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Primary Pharmacology > Resp non table > Flashcards

Resp non table Flashcards

1
Q

Nitric oxide preparation

A

◦ Aluminium cylinders containing 100/800 ppm of NO and nitrogen
◦ Pure NO is toxic and corrosive

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2
Q

Dose of nitric oxide

A

5-20 parts per million

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3
Q

Chemistry of nitric oxide

A

Inorganic acid

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4
Q

Routes of administration of nitric oxide

A

◦ Administered as part of inspired gas mixture, usually as an admixture fraction measured in tens of ppm (5-20 ppm), via a proprietary system (INOMax), or inspiratory circuit fo a ventilator during inspiration only or continuous flow system throughout the respiratory cycle
◦ Inspiratory only reduces bolus effect seen with continuous flow administration; it also reduces nitric dioxide formation - as decreased oxygen time mixture

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5
Q

Mechanism of action of nitric oxide

A

◦ Nitric oxide is produced in vivo by nitric oxide synthase which uses substrate L arginine
◦ Nitric oxide diffuses to vascular smooth layers and stimulates cytosolic guanylate cyclase —> cGMP production
◦ CGMP increased production from GTP in the cytosol —> reduces cytosolic calcium ions via phospholamban phosphorylation _ inactivation fo voltage gated Ca channels and inhibition of IP3 mediated Ca release –> Ca sequestration in SR —> inhibits vasoconstriction adn results in vasodilation

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6
Q

Clinical effects of Nitric oxide

A
  1. PUlmonary vasodilation - inactivated before reaching systemic circulation
  2. Reduction in PVR –> potential RV increased output, may overload LV
  3. Hypotension
  4. Increased cerebral blood flow
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7
Q

Non target orrgan system effects and adverse effects of NO 4

A
  1. Methaemoglobinaemia
    - NO + oxyhaemoglobin –> methaemoglobin
    - NO + DexoxyHb –> nitrosyl Hb –> when contact with O2 results in methaemoglobinaemia
  2. Nitric oxide + O2 + water increased NO2 –> toxicity with ARDS and airway injury and potential increased susceptability to infection
  3. Platelet inactivation and can cause thrombocytopenai
  4. Rebound hypoxia with withdrawal
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8
Q

Toxicity of NO comes from

A

◦ 500-2000 ppm of NO results in methaeomoglobinaemia and pulmonary oedema
‣ Methhaemoglobinaemia rapidly resolves on discontinuation over several hours - persistent methaemoglobinaemia can be related with methylthioninium chloride
◦ Pneumonitis and pulmonary oedema can occur with contamination with nitric dioxide

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9
Q

Absorption of NO

A

Rapidly into systemic circulation as lipid soluble and diffuses freely

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10
Q

NO solubility

A

pKa -1.3

Dissociates into nitric acid

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11
Q

Distribution of NO

A

‣ VOD is impossible to measure, but is potentially very large. NO reacts with oxygen and water to produce nitrogen dioxide and nitrites, which then bind to haemoglobin and produce either nitrosylhaemoglobin or methaemoglobin, i.e. it can be described as “highly protein bound”.

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12
Q

Metabolism of NO

A

‣ One way or another, nitric oxide ends up as methaemoglobin and nitrate. Either it reacts with lung water, becoming nitrite (which reacts with oxyhemoglobin and generates methaemoglobin and nitrate) or it combines directly with oxyhaemoglobin, with the same results. If it encounters hypoxic blood, it can combine with deoxyhaemoglobin to create nitrosyl-haemoglobin, which then rapidly becomes methaemoglobin when it contacts oxygen.
‣ Following inhalation NO combines with oxyhaemoglobin that is 60-100% saturated producing methaemoglobin and nitrate - NO has a half life of <5 seconds, during the first 8 hours of NO exposure methaemoglobin concentrations increase

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13
Q

How is nitric oxide excreted

A

‣ Nitrates (70% metabolites) are eliminated mainly in urine whereas methaemoglobin is metabolised in several hours into haemoglobin by endogenic reductases. The nitrates excreted in urine represent over 70% of the inhaled NO dose.
‣ Time course of action - Onset of effect is seen within seconds

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14
Q

Abrupt cessation of nitric oxide can cause?

A

Rebound hypoxia - downregulation of hypoxic pulmonary vasoconstriction

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15
Q

Prostacyclin used when? Class?

A
  • Uses
    ◦ Anticoagulant during RRT and cardiopulmonary bypass
    ◦ Pre-eclampsia
    ◦ Ray and’s disease
    ◦ HUS
    ◦ Pulmonary hypertension
  • Class
    ◦ Prostaniod formally called prostacyclin
  • Arachadonic acid derivative
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16
Q

How do we give prostacyclin in ARDS

A

inahled

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17
Q

How does prostacyclin come?

A

◦ Vials containing freeze dried epoprostenol sodium diluted before use to mixture of sodium chloride and glycine

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18
Q

MOA of Prostacyclin

A

GPCR –> stimulates adenylate cyclase —> increased cAMP within

  1. platelets —> inhibition of platelet phospholipase and COX —> platelet aggregation inhibited
  2. smooth muscle –> phosholipase A –> myosin light chain kinase phosphorylation –> relaxation
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19
Q

Effects on CVS/Resp of prostacyclin

A

‣ CVS - relaxation of vascular smooth muscle leading to decrased SVR, slight tachycardia and decreased diastolic BP
‣ Resp - decreased PVR, interferes with hypoxic pulmonary vasoconstriction

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20
Q

Abdominal effects of prostacyclin

A

Decreased gastric acid secretion, decreased gastric emptying

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21
Q

Metabolic and haematological feffects of prostacyclin

A

‣ Metabolic - powerful platelet aggregation inhibition, bleeding time may double, fibrinolytic effect, increased red cell deformability
* Stimulates renin secretion
* Increased BSL

22
Q

Effects of prostacyclin

A

‣ CVS - relaxation of vascular smooth muscle leading to decrased SVR, slight tachycardia and decreased diastolic BP
‣ Resp - decreased PVR, interferes with hypoxic pulmonary vasoconstriction
‣ CNS - Cerebral vasodilation, increased blood flow
‣ Absdominal - reduced gastric acid secretion
‣ Metabolic - powerful platelet aggregation inhibition, bleeding time may double, fibrinolytic effect, increased red cell deformability
* Stimulates renin secretion
* Increased BSL

23
Q

Pharmacokinetics of prostacyclin

A

◦ Absorption
‣ IV or Extra-corperally infusion 5 ng/kg/min and started 15-30minutes before anticoagulation desired
◦ Distribution
◦ Metabolism
‣ Effects persist for 30 minutes after ceased
‣ Rapidly removed from circulation by hydrolysis to 6 - oxo - PGF1 alpha in blood and metabolism to a bicyclic 15 - oxo derivative in tissues
◦ Excretion
‣ Plasma half-life 30 seconds to 3 minutes

24
Q

Prostacyclin toxicity

A
25
Q

Sildenafil pharmacokinetics

A
  • 20mg TDS
  • Potent cGMP type 5 inhibitor
  • In vascular smooth muscle relaxation is caused as cGMP levels increase
  • Pharmacokinetics
    ◦ Absorption - rapidly absorbed, 40% oral bioavuilabiltiy
    ◦ Distribution - 95% plasma protein bound, 100L Vd
    ◦ Metabolised by CYP3A4 and CYP2CY to a N demethylated active metbaolite contributing to 40% of overall effect
    ‣ Therefore dose adjustment potentially required if CYP3A4 inducing or inhibiting drugs
    ◦ Elimination half life 3-5 hours, 80% excreted in faeces
    ‣ Renal and hepatic impairment both increase AUC
26
Q

Bosentan acts how? Pharmacokinetics

A
  • Dual endothelin receptor antagonist at both A and B receptor subtypes
  • Decreased pulmonary and systemic vascular resistance without affecting HR
  • Kinetics
    ◦ 50% bioavailability
    ◦ Induces its own metabolism - CYP2CY, CYP3A4
    ◦ Excreted in bile
27
Q

Oxygen available in what preparaition?

A

◦ Compressed gas cylinders 137 bar @ 15 degrees C
‣ Black and white shoulders, available in 6 sizes
* CJ containing 170-6800L
* Size J cylinders are used for cylinder manifolds
* AZ cylinder is MRI compatible and contains 170L
‣ Colourless, odourless, tasteless gas
◦ Also in liquid form - 1 volume —> 840 volumes of O2 at 15 degrees
‣ Pale blue
◦ Wall oxygen - 4 atmospheres of pressure (415 kPa) and close to 0 degrees at the wall outlet

28
Q

Physical chemistry of O2

A

◦ Diatomic gas with density and viscosity slightly higher than air
‣ Specific gravity of 1.1
◦ Critical temp -118
◦ Critical pressure 51 atm
◦ Melting point -218 degrees
◦ Atomic weight 18; molecular weight 32

29
Q

Indications for O2

A
  1. Hypoxaemia
  2. Denitrogenation - air filled body cavities or FRC
  3. Antidote - CO, hyperbaric O2, decompression
30
Q

Contraindications to high dose O2

A

Aspiration
Bleomycin
Paraquat toxicity

31
Q

Fixed and variable performance O2 devices include?

A

‣ Fixed performance - anaesthetic breathing systems with large reservoir and Venturi operated devices
‣ Variable performance - Hudson’s, partial rebreathing masks,nasal cannulae
* Variable performance as FiO2 determined by gas flow rate, peak inspiratory flow rate, respiratory rate, how tightly fitting the mask is

32
Q

Absorption of O2

A

◦ Pulmonary absorption 250ml/min with 21% FiO2 at rest - freely permeable and diffuses according to Ficks principle
◦ Cutaneous - under 1mL/min at normal atmospheric pressure
◦ Oral and other mucosal absorption- usually nil

33
Q

Distribution of O2

A

◦ Transported as OxyHb primarily with a smaller amount dissolved in blood
◦ Each 100ml of plasma contains 0.3mL of dissolved oxygen at normal atmospheric pressure and an FiO2 of 0.21 —>when 100% FiO2 used each 100ml contains 1.7mL

34
Q

Metabolism of O2

A

◦ Metabolised in all tissues - mainly brain, heart and skeletal muscle
◦ Mainly metabolised by cytochrome c mitochondrial enzymes - 90%
‣ O2 combined with H+ to form H20 and CO2 derived from glucose and produce ATP via the ETC in mitochondria
◦ Zero order clearance kinetics roughly 200ml/min
◦ Main metabolites CO2 and H20 cleared via lungs and renally

35
Q

Eliminatino of o2

A

◦ CO2 exhaled and water metabolised or excreted in urine

36
Q

Classes of complications due to O2

A

General
Respratory
Cardiovascular
Neuro
Haem
Electrolytes
Metabolic

37
Q

General complications of O2 toxicity 1

A

‣ Increased reactive oxygen species —>inflammation —> secondary tissue injury and apoptosis
‣ Depletion fo cellular antioxidant defences by same mechanism

38
Q

Respiratory complications of O2 4

A

Divsion
- Secretions
- Mucosal inflammation - tracheobronchitis, alveolar toxicity, bronchopulmonary dysplasia
- Absorption atelectasis
- Decreased resp drive, hypercapnoea due to V/Q mismatch, delayed recognition of hypoventilation

‣ Drying of mucous membranes and inspissation of secretions
	‣ Inflammatory tracheobronchitis - >60% causes tracheal irritation, sore throat, sub sternal pain and pulmonary congestion. Effect worsens with duration of exposure and increasing PO2 
	‣ Bronchopulmonary dysplasia in neonates 
	‣ Alveolar toxicity - can transform into frank ARDS with hyperbaric O2
	‣ Absorption atelectasis secondary to denitrogenation
	‣ Decreased respiratory drive minimally - decreased sensitivity of respiratory centre to CO2
	‣ Hypercapnoea in CO2 retainers 
		* virtue of V/Q mismatch (pulmonary vasodilation) 
		* Reverse Haldane effect as CO2 released from haemoglobin; increased mortality in prehospital RCT
	‣ CO clearance increased
	‣ Denitrogenation of gas cavities e.g. pneumothorax 
	‣ Delay recognition of hypoventilation by SpO2 monitoring during sedation
39
Q

Cardiovascular effects of increased O2 4

A

‣ Increased Left to right shunt in ASD
* Dropped Pulmonary VR
* Increased SVR with vasoconstriction leading to increased BP, decreased cardiac output
‣ Increased peripheral vascular resistance - vasoconstriction due to accelarated rate of oxidative degredation of nitric oxide in endothelium –> hypertension
‣ Reduced heart rate (chemoreceptor effect), decrease in diastolic BP and 8-20% drop in cardiac output. MAP decreases slightly
‣ Cerebral and coronary vasoconstriction - reducing blood flow and increasing myocardial infarction size with hyperoxia. Impaires endothelium mediated vasodilation
‣ Increased mortality post cardiac arrest with hyperoxia ->300mmHg

40
Q

Neuro effects of O2 3

A

‣ Altered mood, vertigo, LOC and convulsions (paul bert effect) with hyperbaric treatment
‣ Retinopathy of prematurity - Retrolental fibroplasia of the newborn
* Myopia can occur with hyperbaric oxygen - reversible
* Cataract formation
‣ Decreased cerebral blood flow by 11-33% in healthy adults increasing mortality after stroke and TBI –> decreased ICP
‣ Euphoria

41
Q

Haem effects of O2

A

‣ Decreased erythropoiesis –> reduced reticulocyte count
‣ Increased risk fo infection due to impaired mucocillary clearance in lungs and decrased bacterocidal capacity of immune cells
‣ Immunosuppressant
‣ Impaired reproduction of anaerobes

42
Q

Oxygen vs vascular tone

A
  • Hypoxaemia induced vasoconstriction
    ◦ Lungs
  • HYPERoxaemia induced vasoconstriction
    ◦ Brain, cardiac, renal and skeletal muscle
    ◦ Oxygen delivery to these tissues then may be paradoxically decreased - as cerebral blood flow decreases 11-33% and coronary 8 - 29%
    ◦ Hyperoxia causes systemic vasoconstriction
    ‣ HR slows reflexively, SV maintained but cardiac output falls
    ‣ May decreased levels of vasodilator PGI2, reduce bioavailability of NO (inactivated by superoxide), RBCs may sense PO2 modulating ATP release which binds to endothelial P2Y receptors that increase NO production, alter RBC deform ability impairing flow in microvascular beds, and is a respiratory stimulant resulting in hyperventilation and hypocapnoea which can lead to paradoxical vasoconstriction in CO2 sensitive vascular beds (CO2 release from increased Haldene effect, ROS on brain stem)
43
Q

How do you make oxygen 3

A
  • Photosynthesis
    ◦ Algaes and plants contain chlorophyll which uses photo energy to convert CO2 to O2
  • Fractional distillation of air
    ◦ Liquefication and fractional distillation
    ◦ Liquid air is a mixture of liquid nitrogen (BP -196) and liquid O2 (BP -183) so nitrogen boils off first
    ◦ Fractionating involves allowing the evaporating gas which will have some O2 in it to bubble through liquid air rich in O2 causing O2 to condense and Nitrogen escapes
  • O2 concentrates
    ◦ Extracts from atomsopheric air
    ◦ Air passed under pressure through a column of zeolite (molecular sieve) trapping nitrogen and H20 vapour while leaving O2 and trace gasses
    ◦ Nitrogen removed by depressurising the column
    ◦ Continuous flow of O2 >90%
44
Q

What is the mechanism of action of epoprostenol?

A

Direct vasodilator of pulmonary and systemic arterial vascular beds via activation of Gs GPCR on endothelial and platelet cells –> adenylate cyclase 00< cAMP inhibiting polatelet activation and activates protein kinase A

cAMP prevents coagulation by prevenitng increase Ca from TXA2 binding

PLA phosphorylates and inhibits myosin light chain kinase in smooth muscle

45
Q

What are the effects of epoprostenol

A

Antithrombotic - inhibits platelet activation and prevents primary haemostasis
Antiproliferative
Anti inflammatory
Anti mitogenic
Vasodilator

46
Q

Pharmacetuics of epoprostenol

A

PH 10
Clear and colourless
Reconstituted in saline and glycerine
Synthetic epoprostenol sodium

47
Q

Dose of epoprostenol

A

Infusion 1ng/kg/min and increase by 2ng/kg/min every 15 minutes

Max dose 50ng/kg/min

48
Q

Adverse effects of epoprostenol?

A

Flushing, headache, hypotension
Cough and bronchospasm (high pH)
Can worsen cardiogenic pulmonary oedema
Haemorrhage
Can block filters in ventilator and prevent eTCO2 from reading

49
Q

Pharmacokinetics of epoprostenol

A

Nil absorption
Vd 0.4L/kg with negligible protein binding
Metabolsied in the blood to less active metabolites
Half life 2-6 minutes
Urinary excretion

50
Q
A

Primary Pharmacology (11 decks)

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