Direct Vasodilators

Direct vasodilators include:

  • Ca2+ channel blockers (see Calcium Channel Blockers)
  • Nitrates
    Increase production of NO:
    • NO activates guanylate cyclase, increasing cGMP
    • cGMP inhibits Ca2+ uptake into smooth muscle and enhances its sequestration into smooth endoplasmic reticulum
      The decrease in cytoplasmic [Ca2+] causes smooth muscle relaxation and vasodilation
  • Hydralazine
    Multimodal mechanism of action, including:
    • Opens K+ channels, hyperpolarising vascular smooth muscle
    • Decreases intracellular Ca2+ in vascular smooth muscle
    • Activation of guanylate cyclase
Property Sodium Nitroprusside GTN Hydralazine
Class Inorganic Nitrate Organic Nitrate Direct vasodilator
Uses Afterload (with some preload) reduction Afterload & preload reduction, angina HTN
Presentation Solution at 10mg.ml-1, must be protected from light Spray, tablets, patch, IV solution which is absorbed into PVC - requires a polyethylene administration set 20mg ampoule or powder. Should not be reconstituted with dextrose.
Route of Administration IV only IV, topical, sublingual PO, IV
Dosing 0.5-6µg.kg-1.min-1 10-200µg.min-1 5-20mg IV
Absorption <5% PO bioavailability 30% bioavailability due to high first pass metabolism
Metabolism Prodrug. Reacts with Oxy-Hb in RBC to form 1x NO, 5x CN-, and MetHb. MetHb reacts with CN to form cyanomethaemoglobin. CN is metabolised in the liver and kidney to form SCN, the majority of which is excreted in urine (though may be re-converted to CN).

CN may also combine with hydroxycobalamin (vitamin B12) to form cyanocobalamin, which is eliminated in urine.
Prodrug. Metabolised to NO and glycerol dinitrate (which is then also converted to NO) in the liver. N-acetylated in gut and liver
Elimination Renal elimination of SCN and cyanocobalamin. Impaired in renal failure which may worsen CN toxicity. t1/2 for SCN is 2-7 days t1/2 1-4mins. Urinary excretion Dependent on acetylation rates
Resp Inhibit hypoxic pulmonary vasoconstriction leading to ↑ shunt Bronchodilation
CVS SVR > venodilation. ↓ SBP and ↓ preload, ↑ HR maintains CO, ↓ MVO2 Vasodilation predominantly of capacitance vessels, ↓ preload, ↓ VR, ↓ EDP, ↓ wall tension improving subendocardial blood flow, ↓MVO2 Arteriolar vasodilation with compensatory tachycardia and increased CO
CNS CBF following cerebral vasodilatation CBF following cerebral vasodilatation, which may cause headache Increased CBF
Haematological Methaemoglobinaemia Methanoglobinaemia
Toxic Effects Three mechanisms: hypotension, thiocynate toxicity, CN toxicity. Methaemoglobinaemia can occur with GTN

GTN patches may explode if left on during DC cardioversion.

Nitrate Toxicity

Nitrate toxicity can be related to:

  • Cyanide
  • Thiocyanate
  • Methaemoglobinaemia

Cyanide Toxicity

Cyanide toxicity occurs only with SNP, as CN- is produced as a byproduct of metabolism.

  • Kinetics
    • Rapid cellular uptake
    • Small VD
    • Hepatically metabolised to thiocyanate, using thiosulfate as a substrate
  • Mechanism
    CN- binds to cytochrome oxidase, preventing oxidative phosphorylation. This causes histotoxic hypoxia, and is characterised by:
    • Rapid loss of consciousness and seizures
    • Metabolic acidosis
    • Lactataemia
    • Arrhythmia
    • Increased MVO2
    • Hypertension
      Due to tachyphylaxis to SNP.
  • Risk of cyanide toxicity from SNP is related to:
    • Infusion rate
    • Infusion duration
  • Management
    • Supportive care, including inotropes
    • Cyanide chelators
      Bind CN, removing it from the circulation. Include:
      • Dicobalt edetate
      • Hydroxycobalamin (Vitamin B12)
      • Sulfur donors
        Provide additional sulfhydryl groups, allowing further hepatic metabolism of CN- to SCN. Include:
        • Thiosulfate
      • Nitrites
        Converts Oxy-Hb to Met-Hb, which has a higher affinity for CN- than cytochrome oxidase. Include:
        • Sodium nitrite
        • Amyl nitrite

Thiocyanate Toxicity

Thiocyante is produced with hepatic metabolism of CN-. Toxicity occurs when thiocyanate accumulates, which occurs in:

  • Long duration SNP infusions
    7-14 days.
  • Patients with renal failure
    Reduced clearance, may occur in 3-6 days.
  • Patients given thiosulfate for management of CN- toxicity.
  • Effects
    Multisystemic, including:
    • Rash
    • Abdominal pain
    • Weakness
    • CNS disturbance
  • Treatment
    • Dialysis

Methaemoglobinaemia

Methaemoglobinaemia occurs when the Fe2+ (ferrous) ion in haemoglobin is oxidised to the Fe3+ (ferric) form, which is unable to bind oxygen.

  • Due to the high concentration of oxygen in erythrocytes, methaemoglobin is continually being formed
  • Several endogenous reduction systems exist to keep MetHb levels stable at ~1%
    • Predominantly cytochrome-b5 reductase
    • NADPH-MHb reductase
      This reduces methaemoglobinaemia in the presence of a reducing agent, classically methylene blue.
    • Reduced glutathione
      More important in preventing oxidative stress in other cells than the RBC.
  • Disease occurs due to the loss in oxygen-carrying capacity from the loss of effective haemoglobin
    • e.g. a 20% MetHb level gives a theoretical oxygen carrying capacity of 80% of the actual haemoglobin
      There is in fact a slight left shift of the oxyhaemoglobin dissociation curve, as oxygen binds more tightly to the partially-oxidised haemoglobin.

References

  1. Smith S, Scarth E, Sasada M. Drugs in Anaesthesia and Intensive Care. 4th Ed. Oxford University Press. 2011.
  2. Peck TE, Hill SA. Pharmacology for Anaesthesia and Intensive Care. 4th Ed. Cambridge University Press. 2014.
  3. Petkov V. Essential Pharmacology For The ANZCA Primary Examination. Vesselin Petkov. 2012.
  4. CICM September/November 2008
  5. LITFL- Cyanide Poisoning
  6. Thomas C, Lumb A. Physiology of haemoglobin. Continuing Education in Anaesthesia Critical Care & Pain, Volume 12, Issue 5, 1 October 2012, Pages 251–256.
  7. Wright RO, Lewander WJ, Woolf AD. Methemoglobinemia: Etiology, Pharmacology, and Clinical Management. Annals of Emergency Medicine, Volume 34, Issue 5, 1999, Pages 646-656.
  8. Russwurm M, Koesling D. NO activation of guanylyl cyclase. The EMBO Journal. 2004;23(22):4443-4450.
Last updated 2018-07-14

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