Medical Pharmacology: Dopamine Background and Therapeutic Use

Some general aspects of dopamine pharmacology have already been discussed, including the important role of dopamine in CNS neurotransmission and dopamine's role in the neuropathologies associated with Parkinson's disease and schizophrenia.
The focus on the section will be on both cardiovascular aspects and therapeutic aspects of dopamine and related agents.
- Peripheral dopamine is synthesized in renal proximal tubule epithelial cells where dopamine is likely involved in both diuretic and natriuretic activities.
- Since dopamine is catabolized both by monoamine oxidase and catechol-O-methyltransferase (MAO, COMT), dopamine is not suitable for oral administration.

The particular cardiovascular effect elicited by dopamine depends principally on its concentration which influences which receptor or receptors are activated.

The vascular D₁ receptor subtype is the likely to be activated at low dopamine concentrations with stimulation resulting in vasodilation of renal, mesenteric and coronary vascular beds.

Vasodilation occurs as a result of activated D₁ receptors increasing adenylyl cyclase activity which in turn increases cAMP.

Low-dose dopamine also has prominent renal effects including an increase in renal blood flow, Na⁺ excretion and enhance glomerular filtration rate.

**Nephron Anatomy**

courtesy of Robert H. Parsons, Ph.D., Rensselaer Polytechnic Institute, used with permission	Anatomy of the Nephron: From Guyton's Textbook of Physiology, 9th edition

Reduction in Na⁺ transport by cAMP-dependent and independent mechanisms occurs following dopamine D₁ receptors activation.¹⁵²

Elevated cAMP in proximal tubule cells and medullary part of the thick ascending limb of the loop of Henle results in inhibition of both the Na⁺-H⁺exchanger and the Na⁺, K⁺-ATPase pump.
Dopamine-induced increase in renal blood flow and glomerular filtration rate probably enhances dopamine-related renal tubular effects that increase natriuresis.

Changes in renal blood flow dynamics following dopamine manifest as both increased peritubular capillary pressure and decreased oncotic pressure which together reduce Na⁺ reabsorption by the proximal tubule.

For the above reasons, poor cardiac output and concomitant poor renal function, as might be found in congestive heart failure, may be under some circumstances effectively managed using dopamine.¹⁵²

**Congestive Heart Failure I**

Attribution: ASKVisualScience https://www.youtube.com/watch?v=3YddwXPWVSc&t=2s (2010) ASKVisualScience Youtube Channel https://www.youtube.com/channel/UCLPuQMM_8UgHQpeRFiFlCzA

**Congestive Heart Failure (Lecture)**

Attribution: Fowler M Ashley E Heart Failure https://www.youtube.com/watch?v=Iyb8okxrMbU ResearchChannel Youtube Channel https://www.youtube.com/channel/UCMi6tHz2CmTA6IRaKr3ppRQ

Dopamine in Therapeutics¹⁵²

As dopamine concentration is increased, other adrenergic receptors are stimulated.

This phenomenon is an example of how drug, in this case dopamine, receptor selectivity is often dependent on concentration.¹⁵²
Dopamine administration, thus, at higher concentrations results in a positive myocardial inotropic effect, mediated by activation of β₁ adrenergic receptors.
- An additional effect is a dopamine-mediated release of norepinephrine from adrenergic terminals, an effect which adds to the dopamine direct cardiac effect.
- Blood pressure effects following dopamine administration typically include increased systolic pressure as well as pulse pressure but minimal effects on diastolic pressure.
- At low/intermediate dose levels, dopamine administration has limited action on total peripheral resistance (TPR).
  - Minimal dopamine effects on TPR is due to an interplay between dopamine-induced decrease in arterial resistance in, for example, mesenteric and renal vascular beds and by an increase in arterial resistance in other vascular beds.
- At still higher concentrations dopamine activates α₁ receptors which results in vasoconstriction across vascular beds.

Dopamine may be helpful in management of severe congestive heart failure, typically in the short-term.¹⁵²

Patients most likely to benefit from dopamine infusion exhibit reduced urine production (oliguria) with either low or normal peripheral vascular resistance.

Dopamine may also assist in the management of septic and cardiogenic shock.

Cardiogenic Shock¹⁵³

Cardiogenic shock occurs due to inadequate blood circulation secondary to inadequate ventricular function.
Consequences of cardiogenic shock are typically serious as a result of both insufficient oxygen delivery to tissues and insufficient nutrient delivery as well.
This type of shock is characterized by extended hypotension and tissue hypoperfusion, despite sufficient left ventricular filling.
- Altered consciousness and oliguria, defined as <30 mL/hour, are part of a typical clinical presentation.
Therapeutic options for management of cardiogenic shock may include fluid infusion and administration of inotropic agents which enhance cardiac contractility, perhaps correcting hypotensive states.
- Mechanical assist devices such as intra-aortic balloon pump or a more specific left ventricular assist device may also be efficacious.
  - Ventricular Assist Device^154,155

Dopamine infusion in the management of shock requires clinical assessment during treatment.¹⁵²
- Special attention with respect to myocardial function, CNS perfusion and urine production might be typically provided in the intensive care unit setting.
- Cessation of dopamine infusion may be required in the event of development of reduced urine flow, tachycardia or arrhythmia.
- Dopamine effects, given its short duration of action, can be readily titrated.

Fenoldapam (Corlopam), a dopamine D₁ receptor agonist, is effective in relaxing smooth muscle vasculature and is suitable for management of hypertension.^35,152

Fenoldopam (Corlopam)

This agent is classified as a rapidly acting vasodilator that can be used in the hospital setting for management of severe (malignant) hypertension associated with end-organ damage.¹⁵²

Malignant Hypertension¹⁵⁶

Malignant hypertension may present in hypertensive patients or in previously normotensive patients and is characterized by a sudden onset, substantial increase in blood pressure.¹⁵⁶
- Rate of rise in blood pressure, rather than the absolute maximal value, appears to be the more important parameter.
  - Malignant hypertension may be associated with certain pathologies such as arteriolar thrombi, fibrin localization in arteriolar walls and diffuse necrotizing vasculitis.
  - Clinical recognition of malignant hypertension is often based on a progressive retinopathy characterized by arteriolar spasm, hemorrhages, exudates and papilledema as well as by impaired renal function with proteinuria, encephalopathy, and microangiopathic hemolytic anemia.
- Patient histories may include questions concerning patient recreational drug use (e.g. cocaine or amphetamines) or treatment with drugs belonging to the class of monoamine oxidase inhibitors (MAO inhibitors).¹⁵⁶
- Excessively rapid reduction in blood pressure due to pharmacological intervention carries a risk in this setting of cerebral ischemia or infarction due to reduced cerebral blood flow.¹⁵⁶
  - The physiological basis for this concern rests on a change in limits associated with the cerebral blood flow autoregulation system.
  - Excessively rapid blood pressure reduction may also compromise both renal and coronary blood flow.
- Thus, initial therapeutic goals would include a reduction in pressure perhaps not to exceed 25% within a timeframe of minutes to two hours or to the pressure not lower than about 160/100-110 mmHg. ¹⁵⁶
- One agent typically useful in management of malignant hypertension is IV nitroprusside which is both short-acting and titratable-to-effect through adjustment of infusion rate. ¹⁵⁶
  - Alternatively, therapeutic goals may be initially achieved with the use of repetitive dosing of short-acting, orally administered drugs including captopril, labetalol, or clonidine.

**Nitroprusside (Nipride, Nitropress), direct acting vasodilator**

**Captopril (Capoten), angiotensin converting enzyme inhibitor (ACE Inhibitor)**

**Labetalol (Normodyne, Trandate), α- and β-adrenergic receptor antagonist**

**Clonidine (Cataores), centrally-acting, direct α₂-agonist which decreases central sympathetic outflow**

**Hypertensive Retinopathy: "Hypertensive Retinopathy with AV Nicking and Mild Vascular Tortuosity"** ¹⁵⁷

Retinal small blood vessels, when subjected to substantially elevated blood pressures over extended periods, may be damaged and exhibit thickening, bulging and leaking. Indications of retinal damage secondary to hypertension include atherosclerotic changes with the narrowing tending to be bilateral, ischemic changes ("cotton wool spots"), hemorrhages, edema, papilledema or optic disc edema (malignant hypertension) and a reduction in visual acuity.

In addition to fenoldapam's activity at D₁ receptors, fenoldopam also binds to α₂ adrenergic receptors; however, fenoldopam does not bind appreciably to D₂ dopamine receptors, α₁ adrenergic receptors or β adrenergic receptors.

Fenoldopam is a racemate (R- and S- forms both present) with the R-isomer representing the active form¹⁵².
- Enantiomer refers to a type of stereoisomer. Recall that enantioners are nonsuperimposible mirror-images of each other.
  - Enantiomers have identical physical properties other than the direction that a solution of each enantiomer rotates plane-polarized light.
  - The asymmetric center of one enantiomer exhibits an opposite configuration, meaning R or S designation, compared to the other enantiomer.
    - The relationship between the absolute configuration (R or S) and the direction of rotation of plane-polarized light (dextrorotatory or levorotatory, i.e. d- or l- form) is not simple.
- Usually one enantiomer will be more effective than its mirror structural image-- suggesting a more complementary fit between the drug with its receptor binding region.
  - Other examples:
    - S(+)- methacholine enantiomer > 250 times more potent than the R(-) enantiomer form
    - Ketamine (Ketalar): (+) enantiomer more potent, less toxic then the (-) enantiomer; however, the drug is used as the racemate (includes both enantiomeric forms)
Vascular dilatation following fenoldopam has been observed in coronary arteries, renal afferent and efferent arterioles and mesenteric arteries.¹⁵²
Fenoldapam must be administered using an infusion pump both because of the need to titrate-to-effect and because <6% of an orally ingested dose is available to exert pharmacological activity.¹⁵²
- The limited effect following oral dosages due to extensive hepatic "first-pass" metabolism principally through conjugation (sulfate-, methyl-and glucuronide-conjugates).
- IV fenoldopam is associated with a elimination half-life (t_½) of 10 min.

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