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Pharmacology for Anaesthetists > Adrenoreceptor antagonists > Flashcards

Adrenoreceptor antagonists Flashcards

1
Q

Name and classify the alpha adrenergic blockers

A

NON-SELECTIVE (block alpha 1 and alpha 2)

  1. Phentolamine
  2. Phenoxybenzamine

ALPHA 1 BLOCKERS

  1. Prazosin
  2. Doxazosin

ALPHA 2 blockers
1. Yohimbine

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2
Q

How does phentolamine’s affinity for alpha 1 receptors compare with that for alpha 2 receptors

A

3 x greater affinity for alpha 1 receptors than alpha 2 receptors

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3
Q

What are the uses of phentolamine

A
  1. Hypertensive crises
    - Excessive sympathomimmetics
    - Phaeochromocytoma tumour manipulation
    - MAOI reactions with tyramine
  2. Assessment of SNS mediated chronic pain
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4
Q

What is phentolamine

A

It is a competitive non-selective alpha blocker with affinity for alpha 1 receptors 3 times greater that its affinity for alpha 2 receptors

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5
Q

Describe phentolamine

A

Chemistry:
Uses: HPT crises, chronic pain assessment
Presentation:

Action: Short acting competitive non-selective alpha antagonist with 3 X increased affinity for alpha 1 receptors.

Dose: 1 - 5mg titrated to effect
Onset: 1 - 2 minutes. Duration 5 - 20 minutes
Route: IV
Side effects: Hypotension, tachycardia, nasal congestion
Everything else:
Toxicity: Sulfites in ampoule –> hypersenstivity –> Bronchospasm in susceptible asthmatics.

Distribution: 50% protein bound
Absorption: Bioavailability 20% (Oral rarely used)
Metabolism: Extensively. 10% unchanged in urine
Elimination: t1/2 = 20 minutes

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6
Q

What are the effects of post-synaptic alpha 1 vs alpha 2 agonists

What are the effects of pre-synaptic alpha 2 agonists

A

ALPHA 1 (POST SYNAPTIC)

  1. Vasoconstriction
  2. Mydriasis
  3. Contraction bladder sphincter

ALPHA 2 (POST SYNAPTIC)

  1. Platelet aggregation
  2. Hyperpolarization of some CNS neurons
ALPHA 2 (PRESYNAPTIC)
1. Inhibition of noradrenalin release
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7
Q

What is phenoxybenzamine

A

Long acting non-selective irreversible alpha adrenoreceptor blocker

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8
Q

When is phenoxybenzamine used

A
  1. Pre-operatively in phaeochromocytoma (to allow expansion of the intravascular compartment)
  2. Hypertensive crises
  3. Neonatal cardiac surgery
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9
Q

What is the difference between phentolamine and phenoxybenzamine

A

Phentolamine

  • Onset 1 -2 minutes
  • Duration 20 minutes
  • Used: treat hypertensive crises

Phenoxybenzamine
- Irreversible blockade alpha 1 (higher affinity) and alpha 2 receptors
Onset 1 hour
- Duration 24 hours - 3 days (new alpha receptors need to be synthesized)
- Used: Pre-op to allow expansion of intravasc compartment

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10
Q

Why shouldn’t adrenalin be used in the treatment of phenoxybenzamine overdose?

A

Excessive alpha 1 blockade –> profound vasodilatation and hypotension.

If adrenalin is used:
1. Alpha 1 adrenoreceptor stimulation - opposed by existing blockade
2. Beta adrenoreceptor agonism - unopposed, not beta receptors not blocked.
THIS WILL COMPOUND THE TACHYCARDIA (B1 HEART) AND HYPOTENSION (B1 skeletal muscle).

Use noradrenalin not adrenalin.

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11
Q

Why should phenoxybenzamine be infused slowly through a central line

A

Rapid infusion can lead to seizures

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12
Q

Why are phneoxybenzamine and phentolamine not usually given PO

A

Poor bioavailability of 2% to 20%

Used to treat HPT crises, must work fast

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13
Q

What are the uses and dose of prazosin

A

Uses

  1. BPH
  2. HPT
  3. Raynaud’s
  4. CCF

Inititial dose 0.5 mg –> increased 20 mg daily

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14
Q

What are the effects of prazosin

A

Highly selective alpha 1 receptor antagonist

CVS
Vaso and venodilation with little or no reflex tachycardia (Diastolic pressures fall the most)

URO
Relaxes bladder trigone and sphincter muscle

False positive urinary VMA / MHPG (Phaeo)

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15
Q

What are the uses of beta blockers

A
  1. Hypertension
  2. CCF
  3. Secondary prevention after MI
  4. Angina
  5. Hyperthyroidism (propranolol)
  6. HOCM (control infundibular spasm)
  7. Anxiety
  8. Glaucoma
  9. Prophylaxis migraine

Anaesthetic Specific

  1. Suppress SNS response to laryngoscopy and extubation (esmolol)
  2. Phaeochromocytoma (prevent unopposed beta effects after alpha blockade)
  3. Rx tachydysrhythmia
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16
Q

What can happen with prolonged beta blocker administration

A

Increase in the number of beta-adrenoreceptors

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17
Q

Which beta blockers have great GI absorption. Which do not

A

All of them (>90%)

Except.. esmolol (0%) and atenolol (50%)

However, oral bioavailability for most beta blockers is less than 50%
Exceptions
1) Bisoprolol (90%)
2) Nebivolol (96% in poor CYP2D6 metabolizers) 12 % in normal metabolizers

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18
Q

Which is the volume of distribution and protein binding of beta blockers. Are there exceptions?

A

Large Vd
High Protein binding

Exception is atenolol (0.5 L/kg and 3% bound)

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19
Q

Which beta blocker cannot be administered oral

A

Only esmolol

20
Q

What is the solubility of beta blockers. Any exceptions?

A

High lipid solubility

Exception: Esmolol and Atenolol

21
Q

How are beta blockers metabolised. Which are the exceptions

A

Extensive hepatic metabolism

Exceptions: Esmolol (Mostly RBC esterases) and atenolol (Renal 100%)

22
Q

Describe the mechanism of action of beta blockers

A

Antagonists of Gs-coupled beta 1 receptors –> reduced cAMP

  1. –> reduced IC calcium –> reduced contractility
  2. –> decrease automatic self-depolarisation by affecting cAMP sensitive If (funny current) in pacemaker cells

Also, some have

  • Alpha 1 block –> VD –> afterload reduction
  • Membrane-stabilising (Na channel block) - propranolol, sotalol, carvedilol
  • Intrinsic sympathomimmetic activity (acetbutalol)
23
Q

What are the pharmacodynamic effects of beta blockers

A

Beta 1 effects (mostly favourable)

  1. Decreased HR
  2. Decreased contractility
  3. Decreased BP
  4. Decreased myocardial O2 demand
  5. Increased diastolic coronary filling time
  6. Decreased arrhythmogenicity

Beta 2 effects (mostly unfavourable)

  1. Increased peripheral vascular resistance
  2. Bronchospasm
  3. Decreased insulin release
  4. Increased bladder tone
  5. Increased uterine tone
24
Q

Classify common beta blockers by receptor selectivity

A

NON-SELECTIVE

  • Propanolol
  • Sotolol

BETA 1 SELECTIVE

  • Atenolol
  • Esmolol
  • Metoprolol
  • Bisoprolol

COMBINED ALPHA AND BETA BLOCKER EFFECT

  • Carvedilol
  • Labetalol
25
Q

Which of the beta blockers have membrane stabilising effect (i.e. block sodium channels)? Why is this relevant

A

Carvedilol
Propanolol
Sotalol

Severe overdose will induce Na channel block
Other than this, the clinical relevance of this property is unknown.

26
Q

Which beta blockers have intrinsic sympathomimmetic activity. why is this relevant

A

Labetalol
Acebutolol
Nebivolol

Relevance: positive vasodilatory afterload-reducing effects and reduced risk bronchospasm

27
Q

What molecule are beta blockers derived from

A

arloxy-propanol-amine

28
Q

What chemical structural attribute of beta blockers is predominantly responsible for the degree of B1 selectivity

A

Whether the side chain on the arlyl ring is connected to the:

    • para (highest beta 1 selectivity)
    • meta (Intermediate beta 1 selectivity)
    • ortho (Least beta 1 selectivity)

positions.

29
Q

Which of the beta blockers is commonly given oral OR IV. Why does the oral and IV dose differ

A

Metoprolol (bioavailability 50%)

Labetalol (bioavailability 25%)

Need higher dose if giving oral as low bioavailability

30
Q

What is the bioavailability of Nebivolol and why is this interesting

A

Nebivolol undegoes first pass metabolism in the liver by the enzyme CYP26D. This isoform has a high incidence of genetic polymorphism which means that in certain patients the enzyme will be ineffective. This results in a high range of bioavailability for the drug: 12% - 96%.

But no increase in toxicity in the slow metabolizers (i.e. high bioavailability) with the same dose as the fast metabolizers

31
Q

How does lipid solubility affect GI absorption

A

Increased lipid solubility increased GI absorption (the absorption of atenolol is usually incomplete –> very low lipid solubility)

32
Q

How does lipid solubility affect plasma half life

A

Increased lipid solubility shortens plasma half life (rapid distribution)

33
Q

How does lipid solubility affect protein binding

A

Increases protein binding

34
Q

What are the concerns with a highly protein bound drug in critical illness

A

Less predictable pharmacokinetics during critical illness with high protein binding

35
Q

How is the dose of atenolol adjusted for renal dysfunction

A

Don’t bother. Just choose any other beta blocker as they are all eliminated in the liver into inactive metabolites

36
Q

Esmolol: onset, peak effect and duration

A

Onset: 2 mins
Peak: 5 - 20 mins
Duration: 5 - 15 mins

37
Q

Labetalol: onset, peak effect and duration

A

Onset: 5 - 10 mins
Peak: 10 mins
Duration: 2 - 10 hours

38
Q

IV Metoprolol: onset, peak effect and duration

vs

Oral metoprolol: onset, peak effect and duration

A

Onset: 5 - 10 mins
Peak: 10 mins
Duration: 1 - 8 hours

Onset: 30 mins
Peak: 2 hours
Duration: 3 - 10 hours

39
Q

Atenolol: onset, peak effect and duration

A

Onset: 1 hour
Peak: 2 hours
Duration: 2 - 10 hours

40
Q

Carvedilol: onset, peak effect and duration

A

Onset: 1 hour
Peak: 2 hours
Duration: 12 hours

41
Q

How is receptor affinity of the beta blockers measured

A

Kd = Koff/Kon

Kd - rate constant of dissociation at equilibrium

So when Kd is high it means that a large concentration of drug is required to occupy 50% of the receptors.

The above is calculated for both B1 and B2 receptors and then a selectivity ratio is calculated.

B1: B2 selectivity ratio of 0.5 means that the drug has 50 % less affinity for B1 than it does B2

42
Q

How do beta blockers slow the heart rate?

A

Block B1 –> reduced intracellular cAMP.

The funny current ‘If’ in pacemaker cells is a constant inward sodium leak (with K outlow) via HCN channels.

HCN channels = Hyperpolarization-activated, cyclic nucleotide-gated channels.
–> this means that these HCN channels depend on levels of cAMP. If cAMP is reduced (by BB) this means that the inward sodium slows making the pacemaker depolarise less frequently ultimately reducing heart rate.

43
Q

By what % does in hospital CVS mortality reduced when BB are used after acute MI

A

13 - 15% (Reduced Myocardial O2 demand. Improved supply)

44
Q

How do beta blockers act as antiarrhythmic agents

A
  1. Reduced automaticity of ectopic pacemakers
  2. Prolonged refractory period for all excitable myocardial tissues (reduced propogation of malignant arrhythmias)
  3. Decrease in VF threshold
  4. Prevention of catecholamine reversal of Class I / III antiarrhythmic drugs
  5. Reverse ischaemia/reperfusion unduced proarrhythmic tendency by their effects on myocardial O2 supply and demand
45
Q

Summarise the effects of blockade of Beta 1 receptors

A
  1. Slow SA node
  2. Decelerate ectopic pacemakers
  3. Decrease contractility
  4. Decrease lusitropy
  5. Decrease renin from kidney
46
Q

Summarise the effects of blockade of Beta 2 receptor

A
  1. Opposes skeletal muscle VD –> increase SVR
  2. Opposes relaxation bronchiolar smooth muscle
  3. Contracts gut wall smooth muscle
  4. Contracts bladder wall
  5. Contracts pregnant uterus
  6. Decreases gluconeogenesis and glycogenolysis (liver)
  7. Decreases insulin release

Pharmacology for Anaesthetists (37 decks)

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