Adrenoreceptor antagonists Flashcards
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
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
What are the uses of phentolamine
- Hypertensive crises
- Excessive sympathomimmetics
- Phaeochromocytoma tumour manipulation
- MAOI reactions with tyramine - Assessment of SNS mediated chronic pain
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
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
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
What is phenoxybenzamine
Long acting non-selective irreversible alpha adrenoreceptor blocker
When is phenoxybenzamine used
- Pre-operatively in phaeochromocytoma (to allow expansion of the intravascular compartment)
- Hypertensive crises
- Neonatal cardiac surgery
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
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.
Why should phenoxybenzamine be infused slowly through a central line
Rapid infusion can lead to seizures
Why are phneoxybenzamine and phentolamine not usually given PO
Poor bioavailability of 2% to 20%
Used to treat HPT crises, must work fast
What are the uses and dose of prazosin
Uses
- BPH
- HPT
- Raynaud’s
- CCF
Inititial dose 0.5 mg –> increased 20 mg daily
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)
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
What can happen with prolonged beta blocker administration
Increase in the number of beta-adrenoreceptors
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
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)
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:
- para (highest beta 1 selectivity)
- meta (Intermediate beta 1 selectivity)
- 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
- Reduced automaticity of ectopic pacemakers
- Prolonged refractory period for all excitable myocardial tissues (reduced propogation of malignant arrhythmias)
- Decrease in VF threshold
- Prevention of catecholamine reversal of Class I / III antiarrhythmic drugs
- Reverse ischaemia/reperfusion unduced proarrhythmic tendency by their effects on myocardial O2 supply and demand
Summarise the effects of blockade of Beta 1 receptors
- Slow SA node
- Decelerate ectopic pacemakers
- Decrease contractility
- Decrease lusitropy
- Decrease renin from kidney
Summarise the effects of blockade of Beta 2 receptor
- Opposes skeletal muscle VD –> increase SVR
- Opposes relaxation bronchiolar smooth muscle
- Contracts gut wall smooth muscle
- Contracts bladder wall
- Contracts pregnant uterus
- Decreases gluconeogenesis and glycogenolysis (liver)
- Decreases insulin release
