Some beta blockers have intrinsic sympathomimetic activity - what does that mean?
- Weak partial agonists that will provide some cardio stimulation, but prevent excessive stimulation via the endogenous neurotransmitters, E and NE
- Several blockers (e.g., pindolol, acebutolol) activate receptors partially in absence of catecholamines
1. Slight residual activity may prevent profound bradycardia or negative inotropy in resting heart
2. Clinical advantage unclear; may be disadvantage in secondary prevention of MI
- Other drugs inverse agonists: selectively bind inactive form of receptor and shift conformational equilibrium toward inactive state -> behave like competitive antagonists in systems that are not constitutively active
Which beta blockers have B-1 selective activity?
- Drugs from A to M that end in "OLOL":
1. Acebutolol (partial agonist)
3. Betaxolol (15-hr 1/2-life)
4. Esmolol (really short half-life: 0.15 hrs)
- Others have half-life around 3-7 hours
What are the potential off-target lipid-profile effects of beta-blockers?
- A-1, B-1, 2, 3 receptors mediate lipolysis: energy source for exercising muscle
- Beta-blockers cause: little effect on total cholesterol and plasma LDL's, but INC TG's and DEC plasma HDL (may be deleterious to pts w/CHD; have to weigh these risks vs. benefits of relieving HTN)
- Agent-specific effects: 1) those with ISA or cardio-selectivity tend to have less effect on TG & HDL, but 2) those w/both characteristics tended to reduce total chol and LDL
How is the SYM nervous system (SNS) implicated in HTN?
- SNS and HTN: important factor in heart failure and metabolic syndrome
- Centrally acting anti-HTN's remain effective, even in absence of apparent signs of SNS activation
- SNS activity can perpetuate HTN if inappropriately increased relative to pt's hemodynamic, volume, and neurohumoral circumstances
- SNS interacts w/other regulatory pathways, e.g., RAS, that contribute to prevailing BP
- As many as 30% of essential HTN pts have primary neurogenic stimulus contributing to the condition
What is the MOA of the ganglionic blockers?
- Compete with Ach for ganglionic nicotinic receptor (Nn) sites, or block the ion channel
- Trimethaphan, mecamylamine act by competition w/Ach for receptor binding
1. Hexamethonium blocks channel after it opens, shortening duration of current flow bc open channel becomes occluded or closes
- Regardless of mech, initial EPSP blocked (if 1 of 2 required Ach blocked), and gang transmission INH
What is Phentolamine?
- Short-acting competitive antagonist at alpha-1, 2
- TX: pheochromocytoma, hypertensive emergency
- Antagonism at alpha-2 INC circulating levels of NE due to loss of negative feedback -> cardio stimulation
1. In smaller doses, positive inotropic effect predominates (INC BP; cardio stimulation)
2. In larger doses, peripheral vasodilation predominates (DEC BP)
- Postural hypotension a prominent feature
- Reflex tachycardia that precipitates cardiac arrhythmias -> severely limits use for esssential HTN
What are the beta receptors? What do they do?
- Beta‐1 and beta‐2 receptor systems primarily in the heart and skeletal muscle vasculature
- In context of skeletal muscle, stimulation of alpha has inhibitory action, preventing entry of calcium critical to contraction of vascular smooth muscle
- Stimulation of cardiac beta‐1 receptors (predominant subtype in CV system) leads to acceleration in HR and increase in force of cardiac contraction
- Activation of beta‐2 receptors in skeletal muscle leads to relaxation and INC perfusion of the skeletal muscle, critical to fight-or-flight at center of SYM NS
Why is there a dip below baseline in the epinephrine control graph?
- Alpha receptors active when the drug is at high concentrations
- The dip is due to the beta-2 hypotensive effect that remains after the alpha effect has tapered due to decreased drug concentration
- Remember: beta-2 elicits a decline in BP
Which beta blockers have membrane stabilizing activity? What does this mean?
- Propranolol, Acebutolol, Carvedilol (pindo, metopro, betaxo, and labeta only at high doses)
- Used as class II antiarrhythmic agents
- Bind and block fast Na+ channels responsible for rapid depolarization (phase 0) of fast-response cardiac action potentials -> decreases phase 0 slope, leading to decrease in amplitude of action potential
- Non-nodal cardiomyocytes (e.g., atrial, ventricular myocytes; Purkinje tissue)
- These are separate from their other effects mediated via beta-1 adrenergic receptors
How is Dopamine given? Describe where it lies in the E metabolic pathway.
- Given IV by infusion
1. Short duration of action (ONLY suitable for inpatient tx)
2. Monitor urine output as secondary marker of drug effect
- Tyrosine -> Dopa -> Dopamine -> NE -> E; precursor
1. Still has its own dopaminergic receptor system, most notably in renal vasculature where activation of D1 receptors leads to vasodilation
- Proven benefits in CHD and RF
What are the alpha-2 agonists and NE storage depletion drugs?
- Alpha-2 agonists: Clonidine, Guanfacine
- Alpha-2 agonist prodrug: Methyldopa
- NE storage depletion: Reserpine, Metyrosine
How do beta blockers produce their antihypertensive effects?
- Mechanism of antihypertensive effect still unclear
- Inhibit stimulation of renin production by catecholamines (mediated by β1 receptors) -> effect is due in part to this depression of renin‐ angiotensin‐aldosterone system
- Although most effective in pts w/high plasma renin activity, also reduce blood pressure in HTN pts with normal, or even low renin activity
- Some clinical effect might arise from the inhibition of presynaptic β adrenoceptors -> this would reduce sympathetic vasoconstrictor nerve activity
Are the beta blockers "interchangeable?" Why or why not?
- NO -> for example, only β antagonists known to be effective in stable heart failure or in prophylactic therapy after MI should be used for those indications
- Possible that beneficial effects of one drug might not be shared by another drug in same class
- Possible advantages/disadvantages of β‐receptor partial agonists have not been clearly defined in clinical settings, although current evidence suggests they are probably less efficacious in secondary prevention after MI compared with pure antagonists
How does ganglionic signaling work?
- Pregang N releases ACh onto postganglionic cells
- When 2 Ach bind nicotinic AchR, conformational change occurs in receptor, forming ion pore
- Initial EPSP result of inward Na+ current (and Ca2+) through nicotinic receptor channel; if EPSP sufficient magnitude, triggers action potential spike, then slow IPSP, slow EPSP, and late, slow EPSP
- Slow IPSP and slow EPSP not seen in all ganglia.
- Electrical events after initial EPSP thought to modulate probability that subsequent EPSP will reach the threshold for triggering a spike
- Other interneurons, like catecholamine-containing, small, intensely fluorescent (SIF) cells, axon terminals from sensory, afferent neurons release transmitters, that may influence slow potential in postgang neuron
What are some AE's associated with beta-blocker OD?
- Bradycardia, bradyarrhythmia typical symptoms
- Beta receptor specificity lost in overdose
- Membrane stabilizing drugs further depress myocardial contractility and conduction, and may be associated w/ventricular tachyarrhythmias
- Propranolol (lipid-soluble) can cause seizures, coma
- Drugs w/intrinsic sympathomimetic activity (ISA) may cause tachycardia, HTN
- Sotalol, an antiarrhythmic agent, also has type III activity (K+ blockade), prolongs QT interval, and may cause torsade de pointes & ventricular fibrillation
- 3rd gen drugs w/extended actions: direct vasodilation can contribute to hypotension in OD
- Underlying CV/pulmonary disease places pt at increased risk of lethal outcome
What are some of the non-CV applications of beta-blockers?
- Essential tremor (NS issue -> rhythmic shaking)
- Thyrotoxicosis (hyperthyroidism)
- Prophylaxis of migraine headache
- Secondary prophylaxis of bleeding associated with esophageal varices -> non-specific blockers better bc reduce BP and splanchnic blood flow by blocking B2-mediated vasodilation
- Glaucoma (topical application)
What are the attributes of Ephedrine?
- Mixed-acting sympathomimetic
1. Direct agonist at A and B receptors (esp. in bronchiolar sm m -> asthma, cold, sinus)
2. Enhances release of NE from SYM neurons
- Orally active; elim largely unchanged in urine
- Used for hypotension & hypotension of analgesia
- INC HR and CO; variable INC in peripheral resistance; INC BP
1. INC cardiac workload -> angina
2. Stimulates myocardium -> ventricular dysfunction, palpitations, s-TACH
3. Fatal arrhythmias, incl ventricular fibrillation
- Herbal products w/ephedra alkaloids: FDA ban
- Precursor of illicit amphetamine/meth
What are the attributes of Norepinephrine?
- 10-20% of adrenal medulla catecholamines; >97% in some pheochromocytomas
- DEC CO (opposite of E), INC TPR (most vascular beds), INC stroke volume, INC coronary BF
1. Predisposes to arrhythmias, but no major role in stimulating HR
- Vagal opposition of direct cardio accelerator action
- AE's similar to E, but INC BP more prominent -> careful monitoring of BP, incl. pulmonary (INC DP, MAP bc INC TPR)
- IV; necrosis at infusion site responsive to infiltrated phentolamine, an alpha antagonist (caution for diminished organ BF)
- NE (LEVOPHED)
- Vasoconstrictor to raise or support BP under certain ICU conditions
What are the attributes of Dobutamine?
- Racemic mixture
1. B1-agonist & A1-antagonist (+ enantiomer); A1-agonist (- enantiomer) -> no effect on Dopa receptors
- INC CO and stroke volume w/o marked effect on HR
1. INC myocardial contractility w/DEC left ventricular filling pressures
2. INC urinary output secondary to INC CO
- Short-term tx of cardiac decompensation (after cardiac sx, CHF, or acute MI)
- Ultra short T(1/2): 2 min (given by infusion)
What are the clinical effects of the alpha-2 agonists?
- Withdrawal of SNS tone producing parallel, balanced fall in PVR & SBP, DBP
1. Effect persists in long-term therapy
2. Exercise-induced INC in SNS activity blocked
- NO reflex tachycardia; HR may reduce
- CO, renal blood flow typically unaffected
- DEC plasma renin activity
- Regression of left ventricular hypertrophy
- Combo w/diuretic, i.e., thiazide, chlorthalidone, or furosemide to produce > DEC in BP
1. May aid in overcoming tolerance, and permit reduction in dose
What are the 3 subtypes of Alpha-1 receptors? Why is this important?
- 1a: 70% of alpha receptors in prostate
1. Alfuzosin: > affinity for Alpha-1a than the others, so it is used to improve urine flow rate, and reduce symptoms of BPH
- 1b and 1d: in the vasculature
- All involved in smooth muscle contraction
What is Reserpine toxicity?
- Most significantly CNS toxicities: sedation, inability to concentrate, perform complex tasks
- Occasionally psychotic depression -> suicide
1. Contra in pts w/hx of major depression, esp. those who have suicidal ideation
2. Discontinue at 1st sign of depression
3. May last several mos post-discontinuation
- Contra in PUD, ulcerative colitis bc can exacerbate
- Avoid in pregnancy; teratogenic in animal models
- Avoid breastfeeding; neonatal effects -> resp tract secretions, nasal congestion, anorexia
What are the indirect effects of Ach in the CV system?
- Opposition of B-1 increase in cardiac activity
- Inhibition of NE release from SYM NN -> presynaptic M2, M3 receptors, presynaptic M2 auto-receptors
What receptors are inhibited by ganglionic blockers?
- Cholinergic nicotinic (Nn) receptors found in autonomic ganglia and in the adrenal medulla
- Distinct from the nicotinic (Nm) receptor found on the neuromuscular junction
What is Metyrosine?
- Works by reducing availability of E and NE in pre-synaptic vesicles -> blocks activity of rate‐ limiting step (tyrosine hydroxylase) in sequential syn of catecholamines from comm precursor, tyrosine
- Not used to treat HTN, but consequences of pheochromocytoma, rare adrenal medulla tumor that causes release of lots of NE and to lesser extent E
1. Until definitive tx of sx excision accomplished, metyrosine can be used to modulate SYM excess that leads to severe HTN; often poorly controlled w/customary antihypertensive meds
2. Alleviates attacks of HTN, and then reduces headaches, nausea, sweating, and tachycardia
What off-target pulmonary effects are possible with beta-blockers?
- Blockade of bronchial sm m B-2 receptors that promote endogenous bronchodilation in pts with bronchospastic disease (i.e., asthma, COPD)
- Life-threatening increase in airway resistance
- B-1 selective drugs, or those w/ISA less likely to induce bronchospasm (but remember, specificity is DOSE-RELATED)
- Selectivity of blockers NOT absolute:
1) should be avoided if possible in asthmatics (non-specific B-blockers CONTRAINDICATED)
2) in some pts w/COPD/CV disease, advantages of using B-1 antagonists may outweigh risk of worsening pulmonary function
Describe the dose-dependent effect of Dopamine. Why does this happen?
- Low (0.5-2mcg/kg/min): predominantly D1 action
1. RENAL, mesenteric, coronary, intracerebral vasculature stimulation -> vasodilation
2. Improves GFR; critical in pts with diminished renal perfusion (used as indicator of drug effect elsewhere)
- Moderate (2-10mcg/kg/min): D1 + B1
1. INC CO (contractility >> HR), D1 vasodilation
2. Also causes release of NE from nerve terminals, contributing to heart effects
- High (>10mcg/kg/min): alpha agonism predominates
1. INC peripheral vascular resistance and renal vasoconstriction
- NOTE: change in receptor specificity reflects relative sensitivity of different receptors to ligand & arrangement on comparison dose-response overlay
What are the AE's associated with the ganglionic blockers?
- Postural hypotension, tachycardia, arrhythmias
- Blurred, or double vision
- Asthma, secondary to histamine release (Trimethaphan -> bronchoconstriction)
- Dry mouth, constipation, paralytic ileus, N/V
- Urinary retention, impotence
- Drowsiness, seizures, hallucinations, tremor, confusion
- Neuromuscular blockade
Where do ganglionic blockers act?
- Primarily upon autonomic ganglia, thereby reducing HTN arising from SYM overactivity
What are some of the various mechanisms by which beta blockers (which ones?) with extended actions can prevent vasoconstriction from reducing their clinical effectiveness?
- Nitric oxide production: Nebivolol
- Alpha-1 antagonism: Carvedilol, Labetalol
- Ca entry blockade: Carvedilol, Betaxolol
- Antioxidant activity: Carvedilol, Nebivolol
For which types of patients are alpha agonists helpful? How are they administered, and what are their T(1/2)'s?
- Useful adjuntive tx, esp. to block reflex tachycardia (as with vasodilators)
- No meaningful effect on blood glucose, lung func
1. Useful in diabetics, asthmatics
- Clonidine, methyldopa available by IV; others oral only (clonidine transdermal patch, but 1-2 days to reach peak effect, and up to 1 day to disappear)
- T(1/2) varies: methyldopa > guanfacine, and often poor correlation with duration of central effect
Why are alpha blockers no longer used as extensively as they once were to tx HTN?
- Primarily due to availability of alternative drugs that, based upon clinical trials, are more effective
- Fall from grace was initiated by publication of the ALLHAT trial in early 2000
- Physicians have modified their opinion of alpha‐blockers, and redefined their place in the treatment of CV diseases
What are the effects of SC Epinephrine on BP?
- Absorption slowed by local vasoconstrictive effect
1. Co-formulated w/local anesthetics for this
- Moderate INC in SBP secondary to inotropic effect and INC cardiac output
- DEC in DBP; dominant B-2 mediated decrease in peripheral resistance (compensatory baroreflexes not evoked)
- INC HR, CO, stroke vol, & left ventricular work/beat
- Depending on dose/rate and resultant ratio of B-2 to A responses in various vascular beds, may be sligh INC in peripheral resistance and DBP (compensatory reflexes may also be evoked)
Where is the nicotinic receptor located, and what is the result of ligand binding?
- Nicotinic, Nn
- Typical locations: postganglionic neurons, some presynaptic cholinergic terminals
- Result of ligand binding: opening of Na, K, channels, depolarization
Describe the actions of the M3 receptors at the molecular level.
- Couples by Gq/11 -> activation of phospholipase C, increasing inositol triphosphate (IP3) & diacylglycerol (DAG)
- Consistent increases in Ca & protein kinase C
- Activation of phospholipase A2, D2, & arachidonic acid
- Depolarization and excitation (INC sEPSP) -> syn & release of NO in the context of the vasculature
Know these details about the direct effects of Ach on the CV system. For the visual learners.
How does Ach affect vascular tone?
- Vasculature does NOT receive direct PARA innervation, but will respond to exogenous muscarinic antagonists/agonists
- IV Ach produces a transient decrease in BP (via NO) and reflex tachycardia -> large dose = bradycardia or AV nodal conduction block
- Stimulates M3 receptors in vascular endo to vasodilate
- With pathological endo damage, Ach acts predominantly on M3 receptors located on underlying vascular smooth muscle cells, causing vasoconstriction
What is the utility of Atropine?
- Abolishes reflex vagal cardiac slowing or asystole:
1. From inhalation of irritant vapors, stimulation of carotid sinus, pressure on the eyeballs, peritoneal stimulation, injection of contrast dye during cardiac catheterization
- Prevents of abolishes bradycardia or asystole from:
1. Parasympathomimetic drugs, and cardiac arrest from electrical stimulation of vagus
- Facilitates AV conduction:
1. Shortens functional refractory period of AV node, improves patients with posterior wall MI by relieving severe sinus or nodal bradycardia or AV block
What beta blockers have non-selective activity (B1 = B2)?
- Those from N to T that end in "OLOL" (except Nebivolol):
1. Nadolol (long half-life: 20-24 hrs)
2. Pindolol (partial agonist)
3. Propranolol (high lipid solubility)
- Others have half-life around 3-5 hours
What types of mediators regulate Ach?
- Ach regulated by many mediators, incl:
1. Ach itself acting on M2, M4 autoreceptors
2. Other transmitters (e.g., NE acting on A-2 receptors)
3. Adenosine A1, histamine A3, opioid receptors
4. Substances produced locally (e.g., NO)
What is Reserpine, and what does it do?
- Binds tightly (long-lasting) to adrenergic storage vesicles in central/peripheral adrenergic neurons
1. Inhibits vesicular catecholamine transporter (VMAT2)
2. Lost capacity to conc, store NE and dopamine
- Catecholamines leak into cyto -> metabolized (pharmacological sympathectomy)
- Recovery requires synthesis of new storage vesicles (days to weeks)
- Anti-HTN effects related to both central, peripheral actions
- Completely metabolized to inactive products
What may happen with long-term exposure to alpha-2 agonists?
- Long‐term exposure down‐regulates receptor expression for alpha‐2 agonists, as with many G protein‐coupled receptors
- Decrease in receptor density could occur through increase in receptor degradation or decrease in receptor synthesis
- Loss of drug target leads to a reduction in dose‐related effectiveness and the phenomenon termed tolerance
Describe the different effects of IV infusion of NE, E, and Isoproterenol in humans.
- NE: strong vasoconstrictive action via A‐1 receptors, so rise in SBP & DBP and in MAP; HR reduced via a baroreceptor‐mediated reflexive action
- E: B‐2 relaxation of skeletal muscle vasculature, so wide pulse pressure, but no significant change in MAP; INC in pulse rate mediated by B‐1 stimulation unopposed by baroreceptor mechanism
- Isoproterenol: stimulates B‐2 receptors, so fall in DBP, but small rise in SBP attributable to B‐1 INC in cardiac output, rather than non‐existent A‐1 effects
1. Compared to E, isoproterenol tends to INC pulse rate more & reduce peripheral resistance more due to lack of alpha‐1 mediated effect
- TAKE-HOME MESSAGE: net effect of any drug depends not only on its relative receptor selectivity, but also compensatory baroreflex mechanisms aimed at restoring BP homeostasis
Describe the molecular mediators of alpha-2 stimulation.
- Binding of presynaptic alpha2‐adrenoceptor ligands inhibits adenylyl cyclase by causing dissociation of the inhibitory G protein, Gi, into its subunits
- Mechanism by which these subunits inhibit adenylyl cyclase uncertain
What is an inotrope?
- An agent that alters the force or energy of muscular contractions
- Negatively inotropic agents weaken the force of muscular contractions
- Positively inotropic agents increase the strength of muscular contraction
Briefly describe the nature of the interaction of the PARA and SYM systems.
- Produce opposing signals; either may win by INC activity of its own transmitter release, or by INH the opposing system
1. Ex: opposing effects of NE, Ach result from directly opposing effects of transmitters on cardiac cells, and mutual inhibition of release of heteroreceptors (juxtaposition of NE/Ach terminals in SA node)
- Both controlled through complex system involving hetero-receptors and non-adrenergic non-cholinergic neurotransmitters (NANC)
What are the distinguishing features of methyldopa?
- Metabolized to alpha-methylNE
- Other drugs active as parental molecule
- Dose adjustment in renal failure (not true for other drugs)
- Chelated by concurrent iron supplements (adjust timing - 2 hour gap)
What are the effects of Epinephrine on the heart?
- Powerful/direct cardiac stimulant: B-1 receptors in myocardium, pacemaker, and conducting tissues
- INC HR, short systole, INC CO, INC O2 consumption
1. INC relaxation rate of ventricular muscle
2. Accelerate SA node slow depolarization rate
3. Amplitude of action potential and max rate of depolarization (phase 0) also increased
4. Activates latent pacemaker cells in SA node
5. Directly shortens AV node refractory period; opposed by reflex vagal discharge
- Premature ventricular contractions may occur: ventricular extrasystoles, tachycardia, even fibrillation may be precipitated in (drug) sensitized heart
Covered in other cards, but know this.
Note: dose-related effects of Dopamine, which has reno-specific actions only at low doses
What drug would you use to treat pre-eclampsia?
- Pre-eclampsia: HTN of pregnancy
- Methyldopa: extensive track record of safety for this indication (amongst various vasodilators, diuretics, and beta-blockers)
How does E effect the rate of depolarization in the SA node?
Accelerates the rate of depolarization (Ach would decelerate it)
What is the typical tx for pts experiencing bradycardia/bradyarrhythmia due to beta blocker OD?
- Drug support can't employ beta-agonist bc their receptor systems are blocked
- Typical tx involves use of glucagon or high-dose glucose/insulin
- NOTE: toxicity from excessive beta-blocker consumption not uncommon
What are the vascular effects of Epinephrine?
- Chiefly on smaller arterioles and precapillary sphincters -> substantial redistribution of flow
- DEC cutaneous BF, but INC B-2 mediated skeletal muscle BF
- INC renal vascular resistance; DEC renal BF
1. GFR unchanged, DEC excretion of NA, K, Cl
2. INC renin secretion (B-1 in JGA)
- INC pulmonary (aa/vv) pressures: redistribution of blood from other constricted areas (pulm edema precipitated by high concentrations)
- INC coronary BF (INC diastole duration)
1. INC aortic pressure; metabolic dilator effect secondary to myocardial O2 consumption
How does Atropine affect the circulation?
- Completely counteracts peripheral vasodilation and sharp fall in BP caused by choline esters
- When given alone, effect on blood vessels and BP neither striking nor constant
1. Most vascular beds lack significant cholinergic innervation
- In high doses, Atropine can dilate cutaneous blood vessels, esp in the blush area (atropine flush)
1. Compensatory rxn permitting radiation of heat to offset atropine-induced rise in temp that can accompany inhibition of sweating
What beta blocker exhibits beta-1 blockade + beta-3 stimulation in vasculature? What does beta-3 do?
- Nebivolol (1/2-life: 11-30 hrs)
- Beta-3 stimulation in vasculature leads to NO synthase activation
Summarize the effects of PARA activity in the heart. Where does most of this activity take place?
- SA node: Ach DEC HR primarily by DEC rate of spontaneous depolarization (attainment of threshold potential and cardiac cycle delayed)
- Atria: Ach causes hyperpolarization and DEC action potential duration by INC I(K)-Ach; also DEC cAMP, decreasing NE release and atrial contractility
- AV node: Ach DEC conduction and INC refractory period by inhibiting I(Ca)-L; responsible for drug-induced complete heart block
- His-Purkinje system, ventricular myocard: smaller effects than those observed in atria/nodal tissues
- NOTE: most activity in SA/AV nodes, with little involvement of other tissues
How does Reserpine affect the CV stimulatory drugs?
- Direct-acting: responses NOT reduced by prior tx with Reserpine, which depletes NE from sympathetic neurons; may increase bc NE induces compensatory changes that upregulate receptors or enhance signaling pathway
- Indirect-acting: responses ARE abolished by prior tx with Reserpine
- Mixed-acting: effects blunted, but not abolished by Reserpine
I'm taking a beta blocker and I want to stop. Now. Can I?
- NO -> abrupt discontinuation of beta‐blocker tx is ill advised
- Doses should be tapered over time
- Upregulation in beta‐receptor expression can lead to rebound and life‐ threatening cardiotoxic effects
What two anatomic sites of beta receptors are we to focus on?
- Juxtaglomerular apparatus in kidney
What are the attributes of Isoproterenol?
- Powerful effects on B receptors >>>> A receptors
- INC CO (+ inotropic and chronotropic, i.e., change HR, effects): sinus tachycardia, palpitations, more serious arrhythmias possible
- DEC DP: DEC peripheral vascular resistance, primarily in skeletal muscle, but also in renal and mesenteric vascular beds
- Parenteral, or by aerosol
- Palpitations, headache, tachycardia, and flushing common
- Used in emergencies to stimulate HR in pts with bradycardia or heart block, esp in anticipation of inserting artificial cardiac pacemaker or in pts with ventricular arrhythmia, torsades de pointes
- Limited therapeutic use, but may be used in some emergent situations
How does Atropine affect the heart?
- Main effect is to alter HR
- Transient decrease (4-8 bpm) with low dose: blockade of presynaptic M1 auto-receptors -> INC Ach release and slight slowing of the heart
- Progressive tachycardia with higher dose: blockade of M2 receptors on SA nodal pacemaker cells (vagal tone antagonized)
- INC resting HR; maximal HR unaffected: esp. in young, healthy adults (less in infancy, old age)
What are the three categories of alpha blockers that we need to know (based on their receptor affinity)?
- Alpha-1 >>>>> Alpha-2
1. Terazosin, Doxazosin, Prazosin
- Alpha-1 > Alpha-2
- Alpha-1 = Alpha-2
How does stimulation of beta-1 and -2 receptors affect the heart and vasculature?
- Beta-2: receptor stimulation has an inhibitory action, preventing entry of Ca critical to vascular smooth muscle contraction
1. Activation in skeletal muscle leads to relaxation and INC perfusion of this muscle group (fight-or-flight)
- Beta-1: predominant subtype in the CV system; leads to accelerated heart rate and increase in force of cardiac contraction
What are the 3 MOA's of CV stimulants?
- Direct-acting drugs: stimulate post- or pre-synaptic receptors
- Indirect-acting drugs: increase availability of NE or E
1. Releasing, displacing NE from SYM nerve varicosities (bulbous ends)
2. Blocking transport of NE into SYM neurons, e.g., cocaine
3. Blocking metabolizing enzymes, monoamine oxidase, catechol-O-methyltransferase (COMT)
- Mixed acting: direct activation + indirect NE release
- NOTE: in each case, drugs may show considerable selectivity for specific receptor subtype or minimal selectivity and act on several receptor subtypes
What G proteins do each of the various receptors act through?
- G(q): A-1, M-1, M-3
- G(i): A-2, D-2, M-2
- G(s): B-1, B-2, D-1
What does blockade of alpha-1 receptors do? How?
- Leads to hypotension
- By preventing NE-stimulated smooth muscle contraction in the vasculature (NO increase in IC Ca ions via DAG and IP)
What are the attributes of phenylephrine?
- Potent, direct-acting alpha1-adrenergic agonist with virtually NO beta-adrenergic activity
- Systemic arterial vasoconstriction: INC SBP, DBP
- Reflex DEC HR and CO
- SC, IM, IV (usually titrated to effect)
- Control of hypotension, incl hypotension associated with regional or spinal anesthesia
- Mixed w/local anesthetics as vasoconstrictive agent; used to produce mydriasis prior to optho exam
- AE's: angina, anciety, hallucinations or psychosis (rare), HTN, excitability, dizziness, insomnia, pallor, and restlessness (more likely secondary to parenteral administration)
What is Phenoxybenzamine?
- Non-competitive (covalent: LONG-LASTING) alpha-1 and 2 antagonist -> less substantial vasodilation (and reduction in BP) than alpha-1 specific antagonists due to mitigating action of increased CO (alpha-2 INH)
- TX: sympathetic excess (high circulating levels of catecholamines) via pheochromocytoma, Raynaud's, frostbite, and acrocyanosis (off-label use)
- Slow onset (several hrs); long duration (3-4 days)
- Minor actions in blocking serotonin, histamine, Ach
- AE's: sinus-tach, nasal congestion, drowsiness, fatigue, weakness, malaise, confusion, headache, xerostomia, and ejaculation dysfunction
Describe the actions of the M2 receptors at the molecular level.
- Couples by Gi/Go signaling, inhibiting adenylate cyclase and decreasing cAMP
- Activation of inwardly rectifying K+ channels; INH of voltage-gated Ca channels -> hyperpolarization and inhibition of neuronal activity
1. DEC: HR via SA, conduction velocity in AV, and atrial contraction; INC atrial refractory period
- Predominantly affect SA, AV nodes and atria (w/little effect in ventricles -> slight DEC in contraction)
- Peripheral NN: INH via auto/hetero-receptors (DEC ganglionic transmission)
What is the primary role of the alpha blockers?
- Antagonize alpha receptors in the vasculature that activate smooth muscle, producing vasoconstriction
- These drugs cause VASODILATION (reduce HTN)
What are the AE's of the alpha agonists?
- Somnolence (drowsiness)
1. Dose qHS (evening) to minimize significance
2. Avoid o/CNS depressants (alcohol, sedative/hypnotics, 1st gen antihistamines)
- Dry mouth (xerostomia)
1. A2-mediated DEC in salivary flow
2. INC likelihood of carries, periodontal disease, oral candidiasis
- Less likely: abdominal pain, constipation, sinus bradycardia, hypotension, DEC libido, impotence
- Methyldopa interferes w/catecholamine quantitation (relatively contraindicated in pheochromocytoma)
Describe Epinephrine admin, AE's, and utility.
- IV, inhaled, IM: not oral bc metabolized; SC slow due to vasoconstriction
- Adverse effects: cerebral hemorrhage, esp. with non-specific beta-blockers, ventricular arrhythmias, angina
- Therapeutic utility: sympathomimetic
1. Emergency relief of hypersensitivity reactions, including anaphylaxis
2. Vasoconstrictor with local anesthetics; topical hemostatic agent
3. Restoring cardiac rhythm in pts w/cardiac arrest
- NOTE: giving this drug to pts on non-specific beta-blockers would result in unopposed alpha‐1 mediated HTN that might be fatal
When are ganglionic blockers used?
- Occasionally used IV for intraoperative & malignant HTN emergencies and to control arteriolar bed bleeding in sx
- Trimethaphan preferred by many clinicians for emergency control of BP in pts w/acute dissecting aortic aneurysm
- Mecamylamine has shown promise in treating various nicotine‐responsive neurological diseases, including Tourette's syndrome, and some activity in treating cocaine and nicotine addictions
How does Epinephrine affect the kidney?
- Doses that have little effect on mean arterial pressure (MAP) consistently increase renal vascular resistance and reduce renal blood flow by as much as 40%
- All segments of renal vascular bed contribute to INC resistance in the kidney
- Direct beta‐1 stimulation of renin release, activation of the renin‐angiotensin system also occurs
What is the role of alpha-2 receptors in the vasculature and CNS?
- Alpha-1 receptors predominate in vasculature, but alpha-2 receptors also there (and also vasoconstrict); little contribution to pharmacology of oral alpha-2 agonists bc central hypotensive actions of drugs prevail over peripheral vasoconstrictive effects
- In pts w/pure autonomic failure (neural degen of postganglionic noradrenergic fibers), alpha‐2 agonist, like clonidine, may INC BP bc central sympatholytic effects of clonidine become irrelevant, whereas the peripheral vasoconstriction remains intact
- Role in CNS functions: such as sedation, analgesia and anxiolysis; there are drugs used specifically for these indications
- Don't forget role of presynaptic auto‐receptor in terminating cont'd release of NE from presynaptic terminal
What does stimulation of the muscarinic receptors cause?
1. Decreases neuronal activity in the SA node
2. Decreases contractility in atiral tissue
- M3, 5: in the vasculature, induce the synthesis and release of endothelin-derived relaxing factor (EDFR), the best characterized of which is NO (vasodilating intermediate)
Describe the molecular mediators of beta stimulation.
- Beta adrenergic receptor is a transmem spanning protein complex
- Binding of E or NE to β adrenoceptors activates a Gs protein which, in turn, stimulates adenylyl cyclase, resulting in an increased rate of synthesis of cAMP
- cAMP binds to the regulatory subunit (R) of cAMP‐dependent protein kinase, leading to the liberation of active catalytic subunits (C) that phosphorylate specific protein substrates and modify their activity
1. Also phosphorylate cAMP response element binding protein (CREB), which modifies gene expression
What is the molecular result of binding of beta adrenoreceptors?
- Stimulates adenylyl cyclase by activating stimulatory G protein, Gs, leading to dissociation of its subunit charged with GTP
- Activated subunit directly activates adenylyl cyclase, resulting in increased rate of synthesis of cAMP
What receptors are affected by each of the drugs in this chart? Describe what this chart means.
- Norepinephrine: alpha-1, -2, beta-1
- Epinephrine: alpha-1, -2, beta-1, -2
1. Phenomenon of alpha blocker causing EPI to reduce BP rather than increase it is referred to as EPI reversal -> overall, this drug combo would increase HR and renal bloodflow, and decrease total peripheral resistance (TPR), BP and effective refractory period (ERP) in the heart
- Isoproterenol: beta-1, -2
What are the predominant tone and effect of ganglionic blockers in the arterioles, veins, and heart?
1. Predominant tone: SYM
2. Blockers: vasodilation, increased peripheral blood flow, hypotension
1. Predominant tone: SYM (adrenergic)
2. Blockers: dilation, peripheral pooling of blood, decreased venous return, decreased CO
1. Predominant tone: PARA (cholinergic); logical given spontaneous nature of depolarization of pacemaker cells -> regulatory control of SA, AV
2. Blockers: tachycardia
What off-target CNS effects are possible with beta-blockers?
- CNS depression can occur, resulting in mental disorders, fatigue, and in some cases, vivid dreams
- Much less common with hydrophilic beta-blockers
What are the classes of cardiac stimulants? How are they affected by Reserpine pre-treatment?
- Direct-acting: NOT reduced by Reserpine tx; may be potentiated by concurrent Reserpine/cocaine
1. Selective: phenylephrine (A-1), clonidine (A-2), dobutamine (B-1), terbutaline (B-2)
2. Non-selective: oxymetazoline (A-1,2), isoproteronol (B-1,2), E, NE
- Mixed-acting: ephedrine (NE releasing agent & direct B2 agonist; reduced by prior tx with Reserpine)
- Indirect acting:
1. Cocaine, MAOI, COMTI: prevent breakdown of released neurotransmitter
2. Releasing agents: tyramine, amphetamine (release of transmitter stored in pre-synaptic vesicles; abolished by prior tx with Reserpine)
How are the beta receptors involved in modulating renin release?
- Beta‐1 receptors acting on juxtaglomerular cells leads to release of renin -> converts angiotensinogen to angiotensin I and II, potent vasoconstricting agents
- Beta blockers can therefore reduce HTN due to excessive renin release
- Chronic NSAID use will diminish production of PGs and can have AE on renal perfusion, esp in elderly, by preventing the vasoconstrictor actions instigated through renin release
What off-target glucose effects are possible with beta-blockers?
- Hypoglycemia: beta-2 adrenoreceptors normally stimulate hepatic glycogen breakdown (glycogenolysis) and pancreatic glucagon release
1. Together increase plasma glucose
- Diabetics: B-1 blockers mask the tachycardia that serves as warning sign insulin-induced hypoglycemia
1. To be used cautiously in diabetics
What are the 4 primary effects of Ach on the CV system?
2. Decrease HR (negative chronotropic effect)
3. Decrease AV node conduction velocity (negative dromotropic effect)
4. Decrease force of atrial cardiac contraction (negative inotropic effect)
- Responses may be obscured by baroreceptor and other effects that dampen direct responses to Ach
How does Ach affect the SA node at the molecular level?
- ACh from postganglionic cholinergic axon interacts with SA node M2R linked via Gi/o to K+ channel opening -> hyperpolarization, inhibition of cAMP syn
- DEC cAMP shifts voltage‐dependent opening of pacemaker channels (If) to more negative potentials, reducing phosphorylation and availability of L‐type Ca2+ channels (ICa)
- Released ACh also acts on axonal muscarinic receptor (autoreceptor) to cause inhibition of ACh release (auto inhibition)
- Net effect of activation of inward rectifying K+ channels and inhibition of L‐type calcium channels is inhibition of pacemaker (HCN) activity -> results in fall in rate of spontaneous depolarization
What does stimulation of alpha-1 receptors produce?
- Vasoconstriction: in skin, skeletal muscle, and splanchnic vessels
What dose-related drug effects are observed with Epinephrine?
- At low doses, produces a widening of the pulse pressure due to effects on B-2 receptors
- B-2 effects obscured at higher doses, which produce overall vasoconstriction via strong A-1 mediated action
What clinical agents are ganglionic blockers? Why are they generally not used anymore?
- Have been replaced in the tx of HTN by virtue of more specific drugs with less global effects on the SYM nervous system
What are the clinical utilities for the beta blockers?
- HTN: effective, well tolerated; often used w/diuretic or vasodilator
- Ischemic heart disease: reduce angina frequency & improve exercise tolerance; decrease cardiac work, reduce O2 demand, slow/regularize HR -> Timolol, Propranolol, or Metoprolol
- Supraventricular/ventricular arrhythmias: by INC AV nodal refractory period, B-antagonists slow ventricular response rates in atrial flutter/fibrillation
- CHF: Metoprolol ER, Bisoprolol, Carvedilol are effective in reducing mortality in select patients
What are the adverse effects of the alpha blockers?
- First dose orthostatic hypotension
1. Most prominent w/Prazosin (also disadvantage w/Prazo bc Q8hr, not daily like other alpha-1's)
2. Not correlated w/serum level
3. Reduced dose, take with food
4. Take first dose before bed
- Sinus-tach (angina, palpitations), syncope, vertigo
1. Tachycardia more marked w/blockade of cardiac alpha-2-presynaptic receptors (i.e., phentolamine -> augmented release of NE, which can also act on beta-1 receptors in heart, esp. at low doses)
What beta blockers are non-specific alpha and beta antagonists (B > a)?
- Those with unusual spelling:
1. Carvedilol (1/2-life: 7-10 hrs)
2. Labetalol (1/2-life: 3-4 hrs)
- NOTE: have extended actions in preventing alpha-mediated reflex vasoconstriction -> REMEMBER: baroreceptors will sense decline in BP produced by beta blockade and activate alpha‐1 mediated vasoconstriction
Why are there significant differences in the effects of NE and E on cardiac output and DP/MAP?
Reflect the relative activities on alpha-1 vs. beta-2 receptor function
What are the central effects of alpha-2 receptor activity?
- A2 autoreceptors limit release of NE from SYM NN and E from adrenal chromaffin cells at rest
1. Desensitized w/chronic activation, e.g., during advanced SYM activity of chronic heart failure
- A2 heteroreceptors (i.e., serotonin) in non-adrenergic neurons: bradycardia and hypotension (vagal activation via cholinergic action), analgesia, sedation, hypothermia, anesthetic-sparing effect
1. Ex: dexmedetomidine agonist has sedative, analgesic props w/o ventilatory effects (in CNS)