Leblanc: Alpha-Beta Blockers Flashcards
What are the actions of catecholamines?
peripheral excitatory or inhibitory activity on certain vascular smooth muscles
peripheral inhibitory activity on some smooth muscles (gut, bronchials)
cardiac excitation (increased HR and contractile force, increased conduction velocity)
increased glycogenolysis in liver and skeletal muscle
increased release of FFAs from adipose tissue
modulates secretion of insulin, renin, pituitary hormones
CNS: wakefulness, appetite
also inhibits or increases neurotransmitter release
What do alpha-1 receptors do?
smooth muscle - contraction
What do alpha-2 receptors do?
nerve terminals - decrease neurotransmitter release
smooth muscle - contraction
What do beta-1 receptors do?
cardiac muscle - + chronotropic (heart rate), ionotropic (contractility), and dromotropic (conduction velocity)
smooth muscle relaxation
glycogenolysis
What do beta-2 receptors do?
smooth muscle - relaxation
What is the order of the affinity of catecholamines for alpha receptors?
Epi > NE»_space; Iso
What is the order of the affinity of catecholamines for beta receptors?
B1: Iso > Epi = NE
B2: Iso > Epi»_space; NE
Which G proteins do the following receptors act on?
alpha-1
alpha-2
beta
alpha 1: Gq
alpha 2: Gi/o
beta: Gs
Describe the pathway following alpha 1 activation
alpha 1 –> Gq –> PLC –> PIP2 –> IP3 (increases Ca++) and DAG (PKC) –> smooth muscle contraction
Describe the pathway following alpha 2 activation
alpha 2 –> Gi/o –> blocks Ca++ –> inhibits neurotransmitter release
alpha 2 –> Gi/o –> inhibits AC –> no cAMP –> increases Ca++ –> smooth muscle contraction
Describe the pathway following beta receptor activation
beta –> Gs –> stimulates AC –> increased cAMP –> increased cardiac contractility, smooth muscle relaxation, glycogenolysis
These two receptors have opposing effects on adenylate cyclase and cAMP production
alpha 2 (inhibits cAMP) and beta (increases cAMP)
Explain what norepinephrine does to pulse rate, blood pressure, and peripheral resistance
α1 effect: ↑ TPR, ↑ systolic pressure, ↑ diastolic pressure
β1 effect: ↑ SV ↑ pulse pressure, but decreased pulse rate
**decreases in pulse rate is reflex response (NE activates alpha 1 causing constriction of blood vessels and increased blood pressure and TPR, so HR decreases in order to compensate)
Explain what epinephrine does to pulse rate, blood pressure, and peripheral resistance
epi increases pulse rate (Beta 1)
increases systolic pressure (Alpha 1), but decreases diastolic pressure (decreases TPR) so BP stays the same
decreases TPR
Explain what isoproterenol does to pulse rate, blood pressure, and peripheral resistance
Works on beta receptors (unopposed)
increases pulse rate
increases systolic, decreases diastolic BP
decreases peripheral resistance
Except for Phenoxybenzamine (PBZ) and related compounds, all α receptor antagonists are (blank)
competitive antagonists
**this means they are reversible and can be competed off to reverse effects
alpha antagonists work primarily through effects on (blank) receptors in smooth muscle cells
alpha 1
What do alpha 2 receptors primarily act on?
CNS
**limit sympathetic outflow, and increase parasympathetic outflow
How are alpha 2 receptors involved in metabolic activity?
decrease insulin release (insulin promotes fat storage)
decrease lipolysis
What effects do alpha-1 antagonists have on the cardiovascular system?
decrease BP, esp in the upright position
**when BP drops low enough, it is compensated for by a baroreflex response
T/F: α1-Adrenergic receptor antagonists will also inhibit the effects of sympathomimetic drugs administered externally (e.g. to reverse an adverse effect)
True
**ex: can block the effects of phenylephrine (alpha1 agonist) completely!
What do alpha 2 antagonists do?
In the periphery, they increase the release of NE from nerve endings
CNS – Pontomedullary Region:
Increase Σ outflow by augmenting the release of NE which will increase by stimulation both α1 and β1 receptors in the periphery → ↑ BP
Blocks α1 and α2 “irreversably” by a covalent modification of the receptors
Phenoxybenzamine
What are the major effects of phenoxybenzamine (alpha 1 and 2 blocker)?
blocks alpha receptors in smooth muscles, leads to decrease in peripheral resistance
enhanced baroreflex response increases HR
**blockage of alpha 2 also may increase HR further by increasing sympathetic outflow
What are the therapeutic used for phenoxybenzamine?
pheochromocytoma: tumors of adrenal medulla which cause secretion of enormous quantities of catecholamines –> severe hypertension **can be used to counteract this
can be used in prep for surgery for pheochromocytoma removal
first drug prescribed to treat benign prosthatic hypertrophy in men!
What are the adverse effects of phenoxybenzamine?
postural hypotension **can be bad in patients that are hypovolemic or already taking a vasodilator, also can induce arrhythmias due to reflex tachycardia
Blocks α1 and α2 with a similar affinity; the interaction is competitive and reversible
Cardiovascular effects are similar to PBZ
Stimulates GI smooth muscles and enhances gastric acid secretion
Phentolamine
What are the therapeutic uses for phentolamine?
used in pheochromocytoma patients for short term control of hypertension, can also relieve pseudo-obstruction of the bowel by suppressing inhibitory effects of catecholamines on GI smooth muscle
can be rapidly infused to alleviate a sever hypertensive episode
can be used to limit dental necrosis after given an alpha agonist to prevent loss of local anesthetic (in some pts, will completely inhibit blood supply to the mouth and lead to necrosis)
can be used in Raynaud’s disease
can be used after rapid withdrawal of clonidine or following the ingestion of tyramine-rich food during use of MAOIs
impaired erection in men
Prototype of a growing family of α1-selective antagonists with greater clinical utility
Affinity for α1 over α2 is ~ 1000 –fold
Displays similar affinities for the different subtypes of α1 receptors: α1A ≈ α1B ≈ α1D
Also a potent inhibitor of cyclic nucleotide phosphodiesterases (PDE)
Block of α1 receptors in arterioles and veins → ↓ peripheral vascular resistance → ↓ BP → ↓ venous return to the heart
Does not generally increase heart rate
Although much weaker, may also decrease ↓ Σ outflow in the CNS
Prazosin
Prazosin blocks α1 receptors in arterioles and veins. What does this do?
decreases TPR and BP and decreases venous return to the heart
**blocks the baroreflex mechanism (doesn’t increase HR) - can be good for pts with HTN
Prazosin has favorable effects on (blank)
lipids!
↓ LDL, ↓ triglycerides and ↑ HDL levels
What is prazosin used for therapeutically?
Essential Hypertension (mild to moderate)
Vasodilator used in Congestive Heart Failure
Benign Prosthatic Hypertrophy (BPH):
↓ Smooth muscle tone
↓ Growth of smooth muscle cells
Marked interest in these compounds due to their hypolipidemic effects
Adverse effects of prazosin?
First dose effect: marked postural hypotension and syncope can be seen 30 to 90 min after the initial dose
Important to check both supine and standing BP
Newer well absorbed α1 antagonist with some subtype selectivity: α1A ≈ α1D > α1B
Useful in BPH due to favorable blockade of α1A receptors with little undesirable effect on BP
Side effect: abnormal ejaculation
Tamsulosin
Selective α2 receptor antagonist that is structurally similar to reserpine
Readily enters the CNS: ↑ BP and ↑ heart rate
↑ motor activity and produces tremors
Historically: extensively used to treat male sexual dysfunction; efficacy by far surpassed by the development of PDE5 inhibitors
yohimbine
**no real clinical use
What are beta blockers used for?
HTN
CHF
ischemic heart diseases
certain arrhythmias
What is the prototype beta-blocker?
isoproterenol
Recall the effects of Beta adrenergic stimulation
low tonic stimulation –> modest positive chronotropic and inotropic effects
more prominent effects during intense stimulation (stress and exercise)
What effect does short-term administration of beta blockers have?
decreased cardiac output
decreased peripheral resistance
**effects increase in proportion to the potency of inhibition and compensatory reflex mechanisms
What effect does long-term administration of beta-blockers have?
pulse rate returns to normal levels or decreases in HTN patients
can decrease pulse rate, while maintaining cardiac output
What effects do beta blockers have on cardiac chronotropy and dromotropy?
↓ Automaticity in the SA and AV nodes, as well as in the Purkinje system by decreasing the slope of Phase 4 depolarization
↓ Conduction velocity in atria and the conduction system
↑ refractory period of the AV node
**basically decrease conduction velocity
Beta blockers are also (blank), because they decrease cardiac contractility, O2 consumption of the heart, and incidence of supraventricular and ventricular deleterious arrhythmias
antiarrhythmic
**β blockers are considered Class II antiarrhythmic agents
Some β blockers display (blank) activity that may contribute to their antiarrhythmic activity:
stabilizing
**Local anesthetic effects by blocking voltage-dependent Na+ channels (e.g. propranolol)
How are beta blockers thought to work as antihypertensive agents?
↓ CO
↓ β1-mediated renin
- *these are postulated mechanisms
- *generally, no effect in normal patients
some beta blockers are vasodilators
↑ NO Activation of β2 receptors Block of α1 receptors Block of Ca2+ channels in VSMCs Stimulation of K+ channels in VSMCs Antioxidant activity
How are beta blockers thought to work as antianginal agents?
↓ 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)
β blockers with vasodilating properties can reduce the incidence of vasospastic episodes in patients with CAD
What effect can B2 blockers have on the pulmonary system?
can produce life threatening bronchoconstriction in COPD and asthma patients
What are the metabolic effects of beta blockers? For this reason, beta blockers should be used with caution in what patient population?
blunt the responses of glucose mobilization during hypoglycemia and glycogenolysis in Type 1 DM
decrease insulin sensitivity
decrease lipid mobilization and release of FFA from adipose tissue
**should be used with caution in diabetics
What role do beta blockers have on insulin sensitivity?
↓ by “Classical” β blockers
Worsen the glycemic index of normal as well as insulin-resistant patients
What role do beta blockers have on lipid metabolism?
β blockers ↓ hormone-mediated lipase activation and ↓ release of free fatty acids from adipose tissue
Non-selective β blockers → ↓ HDL, ↑ LDL and ↑ Triglyceride levels whereas β1-selective antagonists produce the opposite
What are the most common uses for beta blockers?
Essential Hypertension Angina Pectoris Arrhythmias Glaucoma Post-MI Therapy Congestive Heart Failure (all grades)
In what patient populations are beta blockers contraindicated?
patients with COPD or asthma
patients with cardiac conduction disturbances
patients with hypoglycemia (can block B2 glycogenolysis effects)
rapid withdrawal can cause adverse effects (angina attacks)
Side effects of beta blockers?
Tiredness Dizziness Vivid Dreams Insomnia Hallucinations Depression
How are beta blockers administered?
orally
IV (in critical ER settings)
ophthalmic solutions (glaucoma)
Many beta blockers display prominent 1st passage metabolism through the portal system. Why is this important to consider?
this may decrease their bioavailability
**ex: only 25% of propranolol reaches the systemic circulation even though its absorption is nearly complete
If you OD on beta blockers, what can occur and what can be used to treat these conditions?
hypotension: isoproterenol (or an alpha agonist)
bradycardia: atropine, pacemaker
prolonged conduction times (increased PR interval)
widened QRS
seizures, depression
