The mode of action of levodopa involves absorption from the gastrointestinal tract, crossing through the blood-brain barrier (BBB), uptake by neurons, enzymatic action of the aromatic amino acid decarboxylase to be converted into dopamine and the synaptic release of dopamine [30]. The disruption of the nigrostriatal pathway reduces dopamine levels and produces the symptoms of Parkinson’s disease (PD)[31]. Hence, the dopamine from exogenous levodopa will activate the central dopamine receptors, thus improving the symptoms of PD. Since aromatic-L-amino-acid decarboxylase (AADC) and COMT are responsible for the metabolism of levodopa peripherally, it is usually in combination with AADC inhibitors such as carbidopa and benserazide or COMT inhibitors such as entacapone and tolcapone. Levodopa has to be administered multiple times daily since it has a short half-life of about 36–96 min which will cause the fluctuation in plasma levels [30]. Treatment with Levodopa alleviates bradykinesia and other typical motor manifestations of PD. Long-term Levodopa treatment, on the other hand, is associated with complications such as motor fluctuations and dyskinesia, which severely impair quality of life. The combination of levodopa and carbidopa is most widely used to treat PD and Parkinson-like symptoms that may develop after encephalitis (brain swelling), or nervous system injury caused by carbon monoxide or manganese poisoning [32].

Dopamine agonists can be categorized into two classes, which are ergot and non-ergot dopamine agonists. They have antiparkinsonian activity due to the direct-acting effect on dopamine receptors which mimic the neurotransmitter. Bromocriptine, cabergoline, pergolide, and lisuride are examples of ergot dopamine agonists whereas non-ergot dopamine agonists include ropinirole and pramipexole. Ergot dopamine agonists act primarily on the D2-like dopamine receptors including D2, D3, and D4 [33]. On the other hand, non-ergot dopamine agonist ropinirole is a potent and selective agonist of the D2 dopamine receptors while pramipexole has a higher affinity towards D3 receptors [33,34].

In PD patients, it has been theorized that a lesion is formed in the nigra striatum. This results in the reduction of intranigral dopamine concentrations. Imbalances of the dopaminergic and cholinergic neurological pathway lead to more cholinergic firing. The stimulation causes dyskinesia and tremors. Thus, the mechanism of anticholinergics is to block the cholinergic receptors from the activation of acetylcholine. They act to counteract the imbalance of neurotransmitters in the nigra striatal pathway [35]. Specifically, M4 receptor is targeted for the block by anticholinergics [36]. This eventually will reduce the tremor and dyskinesia conditions of the patient.

A COMT inhibitor acts by breaking down catecholamines such as dopamine and norepinephrine by inhibiting the enzyme COMT. The enzyme COMT can be found in peripheral and central circulation and the aim is to prevent the breakdown of levodopa while travelling to the brain region and crossing through the BBB. It works in combination with levodopa to prevent methylation of levodopa to 3-O-methyldopa in peripheral circulation, thus improving the bioavailability of levodopa [37]. Besides, low doses of levodopa in combination with COMT inhibitors may prevent dyskinesia.

MAO-B inhibitors (MAO-BIs) are the antiparkinsonian drugs that have the mechanism of action of preventing monoamine oxidase-B (MAO-B) from catalyzing dopamine metabolism, hence prolonging dopamine action in basal ganglia. It is considered as an adjuvant for PD, and it is usually used with L-Dopa for PD therapy. Besides PD, MAO-BIs are also the adjuvant for treating Alzheimer’s disease. MAO-BIs exhibit neuroprotection which is the protective effect of neuronal structure and function. Other than that, they also exhibit antioxidant effects and can prolong neuronal death caused by apoptosis as well as protect functions of mitochondria [38]. Current MAO-BI consists of selegiline and rasagiline. Both are selective and irreversible MAO-BIs [39].

The mechanism of amantadine in the brain is not well understood. Generally, amantadine works by inhibiting the N-methyl-D-aspartate (NMDA)-glutamate receptor and cholinergic muscarinic receptors, thereby increasing dopamine release, and blocking dopamine reuptake [40]. It reduces dyskinesia in PD patients receiving levodopa, as well as extrapyramidal side effects of medications. Multiple studies showed that NMDA-blocking is the most important mechanism to explain its antidyskinetic effect [41].

Safinamide is an FDA newly approved drug used in treating PD. It is a derivative of benzylamino which has various modes of action [2,53]. The main mode of action of safinamide is that it inhibits MAO-B selectively and reversibly [2,7,11,53,54]. Moreover, safinamide has the non-dopaminergic mechanism of action which includes the state-dependent block of voltage-gated sodium channels in the inactivated state. Furthermore, safinamide also has antiglutamatergic activity. These actions may be responsible for its pain mitigating effects [2,7,11,53,54]. Safinamide also prevents the formation of free radicals through the inhibition of MAO-B [53].

Istradefylline is known as the selective adenosine A2A receptor antagonist [3]. Adenosine A2A receptors are demonstrated to suppress the activity of GP projection by suppressing GABA which is transmitted and released in the striatum. This will lead to the enhancement of GABA in the GP [55]. Therefore, when istradefylline blocks A2A receptors, it can reduce outrageous excitability of the indirect output pathway, thereby minimizing the occurrence of the motor symptoms in PD patients [56]. In addition, istradefylline is considered as nondopaminergic due to the lack of effects on dopamine receptors and dopamine-metabolizing enzymes [57]. It does not have the inhibitory activity toward enzymes such as COMT, MAO-A, and MAO-B which metabolize dopamine or levodopa. It also has a low affinity for receptors such as dopamine (D1, D2), serotonin (5-HT1A, 5-HT2, 5-HT3), and noradrenaline receptors [50].

Pimavanserin is known as the selective antagonist or inverse agonist of 5-hydroxytryptamine (HT)2A receptor [1,49,58,59,60]. This is because of its ability to reduce 5-HT2 receptor activity without acting on other receptors. Thus, it does not induce a pharmacological reaction to agonists on other receptors [49]. Pimavanserin has a 40 folds higher affinity towards 5-HT2A receptors compared to 5-HT2C receptors [60]. However, it has a low affinity towards dopaminergic, muscarinic, histaminergic, or adrenergic receptors and has a low ability in blocking D2 receptors [1,49,59]. Therefore, the deleterious effect of pimavanserin on dopamine replacement therapy will not be the same as atypical psychotic drugs and it does not worsen motor symptoms [49]. Thus, pimavanserin is the first medication licensed in the United States for the treatment of Parkinson’s disease psychosis (PDP)-related hallucinations and delusions, eventually making pimavanserin the first agent approved by FDA in 2016 for treatment of PDP [1,5].