Indirect Sympathomimetics: Amphetamine Derivatives

Indirect Sympathomimetics

• Increase norepinephrine release
• Includes Amphetamine and its derivatives

Amphetamines and Methamphetamine

• Synthetic and controlled substances classified under Schedule II
• Can cause dependence/addiction
• Can be administered orally
• They have CNS stimulant actions in addition to peripheral sympathomimetic effects

Results From Use

• Wakefulness increases with fatigue decrease
• Mood elevation along with self-confidence
• Motor and speech activities, and physical performance get improved
• Increased blood pressure and cardiac arrhythmias can occur with large doses

Methylphenidate

• A derivative of amphetamine
• Has mild CNS stimulant effects, primarily on mental activities
• Large doses can lead to generalized CNS stimulation and may lead to convulsions
• Used in the treatment of ADHD and narcolepsy
• Contraindicated in patients with glaucoma

Modafinil

• CNS stimulant similar to Methylphenidate, but has a different chemical structure
• Used for narcolepsy and some other sleep disorders

MAO Inhibitors: Selegiline

• Selective and irreversible MAO-B inhibitor, present in the brain and platelets
• Decrease intra-cerebral degradation of dopamine
• Used for the treatment of parkinsonism disease, as an adjuvant given with levodopa

COMT Inhibitors: Entacapone

• Used as adjuvants to levodopa-carbidopa for advanced parkinsonism disease
• Entacapone prolongs the half-life of levodopa, this allows a larger fraction of the dose to cross to the brain

Tri-Cyclic Antidepressants (TCA)

• Includes many drugs
• Used for depression and other psychiatric diseases like phobias and panic attacks
• Can assist with anxiety disorders and obsessive compulsive neurosis
• Can be used for neuropathic pain, migraine, ADHD, and nocturnal enuresis

Classification of Sympatholytics

• Alpha blockers, beta blockers, and centrally acting drugs

Non-Selective Alpha Blockers

• Block both a1 and a2 receptors
• Includes Phentolamine and Phenoxybenzamine

Selective Alpha Blockers

• Blocks a1 receptors
• Includes Prazosin and Doxazocin

Non-Selective Beta Blockers

• Blocks B1 and B2 receptors

Selective Beta Blockers

• Blocks B1 receptors only

Centrally Acting Sympatholytics

• Includes Alpha-methyldopa and Clonidine

Phentolamine

• A reversible alpha receptor blocker

Phenoxybenzamine

• An irreversible alpha receptor blocker with long-lasting effects, from 15 to 50 hours

Phentolamine and Phenoxybenzamine

• Blockade of alpha receptors with these drugs can lead to orthostatic hypotension and reflex tachycardia

Therapeutic Uses: Management of Pheochromocytoma

• It is a rare tumor of adrenal medullary cells and is mostly begnin
• Excess catecholamines are secreted, this can cause intermittent or persistent hypertension and other symptoms
• Estimation of urinary catecholamines metabolites is diagnostic

Phenoxybenzamine Use

• Given orally typically for one to two weeks preoperatively and intravenously during surgery

Treatment for inoperable and malignant pheochromocytoma

• Can be treated with phenoxybenzamine as a definitive therapy
• Prazosin is an alternative

Alpha and Beta Blockers

• It should be combined with beta blockers to block all adrenergic receptors

Selective α1-blockers

• Including Prazosin which is a prototype drug, and Doxazosin, which has a longer duration of action
• They decrease peripheral resistance and lower blood pressure through α1-receptor blockade and direct vasodilation of arteries and veins

Selective α1-blockers Side-Effects

• Trigger reflex tachycardia, but not to the same degree as non-selective
• Can improve plasma lipid profiles and decrease LDL and TGs

Adverse effects of α1-blockers

• First-dose postural hypotension and syncope can occur and also occur with a rapid increase in dose
• The risk of this is minimized by decreasing the initial dose, taking it at bedtime, and increasing the dose slowly
• Can cause Dizziness, headache, drowsiness, salt and water retention and Sexual dysfunction

Therapeutic Uses: Mild to Moderate Hypertension

• Congestive heart failure is not included in first line drugs
• Decrease afterload and preload of the heart

Benign Prostatic Hyperplasia (BPH)

• Can be treated by blocking α1 in the bladder neck and prostate to decrease the resistance to urine flow
• Tamsulosin has some selectivity for α receptors in the prostate (α1A & α1D)

Treatment for Benign Prostatic Hyperplasia (BPH)

• Tamsulosin: some selectivity for α receptor in prostate (α1A & α1D)
• Tamsulosin is effective in the treatment of BPH with very little effect on blood pressure
• Alpha blockers can be used in combination with Finasteride, which reduces testosterone to dihydrotestosterone to reduce prostate volume

Alpha-Methyldopa

• An α2 receptor agonist and centrally acting sympatholytic
• Alpha-methyldopa is an analog of l-DOPA and competes with it for DOPA-decarboxylase enzyme

Action

• Converted by this enzyme to α-methyl-norepinephrine
• This stimulates central α2 receptors, decreasing central sympathetic outflow
• Leads to reduced total peripheral resistance and decreased systemic blood pressure

Therapeutic Uses: Alpha-Methyldopa

• Drug of choice for those with hypertension during pregnancy

Alpha-Methyldopa Adverse effects

• Sedation and/or transient depression may occur
• May cause a positive Coombs test which is less than 5% of patients develop a hemolytic anemia
• Can cause dry mouth, hyperprolactinemia, gynecomastia, galactorrhea, and Bradycardia with overdose

Clonidine

• Alpha-Methyldopa is a centrally acting sympatholytic and α2 adrenergic agonist
• It activates central α2 receptors in the brainstem --> central sympathetic outflow decreases and blood pressure falls due to a drop in peripheral resistance and heart rate
• It activates presynaptic α2 receptors in sympathetic nerves, decreasing norepinephrine release
• It is well absorbed after oral administration

Clonidine Uses

• Treatment of hypertension
• Treats and prepares addicted subjects for withdrawal from narcotics, alcohol/tobacco {decrease some of the adverse sympathetic nervous activity associated with withdrawal}
• Attention deficit hyperactivity disorder (ADHD)

Clonidine Adverse effects

• Dose-dependent effects
• Dry Mouth
• Sedation
• Marked bradycardia, some patients
• Withdrawal reactions can take place, rebound hypertension --> Withdrawal reactions (rebound hypertension) follows a stop of long-term therapy with clonidine

Clonidine Derivatives

• Two derivatives include apraclonidine & brimonidine are applied topically to decrease the intraocular pressure in glaucoma

Apraclonidine

• Clonidine derivative in polar form
• Decreases aqueous production of primary α2 action in the ciliary body
• Used to reduce increased pressure in the eye during and after certain types of laser eye surgery