Indirect Adrenergic Agonists

Indirect Adrenergic Agonists

• These drugs increase norepinephrine in the synapse without directly acting on receptors.
• This leads to a sympathetic stimulant-like effect.

Mechanisms of Action

• Indirect agonists increase norepinephrine levels through different mechanisms.

Amphetamines

• Enhances norepinephrine and dopamine release.
• Blocks reuptake of norepinephrine and dopamine from adrenergic terminals, increasing norepinephrine levels in the synapse.
• Dopamine effects are therapeutically imporant, norepinephrine-related actions are the focus here.

Tyramine

• Found in fermented foods like cheese, red wine, and beer.
• Enhances norepinephrine release, similar to amphetamines.
• Normally metabolized by monoamine oxidase (MAO), preventing stimulant effects.

Tyramine Interaction with MAOIs

• When MAO is inhibited, tyramine promotes excessive norepinephrine release.
• This can lead to a hypertensive crisis, which is rare because MAOI are not common.
• Suspect tyramine interaction if a patient is depressed and treated with an MAOI.

Cocaine

• Blocks norepinephrine reuptake, increasing norepinephrine levels.
• Produces a powerful stimulant effect.
  • Alpha-1 activation causes vasoconstriction.
  • Beta-1 activation increases the heart rate.
• Effects come from blocking norepinephrine reuptake, and not through direct activation of Alpha-1 nor Beta-1 receptors.

Other Norepinephrine Reuptake Blockers

• Tricyclic Antidepressants (TCAs) and Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs) inhibit norepinephrine and serotonin reuptake, but are categorized separately.
• Depression and smoking cessation medication Bupropion, and ADHD medication Atomoxetine increase norepinephrine levels by blocking reuptake.

Summary of Mechanisms

• Amphetamines promote norepinephrine release from storage vesicles.
• Amphetamines, cocaine, TCAs, and SNRIs all block norepinephrine reuptake.

Mixed-Action Adrenergic Agonists

• Act both directly and indirectly
• Examples include ephedrine and pseudoephedrine.
• Pseudoephedrine enhances norepinephrine release and directly stimulates Alpha and Beta receptors.
• They promote norepinephrine release and directly bind Alpha and Beta receptors.
• Pseudoephedrine is now sold behind the counter due to its use in methamphetamine production.

Clinical Uses of Amphetamines

• Used for narcolepsy due to stimulant effects.
• Used for ADHD with mechanism through norepinephrine and dopamine.
• Used for weight reduction due to stimulant effects.
• Increased dopamine can lead to abuse potential.

Cocaine

• It's a local anesthetic that blocks sodium channels and is a norepinephrine and dopamine reuptake inhibitor.
• Its therapeutic use is restricted due to its abuse potential.

TCAs, SNRIs, and Bupropion

• Increase norepinephrine and serotonin levels and are used as antidepressants
• Depression may involve low levels of norepinephrine and/or serotonin.
• Antidepressants increase levels of one or both neurotransmitters.

Atomoxetine

• Used for ADHD.
• Selectively blocks norepinephrine reuptake, without affecting dopamine, therefore has no abuse potential.

Pseudoephedrine

• Decreases nasal secretions and is used as a decongestant.
• Its availability is limited because it's used to manufacture methamphetamine.
• Over-the-counter decongestants use phenylephrine, an alpha-1 agonist.
• Pseudoephedrine is more effective than phenylephrine at relieving nasal congestion.

Classification of Alpha Adrenergic Blockers

• Can be classified in a couple of ways
• Irreversible, long-acting alpha blocker: Phenoxybenzamine, non-selective (blocks Alpha-1 and Alpha-2).
• Reversible, shorter-acting alpha blocker: Phentolamine; also non-selective.
• Selective Alpha-1 blockers: end in “zosin”
  • Example include Prazosin, terazosin, doxazosin, tamsulosin.
• Selective Alpha-2 blocker: Mirtazapine
• Duration of Action of Alpha Blockers:
  • Phenoxybenzamine lasts ~48 hours (longest duration).
  • All others have shorter durations.
  • Phenoxybenzamine is also the only irreversible, non-competitive inhibitor.

Flowchart Summary of Alpha Blockers

• Non-selective blockers (Alpha-1 & Alpha-2)
  • Phenoxybenzamine (irreversible)
  • Phentolamine (reversible).
• Selective Alpha-1 blockers (all reversible)
  • Drugs ending in “zosin.”
• Selective Alpha-2 blocker
  • Mirtazapine

Clinical Uses of Alpha Blockers

• Not a large number of clinical applications, but some key conditions where alpha blockers are beneficial.
  • Pheochromocytoma
  • Benign Prostatic Hyperplasia (BPH)
  • Hypertension
  • Depression

Pheochromocytoma

• Rare condition, but commonly appears in test questions.
• Catecholamine-secreting tumor of adrenal chromaffin cells.
• Causes high blood pressure due to excessive epinephrine and norepinephrine in circulation.
• Phenoxybenzamine and phentolamine are used to control blood pressure before surgery or long-term if surgery isn’t possible.
• Primary benefit is Alpha-1 blockade, leading to vasodilation and blood pressure reduction.
• Phenoxybenzamine is preferred due to its long-lasting effect and irreversible inhibition.

Benign Prostatic Hyperplasia (BPH)

• Enlarged prostate compresses urethra, leading to urinary obstruction.
• Alpha-1 blockers (“zosins”) help relax smooth muscle in the prostate and bladder neck, improving urinary flow.
• Tamsulosin (an “osin,” but not a “zosin”) is more selective for Alpha-1A, found predominantly in the prostate and bladder neck.
• Zosins block all Alpha-1 receptors, while tamsulosin specifically blocks Alpha-1A, making it more prostate-specific.

Hypertension

• Blocking Alpha-1 receptors on blood vessels causes vasodilation, and lowers blood pressure.
• Zosins are useful for treating hypertension.
• Tamsulosin is selective for Alpha-1A, which is mainly in the prostate, so is not useful for hypertension.

Depression

• Mirtazapine is an Alpha-2 blocker and is used as an antidepressant.
  • Theory of depression: Low norepinephrine & serotonin levels.
  • Treatment goal: Increase norepinephrine and serotonin levels.
  • Mirtazapine mechanism:
    • Blocks Alpha-2 receptors, which are normally inhibitory autoreceptors.
    • Blocking Alpha-2 removes inhibition on norepinephrine and serotonin release, increasing their levels.
    • Essentially a “double negative” because blocking an inhibitory receptor makes it stimulatory.
    • This increase in neurotransmitter levels helps in depression.
• Key clinical uses of alpha blockers include:
  • Pheochromocytoma (Phenoxybenzamine preferred)
  • BPH (Zosins or Tamsulosin)
  • Hypertension (Zosins, NOT Tamsulosin)
  • Depression (Mirtazapine)

Orthostatic (Postural) Hypotension

• Alpha-one blockers are vasodilators and have exaggerated orthostatic hypotensive response, especially to the first dose.
• This is sometimes called the first-dose effect.
• First dose is usually small, the patient intakes at bedtime then titrated up over time.
• Dizziness upon standing indicates orthostatic postural hypotension.
• Alpha-one blockers are most likely drug class implicated with it.

Reflex Tachycardia

• Vasodilation can cause decrease in blood pressure, which can lead to a compensatory reflex tachycardia, where the heart rate rises to compensate.

Other Side Effects

• Dizziness related to orthostatic effect, maybe even a headache related to central vasodilation
• Low-risk sexual dysfunction can occur.
• Alpha blockers can cause sexual dysfunction because of their effects on smooth muscle is found in the vas deferens, seminal vesicles, prostate, and bladder neck.

Introduction to Beta Blockers

• Beta blockers have the common ending -olol
• Beta blockers have two major categories: non-specific blockers and beta-one specific blockers.

Classification of Beta Blockers

• A non-specific blocker blocks beta-one and beta-two
  • A drug like propranolol does this.
• A drug like atenolol or metoprolol is more beta-one selective.

The Alphabet Rule for Beta Blockers

• A through M drugs are beta-one selective.
  • Atenolol to metoprolol.
• N through Z olols are non-selective or non-specific drugs with N representing non-specific or non-selective.
  • Propranolol is a great prototype of that group.

Beta Blockers with Additional Properties

• Labetalol and carvedilol are beta blockers, and are also alpha-one blockers.

Nebivolol: A Unique Beta Blocker

• Nebivolol starts with the letter N.
• Nebivolol is beta-one specific and it’s also a nitric oxide releaser.
• It has some beta-three agonist properties, which, coupled to nitric oxide means vasodilation.

Beta Blockers with Intrinsic Sympathomimetic Activity (ISA)

• Some beta blockers have partial agonist activity.
• Referred to as intrinsic sympathomimetic activity, or ISA.
• Can mimic the sympathetic nervous system because they’re agonists.
  • Pindolol and acebutolol.
• Acebutolol can activate the receptor, however norepinephrine can also bind to the receptor.
• The partial agonist ends up working like an antagonist, which slows down the heart rate.
• They have weak agonist activity, and reduces the effects of full agonist activity.
• They have a lower risk of side effects, including hyperlipidemia.

Cardiovascular Effects of Beta Blockers

• Block of beta-one slows down the heart, and you get a negative inotropic effect and negative chronotropic effect.

Effect of Beta-Two Blockade

• Block of beta-two receptors prevents vasodilation, and promotes vasoconstriction.
• There’s a risk of vasospasm.

Effect on the Kidneys

• Blocking beta-one inhibits the release of renin from your JGA cells, subsequently inhibiting the renin-angiotensin-aldosterone system.

Respiratory Side Effects

• Risk of bronchoconstriction due to blocking beta-two receptors in the lungs.
• This is a problem for COPD and asthma patients.
• COPD/asthma patients need beta-one selective beta blockers if they have to use beta blockers.

Effect on Glucose

• Blocking beta-two receptors decreases glycogenolysis and lowers blood glucose.
  • Stimulating beta-two increases blood glucose.
  • Blocking beta-two gives you a risk of hypoglycemia.

Local Anesthetic Action of Beta Blockers

• A local anesthetic blocks nerve signals (usually by blocking sodium (Na⁺) channels in nerve cells).
• When this happens on the surface of the body, like skin or eyes, it causes numbness.
• Some beta blockers, block sodium channels just like local anesthetics do. This effect is called membrane-stabilizing action.
• Some beta blockers have a local anesthetic action.
• Shouldn’t be used topically in the eye because it will numb the cornea and lead to damage.

Hypertension

• Beta blockers decreases the heart rate
• Labetalol and carvedilol can cause vasodilation.

Ischemic Heart Disease and Angina

• Decreasing the heart rate leads to less oxygen demand, and less likely to get chest pain in that case for stable angina.

Cardiac Arrhythmias

• Decreasing the heart rate, blocking the beta ones on the heart, and it reduces your risk of arrhythmias.

Congestive Heart Failure (CHF)

• Decreasing the heart rate can decrease your risk of arrhythmias.
• Blocking beta ones on JGA cells means beta blockers decrease RAS, and it important in heart failure.

Glaucoma

• Use non-selective beta blockers.
• Blocking beta twos decreases the production of aqueous humor and lowers intraocular pressure.

Hyperthyroidism

• Use beta blockers.
• Propranolol inhibits the peripheral conversion of T4 to T3, which helps inhibit thyroid pathways.

Migraine Prevention

• Propranolol is a very popular treatment for migraine prevention.
• Blocking beta twos causes vasoconstriction.

Performance Anxiety (Stage Fright)

• Some beta blockers are lipophilic (fat-soluble), and can easily cross the blood-brain barrier.
• Beta blockers lower heart rate and blood pressure, which can have a sedating effect.
• Performance anxiety can be diminished.

Essential Tremor

• Propranolol is used in treating essential tremor, since propranolol is lipophilic, it can enter the CNS.
• Skeletal muscle cells have β2-adrenergic receptors:
  • When the sympathetic nervous system is activated (stress, anxiety, hyperthyroidism), epinephrine and norepinephrine bind to these β2 receptors.
  • This makes the muscle spindles and neuromuscular junctions more excitable, and the muscles start to twitch or tremble more, even without stronger ACh signals.

Bradycardia and Hypotension

• Beta-one blockers lower blood pressure because they decrease the heart rate, so expect bradycardia and hypotension.

CNS Depression

• Mostly caused by beta blockers, which can show up in a patient as fatigue, sleep disturbances, maybe even sexual dysfunction.
• Atenolol doesn't enter the CNS, so it's very unlikely to do that.

Effects on Lipids

• Most beta blockers increase triglycerides and LDLs.
• Partial agonist drugs don't tend to raise lipids, such as acebutolol was the beta-one selective and pindolol was the non selective drug.

Bronchoconstriction in Non-Selective Beta Blockers

• Don’t use a non-selective beta blocker in somebody with asthma or COPD.
• Use a beta-one selective drug if you have to use a beta blocker in asthma or COPD.

Reduced Blood Flow to Extremities

• At the extremities, if you're blocking a beta-two on a blood vessel, the beta-two is more likely to cause the vessel to constricted.

Upregulation of Beta-One Receptors and Tapering Off

• Chronic use of a beta blocker causes upregulation of the beta-one receptors in the heart.
• And if you abruptly discontinue, you can get a pretty significant effect—angina, hypertension, or arrhythmia.
• If you need to discontinue a beta blocker, always taper off.

Beta Blocker Overdose Antidote: Glucagon

• Glucagon is an antidote and is beta blocker overdose.
• Glucagon receptors are found on the heart, and they are Gs coupled.
• Beta blockers decreases cyclic AMP, but Glucagon, throguh glucagon receptors, increases these.
• An example of Physiologic antagonism.