| most drugs act on cns by: | Most drugs that act on the central nervous system (CNS) appear to do so by changing ion flow through transmembrane channels of nerve cells. |
| voltage gated ion channels | Voltage-gated ion channels respond to changes in membrane potential. They are concentrated on the axons of nerve cells and include the sodium channels responsible for action potential propagation. Cell bodies and dendrites also have voltage-sensitive ion channels for potassium and calcium. |
| A. Types of Ion Channels | Ion channels of neuronal membranes are of 2 major types: voltage gated and ligand gated. |
| ligand gated ion channel | Ligand-gated ion channels, also called ionotropic receptors, respond to chemical neurotransmitters that bind to receptor subunits present in their macromolecular structure. Neurotransmitters also bind to G protein-coupled receptors (metabotropic receptors) that can modulate voltage-gated ion channels. Neurotransmitter-coupled ion channels are found on cell bodies and on both the presynaptic and postsynaptic sides of synapses. |
| Types of Receptor-Channel Coupling | Coupling may be through a receptor that acts directly on the channel protein (panel B), through a receptor that is coupled to the ion channel through a G protein (C), or through a receptor coupled to a G protein that modulates the formation of diffusible second messengers, including (cAMP), (IP3), and (DAG), which secondarily modulate ion channels (D). |
| A few neurotoxic substances damage or kill nerve cells. | A few neurotoxic substances damage or kill nerve cells. For example, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is cytotoxic to neurons of the nigrostriatal dopaminergic pathway. |
| brain nueronal systems | The CNS contains 2 types of neuronal systems: hierarchical and diffuse. |
| heiarchal systems | These systems are delimited in their anatomic distribution and generally contain large myelinated, rapidly conducting fibers. Hierarchical systems control major sensory and motor functions. The major excitatory transmitters in these systems are aspartate and glutamate. These systems also include numerous small inhibitory interneurons, which use γ-aminobutyric acid (GABA) or glycine as transmitters. Drugs that affect hierarchical systems often have profound effects on the overall excitability of the CNS. |
| norepinephrine | Noradrenergic neuron cell bodies are mainly located in the brain stem and the lateral tegmental area of the pons. These neurons fan out broadly to provide most regions of the CNS with diffuse noradrenergic input. Excitatory effects are produced by activation of α1 and β1 receptors. Inhibitory effects are caused by activation of α2 and β2 receptors. CNS stimulants (eg, amphetamines, cocaine), monoamine oxidase inhibitors (eg, phenelzine), and tricyclic antidepressants (eg, amitriptyline) are examples of drugs that enhance the activity of noradrenergic pathways. |
| serotonnin receptors | Most serotonin (5-hydroxytryptamine; 5-HT) pathways originate from cell bodies in the raphe or midline regions of the pons and upper brain stem; these pathways innervate most regions of the CNS. Multiple 5-HT receptor subtypes have been identified and, with the exception of the 5-HT3 subtype, all are metabotropic. |
| serotonnin pathways | 5-HT1A receptors and GABAB receptors share the same potassium channel. Serotonin can cause excitation or inhibition of CNS neurons depending on the receptor subtype activated. Both excitatory and inhibitory actions can occur on the same neuron if appropriate receptors are present. Most of the agents used in the treatment of major depressive disorders affect serotonergic pathways (eg, tricyclic antidepressants, selective serotonin reuptake inhibitors). |
| Role of the Ion Current Carried by the Channel | (EPSPs) are usually generated by the opening of sodium or calcium channels. In some synapses, similar depolarizing potentials result from the closing of potassium channels.(IPSPs) are usually generated by the opening of potassium or chloride channels. For example, activation of postsynaptic metabotropic receptors increases the efflux of potassium. Presynaptic inhibition can occur via a decrease in calcium influx elicited by activation of metabotropic receptors. |
| SITES & MECHANISMS OF DRUG ACTION | A small number of agents exert their effects through direct interactions with molecular components of ion channels on axons. Examples include certain anticonvulsants (eg, carbamazepine, phenytoin), local anesthetics, and some drugs used in general anesthesia. However, the effects of most important CNS drugs are exerted mainly at synapses. drugs may act presynaptically to alter the synthesis, storage, release, reuptake, or metabolism of transmitter chemicals. Other drugs can activate or block both pre- and postsynaptic receptors for specific transmitters or can interfere with the actions of second messengers. |
| action of cns stimulants serotonnin | The actions of some CNS stimulants and newer antipsychotic drugs (eg, olanzapine) also appear to be mediated via effects on serotonergic transmission. Reserpine, which may cause severe depression of mood, depletes vesicular stores of both serotonin and norepinephrine in CNS neurons. |
| drugs that influence gabaa | Drugs that influence GABAA receptor systems include sedative-hypnotics (eg, barbiturates, benzodiazepines, zolpidem) and some anticonvulsants (eg, gabapentin, tiagabine, vigabatrin). Glycine receptors, which are more numerous in the cord than in the brain, are blocked by strychnine, a spinal convulsant. |
| gaba and glycine | GABA is the primary neurotransmitter mediating IPSPs in neurons in the brain; it is also important in the spinal cord. GABAA receptor activation opens chloride ion channels. GABAB receptors (activated by baclofen, a centrally acting muscle relaxant) are coupled to G proteins that either open potassium channels or close calcium channels. Fast IPSPs are blocked by GABAA receptor antagonists, and slow IPSPs are blocked by GABAB receptor antagonists. |
| endocannabinoids | These are widely distributed brain lipid derivatives (eg, 2-arachidonyl-glycerol) that bind to receptors for cannabinoids found in marijuana. They are synthesized and released postsynaptically after membrane depolarization but travel backward acting presynaptically (retrograde) to decrease transmitter release, via their interaction with a specific cannabinoid receptor. |
| neurotransmission in cns | the CNS communicates through the use of more than 10 (and perhaps as many as 50 ) different neurotransmitters. In contrast, the ans uses only two primary neurotransmitters, acetylcholine and norepinephrine. |
| diffuse stystem | Diffuse or nonspecific systems are broadly distributed, with single cells frequently sending branches to many different areas. The axons are fine and branch repeatedly to form synapses with many cells. Axons commonly have periodic enlargements (varicosities) that contain transmitter vesicles. |
| transmitters and drugs affecting diffuse systems | The transmitters in diffuse systems are often amines (norepinephrine, dopamine, serotonin) or peptides that commonly exert actions on metabotropic receptors. Drugs that affect these systems often have marked effects on such CNS functions as attention, appetite, and emotional states. |
| Criteria for Transmitter Status | To be accepted as a neurotransmitter, a candidate chemical must (1) be present in higher concentration in the synaptic area than in other areas (ie, must be localized in appropriate areas), (2) be released by electrical or chemical stimulation via a calcium-dependent mechanism, and (3) produce the same sort of postsynaptic response that is seen with physiologic activation of the synapse (ie, must exhibit synaptic mimicry). |
| acetylcholine | Approximately 5% of brain neurons have receptors for acetylcholine (ACh). Most CNS responses to ACh are mediated by a large family of G protein-coupled muscarinic M1 receptors that lead to slow excitation when activated. The ionic mechanism of slow excitation involves a decrease in membrane permeability to potassium. Of the nicotinic receptors present in the CNS (they are less common than muscarinic receptors), those on the Renshaw cells activated by motor axon collaterals in the spinal cord are the best characterized. Drugs affecting the activity of cholinergic systems in the brain include the acetylcholinesterase inhibitors used in Alzheimer’s disease (eg, rivastigmine) and the muscarinic blocking agents used in parkinsonism (eg, benztropine). |
| dopamine | Dopamine exerts slow inhibitory actions at synapses in specific neuronal systems, commonly via G protein-coupled activation of potassium channels (postsynaptic) or inhibition of calcium channels (presynaptic). The D2 receptor is the main dopamine subtype in basal ganglia neurons, and it is widely distributed at the supraspinal level. Dopaminergic pathways include the nigrostriatal, mesolimbic, and tuberoinfundibular tracts. |
| dopaminergic pathwasys effects | Drugs that block the activity of dopaminergic pathways include older antipsychotics (eg, chlorpromazine, haloperidol), which may cause parkinsonian symptoms. Drugs that increase brain dopaminergic activity include CNS stimulants (eg, amphetamine), and commonly used antiparkinsonism drugs (eg, levodopa). |
| glutamic acid | Most neurons in the brain are excited by glutamic acid. High concentrations of glutamic acid in synaptic vesicles are achieved by the vesicular glutamate transporter (VGLUT). Both ionotropic and metabotropic receptors have been characterized. Subtypes of glutamate receptors include the N-methyl-d-aspartate (NMDA) receptor, which is blocked by phencyclidine (PCP) and ketamine. NMDA receptors appear to play a role in synaptic plasticity related to learning and memory. Memantine is an NMDA antagonist introduced for treatment of Alzheimer’s dementia. Excessive activation of NMDA receptors after neuronal injury may be responsible for cell death. Glutamate metabotropic receptor activation can result in G protein-coupled activation of phospholipase C or inhibition of adenylyl cyclase. |
| peptide transmitters | Many peptides have been identified in the CNS, and some meet most or all of the criteria for acceptance as neurotransmitters. The best-defined peptides are the opioid peptides (beta-endorphin, met- and leu-enkephalin, and dynorphin), which are distributed at all levels of the neuraxis. |
| peptide descr | Some of the important therapeutic actions of opioid analgesics (eg, morphine) are mediated via activation of receptors for these endogenous peptides. Another peptide, substance P, is a mediator of slow EPSPs in neurons involved in nociceptive sensory pathways in the spinal cord and brain stem. Peptide transmitters differ from nonpeptide transmitters in that (1) the peptides are synthesized in the cell body and transported to the nerve ending via axonal transport, and (2) no reuptake or specific enzyme mechanisms have been identified for terminating their actions. |
| epsp | Stimulation of excitatory neurons causes a movement of ions that results in a depolarization of the postsynaptic membrane. These (EPSP) are generated by the following: 1) Stimulation of an excitatory neuron causes the release of neurotransmitter molecules, such as glutamate or acetylcholine, which bind to receptors on the postsynaptic cell membrane. This causes a transient increase in the permeability of sodium (Na+) ions. 2) The infl ux of Na+ causes a weak depolarization, or EPSP, that moves the postsynaptic potential toward its firing threshold. 3) If the number of stimulated excitatory neurons increases, more excitatory neurotransmitter is released. This ultimately causes the EPSP depolarization of the postsynaptic cell to pass a threshold, thereby generating an all-or-none action potential. [The generation of a nerve impulse typically reflects the activation of synaptic receptors by thousands of excitatory neurotransmitter molecules released from many nerve fibers.] |
| inhibitory pathway | 1) Stimulation of inhibitory neurons releases neurotransmitter molecules, such as γ-aminobutyric acid (GABA) or glycine, which bind to receptors on the postsynaptic cell membrane. This causes a transient increase in the permeability of specific ions, such as potassium (K+) and chloride (Cl–) ions. 2) The influx of Cl– and efflux of K+ cause a weak hyperpolarization, or IPSP, that moves the postsynaptic potential away from its firing threshold. This diminishes the generation of action potentials. |
| Combined effects of the EPSP and IPSP | Most neurons in the CNS receive both EPSP and IPSP input. Thus, several different types of neurotransmitters may act on the same neuron, but each binds to its own specific receptor. The overall resultant action is due to the summation of the individual actions of the various neurotransmitters on the neuron. The neurotransmitters are not uniformly distributed in the CNS but are localized in specific clusters of neurons, the axons of which may synapse with specific regions of the brain. Many neuronal tracts, thus, seem to be chemically coded, and this may offer greater opportunity for selective modulation of certain neuronal pathway |
| neurodegenerative diseases | Neurodegenerative diseases of the CNS include Parkinson disease, Alzheimer disease, MS and ALS. These devastating illnesses are characterized by the progressive loss of selected neurons in discrete brain areas, resulting in characteristic disorders of movement, cognition, or both. For example, Alzheimer disease is characterized by the loss of cholinergic neurons in the nucleus basalis of Maynert, whereas Parkinson disease is associated with a loss of dopaminergic neurons in the substantia nigra. The number of cases is expected to increase as the proportion of elderly people in the population increases. |
| antimuscarinic | The antimuscarinic agents are much less efficacious than levodopa and play only an adjuvant role in antiparkinsonism therapy. The actions of benztropine, trihexyphenidyl, procyclidine, and biperiden are similar, although individual patients may respond more favorably to one drug. Each of these drugs can induce mood changes and produce xerostomia (dryness of the mouth) and visual problems, as do all muscarinic blockers. They interfere with gastrointestinal peristalsis and are contraindicated in patients with glaucoma, prostatic hyperplasia, or pyloric stenosis. Blockage of cholinergic transmission produces effects similar to augmentation of dopaminergic transmission (again, because of the creation of an imbalance in the dopamine/acetylcholine ratio |
| antimusc adverse effects | Adverse effects are similar to those caused by high doses of atropine, for example, pupillary dilation, confusion, hallucination, sinus tachycardia, urinary retention, constipation, and dry mouth. |
| dementia of alzheimer | only palliative and provides modest short-term benefit. None of the currently available therapeutic agents have been shown to alter the underlying neurodegenerative process. Dementia of the Alzheimer typea has three distinguishing features: 1) accumulation of senile plaques (β-myloid accumulations); 2) formation of numerous neurofi brillary tangles; and 3) loss of cortical neurons, particularly cholinergic neurons. Current therapies are aimed at either improving cholinergic transmission within the CNS or preventing excitotoxic actions resulting from overstimulation of NMDA-glutamate receptors in selected brain areas. |
| ache inhibit | Numerous studies have linked the progressive loss of cholinergic neurons and, presumably, cholinergic transmission within the cortex to the memory loss that is a hallmark symptom of Alzheimer disease. It is postulated that inhibition of acetylcholinesterase (AChE) within the CNS will improve cholinergic transmission, at least at those neurons that are still functioning. Currently, four reversible AChE inhibitors are approved for the treatment of mild to moderate Alzheimer disease. They are donepezil, galantamine, rivastigmine, and tacrin. Except for galantamine, which is competitive, all are uncompetitive inhibitors of AChE and appear to have some selectivity for AChE in the CNS as compared to the periphery. Galantamine may also be acting as an allosteric modulator of the nicotinic receptor in the CNS and, therefore, secondarily may increase cholinergic neurotransmission through a separate mechanism. At best, these compounds provide a modest reduction in the rate of loss of cognitive functioning in Alzheimer patients. |
| rivastigmine | Rivastigmine is hydrolyzed by AChE to a carbamylate metabolite and has no interactions with drugs that alter the activity of cytochrome P450-dependent enzymes. The other agents are substrates for cytochrome P450 and have a potential for such interactions. |
| rivastigmine adverse effects | Common adverse effects include nausea, diarrhea, vomiting, anorexia, tremors, bradycardia, and muscle cramps, all of which are predicted by the actions of the drugs to enhance cholinergic neurotransmission. Unlike the others, tacrine is associated with hepatotoxicity. |
| B. NMDA-receptor antagonist | Stimulation of glutamate receptors in the CNS appears to be critical for the formation of certain memories. However, overstimulation of glutamate receptors, particularly of the NMDA type, has been shown to result in excitotoxic eff ects on neurons and is suggested as a mechanism for neurodegenerative or apoptotic (programmed cell death) processes. Binding of glutamate to the NMDA receptor assists in the opening of an associated ion channel that allows Na+ and, particularly, Ca2+ to enter the neuron. Unfortunately, excess intracellular Ca2+ can activate a number of processes that ultimately damage neurons and lead to apoptosis. |
| B. NMDA-receptor antagonist memantine | Antagonists of the NMDA-glutamate receptor are often neuroprotective, preventing the loss of neurons following ischemic and other injuries. Memantine is a dimethyl adamantane derivative. Memantine acts by physically blocking the NMDA receptor–associated ion channel, but, at therapeutic doses, only a fraction of these channels are actually blocked. This partial blockade may allow memantine to limit Ca2+ influx into the neuron, such that toxic intracellular levels are not achieved during NMDA-receptor overstimulation, while still permitting sufficient Ca2+ flow through unblocked channels to preserve other vital processes that depend on Ca2+ (or Na+) influx through these channels. This is in contrast to psychotoxic agents such as phencyclidine, which occupy and block nearly all of these channels. In short term studies, memantine has been shown to slow the rate of memory loss in both vascular-associated and Alzheimer dementia in patients with moderate to severe cognitive losses. However, there is no evidence that memantine prevents or slows the neurodegeneration in patients with Alzheimer disease or is more effective than the AChE inhibitors. Memantine is well tolerated, with few dose-dependent adverse events. |
| side effects nmda m | Expected side effects, such as confusion, agitation, and restlessness, are indistinguishable from the symptoms of Alzheimer disease. Given its different mechanism of action and possible neuroprotective effects, memantine is often given in combination with an AChE inhibitor. Long-term data showing a significant effect of this combination is not available. |
| multiple scelorosis | Multiple sclerosis (MS) is an autoimmune inflammatory demyelinating disease of the (CNS). The course of MS is variable. For some, MS may consist of one or two acute neurologic episodes. In others, it is a chronic, relapsing, or progressive disease that may span 10 to 20 years. |
| drugs used in ms | Historically, medications, such as the corticosteroids (for example, dexamethasone and prednisone), have been used to treat acute attacks of the disease. Other medications that have been used include chemotherapeutic agents, such as cyclophosphamide and azathioprine. |
| new treatment ms | Newer medications that have been approved for the treatment of MS include interferon β1a and interferon β1b as immune system modulators of the interferons and the T-helper cell response, which contribute to the inflammatory responses that lead to demyelination of the axon sheaths. |
| Mitoxantrone: | The cytotoxic anthracycline analog, mitoxantrone, which can kill T cells, may also be used. The major target of these medications is to modify the body’s immune response through inhibition of white blood cell–mediated inflammatory processes that eventually lead to myelin sheath damage and a decreased or inappropriate axonal communication between cells. |
| mitoxantrone adverse | Adverse effects of these medications may include depression; local injection or infusion reactions; hepatic enzyme increases; flulike symptoms, such as fever and myalgias and leukopenia. |
| Fingolimod | Fingolimod is the first oral drug that can slow the progression of disability and reduce the frequency and severity of symptoms in MS, offering patients an alternative to the currently available injectable therapies. Fingolimod alters lymphocyte migration, resulting in sequestration of lymphocytes in lymph nodes. Fingolimod is effective for reducing the relapse rate in patients with MS. However, this benefit is associated with an increased risk of lifethreatening infection. |
| Dalfampridine | Dalfampridine, a potassium channel blocker administered orally, improves walking speeds vs placebo. It is the first drug approved for this use. Currently approved MS drugs are indicated to decrease relapse rates or in some cases to prevent accumulation of disability |
| Other: Glatiramer | Other: Glatiramer is a synthetic polypeptide that resembles myelin protein and may act as a “decoy” to T-cell attack. |
| natalizumab | A monoclonal antibody, natalizumab, is also indicated for MS in patients who have failed first-line therapies. |
| IX. DRUGS USED IN AMYOTROPHIC LATERAL SCLEROSIS | Though not indicated for the treatment of Alzheimer disease, another NMDA-receptor antagonist is indicated for the management of ALS. Riluzole blocks glutamate, sodium channels, and calcium channels. It may improve the survival time and delay the need for ventilator support in patients suffering from ALS |
| Parkinsonism | is a progressive neurological disorder of muscle movement, characterized by tremors, muscular rigidity, bradykinesia (slowness in initiating and carrying out voluntary movements), and postural and gait abnormalities. Most cases involve people over the age of 65, among whom the incidence is about 1 in 100 individuals. |
| parkinsonism etiology | The cause of Parkinson disease is unknown for most patients. The disease is correlated with destruction of dopaminergic neurons in the substantia nigra with a consequent reduction of dopamine actions in the corpus striatum, parts of the brain’s basal ganglia system that are involved in motor control. The loss of dopamine neurons in the substantia nigra is evidenced by diminished overall uptake of dopamine precursors in this region, which can be visualized using positron-emission tomography and the dopamine analog fluorodopa. Genetic factors do not play a dominant role in the etiology of Parkinson disease, although they may exert some influence on an individual’s susceptibility to the disease. It appears increasingly likely that an as-yet unidentified environmental factor may play a role in the loss of dopaminergic neurons. |
| 1. Substantia nigra: | The substantia nigra, part of the extrapyramidal system, is the source of dopaminergic neurons that terminate in the neostriatum. Each dopaminergic neuron makes thousands of synaptic contacts within the neostriatum and, therefore, modulates the activity of a large number of cells. These dopaminergic projections from the substantia nigra fire tonically rather than in response to specific muscular movements or sensory input. Thus, the dopaminergic system appears to serve as a tonic, sustaining influence on motor activity rather than participating in specific movements. |
| 2. Neostriatum | : Normally, the neostriatum is connected to the substantia nigra by neurons that secrete the inhibitory transmitter GABA at their termini in the substantia nigra. In turn, cells of the substantia nigra send neurons back to the neostriatum, secreting the inhibitory transmitter dopamine at their termini. This mutual inhibitory pathway normally maintains a degree of inhibition of the two separate areas. In Parkinson disease, destruction of cells in the substantia nigra results in the degeneration of the nerve terminals responsible for secreting dopamine in the neostriatum. Thus, the normal modulating inhibitory influence of dopamine on cholinergic neurons in the neostriatum is significantly diminished, resulting in overproduction or a relative overactivity of acetylcholine by the stimulatory neurons. This triggers a chain of abnormal signaling, resulting in loss of the control of muscle movements. |
| 3. Secondary parkinsonism: | 3. Secondary parkinsonism: Parkinsonian symptoms infrequently follow viral encephalitis or multiple small vascular lesions. Drugs such as the phenothiazines and haloperidol, whose major pharmacologic action is blockade of dopamine receptors in the brain, may also produce parkinsonian symptoms. These drugs should not be used in Parkinson disease patients. |
| strategy of treatment | In addition to an abundance of inhibitory dopaminergic neurons, the neostriatum is also rich in excitatory cholinergic neurons that oppose the action of dopamine. Many of the symptoms of parkinsonism reflect an imbalance between the excitatory cholinergic neurons and the greatly diminished number of inhibitory dopaminergic neurons. Therapy is aimed at restoring dopamine in the basal ganglia and antagonizing the excitatory effect of cholinergic neurons, thus reestablishing the correct dopamine/acetylcholine balance. Because long-term treatment with levodopa is limited by fl uctuations in therapeutic responses, strategies to maintain CNS dopamine levels as constant as possible have been devised. |
| drug effect | Currently available drugs off er temporary relief from the symptoms of the disorder, but they do not arrest or reverse the neuronal degeneration caused by the disease. |
| A. Levodopa and carbidopa | Levodopa is a metabolic precursor of dopamine. It restores dopaminergic neurotransmission in the corpus striatum by enhancing the synthesis of dopamine in the surviving neurons of the substantia nigra. In patients with early disease, the number of residual dopaminergic neurons in the substantia nigra (typically about 20 percent of normal) is adequate for conversion of levodopa to dopamine. Thus, in new patients, the therapeutic response to levodopa is consistent, and the patient rarely complains that the drug effects “wear off .” Unfortunately, with time, the number of neurons decreases, and fewer cells are capable of taking up exogenously administered levodopa and converting it to dopamine for subsequent storage and release. Consequently, motor control fluctuation develops. Relief provided by levodopa is only symptomatic, and it lasts only while the drug is present in the body. |
| carbidopa | The effects of levodopa on the CNS can be greatly enhanced by coadministering carbidopa, a dopa decarboxylase inhibitor that does not cross the blood-brain barrier. |
| mechanism of action levodopa | Because parkinsonism results from insufficient dopamine in specific regions of the brain, attempts have been made to replenish the dopamine deficiency. Dopamine itself does not cross the blood-brain barrier, but its immediate precursor, levodopa, is actively transported into the CNS and is converted to dopamine in the brain. Large doses of levodopa are required, because much of the drug is decarboxylated to dopamine in the periphery, resulting in side effects that include nausea, vomiting, cardiac arrhythmias, and hypotension. |
| b. Carbidopa: moa | Carbidopa, a dopa decarboxylase inhibitor, diminishes the metabolism of levodopa in the gastrointestinal tract and peripheral tissues, thereby increasing the availability of levodopa to the CNS. The addition of carbidopa lowers the dose of levodopa needed by four- to fivefold and, consequently, decreases the severity of the side effects arising from peripherally formed dopamine. |
| 3. Therapeutic uses: | Levodopa decreases the rigidity, tremors, and other symptoms of parkinsonism. Levodopa in combination with carbidopa is a potent and efficacious drug regimen currently available to treat Parkinson disease. In approximately two-thirds of patients with Parkinson disease, levodopa–carbidopa treatment substantially reduces the severity of the disease for the first few years of treatment. Patients then typically experience a decline in response during the third to fifth year of therapy. |
| 4. Absorption and metabolism: levidopa | The drug is absorbed rapidly from the small intestine (when empty of food). Levodopa has an extremely short half-life (1 to 2 hours), which causes fluctuations in plasma concentration. This may produce fluctuations in motor response, which generally correlate with the plasma concentrations of levodopa, or perhaps give rise to the more troublesome “on-off” phenomenon, in which the motor fluctuations are not related to plasma levels in a simple way. Motor fluctuations may cause the patient to suddenly lose normal mobility and experience tremors, cramps, and immobility. Ingestion of meals, particularly if high in protein, interferes with the transport of levodopa into the CNS. Large, neutral amino acids (for example, leucine and isoleucine) compete with levodopa for absorption from the gut and for transport across the blood-brain barrier. Thus, levodopa should be taken on an empty stomach, typically 45 minutes before a meal. Withdrawal from the drug must be gradual. |
| peripheral adverse effects levidopa | Anorexia, nausea, and vomiting occur because of stimulation of the chemoreceptor trigger zone of the medulla. Tachycardia and ventricular extrasystoles result from dopaminergic action on the heart. Hypotension may also develop. Adrenergic action on the iris causes mydriasis, and, in some individuals, blood dyscrasias and a positive reaction to the Coombs test are seen. Saliva and urine are a brownish color because of the melanin pigment produced from catecholamine oxidation. |
| b. CNS effects: adverse levidopa | Visual and auditory hallucinations and abnormal involuntary movements (dyskinesias) may occur. These CNS effects are the opposite of parkinsonian symptoms and reflect the overactivity of dopamine at receptors in the basal ganglia. Levodopa can also cause mood changes, depression, psychosis, and anxiety. |
| 6. Interactions: levidopa | The vitamin pyridoxine (B6) increases the peripheral breakdown of levodopa and diminishes its effectiveness. Concomitant administration of levodopa and monoamine oxidase inhibitors (MAOIs), such as phenelzine, can produce a hypertensive crisis caused by enhanced catecholamine production. Therefore, caution is required when they are used simultaneously. In many psychotic patients, levodopa exacerbates symptoms, possibly through the buildup of central catecholamines. In patients with glaucoma, the drug can cause an increase in intraocular pressure. Cardiac patients should be carefully monitored because of the possible development of cardiac arrhythmias. Antipsychotic drugs are generally contraindicated in parkinsonian patients, because these potently block dopamine receptors and produce a parkinsonian syndrome themselves. However low doses of certain “atypical” antipsychotic agents are sometimes used to treat levodopa-induced psychiatric symptoms. |
| Rasagiline | Rasagiline, an irreversible and selective inhibitor of brain monoamine oxidase Type B, has five times the potency of selegiline. Unlike selegiline, rasagiline is not metabolized to an amphetaminelike substance. |
| B. Selegiline | Selegiline , also called deprenyl, selectively inhibits MAO Type B (which metabolizes dopamine) at low to moderate doses but does not inhibit MAO Type A (which metabolizes norepinephrine and serotonin) unless given at above recommended doses, where it loses its selectivity. By, thus, decreasing the metabolism of dopamine, selegiline has been found to increase dopamine levels in the brain. Therefore, it enhances the actions of levodopa when these drugs are administered together. Selegiline substantially reduces the required dose of levodopa. Unlike nonselective MAOIs, selegiline at recommended doses has little potential for causing hypertensive crises. However, if selegiline is administered at high doses, the selectivity of the rug is lost, and the patient is at risk for severe hypertension. Selegiline is metabolized to methamphetamine and amphetamine, whose stimulating properties may produce insomnia if the drug is administered later than midafternoon. |
| C. Catechol-O-methyltransferase inhibitors | Normally, the methylation of levodopa by catechol-O-methyltransferase (COMT) to 3-O-methyldopa is a minor pathway for levodopa metabolism. However, when peripheral dopamine decarboxylase activity is inhibited by carbidopa, a signifi cant concentration of 3-O-methyldopa is formed that competes with levodopa for active transport into the CNS. Inhibition of COMT by entacapone or tolcapone leads to decreased plasma concentrations of 3-O-methyldopa, increased central uptake of levodopa, and greater concentrations of brain dopamine. Both of these agents have been demonstrated to reduce the symptoms of “wearing-off ” phenomena seen in patients on levodopa–carbidopa. |
| Entacapone and tolcapone are | Entacapone and tolcapone are nitrocatechol derivatives that selectively and reversibly inhibit COMT. The two drugs diff er primarily in their pharmacokinetics and in some adverse effects. |
| 1. Pharmacokinetics: comt | Oral absorption of both drugs occurs readily and is not infl uenced by food. They are extensively bound to plasma albumin (>98 percent), with limited volumes of distribution. |
| 1. Pharmacokinetics: tolcapone | Tolcapone differs from entacapone in that the former penetrates the blood-brain barrier and inhibits COMT in the CNS. However, the inhibition of COMT in the periphery appears to be the primary therapeutic action. Tolcapone has a relatively long duration of action (probably due to its affinity for the enzyme) compared to entacapone, which requires more frequent dosing. Both drugs are extensively metabolized and eliminated in feces and urine. Dosage may need to be adjusted in patients with moderate or severe cirrhosis. |
| adverse effects talcapone entacapone | Both drugs exhibit adverse effects that are observed in patients taking levodopa–carbidopa, including diarrhea, postural hypotension, nausea, anorexia, dyskinesias, hallucinations, and sleep disorders. Most seriously, fulminating hepatic necrosis is associated with tolcapone use. Therefore, it should be used, along with appropriate hepatic function monitoring, only in patients in whom other modalities have failed. Entacapone does not exhibit this toxicity and has largely replaced tolcapone. |
| D. Dopamine-receptor agonists | This group of anti-Parkinson compounds includes bromocriptine, an ergot derivative, and newer, nonergot drugs, ropinirole, pramipexole, and rotigotine. These agents have durations of action longer than that of levodopa and, thus, have been effective in patients exhibiting fluctuations in their response to levodopa. Initial therapy with the newer drugs is associated particularly with less risk of developing dyskinesias and motor fluctuations when compared to patients started with levodopa therapy. Bromocriptine, pramipexole, and ropinirole are all effective in patients with advanced Parkinson disease complicated by motor fluctuations and dyskinesias. However, these drugs are ineffective in patients who have shown no therapeutic response to levodopa. Apomorphine is also used in severe and advanced stages of the disease as an injectable dopamine agonist to supplement the oral medications commonly prescribed. |
| 1. Bromocriptine: | Bromocriptine a derivative of the vasoconstrictive alkaloid, ergotamine, is a dopamine-receptor agonist. The dose is increased gradually during a period of 2 to 3 months. |
| 2. Apomorphine, pramipexole, ropinirole, and rotigotine: | These are nonergot dopamine agonists that have been approved for the treatment of Parkinson disease. Pramipexole and ropinirole are agonists at dopamine receptors. Apomorphine and rotigotine are newer dopamine agonists available in injectable and transdermal delivery systems, respectively. Apomorphine is meant to be used for the acute management of the hypomobility “off” phenomenon. These agents alleviate the motor deficits in both levodopa-naïve patients (patients who have never been treated with levodopa) and patients with advanced Parkinson disease who are taking levodopa. Dopamine agonists may delay the need to use levodopa therapy in early Parkinson disease and may decrease the dose of levodopa in advanced Parkinson disease. |
| bromocriptine side effect | Side effects severely limit the utility of the dopamine agonists. The actions of bromocriptine are similar to those of levodopa, except that hallucinations, confusion, delirium, nausea, and orthostatic hypotension are more common, whereas dyskinesia is less prominent. In psychiatric illness, bromocriptine and levodopa may cause the mental condition to worsen. Serious cardiac problems may develop, particularly in patients with a history of myocardial infarction. In patients with peripheral vascular disease, a worsening of the vasospasm occurs, and in patients with peptic ulcer, there is a worsening of the ulcer. Because bromocriptine is an ergot derivative, it has the potential to cause pulmonary and retroperitoneal fibrosis. |
| pramipexole and ropinirole | Unlike the ergotamine derivatives, pramipexole and ropinirole do not xacerbate peripheral vasospasm, and they do not cause fibrosis. Nausea, hallucinations, insomnia, dizziness, constipation, and orthostatic hypotension are among the more distressing side effects of these drugs, but dyskinesias are less frequent than with levodopa. |
| The dependence of pramipexole on renal function | The dependence of pramipexole on renal function for its elimination cannot be overly stressed. For example, cimetidine, which inhibits renal tubular secretion of organic bases, increases the half-life of pramipexole by 40 percent. The fluoroquinolone antibiotics and other inhibitors of the CYP1A2 hepatic enzyme have been shown to inhibit the metabolism of ropinirole and to enhance the AUC (area under the concentration vs. time) curve by some 80 percent. Rotigotine is a dopamine agonist used in the treatment of the signs and symptoms of early stage Parkinson disease. It is administered as a once-daily transdermal patch that provides even pharmacokinetics over 24 hours. |
| E. Amantadine | It was accidentally discovered that the antiviral drug amantadine, which is effective in the treatment of influenza, has an antiparkinsonism action. Amantadine has several effects on a number of neurotransmitters implicated in causing parkinsonism, including increasing the release of dopamine, blockading cholinergic receptors, and inhibiting the N-methyl-D-aspartate (NMDA) type of glutamate receptors. Current evidence supports an action at NMDA receptors as the primary action at therapeutic concentrations. [Note: If dopamine release is already at a maximum, amantadine has no effect.] Amantadine is less efficacious than levodopa, and tolerance develops more readily. However, amantadine has fewer side effects. The drug has little effect on tremor, but it is more effective than the anticholinergics against rigidity and bradykinesia. |
| amantadine adverse effects | The drug may cause restlessness, agitation, confusion, and hallucinations, and, at high doses, it may induce acute toxic psychosis. Orthostatic hypotension, urinary retention, peripheral edema, and dry mouth also may occur. |
