PHAR 736 Midterm 2 (Antagonists) Flashcards
General purpose of B-blockers in CHF
CHF is cycle of sympathetic activation. Goal of pharmacological intervention is to inhibit progressive deterioration of cardiac function.
B1-selevtive antagonists (general)
All are competitive (antagonists, inverse agonists, or partial agonists)
Effects most pronounced under conditions of stress or exercise
B1-selective antagonists therapeutic indications
Post MI therapy, Ischemic heart disease, Angina (decrease O2 demand on heart, decrease workload on cardiac muscle)
Prevention of ventricular tachycardic arrhythmias (decrease heart rate, decrease AV nodal conduction, and increase refractory period; classified as Class 2 anti-arrhythmic agents)
Compensatory cardiac hypertrophy (block the overgrowth of the heart muscle - cardiac remodeling - due to excess SNS activity)
Hypertension (see hypertension notecard)
B1-selective antagonists and hypertension
NOT FIRST LINE
Decrease in cardiac output (b1 blockade) resulting in decreased systolic BP
Decrease in renin secretion (b1 blockade in kidney) resulting in vasodilation
Other less understood factors may contribute to decrease in BP with use of B receptor antagonists
Contraindications for B1-selective antagonists
Insulin-dependent diabetes:
>masks symptoms of hypoglycemia (increased HR, tremors) of vital importance to diabetics
- *hyperglycemia is the main problem in diabetics and is toxic in the long-term
- *hypoglycemia, a side effect of insulin treatment, can kill quickly
B1-selective or non-selective antagonists in those with asthma/COPD?
B1-Selective
blocking B2 adrenergic receptors would inhibit pulmonary relaxation
B1-selective antagonists side effects
Bradycardic arrhythmias (block of B1 in heart, particularly a problem for those with inadequate myocardial reserve)
Fatigue and exercise intolerance (blockade of B1 receptors in the heart)
Withdrawal syndrome
Describe B1-selective antagonists withdrawal syndrome
Rebound tachycardia upon abrupt withdrawal due to receptor supersensitization.
MI may ensure in susceptible patients.
Problematic for up to 2 weeks following cessation of therapy.
Discontinue by tapering the dose.
Metoprolol, Atenolol
Reduce basal activity of cardiac B1 receptors
Inverse agonists (awful super-sensitization)
Acebutolol
Weak B1 partial agonist (and partial antagonist) - used by itself has ~20% efficacy
Moderately decreases cardiac output and heart rate
Very little receptor supersensitivity, better withdrawal profile
Effects of blockade are more apparent under conditions of stress or exercise
Acebutolol is particularly useful in patients that can…
Tolerate changes in cardiac output
How does Acebutolol work in the presence of a full agonist?
Acts like an antagonist in presence of full agonist (e.g. NE)
Weak partial agonist as NE presence diminishes
Esmolol
Very short duration B1 blocker
Used to treat ventricular tachycardic arrythmias and in other situations where brief cardiac blockade is warranted
Pharmacogenomic considerations for B1 blockers
People with two Arg alleles more responsive in terms of cardiac stimulation to sympathomimetics than those with at least one Gly allele.
Bucindolol acts as an inverse agonist in patients with the Arg alleles. Acts as a neutral antagonist in patients with at least one Gly allele.
**Effective in HF only if patient has Arg alleles
B2-selective antagonists
NONE of therapeutic value currently marketed
Non-selective B adrenergic antagonists therapeutic indications
Chronic glaucoma (decrease aqueous humor production by blocking B1 and B2 in eye)
Hyperthyroidism symptoms (blocks symptoms mimicking SNS over-activity, no effect on the disease itself)
Performance anxiety (reduced nervousness through CNS effects and fine motor tremors)
Tremors (drug induced tremors, such as accompany lithium carbonate treatment; Familial palsy (NOT PARKINSONS)
Prophylactic Treatment of migraines (MOA unknown; does not work acutely)
Hypertension
Ventricular tachycardic arrhythmias, Post MI therapy, angina, HF (same as B1 selective blockers, which are generally preferred now for these indications)
B non-selective and hypertension
Decrease in cardiac output (B1 blockade) resulting in decreased systolic BP
Decrease in renin secretion (B1 blockade in kidney) resulting in vasodilation
Paradoxical effects:
>short term B2 blockade in normotensives will cause a little bit of vasoconstriction (expected)
>B2 blockade in hypertensives leads to decreased systolic AND diastolic BP (may have to do with adrenergic receptors playing a role in tissue remodeling)
B Non-selective antagonists contraindications
Asthma/COPD (blocks bronchodilation)
Insulin-dependent diabetes (should work by decreasing glucagon release and aiding in lowering blood sugar, BUT can mask symptoms of hypoglycemia)
B non-selective antagonists side effects
Exercise intolerance:
Reduced airflow, restriction of blood flow to skeletal muscles, reduced cardiac output
Hyperkalemia (generally only a problem for those prone to electrolyte imbalance, but can be a problem during exercise as skeletal muscle uptake of potassium is reduced)
Mast cell degranulation
Bradycardic arrhythmias (blockade of B1 receptors in heart, particularly in patients with inadequate myocardial reserve)
Malaise (sedation, fatigue, depression) - due to CNS effects
**depression may occur in susceptible population
Withdrawal syndrome
Describe B non-selective antagonists withdrawal syndrome
Rebound tachycardia upon abrupt withdrawal due to receptor supersensitization.
MI may ensue in susceptible patients.
Problematic for up to 2 weeks following cessation of therapy.
Discontinue by tapering the dose.
Propranolol
Precursor of all B-antagonists
CNS penetrating (decreases nervousness and tremors for performance anxiety, familial and drug-induced tremors)
MOST COMMON agent for performance anxiety.
Decreases HR and cardiac output; decreases systolic BP, inhibits renin production, and peripheral resistance with chronic use to treat hypertension
Used topically to treat glaucoma by inhibiting aqueous humor production
Sotalol
Little or no blood/brain barrier permeability (no sedation)
Used predominantly for cardioprotective effects
Pindolol
Partial agonist (partial antagonist in presence of full agonist)
Similar advantages to acebutolol
Timolol
Used topically to treat glaucoma
Be careful in asthmatics, systemically absorbed
A-1 selective antagonists indications
Benign prostatic hyperplasia (urinary retention and outflow difficulties; blocks a-1 mediated constriction of bladder sphincter and prostate capsule; longterm, may block hypertrophy of the prostate capsule)
Hypertension (blocks a-1 mediated vasoconstriction; decrease peripheral resistance)
Congestive heart failure (decreased peripheral resistance leads to less workload and increases cardiac output; patient MUST be able to tolerate an increase in heart rate)
Frostbite and Reynaud’s syndrome (increased blood flow to the extremities)
Off-label for nightmares in PTSD patients (Prazosin crosses BBB)
a-1 selective antagonist side effects
Tachycardia (reflex tachycardia due to decrease in MABP)
Syncope and orthostatic or postural hypotension (blocks ability to respond to gravitational effects on BP; dose at bedtime and remain supine for 2 hours to avoid syncope; remind patients to be careful after taking a hot shower or hot tub)
Nasal congestion
Sexual side effect in men (inhibition of ejaculation)
Prazosin, Terazosin, Alfuzosin
a-1 selective
Antihypertensives, decrease peripheral resistance
Treatments for benign prostatic hyperplasia
Unique quality of Prazosin
Crosses BBB
Unique quality of Alfuzosin
Less sexual side effects
Tamsulosin, Silodosin
a-1 selective (selective for a1A over a1B)
**70% of receptors in the prostate are a1A
treatment for benign prostatic hyperplasia
Not very effective anti-hypertensive, but dizziness and fainting are possible side effects
Nebivolol
B1 antagonist (10 fold more selective than metoprolol)
Metabolites promote endothelial NO-dependent vasorelaxation (metabolites may have partial B2 agonist properties or act at serotonin receptors on endothelium)
Summative effects include a reduction in HR and a reduction in BP
Labetolol
Mix of 4 stereoisomers, each with unique properties
>RR: B1 antagonist and B2 partial agonist
>SR,SS: a1 antagonist
>RS: no activity
Uptake 1 inhibitor (indirect agonist)
Overall effect:
>block a1 receptors, decrease peripheral resistance
>block B1 receptors, decrease cardiac output, renin secretion
>partial B2 agonist, increased vasodilation in skeletal muscle
Very effective antihypertensive agent
Carvedilol
Mix of 2 enantiomers
>S: B antagonist
>R and S: a1 antagonist
Good antihypertensive agent
Additional antioxidant and antiproliferative effects on vascular smooth muscle protect against atherosclerotic complications of hypertension
Non-selective a1/a2 antagonists
Used to manage pheochromocytoma in combination with propranolol
Considered “dirty” drugs - block serotonin receptors, histamine and muscarinic activity which makes for complex pharmacology
Non-selective a1/a2 antagonist side effects
Much more tachycardia than with a1 selective agents (block of a2 inhibition of baroreflex leads to greater baroreflex response; blockade of a2 inhibition of NE release onto heart leads to greater NE release)
Phentolamine
Competitive a-antagonist
Quick reversal of numbness following dental anesthetics (vasodilates to disperse the local anesthetic more quickly)
GI side effects
Phenoxybenzamine
Irreversible a-antagonist, alkylating agent
Long duration antagonist (effective longer than 24 hours)
Reversal requires synthesis of new receptors
How does a1 mediate urinary retention?
Controls constriction of prostate smooth muscle and constriction of bladder sphincter
