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Pharmacology Unit 2 > Dyshemoglobinemias > Flashcards

Dyshemoglobinemias Flashcards

1
Q

hemoglobin

A
  • conjugated protein, MW 64.5 kDa
  • two pairs of polypeptide chains in which there are 4 heme molecules attached
  • for tissue perfusion
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2
Q

heme

A
  • contains an iron complexed at the center of a porphyrin ring
  • ferrous state (2+) carries o2
  • globin chain protects the iron from inappropriate oxidation
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3
Q

oxidation/reduction

A
  • always occur together
  • reduction- gain electrons=reduced substrate
  • oxidation- lose election= oxidized substrate
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4
Q

carbon monoxide

A
  • gas
  • from incomplete combustion of carbon containing material
  • gasses-methane, coal, gasoline
  • various others
  • internal production is minimal
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5
Q

pharmacokinetics of CO

A
  1. absorption/excretion
    - CO gains entry and exit through direct respiration- increased respiration = increased dose and increased rate of elimination
    - chemical methylene chloride is converted to CO in vivo- only time CO levels will increase after removal from the source
  2. distribution
    - binds to hemoglobin, myoglobin, and other less defined tissues
    * no metabolism
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6
Q

CO “pharmacology”

A
  1. binds to Hb with 200-250 higher affinity, shifts O2 curve to the left
    - decreases 2,3-BPG
    * results in tissue hypoxemia, but dogs infused with toxic blood were fine- this isn’t the only thing that occurs
  2. binds to myoglobin- direct myocardial tox
  3. binds to mito cytochrome oxidase- inhibits cellular respiration- effect increased with hypoxia and hypotension
  4. displaces NO from platelets
    - forms peroxynitrites, results in free radical mediated damage thought to contribute most to CNS system long term tox
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7
Q

CO acute clinical effects

A
  1. mild- HA, NV, dizziness
  2. moderate- chest pain, blurred vision, dyspnea on exertion, tachy, tachypnea, cognitive defects, myonecrosis, ataxia
  3. severe- seizures, coma, dysrhythmias, hypotension, MI/ischemia, skin bullae
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8
Q

CO late/chronic effects

A
  • cognitive dysfunction
  • dementia
  • psychosis
  • amnesia
  • parkinsonism
  • paralysis chorea
  • cortical blindness
  • apraxia
  • agnosias
  • peripheral neuropathy
  • incontinence
  • preceded by a lucent period of 2-40 days
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9
Q

mechanism of late onset effects

A
  • theory
  • reperfusion injury
  • during recovery, WBCs are attracted and adhere to brain microvasculature (COX dysfunction??)
  • WBCs release proteases, converts xanthine dehydrogenase to XO, promotes free radical formation, leading to delayed lipid peroxidation
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10
Q

risk of delayed effects

A
  • incidence varies in the literature from 3-14% -33%-43% at various times of follow up and severity of illness
  • adults over 36 appear to be at greater risk
  • most cases of over signs involve a LOC
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11
Q

evaluation

A
  • look for end organ manifestations of toxicity- CNS, cardiac, perfusion
  • CO level has relative importance
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12
Q

oxygen saturation

A
  • pulse ox- falsely normal, because COHb is read as normal Hb
  • arterial blood gas- Co-ox will be appropriate
  • calculation will be falsely normal because pO2 is not affected
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13
Q

treatment

A
  • ABCs, oxygen
  • shortens CO t/2 (2-7hr to 30-150 min)
  • consider HBO
  • shortens t/2 to 4-86 min, increased O2
  • prevents lipid peroxidation in animal models
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14
Q

controlled human case studies

A
  • 12-43% neuro impairment with 100% oxygen alone

- 0-4% treated with HBO, small studies have done better than larger ones

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15
Q

prospective randomized trial

A
  • 1 hr at 2 atm 3x over 3 days + high flow 104 O2
  • vs 3days high flow alone at 87
  • no impact on outcome
  • this was australia- they use 2, we use 2.8
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16
Q

weaver trial

A
  • LOC, GCS< 15, CO level >10
  • myocardial ischemia, ventricular dysarrhythmias
  • neuro signs 2-4 hours out
  • 3 atm for 1 session than 2 atm 3x over 3 days
  • oxygen and sham dive sessions to mimic study group
  • impact seen on neurocognitive testing
17
Q

Indications for HBO

A
  • LOC- syncope, coma, seizure
  • GCS< 15 on presentation
  • CO level >10%
  • myocardial ischemia, ventricular dysrhythmias
  • neuro signs 2-4 hours out
18
Q

other findings for CO

A

-bilateral low density areas of the globus pallidus, putamen, and caudate nuclei are seldom seen

19
Q

cyanide

A
  • found in many forms
  • gas-chemical warfare/industrial accidents
  • crystal-requires mucous membrane or PO exposure
  • jewelers, electroplating, other industries, house fires
  • lactate >10 mmol/L or if patient doesn’t respond to supportive care after fire
20
Q

pharm of CN

A
  • binds to cytochrom a3 on the ETC

- rapid onset of multisystem organ failure- no ATP

21
Q

treatment for CN

A
  • ABCs, supportive, ACLS don’t work
  • CN antidote kit/package
  • hydroxocobalamin
  • binds with CN to make cyanocobalamin
  • HBO-maybe
22
Q

CN kit

A
  • makes metHb to get rid of CN- sodium nitrite/ amyl
  • thiosulfate increases metabolism of CN
  • can’t use in CO poisoning, because metHb takes even more O2 carry capacity out
  • H2S binds to A3 also, but is reversible
23
Q

hydroxocobalamin

A
  • any smoke inhalation victim that is not improving despite supportive care including o2
  • any intentional CN exposure
  • B12 a+ CN= B12
  • 5 g dose, can be repeated 1 time
  • give with sodium thiosulfate
  • potentially for nitroprusside at risk patients
24
Q

metHb

A
  • heme iron oxidized to ferric 3+ form
  • normal amts of 1-3%
  • rate of heme oxidation increased, reduction is limited, structural abnormalities of heme
  • protective mech include enzymes to reduce back to 2+, mostly NADH reductase, sometimes NADPH
25
Q

causes of MetHb

A

-congenital
-infantile disposition
-external causes
Drugs:
-nitrites, sulfonamides, nitrites in infants, phenazopyridine, dapsone, local anesthetics
Toxins:
-potassium chlorate, nitrites/ in infants, aniline dye, diarrheal illness in infants (makes nitrites)

26
Q

metHb tox

A
  • incapacitates o2 transport

- shifts o2 curve to left- won’t release in tissues

27
Q

metHb sx

A
  • 0-10% asx
  • 10-20% apparent cyanosis
  • 20-50% dizziness, fatigue, HA, exertional dyspnea
  • > 50% lethargy/stupor
  • > 70% coma and death
28
Q

ox sat metHb

A
  • pulse ox- fasely and aberrantly lowered- measured as both oxy and deoxy, will fall rapidly into the high 80s
  • arterial blood gas
  • co-ox- appropriate
  • calc-fasely normal because po2 not affected
29
Q

MetHb treatment

A
  • ABCs
  • decontamination
  • methylene blue- tetramethyl thionin chloride- specific antidote
  • minor antidotes when methylene blue fails- n acetylcysteine, exchange transfusion, HBO
30
Q

methylene blue

A
  • cofactor of NADPH reductase
  • gains electron and donates directly to metHb
  • metHb reduction to 2+
31
Q

methylene blue indication

A
  • metHb >20-30% or sx
  • cautions- hemolytic anemia from weak ox capability, painful at injection site, higher doses can cause dyspnea, restlessness, tremor, precordial pain and apprehension
32
Q

non responders to methylene blue

A
  • hemoglobin M disease
  • G6PD def- lack generation of NADPH dependent metHb reductase
  • CL salts inactivating G6PD
  • sulfhemoglobinemia-acetanilid, phenacitin, nitrites, trinitrotoluene, sulfer. more benign, levels up to 10 g/dl don’t cause cyanosis
  • wrong diagnosis
33
Q

sulfhemoglobinemia

A
  • sx similar to met Hb
  • metHb elevated
  • lab can tease out by adding CN to blood
  • treatment is supportive
34
Q

conclusions

A

patients symptoms are more important than lab tests in all cases of dyshemoglobinemia and should be used in conjugation with levels

  • specific antidotes are required
  • timing is important

Pharmacology Unit 2 (1 decks)

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