Adrenoreceptor antagonists Flashcards by Charles Pryce

Name and classify the alpha adrenergic blockers

NON-SELECTIVE (block alpha 1 and alpha 2)

Phentolamine
Phenoxybenzamine

ALPHA 1 BLOCKERS

Prazosin
Doxazosin

ALPHA 2 blockers
1. Yohimbine

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

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

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What are the uses of phentolamine

Hypertensive crises
- Excessive sympathomimmetics
- Phaeochromocytoma tumour manipulation
- MAOI reactions with tyramine
Assessment of SNS mediated chronic pain

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What is phentolamine

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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Describe phentolamine

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

What are the effects of pre-synaptic alpha 2 agonists

ALPHA 1 (POST SYNAPTIC)

Vasoconstriction
Mydriasis
Contraction bladder sphincter

ALPHA 2 (POST SYNAPTIC)

Platelet aggregation
Hyperpolarization of some CNS neurons

ALPHA 2 (PRESYNAPTIC)
1. Inhibition of noradrenalin release

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What is phenoxybenzamine

Long acting non-selective irreversible alpha adrenoreceptor blocker

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When is phenoxybenzamine used

Pre-operatively in phaeochromocytoma (to allow expansion of the intravascular compartment)
Hypertensive crises
Neonatal cardiac surgery

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What is the difference between phentolamine and phenoxybenzamine

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

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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Why should phenoxybenzamine be infused slowly through a central line

Rapid infusion can lead to seizures

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Why are phneoxybenzamine and phentolamine not usually given PO

Poor bioavailability of 2% to 20%

Used to treat HPT crises, must work fast

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What are the uses and dose of prazosin

Uses

BPH
HPT
Raynaud’s
CCF

Inititial dose 0.5 mg –> increased 20 mg daily

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What are the effects of prazosin

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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What are the uses of beta blockers

Hypertension
CCF
Secondary prevention after MI
Angina
Hyperthyroidism (propranolol)
HOCM (control infundibular spasm)
Anxiety
Glaucoma
Prophylaxis migraine

Anaesthetic Specific

Suppress SNS response to laryngoscopy and extubation (esmolol)
Phaeochromocytoma (prevent unopposed beta effects after alpha blockade)
Rx tachydysrhythmia

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What can happen with prolonged beta blocker administration

Increase in the number of beta-adrenoreceptors

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Which beta blockers have great GI absorption. Which do not

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

Large Vd
High Protein binding

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

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Which beta blocker cannot be administered oral

Only esmolol

What is the solubility of beta blockers. Any exceptions?

High lipid solubility

Exception: Esmolol and Atenolol

How are beta blockers metabolised. Which are the exceptions

Extensive hepatic metabolism

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

Describe the mechanism of action of beta blockers

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

–> reduced IC calcium –> reduced contractility
–> 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)

What are the pharmacodynamic effects of beta blockers

Beta 1 effects (mostly favourable)

Decreased HR
Decreased contractility
Decreased BP
Decreased myocardial O2 demand
Increased diastolic coronary filling time
Decreased arrhythmogenicity

Beta 2 effects (mostly unfavourable)

Increased peripheral vascular resistance
Bronchospasm
Decreased insulin release
Increased bladder tone
Increased uterine tone

Classify common beta blockers by receptor selectivity

NON-SELECTIVE

Propanolol
Sotolol

BETA 1 SELECTIVE

Atenolol
Esmolol
Metoprolol
Bisoprolol

COMBINED ALPHA AND BETA BLOCKER EFFECT

Carvedilol
Labetalol

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

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

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

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

What molecule are beta blockers derived from

arloxy-propanol-amine

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

Whether the side chain on the arlyl ring is connected to the: 1. - para (highest beta 1 selectivity) 2. - meta (Intermediate beta 1 selectivity) 3. - ortho (Least beta 1 selectivity) positions.

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

Metoprolol (bioavailability 50%) Labetalol (bioavailability 25%) Need higher dose if giving oral as low bioavailability

What is the bioavailability of Nebivolol and why is this interesting

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

How does lipid solubility affect GI absorption

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

How does lipid solubility affect plasma half life

Increased lipid solubility shortens plasma half life (rapid distribution)

How does lipid solubility affect protein binding

Increases protein binding

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

Less predictable pharmacokinetics during critical illness with high protein binding

How is the dose of atenolol adjusted for renal dysfunction

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

Esmolol: onset, peak effect and duration

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

Labetalol: onset, peak effect and duration

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

IV Metoprolol: onset, peak effect and duration vs Oral metoprolol: onset, peak effect and duration

Onset: 5 - 10 mins Peak: 10 mins Duration: 1 - 8 hours Onset: 30 mins Peak: 2 hours Duration: 3 - 10 hours

Atenolol: onset, peak effect and duration

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

Carvedilol: onset, peak effect and duration

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

How is receptor affinity of the beta blockers measured

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

How do beta blockers slow the heart rate?

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.

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

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

How do beta blockers act as antiarrhythmic agents

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

Summarise the effects of blockade of Beta 1 receptors

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

Summarise the effects of blockade of Beta 2 receptor

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