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1

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 

2

Which beta blockers have B-1 selective activity?

- 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

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 

2

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 

3

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

4

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

4

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

5

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

5

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 

5

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 

5

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

6

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

6

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

6

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

8

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 

9

What are some of the non-CV applications of beta-blockers?

- 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

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 

10

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

11

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) 

13

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 

14

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 

15

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 

17

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 

17

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

19

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 

20

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 

21

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 

22

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 

24

Where do ganglionic blockers act?

- Primarily upon autonomic ganglia, thereby reducing HTN arising from SYM overactivity 

25

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