Nitrate vasodilators and Sodium Nitroprusside

Question 1

What type of drugs are GTN and Sodium Nitroprusside

Answer 1

They are Nitrate vasodilators

GTN –> Organic nitrate

Nitroprusside –> cyanide

Question 2

How can GTN and Nitroprusside be administered

Answer 2

GTN - Sublingual, Oral, Intravenous, transdermal patch

Nitroprusside - IV only

Question 3

Why can Sodium nitroprusside only be administered IV

Answer 3

Degraded to cyanide immediately upon contact with mucosal surfaces

Question 4

Compare the fat and water solubility of GTN vs Sodium Nitroprusside

Answer 4

GTN - Fat soluble

Sodium Nitroprusside - water soluble

Question 5

Compare the protein binding of GTN and Sodium Nitroprusside

Answer 5

GTN - Highly protein bound

Sodium Nitroprusside - No protein binding

Question 6

GTN is used in the ICU and the Emergency department

Sodium Nitroprusside is only used in the ICU

Why is this

Answer 6

Sodium Nitroprusside is degraded by direct light which requires opaque storage vessels and special handling techniques

Also - Sodium Nitroprusside can cause cyanide toxicity

Question 7

Compare the metabolism of GTN to Sodium Nitroprusside

Answer 7

GTN

• Hepatic metabolism
• Extrahepatic metabolism: RBC and endothelial cell membranes

Nitroprusside
- Spontaneous: 5 cyanides + Ferrous Nitrosyl
or
- Reacts with Hb: 4 cyanides + cyanmethaemoglobin

Question 8

Compare the elimination half life of GTN to Sodium Nitroprusside

Answer 8

GTN t1/2 - 30 minutes

Sodium Nitroprusside t 1/2 - 2 minutes

Question 9

Compare the onset of action of GTN and Na Nitroprusside

Answer 9

GTN

• • Sublingual: 1 - 3 minutes onset and max effect at 5 minutes.
• • Duration: 30 minutes

Sodium Nitroprusside
- Immediate onset (seconds) and offset

Question 10

Describe the mechanism of action of GTN and Sodiu Nitroprusside

Answer 10

Donates NO –> activates guanylyl cyclase –> increase cGMP in VSM –> Increase potassium channel conductivity –> hyperpolarization –> Reduced intracellular calcium –> reduced resting tone and contractility of smooth muscle

Question 11

List the distinguishing features of Nitroprusside vs GTN

Answer 11

GTN:
Venodilation + coronary vasodilation > Vasodilation
Metabolized: Glycerol (enters gluconeogenesis)

NITROPRUSSIDE
Vasodilation = Venodilation
Shorter duration (immediate offset)
Metabolized: Cyanide toxicity (doses > 2 ug/kg/minute)
Methaemoglobinaemia more common than with GTN
Sensitive to light degradation

Question 12

List the clinical effect in common with both GTN and Nitroprusside

Answer 12

1. Reduced preload (VenoD) + Reduced afterload (VasoD)
2. Increased ICP (Headache)
3. Reflex tachycardia
4. Methaemoglobinaemia
5. Tachyphylaxis

Question 13

What does coupling of oxidative phosphorylation mean?

Answer 13

H+ movement inward across inner membrane is coupled with ATP synthesis by ATP synthase enzyme or Complex V.

Brown fat

• -> H+ moves across inner membrane independently complex 5 and without ATP production –> uncoupled
• -> Heat released instead of ATP

Cyanide
–> Binds Ferric (3+) portion of Complex IV (Cytochrome oxidase) preventing O2 binding to H+ and preventing water formation. No electrochemical gradient hence formed between intermembrane space and inner mitochondrial matrix.

Question 14

What is the mechanism of toxicity of cyanide positoning

Answer 14

1. Uncoupling oxidative phosphorylation
   - -> Binds Ferric (Fe3+) portion cytochrome oxidase (Complex IV) preventing H+ binding O2 –> Lactic acidosis
2. Free radicals –> lipid bilayer damage
3. Biogenic amines liberated –> vasoactive
4. Excitatory neurotransmitters release (NMDA/glutamate)

Leading to:

1. Lactic acidosis
2. Multi-organ system failure + pulmonary oedema
3. Seizures

Question 15

What happens to the oxygen extraction ratio in cyanide toxicity

Answer 15

OER = VO2 / DO2

VO2 decreases in cyanide toxicity, therefore OER decreases. this means that ScvO2 will be high as minimal O2 is being extracted by tissues

Question 16

What is diagnosis of cyanide toxicity based on

Answer 16

Context

1. Inhalation of smoke in a plastic based fire
2. Sodium nitroprusside therapy (doses > 2ug/kg/min)

Severe lactic acidosis (absence of CO poisoning)
High ScvO2
Early/developing multi-organ dysfunction

Cyanide level = gold standard but takes long

Question 17

Summarise the antidotes for cyanide poisoning

Answer 17

COBALT-BASED BINDER

Vitamin B12 (Hydroxycobalamin)
- cobalt within binds cyanide to form cyanocobalamin
(Previously: dicobalt edetate was used but more toxic)

SULFUR DONOR

Sodium thiosulfate
- sulfur ion helps convert cyanide to thiocyanate (few side effects)

NITRITE INDUCED METHAEMOGOLOBINAEMIA

Sodium Nitrite and amyl nitrite (also methylene blue but with more side effects)
- binds cyanide and forms cyanmethaemoglobin

Question 18

Why is hydroxycobalamin (vitamin B12) now used as the preferred cobalt-based binder for cyanide toxicity versus the historically used dicobalt edetate?

Answer 18

Side effects of dicobalt edetate

1. Seizures
2. Chest pain and dyspnoea
3. Headache and neck swelling
4. Hypotension, urticaria and vomiting

Side effects of hydroxycobalamin
1. Body fluids change colour –> red-orange

So B12 is much less toxic, can be given empirically and pre-hospital without monitoring with rapid onset of action.