04.08 - Sweatman Flashcards
1
Q
Some beta blockers have intrinsic sympathomimetic activity - what does that mean?
A
- 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
2
Q
Which beta blockers have B-1 selective activity?
A
- Drugs from A to M that end in “OLOL”:
1. Acebutolol (partial agonist)
2. Atenolol
3. Betaxolol (15-hr 1/2-life)
4. Esmolol (really short half-life: 0.15 hrs)
5. Metoprolol - Others have half-life around 3-7 hours
2
Q
What are the potential off-target lipid-profile effects of beta-blockers?
A
- 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
2
Q
How is the SYM nervous system (SNS) implicated in HTN?
A
- 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
3
Q
What is the MOA of the ganglionic blockers?
A
- 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
4
Q
What is Phentolamine?
A
- 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
4
Q
What are the beta receptors? What do they do?
A
- 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
5
Q
Why is there a dip below baseline in the epinephrine control graph?
A
- 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
5
Q
Which beta blockers have membrane stabilizing activity? What does this mean?
A
- 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
5
Q
How is Dopamine given? Describe where it lies in the E metabolic pathway.
A
- 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
5
Q
What are the alpha-2 agonists and NE storage depletion drugs?
A
- Alpha-2 agonists: Clonidine, Guanfacine
- Alpha-2 agonist prodrug: Methyldopa
- NE storage depletion: Reserpine, Metyrosine
6
Q
How do beta blockers produce their antihypertensive effects?
A
- 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
6
Q
Are the beta blockers “interchangeable?” Why or why not?
A
- 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
6
Q
How does ganglionic signaling work?
A
- 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
8
Q
What are some AE’s associated with beta-blocker OD?
A
- 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
9
Q
What are some of the non-CV applications of beta-blockers?
A
- Essential tremor (NS issue -> rhythmic shaking)
- Thyrotoxicosis (hyperthyroidism)
- Anxiety
- 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)
9
Q
What are the attributes of Ephedrine?
A
- 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
10
Q
What are the attributes of Norepinephrine?
A
- 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
11
Q
What are the attributes of Dobutamine?
A
- 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)
13
Q
What are the clinical effects of the alpha-2 agonists?
A
- 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
14
Q
What are the 3 subtypes of Alpha-1 receptors? Why is this important?
A
- 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
15
Q
What is Reserpine toxicity?
A
- 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
17
Q
What are the indirect effects of Ach in the CV system?
A
- Opposition of B-1 increase in cardiac activity
- Inhibition of NE release from SYM NN -> presynaptic M2, M3 receptors, presynaptic M2 auto-receptors
17
Q
What receptors are inhibited by ganglionic blockers?
A
- Cholinergic nicotinic (Nn) receptors found in autonomic ganglia and in the adrenal medulla
- Distinct from the nicotinic (Nm) receptor found on the neuromuscular junction
19
Q
What is Metyrosine?
A
- 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
20
Q
What off-target pulmonary effects are possible with beta-blockers?
A
- 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
21
Q
Describe the dose-dependent effect of Dopamine. Why does this happen?
A
-
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
22
Q
What are the AE’s associated with the ganglionic blockers?
A
- 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
24
Q
Where do ganglionic blockers act?
A
- Primarily upon autonomic ganglia, thereby reducing HTN arising from SYM overactivity
25
Q
What are some of the various mechanisms by which beta blockers (which ones?) with extended actions can prevent vasoconstriction from reducing their clinical effectiveness?
A
- Nitric oxide production: Nebivolol
- Alpha-1 antagonism: Carvedilol, Labetalol
- Ca entry blockade: Carvedilol, Betaxolol
- Antioxidant activity: Carvedilol, Nebivolol
25
Q
For which types of patients are alpha agonists helpful? How are they administered, and what are their T(1/2)’s?
A
- 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
27
Q
Why are alpha blockers no longer used as extensively as they once were to tx HTN?
A
- 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
28
Q
What are the effects of SC Epinephrine on BP?
A
- 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) _
28
Q
Where is the nicotinic receptor located, and what is the result of ligand binding?
A
- Nicotinic, Nn
- Typical locations: postganglionic neurons, some presynaptic cholinergic terminals
- Result of ligand binding: opening of Na, K, channels, depolarization
29
Q
Describe the actions of the M3 receptors at the molecular level.
A
- 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 _
29
Q
Know these details about the direct effects of Ach on the CV system. For the visual learners.
A
Good job!
29
Q
How does Ach affect vascular tone?
A
- 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
34
Q
Describe the different effects of IV infusion of NE, E, and Isoproterenol in humans.
A
- 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
36
Q
Describe the molecular mediators of alpha-2 stimulation.
A
- 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
43
Q
Covered in other cards, but know this.
A
Good job!
Note: dose-related effects of Dopamine, which has reno-specific actions only at low doses
45
Q
What drug would you use to treat pre-eclampsia?
A
- Pre-eclampsia: HTN of pregnancy
- Methyldopa: extensive track record of safety for this indication (amongst various vasodilators, diuretics, and beta-blockers)
46
Q
How does E effect the rate of depolarization in the SA node?
A
Accelerates the rate of depolarization (Ach would decelerate it)
52
Q
How does Reserpine affect the CV stimulatory drugs?
A
- 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
61
Q
What does blockade of alpha-1 receptors do? How?
A
- Leads to hypotension
- By preventing NE-stimulated smooth muscle contraction in the vasculature (NO increase in IC Ca ions via DAG and IP)
73
Q
What is the role of alpha-2 receptors in the vasculature and CNS?
A
- 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
75
Q
Describe the molecular mediators of beta stimulation.
A
- 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
78
Q
What receptors are affected by each of the drugs in this chart? Describe what this chart means.
A
- 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
85
Q
How does Ach affect the SA node at the molecular level?
A
- 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
87
Q
What dose-related drug effects are observed with Epinephrine?
A
- 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
91
Q
What are the adverse effects of the alpha blockers?
A
- 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)
