Chapter 12: Pharmacology of Dopamine

1. Introduction/Overview

Dopamine, a member of the catecholamine family, functions as a critical neurotransmitter in the central nervous system and as a systemic hormone. Its pharmacology is complex and multifaceted, underpinning a wide array of physiological processes and therapeutic interventions. As a precursor to norepinephrine and epinephrine, dopamine occupies a unique position in both neurological and cardiovascular medicine. The clinical manipulation of dopaminergic systems represents a cornerstone in the treatment of conditions ranging from Parkinson’s disease and hyperprolactinemia to shock and heart failure. Understanding its distinct receptor-mediated effects, which vary significantly with dose, is fundamental to its safe and effective clinical application.

Learning Objectives

• Describe the biosynthesis, metabolism, and classification of dopamine and dopaminergic drugs.
• Explain the mechanism of action of dopamine, detailing its affinity and activity at different receptor subtypes and the resulting dose-dependent physiological effects.
• Outline the pharmacokinetic profile of exogenous dopamine administration, including its absorption, distribution, metabolism, and excretion.
• Identify the primary therapeutic uses of dopamine, distinguishing between its roles in cardiogenic shock, renal perfusion, and neurological disorders.
• Analyze the major adverse effects, drug interactions, and special population considerations associated with dopaminergic therapy.

2. Classification

Dopamine and drugs influencing dopaminergic systems can be classified based on their chemical structure, mechanism of action, and therapeutic target.

2.1. Endogenous Dopamine and Direct Agonists

Dopamine itself is an endogenous catecholamine (3,4-dihydroxyphenethylamine). Direct agonists mimic its action by binding to and activating dopamine receptors. These can be further subdivided:

• Non-selective dopamine receptor agonists: Dopamine itself activates D1-like and D2-like receptors, as well as adrenergic receptors at higher doses.
• Selective D1-like receptor agonists: Fenoldopam is a prominent example used for its vasodilatory effects.
• Selective D2-like receptor agonists: This large class includes ergot derivatives (bromocriptine, cabergoline) and non-ergot agents (ropinirole, pramipexole, rotigotine), primarily used in neurology and endocrinology.
• Dopamine precursor: Levodopa (L-DOPA) is metabolized to dopamine in the brain and is the mainstay of Parkinson’s disease therapy.

2.2. Indirect Agonists

These agents increase synaptic dopamine levels without directly stimulating postsynaptic receptors.

• Dopamine reuptake inhibitors (DRIs): Examples include certain stimulants like methylphenidate.
• Monoamine oxidase B (MAO-B) inhibitors: Selegiline and rasagiline prevent the breakdown of dopamine.
• Catechol-O-methyltransferase (COMT) inhibitors: Entacapone and tolcapone prolong the effect of levodopa.
• Dopamine releasers: Amphetamines promote the release of dopamine from presynaptic vesicles.

2.3. Dopamine Receptor Antagonists

These drugs block dopamine receptors and are used primarily as antipsychotics and antiemetics.

• Typical (first-generation) antipsychotics: Primarily D2 receptor antagonists (e.g., haloperidol, chlorpromazine).
• Atypical (second-generation) antipsychotics: Have mixed receptor affinity but often include D2 antagonism (e.g., risperidone, olanzapine).
• Antiemetics: Drugs like metoclopramide and domperidone act as D2 antagonists in the chemoreceptor trigger zone.

3. Mechanism of Action

The actions of dopamine are mediated through its interaction with specific G protein-coupled receptors. Its effects are profoundly dose-dependent, a result of its differing affinities for dopamine receptor families and adrenergic receptors.

3.1. Dopamine Receptors

Five dopamine receptor subtypes (D1 through D5) are categorized into two families based on their structure and signal transduction pathways.

• D1-like receptors (D1, D5): Coupled to G_s proteins. Activation stimulates adenylyl cyclase, increasing intracellular cyclic adenosine monophosphate (cAMP). This generally leads to excitatory postsynaptic potentials and cellular activation. In vascular smooth muscle, particularly in renal, mesenteric, coronary, and cerebral beds, D1 receptor activation causes vasodilation.
• D2-like receptors (D2, D3, D4): Coupled to G_i/o proteins. Activation inhibits adenylyl cyclase, reducing cAMP, and may also modulate potassium and calcium channels. This generally leads to inhibitory postsynaptic potentials. D2 receptor activation in the pituitary inhibits prolactin secretion. In the chemoreceptor trigger zone (area postrema), antagonism of D2 receptors produces an antiemetic effect.

3.2. Dose-Dependent Hemodynamic Effects

The systemic cardiovascular effects of intravenously administered dopamine are a classic example of concentration-dependent pharmacodynamics.

1. Low dose (0.5–2 µg/kg^-1/min^-1): Predominantly activates vascular D1 receptors, leading to vasodilation in renal, mesenteric, coronary, and cerebral arteries. This increases renal blood flow, glomerular filtration rate, and sodium excretion, often termed “renal-dose” dopamine. It may also activate presynaptic D2 receptors, inhibiting norepinephrine release.
2. Intermediate dose (2–10 µg/kg^-1/min^-1): Activates cardiac β₁-adrenergic receptors, producing positive inotropic and chronotropic effects. Cardiac output and stroke volume increase. Some activation of vascular β₂ receptors may contribute to continued vasodilation at the lower end of this range.
3. High dose (>10 µg/kg^-1/min^-1): Predominantly activates α₁-adrenergic receptors on vascular smooth muscle, causing potent vasoconstriction. This increases systemic vascular resistance and blood pressure but can compromise renal and peripheral perfusion.

3.3. Central Nervous System Mechanisms

In the CNS, dopaminergic pathways are critical for motor control, reward, motivation, and endocrine regulation. The nigrostriatal pathway (substantia nigra to striatum) is essential for movement; its degeneration causes Parkinsonism. The mesolimbic and mesocortical pathways (ventral tegmental area to limbic system and cortex) are involved in reward and cognition; overactivity may be implicated in psychosis. The tuberoinfundibular pathway (hypothalamus to pituitary) tonically inhibits prolactin release.

4. Pharmacokinetics

The pharmacokinetics of exogenous dopamine are characterized by rapid onset and short duration of action, necessitating continuous intravenous infusion for clinical effect.

4.1. Absorption and Administration

Dopamine is not effective orally due to extensive first-pass metabolism by monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT) in the intestinal mucosa and liver. It is also poorly absorbed subcutaneously or intramuscularly due to local vasoconstriction. Therefore, it must be administered by continuous intravenous infusion, typically via a central venous line to avoid extravasation injury. Onset of action is within 5 minutes, with a duration of action of less than 10 minutes after discontinuation.

4.2. Distribution

Dopamine is widely distributed but does not cross the blood-brain barrier in significant amounts due to its polarity. This is a critical distinction from its precursor, levodopa, which is actively transported across the barrier. The volume of distribution is approximately 0.9 L/kg. It is rapidly taken up into adrenergic nerve terminals via the norepinephrine transporter (NET).

4.3. Metabolism

Dopamine undergoes extensive and rapid enzymatic metabolism by two primary pathways:

• Monoamine oxidase (MAO): Primarily MAO-A, present in the liver, intestinal wall, and neuronal mitochondria, catalyzes oxidative deamination to 3,4-dihydroxyphenylacetaldehyde (DOPAL).
• Catechol-O-methyltransferase (COMT): Present widely, including in the liver and kidneys, catalyzes methylation of one of the hydroxyl groups to form 3-methoxytyramine (3-MT).

These pathways often operate sequentially. DOPAL is quickly converted by aldehyde dehydrogenase to 3,4-dihydroxyphenylacetic acid (DOPAC). DOPAC can then be methylated by COMT to form homovanillic acid (HVA), the major urinary metabolite. Alternatively, 3-MT can be deaminated by MAO to form HVA. The plasma half-life (t_1/2) of dopamine is extremely short, approximately 1 to 2 minutes.

4.4. Excretion

Metabolites are excreted primarily in the urine, with about 80% of a dose appearing as HVA and 3-MT within 24 hours. Less than 5% is excreted unchanged. Renal clearance of the drug itself is negligible compared to metabolic clearance.

5. Therapeutic Uses/Clinical Applications

5.1. Cardiovascular Support

The use of dopamine in critical care has evolved, and its role is now more limited and specific.

• Cardiogenic Shock and Severe Heart Failure: Dopamine may be used as an inotropic agent to increase cardiac output and blood pressure. Its use is often reserved for situations where both inotropy and vasoconstriction are desired, though other agents like norepinephrine or dobutamine may be preferred based on the specific hemodynamic profile.
• Hypotension: It can be used to treat hypotension, particularly when associated with bradycardia, due to its positive chronotropic effects. However, norepinephrine is generally first-line for vasodilatory shock (e.g., septic shock).

The historical use of “renal-dose” dopamine to prevent or treat acute kidney injury is no longer recommended, as large clinical trials have failed to demonstrate a protective benefit and have suggested potential harm, including arrhythmias.

5.2. Neurological Disorders

While dopamine itself does not cross the blood-brain barrier, manipulation of central dopaminergic transmission is central to several therapies.

• Parkinson’s Disease: Levodopa, the metabolic precursor to dopamine, remains the most effective symptomatic treatment. It is almost always combined with a peripheral decarboxylase inhibitor (carbidopa or benseraside) to minimize peripheral conversion to dopamine and associated side effects. Direct D2/D3 agonists (pramipexole, ropinirole, rotigotine) are used as monotherapy in early disease or as adjuncts to levodopa.
• Restless Legs Syndrome: Dopamine agonists (pramipexole, ropinirole, rotigotine) are first-line treatments for moderate to severe disease.

5.3. Endocrine Disorders

• Hyperprolactinemia: D2 receptor agonists (bromocriptine, cabergoline) are the primary treatment. They inhibit prolactin secretion from pituitary lactotrophs, reducing prolactinoma size and restoring gonadal function.
• Acromegaly: Dopamine agonists can be used as adjunctive therapy to reduce growth hormone secretion, though somatostatin analogs are typically more effective.

5.4. Other Uses

• Fenoldopam: This selective D1 receptor agonist is used as a rapid-acting, titratable intravenous antihypertensive, particularly in perioperative settings and hypertensive emergencies, due to its renal vasodilatory properties.
• Antiemesis: D2 receptor antagonists (e.g., metoclopramide, prochlorperazine, domperidone) are used to treat nausea and vomiting.

6. Adverse Effects

Adverse effects are closely related to the receptor systems activated and are often dose-dependent.

6.1. Cardiovascular Effects

• Tachycardia and Arrhythmias: β₁-adrenergic stimulation at intermediate to high doses can cause sinus tachycardia, atrial fibrillation, ventricular ectopy, and even ventricular tachycardia or fibrillation. This risk is heightened in patients with underlying heart disease or those receiving other sympathomimetic drugs.
• Hypertension: Excessive α₁-mediated vasoconstriction at high infusion rates can lead to severe hypertension, potentially causing headache, hemorrhage, or exacerbation of heart failure.
• Vasoconstriction and Ischemia: High-dose dopamine can cause peripheral digital ischemia, gangrene, and compromised blood flow to mesenteric and renal beds, paradoxically negating its low-dose benefits. Extravasation from intravenous sites can cause severe local necrosis and sloughing.

6.2. Endocrine Effects

• Endocrine Suppression: Chronic use of dopamine or its agonists can suppress prolactin secretion, potentially leading to amenorrhea, galactorrhea, or sexual dysfunction. Conversely, dopamine antagonists frequently cause hyperprolactinemia.

6.3. Neurological and Psychiatric Effects

• Central Dopamine Agonists (Levodopa, Direct Agonists): Nausea, vomiting, orthostatic hypotension, and somnolence are common. Long-term levodopa therapy is associated with motor complications: “wearing-off” phenomena, dyskinesias (involuntary movements), and “on-off” fluctuations. Psychiatric side effects include hallucinations, confusion, and impulse control disorders (e.g., pathological gambling, hypersexuality) with agonists.
• Dopamine Antagonists (Antipsychotics): Extrapyramidal symptoms (acute dystonia, akathisia, parkinsonism, tardive dyskinesia) are common, especially with typical agents. Neuroleptic malignant syndrome, a rare but life-threatening reaction, is characterized by hyperthermia, muscle rigidity, autonomic instability, and altered mental status.

6.4. Gastrointestinal Effects

Nausea and vomiting are common with dopaminergic drugs, often mediated by stimulation of D2 receptors in the chemoreceptor trigger zone. This effect is sometimes utilized therapeutically with antagonists.

7. Drug Interactions

Interactions with dopamine and dopaminergic drugs are numerous and potentially serious.

7.1. Pharmacodynamic Interactions

• Other Sympathomimetic Agents: Concurrent use of drugs like epinephrine, norepinephrine, or isoproterenol can lead to additive cardiovascular effects, dramatically increasing the risk of severe hypertension, arrhythmias, and ischemia.
• Monoamine Oxidase Inhibitors (MAOIs): Non-selective MAOIs (e.g., phenelzine, tranylcypromine) can precipitate a hypertensive crisis if dopamine is administered, as they prevent its metabolic inactivation. A several-week washout period is required. The risk with selective MAO-B inhibitors (selegiline) used in Parkinson’s disease is lower but present, especially at higher doses.
• Antihypertensive Agents: The pressor effects of dopamine may be antagonized by α- and β-adrenergic blockers, diuretics, and other antihypertensives.
• General Anesthetics: Volatile anesthetics (especially halothane) sensitize the myocardium to catecholamines, increasing the risk of ventricular arrhythmias.
• Dopamine Antagonists: Antipsychotics and antiemetics may antagonize the therapeutic effects of dopamine agonists, particularly in Parkinson’s disease, potentially precipitating a parkinsonian crisis.

7.2. Pharmacokinetic Interactions

While less common for intravenous dopamine itself, interactions affecting central dopaminergic drugs are significant.

• Levodopa’s effects are diminished by pyridoxine (vitamin B₆), which enhances its peripheral decarboxylation outside the blood-brain barrier.
• COMT inhibitors (entacapone) and MAO-B inhibitors (rasagiline) potentiate the effects of levodopa, increasing both therapeutic benefit and the risk of dyskinesias and psychiatric side effects.

7.3. Contraindications

Absolute contraindications to dopamine infusion include pheochromocytoma, uncorrected tachyarrhythmias, and ventricular fibrillation. It is relatively contraindicated in patients with severe occlusive vascular disease, Raynaud’s phenomenon, or a history of severe hypersensitivity to sulfites (present in some commercial formulations). Dopamine agonists are generally contraindicated in patients with a history of impulse control disorders or psychotic illness.

8. Special Considerations

8.1. Pregnancy and Lactation

Dopamine is classified as FDA Pregnancy Category C. Animal studies have shown adverse effects, but controlled human data are lacking. It should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus, typically in life-threatening maternal hypotension. It may reduce uterine blood flow. For Parkinson’s disease in pregnancy, levodopa/carbidopa is generally preferred over dopamine agonists due to more extensive experience. Bromocriptine is used postpartum to suppress lactation. Most dopaminergic drugs are excreted in breast milk, and their use during lactation requires caution.

8.2. Pediatric and Geriatric Populations

In pediatric patients, dosing is weight-based (µg/kg/min), and close hemodynamic monitoring is essential. Geriatric patients often have reduced cardiac reserve, increased vascular stiffness, and diminished baroreceptor reflex function. They may be more sensitive to the hypertensive and arrhythmogenic effects of dopamine and may require dose adjustments starting at the lower end of the therapeutic range. The risk of orthostatic hypotension with oral dopaminergic agents is heightened.

8.3. Renal and Hepatic Impairment

Dopamine is extensively metabolized, so its pharmacokinetics are not significantly altered in renal failure. However, its active metabolites may accumulate, though their clinical significance is unclear. The rationale for using “renal-dose” dopamine to improve function in renal impairment is not supported by evidence. In hepatic impairment, metabolism via MAO may be reduced, potentially prolonging the drug’s effect and increasing toxicity risk. Dose titration should be performed with extreme caution.

8.4. Monitoring Parameters

Continuous cardiovascular monitoring is mandatory during dopamine infusion, including continuous ECG for arrhythmias and frequent or continuous blood pressure measurement (preferably via arterial line at high doses). Urine output, peripheral perfusion (color, temperature of extremities), and signs of extravasation should be assessed regularly. For chronic dopaminergic therapy in Parkinson’s disease, monitoring for motor fluctuations, dyskinesias, psychiatric symptoms, and impulse control disorders is necessary.

9. Summary/Key Points

• Dopamine is an endogenous catecholamine neurotransmitter and hormone with complex, dose-dependent effects mediated through D1-like, D2-like, and adrenergic receptors.
• Its intravenous hemodynamic effects are concentration-dependent: low doses cause renal and mesenteric vasodilation (D1), intermediate doses increase cardiac contractility and output (β₁), and high doses cause systemic vasoconstriction (α₁).
• Dopamine has a very short plasma half-life (1–2 minutes) due to rapid metabolism by MAO and COMT, necessitating continuous IV infusion. It does not cross the blood-brain barrier.
• Therapeutic uses include inotropic support in select shock states (though its role has diminished), and, via other drugs, the treatment of Parkinson’s disease (levodopa, agonists), hyperprolactinemia (D2 agonists), and nausea (D2 antagonists).
• Major adverse effects are cardiovascular (tachyarrhythmias, hypertension, ischemia), neurological (dyskinesias, psychosis with agonists; EPS with antagonists), and gastrointestinal (nausea).
• Significant drug interactions occur with MAO inhibitors, other sympathomimetics, and anesthetics, increasing the risk of hypertensive crisis and arrhythmias.
• Use requires careful titration and monitoring, with special caution in geriatric patients and those with cardiovascular disease. The historical use for renal protection is not recommended.

Clinical Pearls

• Always administer dopamine via a central venous catheter to minimize the risk of severe tissue necrosis from extravasation.
• Initiate infusion at a low dose (e.g., 2–5 µg/kg/min) and titrate upward every 10–30 minutes to achieve the desired hemodynamic endpoint, recognizing the overlapping receptor activation at higher doses.
• Norepinephrine, rather than dopamine, is typically the first-line vasopressor for septic shock due to a more favorable risk profile.
• When treating Parkinson’s disease, “start low and go slow” with dopamine agonists to minimize early side effects like nausea and orthostasis.
• Be vigilant for the development of impulse control disorders (gambling, shopping, hypersexuality) in patients on long-term dopamine agonist therapy.

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