Sympathomimetics and Sympatholytics

Learning Outcomes

• The lecture will cover indirect sympathomimetics, ephedrine, and pseudoephedrine
• The material will discuss sympatholytic drug classifications and the uses and adverse effects of alpha-receptor blockers
• Centrally-acting sympatholytic drugs mechanism of action, uses, and adverse effects will be discussed

Indirect Sympathomimetics

• These increase norepinephrine release
• Amphetamine and methamphetamine are examples, and are schedule II controlled substances
• Dependence (addiction) can occur
• This class can be administered orally
• They have powerful CNS stimulant actions alongside Peripheral sympathomimetic effects
• The effects include wakefulness, decreased fatigue, mood elevation, increased self-confidence, increased motor and speech activities, and improved physical performance
• Increased blood pressure and cardiac arrhythmias can occur with large doses

Methylphenidate

• Methylphenidate is a derivative of amphetamine
• It has mild CNS stimulant effects, more mental than motor
• Large doses may cause generalized CNS stimulation and lead to convulsions
• It treats Attention Deficit Hyperactivity Disorder (ADHD) and Narcolepsy
• This is contraindicated in patients with glaucoma

Modafinil

• Modafinil is a CNS stimulant, similar to methylphenidate, but with a different chemical structure
• It is used for narcolepsy and other sleep disorders

MAO Inhibitors: Selegiline

• Selegiline is a selective and irreversible MAO-B inhibitor
• MAO-B is present in the brain and platelets
• It decreases intra-cerebral degradation of dopamine
• This is used for the treatment of parkinsonism disease, as an adjuvant to (given with) levodopa
• This prolongs levodopa action

COMT Inhibitors: Entacapone

• Entacapone is used as an adjuvant to levodopa-carbidopa for advanced parkinsonism disease
• Entacapone prolongs the half-life of levodopa and allows a larger fraction of the dose to cross the brain

Tri-Cyclic Antidepressants (TCA)

• Includes many drugs
• Uses: Depression, other psychiatric diseases (phobias and panic attacks), anxiety disorders, and obsessive-compulsive neurosis
• Also used for neuropathic pain, migraines, ADHD, and nocturnal enuresis

Classification of Sympatholytics

• Alpha blockers: Nonselective (block α1, α2) such as Phentolamine and Phenoxybenzamine. Selective (block α1) such as Prazosin and Doxazocin
• Beta blockers: Non-selective (block β 1, 2). Selective (block β 1) and Beta blockers with added actions
• Centrally acting: Alpha-methyldopa and Clonidine

Alpha Blockers: Non-Selective

• Phentolamine is a reversible alpha-receptor blocker
• Phenoxybenzamine is an irreversible alpha-receptor blocker with long-lasting effects (15-50 hours)
• Blockade of alpha-receptors can lead to orthostatic hypotension and reflex tachycardia

Phentolamine and Phenoxybenzamine: Therapeutic Uses

• Management of Pheochromocytoma: a rare benign tumor of adrenal medullary cells. It leads to excess Catecholamines (CA) secretion responsible for intermittent or persistent hypertension and other symptoms. Estimation of urinary CA metabolites is diagnostic
• Phenoxybenzamine is given orally for 1-2 weeks preoperatively and i.v.i during surgery
• Can be used as definitive therapy for inoperable malignant pheochromocytoma; prazosin can be an alternative
• Combine with beta-blockers to block all adrenergic receptors

Selective α1-Blockers

• Prazosin is the prototype drug
• Doxazosin has a longer duration of action
• These decrease peripheral resistance and lower blood pressure by blocking alpha-1 receptors
• They cause direct vasodilation of both arteries and veins
• Trigger reflex tachycardia, but not to the same degree as non-selective blockers, and improve plasma lipid profile and decrease LDL and TGs

Alpha-1 Blockers: Adverse Effects

• First-dose postural hypotension and syncope occurs
• Risk is minimized by decreasing the initial dose, taking the dose at bedtime, and slowly increasing the dose
• Other adverse effects include dizziness, headache, drowsiness, salt and water retention, and sexual dysfunction

Alpha-1 Blockers: Therapeutic Uses

• Used for mild to moderate hypertension, but not as first line drugs for congestive heart failure
• These decrease both afterload and preload of the heart
• Used for Benign Prostatic Hyperplasia (BPH)
• Block alpha-1 receptors in the bladder neck and prostate to decrease resistance to urine flow
• Tamsulosin: has some selectivity for alpha-receptors in the prostate (α1A and a1D). Effective in treating BPH with little effect on blood pressure
• An alpha-blocker is used in combination with Finasteride to inhibit the conversion of testosterone to dihydrotestosterone and reduce prostate volume

Alpha-Methyldopa

• Centrally acting sympatholytic and an alpha-2 receptor agonist
• Mechanism of action: analog of l-DOPA
• Competes with l-DOPA for DOPA-decarboxylase enzyme
• Converted by this enzyme to alpha-methyl-norepinephrine to stimulate central α2 receptors
• Decreases central sympathetic outflow, leading to reduced total peripheral resistance and decreased systemic blood pressure
• Drug of choice for hypertension in pregnancy
• Adverse effects: Sedation, depression (occasionally), positive Coombs test (less than 5% of patients develop hemolytic anemia), dry mouth, hyperprolactinemia (can cause gynecomastia and galactorrhea), and bradycardia with overdose

Clonidine

• Clonidine is an alpha2-adrenergic agonist
• It activates central alpha2 receptors in the brainstem, leading to decreased central sympathetic outflow, peripheral resistance, heart rate, and blood pressure
• It activates presynaptic alpha2 receptors in sympathetic nerves, leading to decreased norepinephrine release
• It is well absorbed after oral administration
• It is used for the treatment of hypertension
• It is used to treat and prepare addicted subjects for withdrawal from narcotics, alcohol, and tobacco by decreasing adverse sympathetic nervous activity
• Also used for ADHD
• Its adverse effects: dose dependent: dry mouth, sedation, marked bradycardia (in some patients)
• It can cause withdrawal reactions (rebound hypertension) upon sudden cessation of long-term therapy

Clonidine Derivatives

• Two derivatives, apraclonidine and brimonidine, are applied topically to the eye to lower intraocular pressure (IOP) in glaucoma
• Apraclonidine is a polar clonidine congener
• It decreases aqueous production by primary α2 action in the ciliary body
• Used to reduce increased pressure in the eye during and after certain types of laser eye surgery