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Chapter: Clinical Pharmacology: Neurologic and neuromuscular drugs

Dopaminergic drugs

Dopaminergic drugs include several drugs that are chemically un-related: · levodopa, the metabolic precursor to dopamine · carbidopa-levodopa, a combination drug composed of car-bidopa and levodopa

Dopaminergic drugs


Dopaminergic drugs include several drugs that are chemically un-related:


·                 levodopa, the metabolic precursor to dopamine


·                 carbidopa-levodopa, a combination drug composed of car-bidopa and levodopa


·                 amantadine, an antiviral drug with dopaminergic activity


·                 bromocriptine, an ergot-type dopamine agonist


·                 ropinirole and pramipexole, two non-ergot-type dopamine ago-nists


·                 selegiline and rasagiline, type B MAOIs.




Like anticholinergic drugs, dopaminergic drugs are absorbed from the GI tract into the bloodstream and are delivered to their action site in the brain.


Slowing down with food


Absorption of levodopa is slowed and reduced when it’s ingested with food. The body absorbs most levodopa, carbidopa-levodopa, pramipexole, or amantadine from the GI tract after oral adminis-tration, but only about 28% of bromocriptine. About 73% of an oral dose of selegiline is absorbed. Rasagiline is rapidly absorbed into the bloodstream.




Levodopa is widely distributed in body tissues, including the GI tract, liver, pancreas, kidneys, salivary glands, and skin. Carbidopa-levodopa and pramipexole are also widely distributed. Amantadine is distributed in saliva, nasal secretions, and breast milk. Bromocriptine and rasagiline are highly protein-bound. The distribution of selegiline is unknown.


Metabolism and excretion

Dopaminergic drugs are metabolized extensively in various ar-eas of the body and eliminated by the liver, the kidneys, or both.


Large amounts of levodopa are metabolized in the stomach and during the first pass through the liver. The drug is metabo-lized extensively to various compounds that are excreted by the kidneys.


Carbidopa isn’t metabolized extensively. The kidneys excrete approximately one-third of it as unchanged drug within 24 hours.


Amantadine, ropinirole, and pramipexole are excreted mostly unchanged by the kidneys.


Almost all of a bromocriptine or rasagiline dose is metabolized by the liver to pharmacologically inactive compounds, which are then eliminated primarily in feces, with only a small amount ex-creted in urine.


Selegiline is metabolized to L-amphetamine, L-methampheta-mine, and N-desmethyldeprenyl (the major metabolite), which are eliminated in urine.




Dopaminergic drugs act in the brain to improve motor function in one of two ways: by increasing the dopamine concentration or by enhancing neurotransmission of dopamine.


Getting the job done


Levodopa is inactive until it crosses the blood-brain barrier and is converted to dopamine by enzymes in the brain, increasing dopamine concentrations in the basal ganglia. Carbidopa en-hances levodopa’s effectiveness by blocking the peripheral con-version of levodopa, thus permitting increased amounts of lev-odopa to be transported to the brain.


The other dopaminergic drugs have various mechanisms of ac-tion:


·                 Amantadine’s mechanism of action isn’t clear. It’s thought to re-lease dopamine from intact neurons, but it may also have non-dopaminergic mechanisms.


·                 Bromocriptine, ropinirole, and pramipexole stimulate dopamine receptors in the brain, producing effects that are similar to dopamine’s.


·                 Rasagiline has an unknown mechanism of action.


·                 Selegiline can increase dopaminergic activity by inhibiting type B MAO activity or by other mechanisms.




The choice of therapy is highly individualized, depending on the patient’s symptoms and extent of disability. Patients with mild Parkinson’s disease whose main symptom is a tremor are com-monly given anticholinergics or amantadine. Selegiline is indicat-ed for extending the duration of levodopa by blocking its break-down; it has also been used in the early stages of Parkinson’s dis-ease because of its neuroprotective properties and potential to slow the progression of the disease.


Dopaminergic drugs are usually used to treat patients with se-vere Parkinson’s disease or those who don’t respond to anticholin-ergics alone. Levodopa is the most effective drug used to treat Parkinson’s disease; however, it loses its effectiveness after 3 to 5 years. (See Levodopa: Pros and cons.)


Flurry of fluctuations


When the patient’s response to levodopa fluctuates, dosage adjust-ments and increased frequency of administration may be tried. Alternatively, adjunctive therapy, such as dopamine agonists, se-legiline, amantadine, or catechol-O-methyltransferase (COMT) in-hibitors, may be added. Controlled-release forms of carbidopa-levodopa may be helpful in managing the wearing-off effect (when levodopa’s effects don’t last as long as they used to) or delayed-onset motor fluctuations.


Add carbidopa, reduce levodopa


Levodopa is almost always combined with carbidopa as the stan-dard therapy for Parkinson’s disease. When these drugs are given together, the dosage of levodopa can be reduced, decreasing the risk of GI and cardiovascular adverse effects.


Tapered treatment


The dosage of some dopaminergic drugs, such as amantadine, lev-odopa, pramipexole, and bromocriptine, must be gradually ta-pered to avoid precipitating parkinsonian crisis (sudden marked clinical deterioration) and possibly life-threatening complications, including muscle rigidity, elevated body temperature, tachycardia, mental changes, and increased serum creatine kinase (resembling neuroleptic malignant syndrome).

Drug interactions


There are a number of drug interactions related to dopaminergic drugs, including some that are potentially fatal.

·                 Levodopa’s effectiveness may be reduced when used concur-rently with pyridoxine (vitamin B6), phenytoin, benzodiazepines, reserpine, or papaverine.


·                 MAOIs such as tranylcypromine increase the risk of hyperten-sive crisis.


·                 Antipsychotics, such as phenothiazines, thiothixene, haloperi-dol, and loxapine, can reduce the effectiveness of levodopa.


·                 Amantadine may potentiate the anticholinergic adverse effects, such as confusion and hallucinations, of anticholinergic drugs and reduce the absorption of levodopa.


·                 Meperidine taken with selegiline at a higher-than-recommended dose can cause a fatal reaction. (See Adverse reactions todopaminergic drugs)


·                 In some patients, levodopa can produce a significant interac-tion with foods. Dietary amino acids can decrease levodopa’s ef-fectiveness by competing with it for absorption from the intestine and slowing its transport to the brain.


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