• Information
  1. Metabolism of Dopamine
  2. Normal Functions
  3. Central Nervous System Dopamine Receptors
  4. Peripheral Dopamine Receptors
  5. Dopamine
  6. Dopamine Precursors and CNS Receptor Agonists
  7. Fenoldopam
  8. Dopamine Antagonists

A. Metabolism of Dopamine

1. Dopamine is one of the three major natural catecholamines
2. Synthesis of catecholamines from tyrosine:
   1. Tyrosine --> dihydroxyphenylalanine (DOPA) by tyrosine hydroxylase
   2. DOPA --> dopamine by L-amino acid decarboxylase (pyridoxyl phosphate)
   3. Dopamine --> norepinephrine by dopamine ß-hydroxylase (ascorbate)
   4. Norepinephrine --> epinephrine by phenethanolamine N-methyltransferase (SAM)
   5. S-adenosylmethionine (SAM), ascorbate (Vitamin C), pyridoxyl (Vit B6) are cofactors
   6. Hydroxylation of tyrosine is rate limiting step in most cases
3. Degradation my monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT)
4. Specific transporter proteins promote dopamine reuptake

B. Normal Functions

1. Dopamine makes up >50% of central nervous system (CNS) catecholamines
2. Major CNS Locations of Dopamine
   1. Basal ganglia - especially caudate nucleus
   2. Nucleus accumbens (D3 receptor is selectively expressed here)
   3. Olfactory tubercle
   4. Central nucleus of amygdala
   5. Median eminance of hypothalamus
   6. Substantia Nigra
3. Renal Vasculature
   1. DA1 receptors play a role in renal arteriolar vasodilation
   2. With normal renal function, dopamine does cause increased renal blood flow
   3. In intensive care patients, dopamine has no clinical benefit on renal function [3]
4. Cardiac Effects
   1. Moderate pharmacologic doses cause increased inotropy and chronotropy (heart rate)
   2. Due to binding of dopamine to cardiac ß1-adrenergic receptors
5. Blood Vessels
   1. High doses of dopamine in blood cause vasocontriction
   2. Due to binding of dopamine to alpha1-adrenergic receptors
6. Dopamine also plays a role in nausea centers in brain and possibly in the gut

C. Central Nervous System Dopamine Receptors

1. Five receptors in CNS are all G proteins
   1. D1 and D5 are related; D2, D3, D4 are related
   2. D1 has three receptor subtypes (D1A, D1B, D1C)
   3. D2 has two isoforms with different cytoplasmic loops
2. Effects on cyclic AMP (cAMP)
   1. D1 and D5 increase cAMP
   2. D2 decreases cAMP, increases K+ and decreases Ca2+ conductance
   3. D3 - mixed effects depending on system studied
   4. D4 - decreases cAMP
3. Dopamine D2 receptor downregulation in obesity may play a role in reward/motivation [5]
4. D4 receptor knockout mice are supersensitive to cocaine, alcohol and amphetamines
5. Majority of D receptors are polymorphic in humans (unclear significance)
6. Characteristics of Dopamine Receptors

   Characteristics of Receptors	D1	D2	D3	D4	D5
   Link to Adenylate Cyclase	up	down	down	down	up
   Brain Locations	CS & L*		L
   Pituitary	--	++	--
   *CS=corpus Striatum; L=Limbic

D. Peripheral Dopamine Receptors [7]

1. Two receptors: DA1 and DA2
2. DA1 Receptors
   1. Renal arterial vasodilation and natriuresis
   2. Splanchnic bed arterial vasodilation
   3. Other arterial beds, lesser density (cerebral, cardiac)
   4. Increases cAMP; acts also be cAMP independent mechanisms
3. DA2 Receptors
   1. Similar to D2-like CNS receptors
   2. Mainly presynaptic adrenergic nerve terminals and sympathetic ganglia
   3. Pituitary gland prolactin releasing cells
   4. Some activity on natriuresis in kidney

E. Dopamine (Intropin®)

1. Acts on D1, ß1, and alpha-receptors depending on the level of drug administered
2. Low dose (<5µg/kg/minute) is called "Renal Range" Dopamine
   1. This level increases renal and mesenteric blood flow in patients with normal renal function
   2. Renal range dopamine has no beneficial effect in patients in intensive care units (ICU) [3,4]
   3. Renal range dopamine will NOT prevent renal deterioration in ICU patients [8]
3. Moderate "cardiac" doses are inotropic, with increased heart rate and cardiac output
4. Improving cardiac output is most likely responsible for increased urine production in ICU patients with oliguria and acute renal failure
5. At high doses (>10-15µg/kg/min), alpha-adrenergic vasoconstrictor effect predominates
6. Excellent first line agent for hypotension from any cause in ICU setting
7. First or second line agent for severe refractory CHF in ICU setting

F. Dopamine Precursors and CNS Receptor Agonists [1]

1. L-DOPA
   1. Mainstay of therapy in Parkinson's Disease (PD)
   2. Precursor to Dopamine (see above)
   3. Carbidopa blocks systemic dopa decarboxylase
   4. Carbidopa - Levodopa (L-Dopa) combinations allow Dopa to reach the CNS
   5. Levodopa 100mg po qd x 3 weeks with physiotherapy improved hemiplegic recovery [31]
   6. For younger patients with Parkinson's, pramipexole or ropinirole generally recommended over L-Dopa as initial therapy [9]
2. Pergolide (Permax®)
   1. Ergot derivative, dopamine agonist (D1 and D2 receptor agonist)
   2. FDA approved for adjunctive treatment to levidopa/carbidopa in PD
   3. More effective, less expensive, and better tolerated than bromocriptine
   4. Improves on/off phenomena and dyskinesia in patients intolerant to levidopa/carbidopa
   5. Generally allows 5-30% reduction in dose of levidopa/carbidopa
   6. Side effects: hypotension, hallucinations, premature beats, sleep disorders, GI symptoms
   7. Associated with 3-9X increased risk of valvular fibroplasia, some pulmonary hypertension, likely due to activity on 5-HT2B serotonin receptors [14,15]
   8. Dose: 0.05mg qd with increased dosing after 3 days (see recommended schedule)
   9. Dose maximum is 0.5-0.75mg po tid in most patients
   10. May be effective as monotherapy (however, newer agents are preferred)
   11. Effective for restless leg syndrome (RLS) at dose of 0.05mg po qd initially, up to
3. 75mg qd [2]
   1. For all dopamine D2 agonists, compulsive gambling, compulsive eating, hypersexuality, and other compulsive disorders can occur, particularly with long term use
4. Pramipexole (Mirapex®) [9,16]
   1. Dopamine D2 and D3 receptor agonist for mild to severe PD cases
   2. Higher affinity for D3 than D2 receptors
   3. After 10 weeks of treatment, patients showed 20% improvement in symptom scores
   4. Useful for short term monotherapy in patients not on levodopa
   5. Dose is 1.5-4.5mg/day (6mg/d is poorly tolerated)
   6. Approved for RLS, starting dose 0.12mg qd 2-3 hours before bedtime; increase dose to q4-7 days by 0.125mg to maximum dose 0.5mg qd
   7. Main side effects are somnolence and hallucinations; nausea and constipation also occur
5. Ropinirole (Requip®) [9]
   1. Selective binding to D2 and D3 receptors for PD
   2. Improvement of ~24% in symptom scores (versus 3% decline in control) at 6 months
   3. When added to levodopa, it decreased off time and permitted reduction in levodopa dose
   4. Dose is 0.25mg tid initially, increase 0.25mg each dose per week x 4 weeks
   5. After this month, then can increase by 0.5mg per dose each week up to 3mg tid
   6. Finally, dose can be increased by 1mg per dose each week to maximum of 8mg po tid
   7. Approved for use in RLS, starting dose is 0.25mg po qpm; may be increased to 4mg
   8. Syncope, bradycardia may occur, usually with rapid dosage increases
6. Bromocriptine (Parlodel®) [12]
   1. Ergot derived dopamine agonist with D1 and D2 receptor effects
   2. Requires enzymatic transformation to dopamine in brain
   3. Dopamine Receptor Effects are Mixed: D1 antagonist, D2 agonist
   4. Useful in mild to moderate Parkinson's Disease
   5. Also used in hyperprolactinemia, particularly when pregnancy desired
   6. May not lead to late onset dyskinesias and on/off fluctuations
   7. Appears as effective as Levodopa ± Selegiline with better late side effects
   8. Begin on 1.25mg (1/2 tablet of 2.5mg) po qd (prefer to start at night)
   9. Increase to 5-10mg po qd in small increments every 3-5 days
   10. May be effective as monotherapy of mild to moderate disease with low side effects
   11. Side effects include orthostatic hypotension, GI intolerance, mental changes, depression
7. Cabergoline (Dostinex®) [12,13]
   1. D2 dopamine selective agonist
   2. More effective and better tolerated than bromocriptine
   3. Usual starting dose of cabergoline is 0.25mg twice weekly at night
   4. Increase dose to 0.5-1.0 mg twice weekly if needed
   5. Cabergoline also shows shrinkage of macroadenomas resistant to bromocriptine
   6. Reduced incidence of side effects compared with bromocriptine
   7. Also effective in non-tumoral hyperprolactinemia
   8. Associated with 3-9X increased risk of valvular fibroplasia, likely due to activity on 5-HT2B serotonin receptors [14,15]
   9. Drug may be withdrawn slowly after 2 years of normalized PRL (and tumor shrinkage)

G. Fenoldopam (Corlopam®) [7]

1. Intravenous selective DA1 receptor agonist
2. Vasodilatory and natriuretic effects; may be renal protective
3. Approved for treatment of hypertensive crisis
4. Starting dose is 0.1-0.3µg/kg/minute IV infusion; maximum 1.6µg/kg/minute IV
5. Onset 4-5 minutes, duration 10-30 minutes
6. Useful in nearly all hypertensive emergencies; caution with glaucoma
7. Does not prevent radiocontrast induced nephropathy [11]
8. Reduced acute kidney injury and death in critical illness in a meta-analysis and should be considered strongly [32]
9. Side effects typical of vasodilation (hypotension, flushing, headache, dizziness)

H. Dopamine Antagonists

1. Butyrphenones and phenothiazines have high affinity for D2 receptors
   1. Some antischizophrenic acitivity correlates with this receptor
   2. Development of dyskinesia strongly correlates with blocking this receptor
   3. These "typical" neuroleptics also block D3 and D4 receptors
   4. Dopamine blockade may lead to extrapyramidyl symptoms: movement disorders
   5. Reducing doses of tyese typical neuroleptics reduces EPS [10]
2. Atypical Antipsychotics
   1. High affinity for D4 receptors as well as D1 and D2
   2. These agents also have serotonin (mainly HT-2) receptor blocking effects
   3. Variable effects on alpha1-adrenergic receptors
   4. Risperidone is a selective D2 receptor blocker
3. Anti-Nausea Agents
   1. Mainly block peripheral (and central) dopamine D2, D3 receptors
   2. Metoclopramide (Reglan®) also has gastric emptying activity
   3. Prochlorperazine (Compazine®) - 5-10mg po or iv, 25mg suppositories
   4. Perphanazine (Trilafon®)
   5. Thiethylperazine (Torecan®)
   6. Trimethobenzamide (Tiganr) - oral, suppositories, injectable
   7. Promethazine (Phenergan®)

References

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4. Galley HF. 2000. Lancet. 356(9248):2112
5. Wang GJ, Volkow ND, Logan J, et al. 2001. Lancet. 357(9253):354
6. Scheidtmann K, Fries W, Muller F, Koenig E. 2001. Lancet. 358(9284):787
7. Murphy MB, Murray C, Shorten GD. 2001. NEJM. 345(21):1548
8. Kellum JA and Decker JM. 2001. Crit Care Med. 29:1526
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12. Schlechte JA. 2003. NEJM. 349(21):2035
13. Colao A, Di Sarno A, Cappabianca P, et al. 2003. NEJM. 349(21):2023
14. Schade R, Andersohn F, Suissa S, et al. 2007. NEJM. 356(1):29
15. Zanettini R, Antonini A, Gatto G, et al. 2007. NEJM. 356(1):39
16. Pramipexole. 2007. Med Let. 49(1257):25
17. Landoni G, Biondi-Zoccai GG, Tumlin JA, et al. 2007. Am J Kidney Dis. 49(1):56