531 Lec 28

Phenoxybenzamine

Nonselective alpha adrenergic antagonists

 the mechanism by which phenoxybenzamine inhibits the receptor, what intermediate it forms and what bonds are relevant to its action.

• The chlorine leaves and an epoxide forms, this intermediate is called an Aziridinium ion electrophile and it is positively charged

•A nucleophilic residue on the alpha receptor will attack the epoxide causing it to open and forming a covalent bond

why is phenoxybenzamine toxic

Phenoxybenzamine is toxic because it is non selective 

what phenoxybenzamine is used for clinically.

Clinically, phenoxybenzamine is used to treat adrenal medulla tumors (pheochromocytoma) → counteracts release of large amounts of NE epinephrine that lead to hypertension

Quinazolines

Antihypertensive agents 

• Prazosin (Minipres)

• Terazosin (Hytrin)

• Doxazosi (Cardura)

rank the quinazoline class of selective alpha-1 adrenergic antagonists based on half life

Prazosi (Minipres), Terazosin (Hytrin), Doxazosi (Cardura)

What structural changes were made to quinazoline class of selective alpha-1 adrenergic antagonists to alter half life?

Why is half life relevant to the patient treatment plan?

Half life of the drug affects how frequently the patients will have to take the drug. Having a short half life means patients will have to take the drug more frequently which can make medication adherence difficult.

first line treatments for BPH and know why they are not used for hypertension.

• BPH: Benign prostatic hyperplasia (Enlarged prostate)

→Alfuzosin (Uroxatral)

→Silodosin (Rapaflo) - more selective 

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•Treats BPH due to blocking the alpha A1 receptors in the prostate gland 

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•Since they are more selective for a subtype of alpha adrenergic receptors (A1) they are useless for treating hypertension

What is the most selective drug for treating BPH that we discussed?

Silodosin (Rapaflo)

Alpha Blockers 

Prevents NE from tightening the muscles in the walls of smaller arteries and veins→ Causes vasodilation which improves blood flow to the heart and lowers blood pressure

Beta Blockers

Works by blocking effects of epinephrine on heart 

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Blocking epinephrine causes slower and softer heart beat which reduces blood pressure 

Understand why beta blockers may be contraindicated in patients with COPD or uncontrolled Asthma

• B1 receptors are found in the heart and kidneys

• B2 receptors are found in the lungs, GI, liver, uterus, vascular and skeletal muscle (antagonists can cause bronchoconstriction)

Where are beta 1 receptors predominately found? Where are beta 2 receptors predominately Found?

•Heart and Kidneys

•Lungs, GI, liver, uterus, vascular and skeletal muscle

Why is hypoglycemia a concern with certain beta blockers (which ones?) In what patient

population would you be most concerned with this side effect and why?

•Hypoglycemia: low blood sugar

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•Stimulating B2 receptors normally stimulate hepatic glycogen breakdown (glycogenolysis) and pancreatic release glucagon which work together to increase plasma glucose

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Blocking B2 lowers plasma glucose 

Understand the role beta blockers have on renin release and the eventual outcome on hypertension.

beta blockers decrease renin which reduces angiotensin production which means decrease in blood pressure

What are the main differences/differentiating characteristics among the three generations of beta blockers?

1st Generation: nonselective (reactive at B1 and B2 receptors)

→Propanolol, Sotalol

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2nd Generation: B1 selective or cardioselective- low dose

→ Atenolol, metoprolol, bisoprolol

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3rd Generation: additional vasodilating effects and neutral on plasma glucose/lipids 

→ Nebivolol, carvedilol

what is meant by “cardioselective” beta blockers and under what circumstances they are not cardioselective?

Cardioselective agents have a greater affinity for β1-adrenergic receptors located in the heart. However, at high doses cardioselectivity is lost.

What is the general pharmacophoric model of the beta blocker drug class?

Aromatic group

Oxygen linker

Propanolamine

Bulky alkyl group

Compared to all other beta blockers, propranolol has a characteristic than permits it to cross the blood-brain barrier. What is this physiochemical parameter and how does this feature extend the number of indications for which propranolol can be used?

Highly lipophilic → Anti anxiety

 first generation beta blocker

Bunolol

Carteolol

Metipranolol

Nadalol

Pindolol

Penbutolol

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Used for hypertension, angina, cardiac arrythmias, migraine, stage fright, glaucoma, congestive heart failure

second generation beta blocker

Acebutolol

Atenolol

Betaxolol

Esmolol

Metoprolol

Bisopropol

Name two mechanisms by which first generation beta blockers work as antihypertensive agents

Decrease cardiac output and heart rate

Reduce renin release from kidneys

what general structural modification imakes B1 selectivity?

4 substitution

Metoprolol

Exception to 2nd gen- not B1 selective

Use: hypertension, angina, aniarrythmic, congestive heart failure

Signif first pass effect

Bisoprolol

Use: hypertension, angina, aniarrythmic, congestive heart failure

Signif first pass effect

Longer side chain

what functional group is present in Esmolol that imparts a very short half-life and how this is different in Atenolol.

Ester- rapid hydrolysis by esterases in red blood cells

Half life: 9 min

What are key characteristics of third generation beta blockers that distinguishes them from other generations?

Additional vasodilating effects and are most effective in decrease of blood pressure

Nebivolol

→Nitric Oxide potentiating vasodilatory effects: induces endothelium dependent arterial realxation in a dose dependent manner, by stimulation of the release of endothelial nitroc oxide

→ Cardioselective

→Half life: 10 hours

→ Increases Stroke volume without compromising cardiac output

→Less bronchoconstriction

→Reduced side effects such as fatigue, depression, impotence, bradycardia

\-3rd gen beta blocker

→Neutral on plasma glucose or lipids- may be favored in diabetic patients

Carvediol

→ 3rd gen beta blocker

→Nonselective beta blocker and alpha 1 blocker

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Used:

Mild to severe congestive heart failure

Left ventricular dysfunction following heart attack

High blood pressure

 adverse effects of beta blockade

1)Bronchoconstriction (contraindicated in asthma patients)

2)Arrhythmia if stopped suddenly

3)Cold extremities

4)Disturbed metabolism (care should be taken in diabetic patients)

5)Drug interactions/metabolism can reduce beta blocker effect or increase its concentration

6)Decrease nocturnal melatonin release→may account for sleep disturbances in some cases

other drugs available to modify blood pressure that do not involve blockade of beta receptors

1)Drugs interfering with NE/EPi biosynthesis

2)Drugs affecting NE release, reuptake, and metabolism