Indirect Sympathomimetics

Indirect Sympathomimetics

• Increase norepinephrine release.
• Amphetamine and its derivatives are examples.
• Amphetamines & Methamphetamine are synthetic, controlled substances, and Schedule II drugs that can produce dependence or addiction.
• These can be administered orally.
• In addition to peripheral sympathomimetic effects, they have powerful CNS stimulant actions.
• The main results include wakefulness, decreased fatigue, mood elevation, increased self-confidence, improved motor and speech activities, and improved physical performance.
• Increased blood pressure and cardiac arrhythmias can occur with large doses

Methylphenidate

• It is a derivative of amphetamine.
• This has mild CNS stimulant effects, mainly on mental activities.
• Large doses can lead to generalized CNS stimulation and convulsions.
• It is used in the treatment of Attention Deficit Hyperactivity Disorder (ADHD) & Narcolepsy.
• It is contraindicated in patients with glaucoma.

Modafinil

• It is a CNS stimulant similar to methylphenidate but has a different chemical structure.
• This is used for narcolepsy and some other sleep disorders.

MAO Inhibitors: Selegiline

• It is a selective & irreversible MAO-B inhibitor.
• MAO-B is present in the brain and platelets. reduces intra-cerebral degradation of dopamine.
• It is used for the treatment of parkinsonism disease.
• It is an adjuvant to levodopa, prolonging levodopa action.

COMT Inhibitors: Entacapone

• It 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 to the brain.

Uptake Inhibitor

• Cocaine and Tricyclic Antidepressants (TCA) are examples.

Tri-Cyclic Antidepressants (TCA)

• Include many drugs.
• Uses: Depression, other psychiatric diseases like phobias & panic attacks, anxiety disorders, obsessive-compulsive neurosis.
• Other uses include neuropathic pain, migraine, ADHD, and nocturnal enuresis.

Ephedrine

• Has a mixed action.
• It releases norepinephrine from nerve endings.
• It directly stimulates a & β receptors weakly and produces prolonged CNS stimulation.
• Its use is restricted to hypotension in the setting of anesthesia.

Pseudoephedrine

• It is one of the isomers of ephedrine.
• Is present in many nasal decongestants and common cold mixtures.

Side effects from Ephedrine & Pseudoephedrine

• Tolerance

Classification of Sympatholytics

• Alpha blockers:
  • Nonselective (block a1, a2): Phentolamine, Phenoxybenzamine
  • Selective (block a1): Prazosin, Doxazosin
• Beta blockers:
  • Non-selective (block β1, 2)
  • Selective (block β1)
  • Beta blockers with added actions
• Centrally acting: Alpha-methyldopa, Clonidine

Alpha blockers: Non-selective

• Phentolamine causes a reversible block of the a receptors.
• Phenoxybenzamine causes an irreversible block of a receptors that is long-lasting.
• Blockade leads to orthostatic hypotension and reflex tachycardia.

Therapeutic uses for Alpha Blockers Non Selective

• Management of Pheochromocytoma, a rare tumor of adrenal medullary cells.
• Excess Catecholamines (CA) are secreted, causing intermittent or persistent hypertension & other symptoms.
• It is used for Estimation of urinary CA metabolites.
• Phenoxybenzamine is given orally for 1-2 weeks preoperatively and IV during surgery.
• It can be definitive therapy for inoperable malignant pheochromocytoma, with Prazosin as an alternative.
• Combine with beta blockers to block adrenergic receptors.

Selective a1-blockers

• Prazosin is the prototype drug
• Doxazosin has a longer duration of action.
• They decrease peripheral resistance & lower BP by:
  • Blocking a1-receptors.
  • Direct VD of both arteries & veins.
• They can trigger reflex tachycardia but to a lesser degree than non-selective blockers.
• Improve plasma lipid profile and decrease LDL and TGs.

Adverse effects of Selective Alpha Blockers

• First-dose postural hypotension & syncope can occur, especially with rapid increases in dose.
• The risk is minimized by decreasing the initial dose, taking it at bedtime, and slowly increasing the dose.
• Other adverse effects: Dizziness, headache & drowsiness, salt & water retention, and sexual dysfunction.

Therapeutic uses for Selective Alpha Blockers

• Mild to moderate hypertension.
• Benign prostatic hyperplasia (BPH).
  • They can block a1 receptors in the bladder neck and prostate, decreasing resistance to urine flow.
• Tamsulosin has some selectivity for a receptors in the prostate (α1A & a1D).
• It is effective with little effect on blood pressure.
• Alpha blockers can be used in combination with Finasteride
  • Finasteride inhibits conversion of testosterone to dihydrotestosterone, which can reduce prostate volume.

Centrally acting sympatho-lytics

• Alpha-methyldopa:
  • Mechanism of action: It is an analog of L-DOPA and competes with it for DOPA-decarboxylase enzyme.
  • It is converted by this enzyme to a-methyl-norepinephrine, which stimulates central a2 receptors.
  • This decreases central sympathetic outflow, leading to reduced total peripheral resistance and decreased systemic blood pressure.
  • It is a drug of choice for hypertension in pregnancy.
  • Adverse effects: Sedation (transient), Depression (occasionally), a positive Coombs test (5% patients develop a hemolytic anemia), dry mouth, hyperprolactinemia, and bradycardia with overdose.

Clonidine

• It works by activating central a2 receptors in the brainstem, leading to decreased central sympathetic outflow, peripheral resistance, and heart rate, resulting in lower blood pressure.
• It activates presynaptic a2 receptors in sympathetic nerves, leading to decreased norepinephrine release.
• Well absorbed after oral administration.
• Therapeutic uses: Treatment of hypertension, treating and preparing addicted subjects for withdrawal from narcotics, alcohol, and tobacco, and ADHD.
• Adverse Effects: Dose-dependent and include dry mouth, sedation, and marked bradycardia.
  • Withdrawal reactions, like rebound hypertension, can happen with sudden stops after of long-term therapy.

Two derivatives of Clonidine

• Apraclonidine and brimonidine are applied topically to the eye to lower intraocular pressure (IOP) in glaucoma.
• It decreases aqueous production by primary a2 action in the ciliary body.
• Used to reduce increased pressure in the eye during/after certain types of laser eye surgery.