Exam 2 Flashcards
1
Q
Non-selective beta antagonist general information
A
- For antagonists, we want groups at the meta and para positions that cannot hydrogen bond
- An isopropyl group is associated with β selectivity
- Aryloxypropanolamines are more potent β blockers than the corresponding arylethenanolamines, and most β blockers currently being used clinically are aryloxypropanolamines except sotalol
- Therapeutic indications: chronic glaucoma, symptoms of hyperthyroidism, performance anxiety, tremors (drug induced or familial palsy), prophylactic treatment of migraine, hypertension, ventricular tachycardic arrhythmias, post MI therapy, angina, and heart failure
- Contraindications: asthma (bronchoconstriction), COPD (bronchoconstriction), insulin-dependent diabetes (mask the symptoms of hypoglycemia and decreases glucagon release and aids in lowering blood sugar)
- Side effects: exercise intolerance, hyperkalemia, mast cell degranulation, bradycardic arrhythmias, malaise (sedation/fatigue/depression), and withdrawal syndrome (up to 2 weeks after discontinuation patients are at high risk for tachycardia and MI – can be avoided by tapering patients off)
- Patients feel bad when they first start this
2
Q
non-selective beta antagonist MoA for indications
A
- MoA for chronic glaucoma: decrease aqueous humor production by blocking β1 and β2 receptors in the eye; β2 receptors are found in the ciliary body
- MoA for symptoms of hyperthyroidism: blocks the symptoms mimicking SNS over-activity but has no effect on the disease itself
- MoA for performance anxiety: reduce nervousness through CNS effects and fine motor tremors
- MoA for prophylactic treatment of migraine: unknown mechanism; does not work acutely
- MoA for hypertension: decreases in cardiac output results in decreased systolic blood pressure; decrease in renin secretion results in vasodilation; other less understood factors may contribute to decrease in blood pressure with use of β receptor antagonists
- MoA for ventricular tachycardic arrhythmias, post MI therapy, angina, and heart failure: decreases O2 demand in the heart, decreases workload on cardiac muscle by blocking β1 receptors; β1 selective antagonists are preferred
3
Q
Dichloroisoproterenol
A
- Partial agonist
* isoproterenol with catechol hydroxyls replaced with chlorines
4
Q
Pronethalol
A
- Replaced the chlorine substituents on dichloroisoproterenol with a carbon bridge
- Full antagonist but caused tumors in mice
5
Q
Propranolol
A
- Added an oxymethylene bridge
- Moved the side chain from C2 to C1 on the naphthalene ring
- Full antagonist and first general β antagonist (precursor of all β antagonists)
- Used as a racemate, but the S enantiomer is the active one
- No tumors developed
- In the aryloxypropanolamine class
- Fairly lipophilic (isopropyl and naphalene ring) so you get more central effects than the other β antagonists due to crossing the blood-brain barrier. Central effects decrease nervousness and tremors. Most lipophilic β blocker available.
- Decreases heart rate and cardiac output
- Decreases systolic blood pressure, inhibits renin production, and decreases peripheral resistance with chronic use to treat hypertension
- Used topically to treat glaucoma by inhibiting aqueous humor production
- General uses: hypertension, angina, cardiac arrhythmias, and glaucoma
6
Q
Pindolol
A
- Contains an indole hence pINDOLol that may contribute to the partial agonist activity
- Weak partial agonist/partial antagonist
- Similar advantages to acebutolol
7
Q
Timolol
A
- Contains N-t-butyl and thiazide aryl group
- N-t-butyl specified β2 selectivity in agonists, but it doesn’t matter for antagonists
- β1 and β2 antagonist
- Used topically to treat glaucoma
- Be careful in asthmatics because it’s systemically absorbed
8
Q
Sotalol
A
- Phenylethanolamine class of antagonist
- Used as a racemate, but R is the active isomer (as in all phenylethanolamines)
- Methanesulfonamide is bulky and prevents the H bonding necessary for agonist activity
- Less lipophilic than propranolol, which results in fewer central (sedative) effects
- Used predominantly for cardioprotective effects
9
Q
Non-selective beta antagonist drugs we covered
A
dichloroisoproterenol, pronethalol, propranolol, pindolol, timolol, and sotalol
10
Q
Non-selective beta antagonists with alpha1 activity drugs we covered
A
labetolol and carvedilol
11
Q
labetolol
A
- Phenylethanolamine
- Used as a mixture of all 4 isomers
- R,R isomer is a β1 antagonist and a β2 partial agonist
- R,S isomer is inactive
- S,R and S,S isomers are α¬1 antagonists; S,R is ~5x more potent than S,S
- Bulky carboxamide side chain contributes to the β2 partial agonist action
- Overall β antagonist effects are greater than α1 antagonist effects by 1.5 fold
- Uptake I inhibitor, so it’s an indirect agonist
- Very effective antihypertensive agent
- Overall effect:
- blocking α1 receptors decreases peripheral resistance
- blocking β1 receptors decreases cardiac output and renin secretion
- partial β2 agonist increases vasodilation in skeletal muscle
12
Q
Carvedilol
A
- Aryloxypropanolamine
- Used as a racemate
- S enantiomer has β antagonist properties
- Both enantiomers contribute to the α1 antagonism action
- Overall β antagonist is greater than α1 antagonism by 10-100 fold
- The carbazole ring contributes additional antioxidant properties that protects the heart during heart failure
- Additional antioxidant and antiproliferative effects on vascular smooth muscle protect against atherosclerotic complications of hypertension
- Good antihypertensive agent
13
Q
Selective beta1 antagonists general information
A
- All are 4’ substituted (para) aryloxypropanolamines which lack a 3’ (meta) substituent; a small 2’ (ortho) group is possible. They also typically have an N-isopropyl group (no t-butyl)
- All are competitive
- Work best in patients with an overstimulated sympathetic response (stress or exercise)
- Indications: post MI therapy, ischemic heart disease, angina, prevention of tachycardic arrhythmias, compensatory cardiac hypertrophy, hypertension (not first line agents)
- Contraindications: insulin-dependent diabetes (may mask signs of hypoglycemia)
- Side effects: bradycardic arrhythmias, fatigue and exercise intolerance, and withdrawal syndrome (concern for 2 weeks after stopping therapy of tachycardia and MI – can reduce risk by tapering off)
14
Q
MoA for beta1 selective antagonist indications
A
- MoA for post MI therapy, ischedmic heart disease, and angina: decreases O2 demand in the heart, decreases workload on cardiac muscle by blocking β1 receptors
- MoA for prevention of ventricular tacycardic arrhythmias: block cardiac β1 receptors, decrease AV nodal conduction, and increase refractory period. Classified as Class II anti-arrhythmic agents.
- MoA for compensatory cardiac hypertrophy (seen with CHF): block the overgrowth of heart muscle (cardiac remodeling) due to excess SNS activity
- MoA for hypertension: decreases in cardiac output results in decreased systolic blood pressure; decrease in renin secretion results in vasodilation; other less understood factors may contribute to decrease in blood pressure with use of β receptor antagonists
15
Q
beta1 selective antagonist drugs we covered
A
metoprolol, atenolol, esmolol, and acebutolol
