Flashcards in Alpha and Beta blockers - LeBlanc Deck (81):
What are the actions of catecholamines (E, NE and DM)?
1. Peripherally - excitatory (in peripheral vasculature) or inhibitory activity on certain types of vascular smooth muscles (depending on the class of receptors activated)
2. Peripherally inhibitory on other types of SM (gut, bronchial, blood vessels supplying skeletal muscles)
3. Cardiac excitation (↑ frequency and ↑ contractile force; ↑ conduction velocity in the conduction system of the heart)
4. Metabolic actions:
Glycogenolysis from liver and skeletal muscles
Release of free fatty acids from adipose tissue
Beta one receptors are mainly found where?
In the heart.
Alpha one receptors are mainly found where?
In the vasculature.
What are some other actions of catecholamines?
1. Endocrine actions: modulation of the secretion of insulin, renin, pituitary hormones
2. CNS actions: wakefulness, appetite, respiratory stimulation, psychomotor activity
3. Prejunctional actions: inhibition or facilitation of neurotransmitter release
Where are alpha 1 receptors located and what are their agonists?
Are found in smooth muscle. Agonists according to their binding strength include:
E is greater than or equal to NE which is much greater than isoproterenol and phenylephrine.
Where are alpha 2 receptors located and what are their agonists?
They are located at nerve terminals and agonists according to binding strength are:
E greater than or equal to NE and much greater than isoproterenol and clonadine.
Where are beta 1 receptors located and what are their agonists?
They are located in cardiac muscle and their agonists according to binding strength are:
Isoproterenol is greater than E which is equal to NE and dobutamine.
Where are beta 2 receptors located and what are their agonists?
They are located in smooth muscle and their agonists according to binding strength are:
Isoproterenol is greater than E which is much greater than NE and terbutaline
Where are beta 3 receptors located and what are their agonists?
They are located in adipose tissue and their agonists according to binding strength are:
Isoproterenol is equal to NE which is greater than E.
Agonist binding to alpha 1 receptors does what?
Causes contraction of smooth muscle.
Agonist binding to alpha 2 receptors results in what?
Decreased transmitter release.
Agonist binding to Beta 1 receptors on cardiac muscle results in what?
1. inotropic effects - increased force of contraction
2. chronotropic effects - increased frequency of contraction, heart rate and affects at the SA node
3. dromotropic effects - acceleration of relaxation
Agonist binding at Beta 2 receptors results in what?
Relaxation of smooth muscle. Especially important for Asthma and COPD.
Agonist binding at Beta 3 receptors results in what?
Metoprolol is what?
A Beta 1 antagonist.
Prazosin is what?
An alpha 1 antagonist.
Yohimbine is what?
An alpha 2 antagonist. Only used in research - not clinically.
What happens with binding to Alpha 1 receptors?
1. receptor is coupled to Gq protein
2. agonist binds and activates Gq
3. Gq protein activates phospholipase C
4. phospholipase C cleaves PIP2 into IP3 and DAG
5. IP3 increases calcium and leads to smooth muscle contraction
6. DAG stimulates voltage gated calcium channels to increase force of contraction
What happens with binding to Alpha 2 receptors?
1. receptor is coupled to Gi or Go protein
2. If activated it will inhibit adenlylate cyclase
3. adenylate cyclase forms cAMP from ATP and without it cAMP levels decrease
4. decreased cAMP levels cause smooth muscle contraction
5. also inhibit neurotransmitter release via blocking calcium
What happens with binding to Beta receptors?
1. receptor is coupled to Gs protein
2. when activated it will activate adenylate cyclase and will cause increased cAMP which leads to smooth muscle relaxation if B2 receptor, and will increase force of cardiac contraction if B1 receptor
NE is an agonist to all adrenergic receptors but is second most potent for which receptors?
Alpha 1 and Alpha 2.
E is an agonist at all adrenergic receptors but is especially potent for which receptors?
Alpha 1 and 2 and is second most potent at Beta 1 and 2.
The most potent agonist for the Beta 1 and Beta 2 receptors is?
Isoproterenol and then E.
What effects does NE have on pulse rate, BP and peripheral resistance?
1. Works the best at Alpha receptors
2. at Alpha 1 it will increase peripheral resistance which leads to increased blood pressure
3. increased blood pressure leads to decreased pulse rate as a compensatory mechanism
What effects does E have on pulse rate, BP and peripheral resistance?
1. binds to Alpha 1 but binds better to Beta 1 and Beta 2
2. At B1 it will increase heart rate but at B2 it will cause decrease in peripheral resistance
3. in response - MAP will not change much because B1 stimulation increases systolic pressure but B2 will decrease diastolic pressure
What effects does Isoproterenol have on pulse rate, BP and peripheral resistance?
1. Binds best to Beta receptors
2. at B1 it will increase pulse rate
3. at B2 it will decrease peripheral resistance
4. no A1 response since it does not bind to those
All alpha antagonists are competitive inhibitors except which one?
Phenoxybenzamine or PBZ.
Which alpha receptors have the most important clinical response to alpha blockers?
Alpha 1 receptors.
What is important about competitive inhibitors?
They are reversible and can be competed off of their receptors.
Describe what happens in the CNS and periphery when Alpha 2 receptors are stimulated?
1. limit sympathetic outflow, increase vagal tone
1. increase platelet aggregation
2. decrease release of transmitters - NE and Ach
3. regulate metabolic activity - decrease insulin release and decrease lipolysis
When Alpha 1 receptors are blocked what are the consequences?
1. vasoconstriction is blocked
2. will have vasorelaxation so a decrease in BP - especially when upright as compared to supine so be careful if patient is already hypovolemic
3. The baroreceptors will sense decrease in BP and will compensate by increasing heart rate and cardiac output - affects can be exaggerated if a non-selective alpha blocker is used because it will also block alpha 2 receptors leading to increased NE release which normally work on B1 receptors to increase heart rate
What is another function of alpha 1 blockers?
They can inhibit the effects of sympathomimetic drugs administered externally to reverse an adverse effect.
What is a pure Alpha 1 agonist that can have its affects reversed by giving an Alpha 1 blocker?
If Epinephrine causes adverse affects can an Alpha 1 blocker be given?
Yes. This reduces the adverse affects of the B1 responses by turning the B1 response of a vassopressor into a vasodilator response (the B2 effects are still intact).
Alpha 2 blockers cause what?
1. increased sympathetic outflow which augments NE release and causes more Alpha1 and Beta 1 stimulation and an increase in BP
1. increases release of NE from nerve endings
2. non-selective alpha blocker
3. blocks irreversibly by covalent modification of receptors. must make new receptors to restore function
4. causes progressive decrease in peripheral resistance - will lead to compensatory increase in Heart rate
5. the tachycardia may be accentuated due to block of alpha 2 receptors which increase sympathetic outflow leading to increased B1 stimulation- contraindicated in those with CHF
What is a problem to consider when using PBZ?
Since Alpha1 and Alpha2 receptors are blocked permanently, Epinephrine can produce severe hypotension due to unopposed Beta 2 receptors. The effect is not prominent when supine but when standing up the baroreceptor reflex tries to kick in but the Alpha receptors are gone and so they can't cause vasoconstriction to compensate.
What are other effects of PBZ?
1. at higher doses it can irreversibly inhibit responses to serotonin, histamine and Ach.
Describe the pharmacokinetics of PBZ.
Not well understood. ½ Life is probably less than 24 hours. Impact is longer as several days are necessary for the number of receptors to return to baseline.
What are the main therapeutic uses of PBZ?
1. Pheochromocytoma: Tumors of the adrenal medulla and adrenergic neurons → secretion of enormous quantities of catecholamines → severe hypertension. Prolonged use is only in patients who are not operable.
2. Pheochromocytoma patients: majority of patients undergo surgical removal of the tumors; PBZ is used in preparation for surgery
3. Off label use - treatment of BPH - tends to block growth
What are the adverse affects of PBZ?
1. Postural hypotension → reflex tachycardias and arrhythmias; can be severe in hypovolemic patients or if a patient is already treated with a vasodilator
2. Nasal stuffiness; miosis
3. Sexual dysfunction in men: impaired ejaculation due to inhibition of vas deferens SMCs
4. contraindicated in those with CHF (may cause tachycardia)
How does PBZ cause reflex tachycardia?
PBZ actually ‘gets rid of’ the receptor so that when a person stands up and the body would normally cause vasoconstriction to keep blood flowing against gravity and back to the heart, the reflex is still there but the receptors are gone. The body then increases heart rate.
What is phentolamine?
1. also called Regitine
2. non-selective Alpha blocker
3. blockade is reversible and competitive
4. cardiovascular effects are similar to PBZ
5. also stimulates GI smooth muscle and stimulates gastric acid secretion
6. extensively metabolized
What are the therapeutic uses of phentolamine?
1. Pheochromocytoma patients: short term control of hypertension
2. may relieve pseudo-obstruction of the bowel by suppressing the inhibitory effects of catecholamines on GI smooth muscles
3. Can be rapidly infused to alleviate a severe hypertensive episode
4. May limit dental necrosis after inadvertent extravasation of an α agonist (e.g. Phenylephrine) used to limit the loss of local anesthetics
5. Raynaud’s disease
6. Useful after the rapid withdrawal of Clonidine, or following the ingestion of Tyramine-rich food during the use of non-selective inhibitors of MAO
7. Impaired erection in men: direct penile injections and possibly following oral intake
What are the adverse effects of phentolamine?
Reflex tachycardia, arrhythmias, ischemic cardiac events, myocardial infarction
GI stimulation: abdominal pain, nausea, peptic ulcer exacerbation
Should be used with caution in patients with coronary artery disease or a history of peptic ulcers
1. also called Minipress
2. a selective Alpha 1 antagonist
3.Displays similar affinities for the different subtypes of α1 receptors: α1A ≈ α1B ≈ α1D
4. Also a potent inhibitor of cyclic nucleotide phosphodiesterases (PDE) - which will lead to increase in cAMP and relaxation of smooth muscle
What are the results of the use of Prazosin?
1. blocks alpha 1 receptors in arterioles and veins leading to a decrease in resistance, decrease in BP and decrease in venous return to the heart
2. does not increase heart rate usually unlike other alpha blockers
3. weakly increases sympathetic outflow in the CNS
4. Decreases baroreflex mechanisms in hypertensive patients
5. Favorable effects on lipids: ↓ LDL, ↓ triglycerides and ↑ HDL levels
6. Newer generations of selective α1 receptor antagonists such as Terazosin and Doxazosin increase apoptosis of prosthatic smooth muscle cells which block proliferation and alleviate symptoms in BPH patients
Describe the pharmacokinetics of Prazosin.
1. Well absorbed orally; bioavailability is 50-70%; tightly bound to plasma proteins
2. Extensively metabolized by the liver
3. ½ Life in the plasma is 2-3 hours (longer in CHF patients: 6-8 hours)
What are the therapeutic uses of Prazosin?
1. Essential Hypertension (mild to moderate)
2. Vasodilator used in Congestive Heart Failure
3. Benign Prostatic Hypertrophy (BPH):
↓ Smooth muscle tone
↓ Growth of smooth muscle cells
4. Marked interest in these compounds due to their hypolipidemic effects
Describe the adverse affects of Prazosin.
1. First dose effect: marked postural hypotension and syncope can be seen 30 to 90 min after the initial dose
2. Important to check both supine and standing BP
1. also called Flowmax
2.Newer well absorbed α1 antagonist with some subtype selectivity: α1A ≈ α1D > α1B
3. Useful in BPH due to favorable blockade of α1A receptors with little undesirable effect on BP
4. ½ Life of 5 to 10 hours
5. Side effect: abnormal ejaculation
1. Selective α2 receptor antagonist that is structurally similar to reserpine
2. Readily enters the CNS: ↑ BP and ↑ heart rate
↑ motor activity and produces tremors
3. Historically: extensively used to treat male sexual dysfunction; efficacy by far surpassed by the development of PDE5 inhibitors - not used in US except for research
Beta blockers belong to what class of anti-arrhythmics?
Beta blockers are efficacious in the treatment of what?
3. certain types of arrhythmias
4. ischemic heart diseases
Describe some general properties of Beta blockers.
1. Relative affinity for β1 and β2 receptors
2. Intrinsic sympathomimetic activity - some have this and it is called partial agonism
3. Block of α receptors – third generation beta blockers
4. Differences in lipid solubility
5. Ability to induce vasodilation - some have and is called partial agonism
6. Stabilizing properties – stabilizes heart rhythm - prevents arrhythmias
First generation Beta blockers are what?
Second generation Beta blockers are what?
B1 selective antagonists.
Third generation Beta blockers include?
Non-subtype selective β antagonists or β1-selective antagonists with additional effect(s) on the cardiovascular system that are unrelated to their effect on β receptors.
What are the general effects of the Beta blockers?
Short-term administration of β blockers:
↓ Cardiac Output (CO) and Peripheral Resistance (PR) increases in proportion to the potency of inhibition of β2 receptors and compensatory reflex mechanisms
Long-term administration of β blockers:
PR returns to normal levels or decreases in hypertensive patients
With the β1 subclass or the direct vasodilator subclass, CO is maintained with a greater fall in PR – important in patients with CHF
What are the effects of Beta blockers on cardiac chronotropy and dromotropy?
1. ↓ Automaticity in the SA and AV nodes, as well as in the Purkinje system by decreasing the slope of Phase 4 depolarization
2. ↓ Conduction velocity in atria and the conduction system
3. ↑ refractory period of the AV node
What are the effects of Beta blockers on cardiac inotropy?
1. ↓ Atrial and ventricular contraction:
↓ L-type Ca2+ current
↓ Ca2+-induced Ca2+ release or CICR
2. ↓ Rate of cardiac relaxation:
↓ Ca2+-ATPase activity by reducing phospholamban phosphorylation
↓ Phosphorylation of Troponin I
What are the anti arrhythmic properties of Beta blockers?
1. β blockers are considered Class II antiarrhythmic agents:
↓ Cardiac contractility → ↓ O2 consumption/demand of the heart → ↓ incidence of supraventricular and ventricular deleterious arrhythmias
Decreased O2 demand preserves stable Ca levels in the cells which inhibits Ca overload thus inhibiting arrhythmias
2. Some β blockers display “stabilizing” activity that may contribute to their antiarrhythmic activity:
Local anesthetic effects by blocking voltage-dependent Na+ channels (e.g. propranolol)
Partial blockage of Na channels
How do Beta blockers work as antihypertensive agents?
1. Blood Pressure:
Generally, no effect in normal patients; ↓ BP in hypertensive subjects, especially after long-term administration
2. Postulated Mechanisms:
↓ β1-mediated renin release → ↓ Angiotensin II → ↓ vascular tone and ↓ PR
3. CNS Effects?
No or little evidence
4. Some have proposed the existence of facilitating presynaptic β receptors in the periphery; β blockers → ↓ release of NE from nerve terminals
5. Some β blockers are vasodilators:
Activation of β2 receptors (causing vaso-relaxation - called partial agonism)
Block of α1 receptors (causing vasorelaxation and decreased peripheral resistance)
Block of Ca2+ channels in VSMCs - some have this
Stimulation of K+ channels in VSMCs - some have this
Antioxidant activity (helps with inflammation and scar formation)- some have this
How do Beta blockers work as antianginal agents?
1. ↓ Sympathetic influence on the heart → ↓ cardiac contractility → ↓ O2 consumption of the heart → improves the cardiac reserve for a better match between the metabolic demands of the heart and its ability to generate work in patients with Coronary Artery Diseases (CAD)
2. β blockers with vasodilating properties (partial agonism) can reduce the incidence of vasospastic episodes in patients with CAD
What effects do Beta blockers have on the pulmonary system?
1. Non-selective β blockers:
Little effect on normal patients
Block of β2 receptors can produce life threatening bronchoconstriction in COPD and asthmatic patients - so don't give to COPD or asthmatic patients
2. β1-selective blockers:
Should be used with extreme care because can still effect B2 receptors at certain doses
What are the metabolic effects of Beta blockers?
1. Because catecholamines promote glycogenolysis and glucose mobilization during hypoglycemia, β blockers tend to blunt these responses in Type 1 Diabetes Mellitus (insulin-dependent), but rather infrequently in Type 2 Diabetes Mellitus
2. For these reasons, β blockers should be used with caution in diabetics; if a β blocker must be used, a β1-selective antagonist should be considered
3. Insulin sensitivity:
↓ by “Classical” β blockers
Worsen the glycemic index of normal as well as insulin-resistant patients
4. Lipid metabolism:
β blockers ↓ hormone-mediated lipase activation and ↓ release of free fatty acids from adipose tissue
5. Non-selective β blockers → ↓ HDL, ↑ LDL and ↑ Triglyceride levels whereas β1-selective antagonists produce the opposite
Beta blockers are most commonly used to treat what?
Glaucoma – decreases formation of humor
Congestive Heart Failure (all grades)
What are some other conditions that Beta blockers may be used to treat?
Acute dissecting aortic aneurysm
Migraine as prophylactic agents
What are some conditions in which Beta blockers should be used very carefully or not at all?
1. Patients with Chronic Obstructive Pulmonary Diseases (COPD) or enhanced spastic diseases of the airways (e.g. Asthma)
2. Cardiac Conduction Disturbances:
Patients with bradycardia
Patients taking antiarrhythmic drugs (e.g. verapamil)
4. Rapid withdrawal may cause adverse sympathetic rebound effects (e.g. angina attacks)
Gradual withdrawal is warranted especially in highly compromised patients
What are some side effects of Beta blockers?
Describe the pharmacokinetics of Beta blockers.
1. Some are water-soluble (e.g. atenolol), others highly lipophilic (e.g. propranolol)
2. Many display prominent 1st passage metabolism through the portal system that ↓ their bioavailability; as an example only 25% of propranolol reaches the systemic circulation even though its absorption is nearly complete
Which Beta blocker can be given IV and is good for acute hypertension because its half life is only 20 minutes?
Which Beta blocker blocks the formation of humor and is therefore used to treat Glaucoma?
What are some effects of overdose of Beta blockers?
Can be treated with Isoproterenol or an α agonist
Can be treated with Atropine; often a pacemaker is required
3. EKG may show:
Prolonged conduction times (↑ PR interval)
Widened QRS complexes (slowed conduction through the ventricle= slower depolarization)
4. Seizures and depression may occur
Which drugs are first generation Beta blockers and what is their selectivity?
Propranolol, Timolol and Pindolol are all first generation and they are all non-selective Beta blockers.
Which Beta blockers have membrane stabilizing activity and would be good for treating arrhythmias?
Propranolol, Acebutolol, Carvedolol and Esmolol also has slight stabilizing activity
Which Beta blocker exhibits partial agonism of B2 receptors leading to vasodilation?
Pindolol - so this drug (if any B blocker is given at all) would be better for those with Asthma, COPD and bradycardia
What are the second generation Beta blockers and what is their selectivity?
Metoprolol, Atenolol, Esmolol and Acebutolol are second generation and they are all B1 selective.
What are the third generation Beta blockers and what is their selectivity?
Sotalol, Labetolol and Carvedilol are all third generation and they are all non-selective antagonists.
Which Beta blocker is a Potassium channel blocker and why is this useful?
Sotalol. By blocking potassium channels this drug makes the AP longer and increases refractoriness leading to blockage of abnormal excitations. It is especially good for use in cases of A-fib.