fibrosis
  • AT2R
    • natriuresis
    • neuronal activity
    • vasodilation
    • anti-inflammation
    • pro-apoptotic
    • antioxidative
    • anti-hypertrophic
    • anti-fibrotic
39
Q

Drugs that inhibit the RAAS pathways:

B1AR antagonists (metop)

Renin inhibitor

ACE inhibitor

ANG II Receptor Antagonists (ARB)

Aldosterone Antagonists

A
  • B1AR antagonists (metop)
    • block SNS stimulation at renal JGC
  • Renin inhibitor
    • prevent Renin from converting Angiotensinogen to ANG I
  • ACE inhibitor (enalapril, lisinopril …)
    • prevents ACE from converting ANG I to ANG II
  • ANG II Receptor Antagonists (ARB) (Losartan, valsartan)
    • prevents ANG II from binding to AT1 subtype of ANG II receptor
  • Aldosterone Antagonists (spironolactone, eplerenone)
    • prevents increase in aldosterone
    • AT1 can be blocked by ARBs also!
40
Q

ACE inhibitor mechanism of action and effects

A
  • MOA
    • prevents ACE from converting ANG I to ANG II
    • prevents ACE from converting bradykinin (BKN) to its inactive form
  • Effects
    • decrease in ANG II
      • vasodilation
      • ↓ remodeling
      • ↓ aldosterone (↓ Na/H2O retention, ↑ K+ retention)
      • ↓ SNS output
      • ↑ natriuresis
    • increase in bradykinin
      • vasodilation
      • cough
      • angioedema
  • The blocking of BKN breakdown is what contributes to the bad SEs of ACE inhibitors
  • d/c the drug if they have angioedema/cough
41
Q

Bradykinin picture

A
42
Q

BKN: Bradykinin

A
  • Endogenous peptide
  • T1/2 = 17 sec
  • Constitutive actions:
    • Stimulates NO & prostacyclin formation
    • Vasodilation (heart, kidney, microvascular beds)
  • Inflammatory actions:
    • ­ capillary permeability
43
Q

ACE inhibitor brands

A
  • generic name (Brand)
  • Captopril (Capoten)
  • Benazepril (Lotensin)
  • Enalapril (Vasotec)
  • Fosinopril (Monopril)
  • Lisinopril (Zestril, Prinivil)
  • Moexipril (Univasc)
  • Perindopril (Aceon)
  • Quinapril (Accupril)
  • Ramipril (Altace)
  • Trandorapril (Mavik)
44
Q

ACE inhibitor MOA & uses as 1st-line therapy

A
  • Mechanism of Action
    • Block the conversion of Angiotensin I to Angiotensin II
    • Prevent vasoconstriction
    • Prevent aldosterone secretion, decreasing sodium and water retention
  • First-line therapy
    • HTN
    • CHF
    • Mitral Regurgitation
  • More effective in diabetes mellitus pts
  • Delay progression of renal disease
45
Q

ACE inhibitor Clinical effects and common clinical uses

A
  • Clinical effects
    • ¯ BP, peripheral vascular resistance
    • ¯ preload, afterload
    • ¯ cardiac workload
    • Do not result in reflex tachycardia (compared to the direct vasodilators
    • improves/prevents LV hypertrophy, remodeling
    • improves morbidity/mortality HF
    • diabetic nephropathy-delays progression (improves renal hemodynamics)
  • Common Clinical Uses
    • *HTN - most commonly used for
    • Post MI
    • *HF (systolic dysfxn)
    • Diabetic nephropathy
46
Q

ACE inhibitor PK & drug interactions

A
  • Metabolism & Elimination
    • Many are pro-drugs → Enalapril & ramipril – ester prodrugs (plasma conversion)
    • Usually renal
    • Oral dosage forms
      • Exception: enalaprilat (IV)
    • Lots of combo (+ diuretic, etc.)
  • Drug Interactions
    • K+ sparing diuretic
    • K+ supplements
47
Q

ACE inhib common adverse effects: CV, electrolyte, renal, inflammatory

A
  • CV
    • Hypotensive sx’s, syncope
    • “1st dose effect” possible – more significant hypotensive effect initially
  • Electrolyte
    • • HYPERkalemia
    • Caution with K+ sparing diuretics & K+ supplements
  • Renal
    • ¯ GFR, ­ BUN & serum Cr, renal dysfxn
    • Contraindicated – bilateral renal artery stenosis (they have↑ ANGII to promote BF, so if you block that it might be bad)
  • Inflammatory
    • Dry cough (~5-20%), reversible if d/c’d; BKN-related
      • Not self-limiting
    • Angioedema (~1%); BKN-related – they would be taken off this if this happened
      • Ex of pt who had stopped ACE inhibitor before surgery, and got the angioedema when they restarted it
  • In surgery/anesthesia–can result in prolonged hypotension
  • Neutropenia/agranulocytosis (captopril)
  • Proteinuria
48
Q

ACE inhib common adverse effects: fetal dev’t

A
  • Fetal malformations - teratogenic
  • Contraindicated in pregnancy
    • Seen effects in 1st trimester, but more profound effects during 2nd and 3rd trimester
  • Any drug that works on the RAAS system – ACE inhibitor, ARB
  • Neonatal
    • Skull hypoplasia
    • Anuria
    • Hypotension, death
49
Q

ACE inhibitor contraindications

A
  • renal artery stenosis
  • Renal artery stenosis patients may develop renal failure due to efferent arteriole constriction
50
Q

Captopril SEs

A
  • C A P T O P R I L
  • Cough/C1 esterase deficiency (contraindication)
  • Angioedema/Agranulocytosis
  • Proteinuria/Potassium excess (hyperK+)
  • Taste change
  • Ortho hypoTN
  • Pregnancy (contraindication – fetal renal damage)
  • Renal artery stenosis (contraindication)
  • Increases Renin
  • Leukopenia/Liver toxicity
51
Q

ARB brands

A
  • generic name (Brand)
  • Azilsartan (Edarbi)
  • Candesartan (Atacand)
  • Eprosartan (Teveten)
  • Irbesartan (Avapro)
  • Losartan (Cozaar)
  • Olmesartan (Benicar)
  • Telmisartan (Micardis)
  • Valsartan (Diovan, Prexxatran)
52
Q

ARB prototype: Losartan

MOA, PK

A

Again, have extensive T1/2

  • Mechanism
    • Competitive antagonist @ AT1 rec
    • Blocks effects of Ang II mediated by AT1 rec
    • Does not block breakdown of BKN – thus BKN does not accumulate
  • Clinical Effects & Uses • Similar to ACEi
  • PK
    • Varies with various agents
    • Metabolism - CYP 450 enzymes
      • CYP2C9 - losartan, irbesartan
53
Q

ARB prototype: Losartan

Adverse Effects, Interactions, Contraindication

A
  • Adverse effects
    • similar to ACEi (see ACEi list)
    • Less frequent …
      • Cough (~30% rate of ACEi)
      • Angioedema (rare)
  • Interactions
    • K+ sparing diuretics
    • K+ supplements
  • Contraindication
    • renal artery stenosis
    • pregnancy
54
Q

ACEi vs ARB - So what’s the difference?

A
  • Efficacy in HTN - No differences
    • Total mortality
    • CV morbidity, mortality (cardiac, stroke)
  • ARBs slightly more tolerable, less likely to be discontinued
    • Main reason: ¯ dry cough (~1% vs 4%)
  • ACEi – higher quality of data
    • ARBs no comparison vs placebo (ARBs compared to ACE inhibitors, but never really against the placebo)
55
Q

Aldosterone antagonists (spironolactone, eplerenone)

MOA, Effects, Uses

A
  • Mechanism
    • Competitive antagonist at mineralocorticoid rec (kidney, but also heart, blood vessels, brain)
    • Prevent nuclear translocation of rec
    • Blocks transcription of genes coding for Na+ channels
    • Spironolactone – Off-target effects include androgen, progesterone rec blocking
    • Often combined with non-K-sparing drugs to offset the K+ excretion
  • Effects
    • ­ Na+ , H20 excretion, mild diuresis
    • ­ K+ reabsorption
  • Uses
    • HTN, HF
    • K+ sparing diuresis
    • 1° hyperaldosteronism
    • Spironolactone, off-label
    • Acne, hirsutism, PCOS
56
Q

Aldosterone antagonists (spironolactone, eplerenone)

PK, AEs, Drug Interactions

A
  • PK - Metabolism (both hepatic, just different enzymes)
    • Spironolactone
      • Hepatic
      • active metabolites-canrenone & 7- alpha-spironolactone (t1/2 : 12-20 hrs)
      • P-gp inhibitor
    • Eplerenone • CYP3A4
  • AEs include…
    • Hyperkalemia
    • Spironolactone—broad; includes hepatic, renal, serious derm (S-J, TEN, etc), GI, gynecomastia, menstrual irregularities, tumorigenic in animals
      • Blocking androgen and progesterone
  • Drug Interactions
    • Other K+ sparing (e.g., ACEi, ARBs, etc.)
    • K+ supplements
    • NSAID (­ renal risks)
    • Eplerenone - CYP3A4 inhibitors
57
Q

Direct Arterial Vasodilators - minoxidil, hydralazine

  • Hydralazine: Mechanism of action, Effects, PK
A
  • Mechanism of action
    • Release of NO from endothelial cells
    • Inhibition of Ca release from SR?
  • Effects
    • Vasodilates arterioles
    • Minimal venous effect
    • Decreased SVR
    • DBP reduced >SBP
    • Increase HR, SV, CO
  • PK
    • Extensive first-pass
    • Bioavailability ~25%
    • Half-life 1.5 – 3 hours
58
Q

Hydralazine Clinical Uses, AEs, contraindications

A
  • Clinical uses
    • Hypertension
    • Usually in combination with beta blocker & diuretic (to limit SNS effects)
    • HF – reduced ejection fraction (off-label)
  • Adverse effects
    • Headache, nausea, palpitations, sweating, flushing
    • Reflex tachycardia, tolerance/tachyphylaxis
    • Sodium and H20 retention
    • Angina with EKG changes – r/t reflex responses in response to vasodilation
    • Lupus erythematosus (reversible)
    • Rash, arthralgias/myalgias, fever – reversible
    • Used in combo with _______ isosorbide?
    • Particularly effective in Black patients
    • Not a lot of orthostatic hypotension
  • Contraindication
    • CAD, mitral valve RH disease
59
Q

Direct Arterial Vasodilators - minoxidil, hydralazine

Minoxidil: MOA, Effects, PK

A
  • Mechanism of action
    • Directly relaxes the arteriolar smooth muscle little effect on venous capacitance
    • increases the efflux of potassium from vascular smooth muscle resulting in hyperpolarization and vasodilation
  • Effects
    • Dilates arterioles, not veins
    • Use in hypertension (limited to later-line therapy due to risk-benefit profile)
  • PK
    • 90% oral dose absorbed from the GI tract
    • Peak effects 2-3 hours
    • Half-life ~ 4 hours
    • 10% of drug is recovered unchanged in the urine
60
Q

Minoxidil: Clinical Uses, AEs, Warnings

A
  • Clinical uses
    • Hypertension—later line therapy
    • Usually in combination with beta blocker & diuretic (to limit SNS effects)
  • Adverse effects
    • Tachycardia, increased myocardial workload
    • Palpitations, angina
    • Sodium/fluid retention, edema
    • Weight gain
    • hypertrichosis = excessive hair growth , vasodilation/stimulation of resting hair follicles
  • Warnings
    • Fluid retention
    • Pericardial effusion/tamponade
    • Rapid BP response
    • Sinus tachycardia
    • Elderly
61
Q

Peripheral Vasodilators: SNP

MOA, metab

A
  • Direct acting , nonselective peripheral vasodilator
  • Relaxation of arterial and venous vascular smooth muscle
  • Lacks significant effects on nonvascular smooth muscle and cardiac muscle
  • Mechanism of action
    • SNP interacts with oxyhemoglobin
    • dissociates immediately to form
      • Methemoglobin
      • Releasing Nitric Oxide (NO) and cyanide
    • Nitric Oxide activates guanylate cyclase (in the vascular muscle) thus increasing cGMP
    • cGMP inhibits calcium entry into vascular smooth muscle but increases uptake of Ca into the smooth Endoplasmic Recticulum.
    • Results in vasodilation via NO
  • Metabolism
    • Transfer of an electron from the Iron (Fe) of oxyhemoglobin to SNP yields → metHGb and an unstable SNP radical
    • Unstable SNP radical breaks down → all 5 cyanide ions are released.
    • One of these cyanide ions reacts with metHGb to form cyanomethemoglobin (nontoxic)
    • Remainder are metabolized in the liver and kidney → converted to thiocyanate
62
Q

SNP toxicity & treatment

A
  • Toxicity: occurs due to the effects of high plasma concentrations of thiocyanate
    • Cyanide Toxicity
      • Can occur at rates >2ug/kg/min for long periods
      • Suspect when the pt starts demonstrating resistance to hypotensive effects or a previous responsive patient who is unresponsive (tachyphylaxis) at rates >2-10 ug/kg/min
      • May precipitate tissue anoxia, anaerobic metabolism, and lactic acidosis
    • Treatment of Cyanide Toxicity
      • Immediate discontinuation of SNP
      • 100% 02 administration despite normal oxygen saturation
      • Sodium bicarbonate to correct metabolic acidosis
      • Sodium thiosulfate 150mg/kg over 15 minutes
      • Sodium thiosulfate Acts as a sulfur donor to convert cyanide to thiocyanate
    • Sodium nitrate 5mg/kg if severe toxicity
      • Converts hemoglobin to metHgb which coverts cyanide to cyanometHemoglobin
    • Thiocyanate Toxicity
      • Rare as thiocyanate is cleared by the kidney in 3-7 days
      • Less toxic than cyanide
      • Symptoms include:
        • N/V, tinnutis, fatigue, CNS hyperreflexia, confusion, psychosis, miosis seizure and coma
      • Methemoglobinemia
        • Rare
    • Should be considered as a differential diagnosis in patients with impaired oxygenation despite adequate cardiac output and arterial oxygenation
  • Phototoxicity
    • SNP should be mixed with 5% glucose in water and be protected from exposure to light.
    • With continuous exposure to light SNP is converted to aquapentacyanoferrate in the presence of light and the release of hydrogen cyanide
    • Wrap the solution and tubing in foil or dark plastic bag.
63
Q

SNP dosage

A
  • 0.3ug/kg/min - 10ug/kg/min IV
  • Max dose: should not be infused for greater that 10 minutes
  • Immediate onset
  • Short duration of action
  • Requires continuous IV administration to maintain therapeutic effect
  • Extremely potent: use A-line
64
Q

SNP effects

A
  • CV:
    • Direct venous and arterial vasodilation, decreased venous capacitance due to venous return Baroreceptor mediated reflex responses increased HR
    • ↓ SBP, ↓ SVR,↓ PVR, ­contractility, causes an intracoronary steal in areas of damage associated with MI; decreased diastolic BPàdecrease coronary perfusion
  • CNS:
    • ↑ ­CBF, and ICP with modest decrease in MAP or with greater decrease in MAP can reduce cerebral blood flow (caution with carotid disease)
  • Pulmonary:
    • Attenuation of hypoxic vasoconstriction.
  • Blood: Increases in intracellular GMP → inhibit platelet aggregation and increase bleeding time
65
Q

SNP clinical uses & associated dosages

A
  • Controlled hypotension: 0.3-0.5ug/kg/min not to exceed 2 ug/kg/min
  • Hypertensive crises: infusion 1-2ug/kg IV can be given as bolus
  • Cardiac disease:
    • decreases LV afterload, benefits management of MR or AR, CHF, and heart failure.
    • Consider coronary steal
66
Q

D/C B-blockers preop?

A

NO

BB therapy reduces perioperative MI

67
Q

D/C CC blockers preop?

A

NO

Benefits outweigh risks, UNLESS severe LV dysfn

-no good evidence one way or the other

68
Q

D/C ACE inhibitors preop?

A

YES

Withholding for 1 dosing interval (best if they don’t take the night before)

Dr. Walker: Give them back their RAAS! They need some compensatory mechanism

69
Q

D/C centrally acting agent?

A

NO

risk for rebound HTN if you hold it

70
Q

Ca-channel blockers

A

Ca-channel blockers – reduced inotropy

Inhalational agents will cause myocardial depression

Potential that it can improve outcomes?

Prolongs paralytics

71
Q

Deliberate Controlled Hypotension

A
  • Indications: Minimize blood loss, fluid replacement and electrolyte disturbances
    • Think of surgery that has high expected blood loss, and someone who you don’t want to/can’t transfuse
      • Antibodies
      • Jehovah’s witness
      • Pre-transplant
      • Severe CAD – avoid losing blood
      • Pt Refuses
  • Not used as much today
    • Stroke
    • POVL
    • Keep them within 20% of their b/l range
    • Still use – jaw/dental surgery on young pts (16-21 yo) – their SNS system works!
  • Reduce MAP to pre-determined level
    • 50-60 mm Hg; may need higher MAP
  • Maintain cerebral and renal blood flow and autoregulation
  • Arterial line is REQUIRED
  • Ways to do it
    • Increase inhalational agent
    • SNP
72
Q

Controlled hypotension dosages:

SNP

NTG

Nicardipine

Dexmedetomidine

Propofol

Labetalol (no dosage, just info for this one)

A
  • Sodium Nitroprusside: 0.3-0.5mcg/kg/min not to exceed 2 mcg/kg/min (really high dose, usually ≅ 1 mcg/kg/min – and that’s for a carotid case)
    • More Arterial
  • Hypertensive crises: infusion 1-2mcg/kg IV can be given as bolus
  • Nitroglycerin: 125-500 mcg/Kg/min
    • More venous
  • Nicardipine: 5mcg/kg/min
  • Dexmedetomidine: 0.2-0.7mcg/kg/hr
    • Decreases release of NE
    • No amnesia
  • Propofol infusion – vasodilation
  • Labetalol/B-blockers IVP
    • Alpha and beta
    • 15-1 hr? Will get you thru the surgery, but be careful bc it will stick around
    • Will often see asthma in young ppl – bronchoconstriction B2 blockade
    • Esmolol – higher doses = non-selective, and so short acting that you’ll have to keep re-dosing it
      • <10 minutes

Angeli - N929 Pharmacology (12 decks)

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