Alcohols,

Drugs used in Parkinsonism , convulsions and Epilepsy

Hypnotics
Ethanol
Pharmacokinetics: After ingestion, ethanol is rapidly and completely absorbed : the drug is then
distributed to most body tissues, and its volume of distribution is equivalent to that of total body
water. Mechanism of action: are not fully understood. Specific receptors for ethanol have not
been identified, but ethanol appears to facilitate the action of GABA at GABA A receptors and
inhibits the ability of glutamate to activate NMDA receptors. It has been suggested that alcohol
blackouts may result from the latter action.
Effects:
CNS
Analgesia excitation somnolence. Depression, insomnia, anxiety, in severe cases, delirium
tremens.
III stages:
1) Decrease of eyes acuity
2) Reduce of informations perception
3) Deregulation of movements coordination
Cardiovascular system
1) Myocardial hypoxia myocardial infarction
2) Vasodilatation-hypothermia
3) Hypertension
4) Anemia
5) The ingestion of modest quantities of ethanol (10-15 g/d) may protect against heart disease.
Digestive system
1) irritation, inflammation, bleeding and scarring of the gut wall occur after chronic heavy use
of ethanol and may cause absorption defects.
2) Hepatitis and cirrhosis.
Endocrine system
Ginecomastia, testicular atrophy and salt retention occur, partly because of altered steroid
metabolism in the cirrhotic liver.
Fetal alcohol syndrome: Ethanol use in pregnancy is associated with teratogenic effects that
include mental retardation, growth deficiencies, microcephaly, and characteristic
underdevelopment of the mid face region.
Neoplasia: Ethanol is not a primary carcinogen, but its chronic use is associated with an
increased incidence of neoplastic disease.
Treatment: Disulfiram is used in some treatment programs. If ethanol is consumed by a patients
who has taken disulfiram , appear nausea, headache, hypotention. Naltrexone, fluoxetine can also
be used helpful in some patients.
Disulfiram- Inhibits hepatic microsomal drugmetabolizing enzymes. Inhibits aldehyde
dehydrogenase.
Chronic alcoholism results in enzyme induction. Acute alcoholic intoxication tends to inhibit
drug metabolism (whether person is alcoholic or not). Severe alcoholinduced hepatic dysfunction
may inhibit ability to metabolize drugs. Disulfiram-like reaction in the presence of certain drugs.
Additive central nervous system depression with other central nervous system depressants.
Hypnotic drugs (Soporifics)
Internal sleep cycles recur 4 to 5 times per night, each cycle being interrupted by a Rapid
Eye Movement (REM) sleep phase. The REM stage is characterized by EEG activity similar to
that seen in the waking state, rapid eye movements, vivid dreams, and occasional twitches of
individual muscle groups against a background of generalized atonia of skeletal musculature.
Normally, the REM stage is entered only after a preceding non-REM cycle. Frequent interruption
1

of sleep will, therefore, decrease the REM portion. Shortening of REM sleep (normally approx.
25% of total sleep duration) results in increased irritability and restlessness
during the daytime. With undisturbed night rest, REM deficits are compensated by increased
REM sleep on subsequent nights

Classification oh hypnotics
1. Agonist of benzodiazepine receptors.
1) Benzodiazepine derivates
a) Short action T 0,5 1,5-3 hours
- Tiazolam
- Midazolam
- Estazolam
- Ketazolam
b) Medium action T0,5 12-24 hours
- Temazepam
- Nitrazepam
- Lorazepam
- Oxazepam
- Clonazepam
c) Long action T 0,5 30-40 hours
I..Benzodiazepines
- Diazepam
- Flurazepam
- Flunitrazepam
- Fenazepam
II Not benzodiazepines
- Zopiclon
- Zolpidem
- buspiron
II. Hypnotics with anesthetic action (narcotic)
Heterocycles
barbiturics
Medium action
- Pentobarbital
Long action
- Phenobarbital
Aliphatic drugs
- Chloral hydrate
III. Remedies from various groups
- Sedatives
- Tranquilisators
- Neuroleptics (a little doses)
- Antihistamines
Mechanism of action:
Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the central
nervous system. Electrophysiologic studies have shown that benzodiazepines potentiate
GABAergic inhibition at all levels of the neuraxis, including the spinal cord, hypothalamus,
hippocampus, substantia nigra, cerebellar cortex, and cerebral cortex. Benzodiazepines appear to
increase the efficiency of GABAergic synaptic inhibition. The benzodiazepines do not substitute
for GABA but appear to enhance GABA's effects without directly activating GABA receptors or
opening the associated chloride channels. The enhancement in chloride ion conductance induced
by the interaction of benzodiazepines with GABA takes the form of an increase in the frequency
of channel-opening events.
2

The benzodiazepines, the barbiturates, zolpidem, and many other drugs bind to
molecular components of the GABAA receptor present in neuronal membranes in the central
nervous system.This receptor, which functions as a chloride ion channel, is activated by the
inhibitory neurotransmitter GABA
Benzodiazepines interact with specific receptors on the GABA receptor-chloride ion channel
macromolecular complex. The frequency of chloride ion channel opening is increased: these
drugs facilitate the inhibitory actions of GABA

.
Barbiturates also facilitate the actions of GABA at multiple sites in the central nervous
system, butin contrast to benzodiazepinesthey appear to increase the duration of the GABAgated chloride channel openings. At high concentrations, the barbiturates may also be GABAmimetic, directly activating chloride channels. These effects involve a binding site or sites
distinct from the benzodiazepine binding sites. Barbiturates are less selective in their actions than
benzodiazepines, since they also depress the actions of excitatory neurotransmitters (eg, glutamic
acid) and exert nonsynaptic membrane effects in parallel with their effects on GABA
neurotransmission. This multiplicity of sites of action of barbiturates may be the basis for their
ability to induce full surgical anesthesia and for their more pronounced central depressant effects
(which result in their low margin of safety) compared to benzodiazepines.
(Phenobarbital and other barbiturates also enhance the inhibitory actions of GABA but interact with a
different receptor site on chloride ion channels that results in an increased duration of chloride ion channel
opining.)

Effects:
- sedation and induction of sleep,
- reduction of anxiety and aggression
Benzodiazepines, barbiturates, and most older sedative-hypnotic drugs exert calming effects with
concomitant reduction of anxiety at relatively low doses. In most cases, however, the anxiolytic
actions of sedative-hypnotics are accompanied by some decremental effects on psychomotor and
cognitive functions. In experimental animal models, sedative-hypnotic drugs are able to
disinhibit punishment-suppressed behavior. This disinhibition has been equated with antianxiety
effects of sedative-hypnotics, and it is not a characteristic of all drugs that have sedative effects,.
However, the disinhibition of previously suppressed behavior may be more related to behavioral
disinhibitory effects of sedative-hypnotics, including euphoria, impaired judgment, and loss of
self-control, which can occur at dosages in the range of those used for management of anxiety.
The benzodiazepines also exert dose-dependent anterograde amnesic effects (inability to
remember events occurring during the drug's duration of action).
- hypnosis,
3

By definition, all of the sedative-hypnotics will induce sleep if high enough doses are
given. The effects of sedative-hypnotics on the stages of sleep depend on several factors,
including the specific drug, the dose, and the frequency of its administration. The effects of
benzodiazepines and older sedative-hypnotics on patterns of normal sleep are as follows: (1) the
latency of sleep onset is decreased (time to fall asleep); (2) the duration of stage 2 NREM sleep
is increased; (3) the duration of REM sleep is decreased; and (4) the duration of stage 4 NREM
slow-wave sleep is decreased. Zolpidem also decreases REM sleep but has minimal effect on
slow-wave sleep. Zaleplon decreases the latency of sleep onset with little effect on total sleep
time, NREM, or REM sleep. More rapid onset of sleep and prolongation of stage 2 are
presumably clinically useful effects. However, the significance of sedative-hypnotic drug effects
on REM and slow-wave sleep is not clear. Deliberate interruption of REM sleep causes anxiety
and irritability followed by a rebound increase in REM sleep at the end of the experiment. A
similar pattern of "REM rebound" can be detected following abrupt cessation of drug treatment
with sedative-hypnotics, especially when drugs with short durations of action are used at high
doses. Despite possible reductions in slow wave sleep, there are no reports of disturbances in the
secretion of pituitary or adrenal hormones when either barbiturates or benzodiazepines are used
as hypnotics. The use of sedative-hypnotics for more than 12 weeks leads to some tolerance to
their effects on sleep patterns.
- anesthesia,
Certain sedative-hypnotics in high doses will depress the central nervous
system to the point known as stage III of general anesthesia. However, the suitability of a
particular agent as an adjunct in anesthesia depends mainly on the physicochemical properties
that determine its rapidity of onset and duration of effect. Among the barbiturates, thiopental and
methohexital are very lipid-soluble, penetrating brain tissue rapidly following intravenous
administration, a characteristic favoring their use for induction of the anesthetic state. Rapid
tissue redistribution accounts for the short duration of action of these drugs, a feature useful in
recovery from anesthesia.
Benzodiazepinesincluding diazepam, lorazepam, and midazolamare used intravenously in
anesthesia, often in combination with other agents. Not surprisingly, benzodiazepines given in
large doses as adjuncts to general anesthetics may contribute to a persistent postanesthetic
respiratory depression. This is probably related to their relatively long half-lives and the
formation of active metabolites.
- muscle relaxation,
Most of the sedative-hypnotics are capable of inhibiting the development and spread of
epileptiform activity in the central nervous system. Some selectivity exists in that some members
of the group can exert anticonvulsant effects without marked central nervous system depression
(although psychomotor function may be impaired). Several benzodiazepinesincluding
clonazepam, nitrazepam, lorazepam, and diazepamare sufficiently selective to be clinically
useful in the management of seizure states (see Chapter 24: Antiseizure Drugs). Of the
barbiturates, phenobarbital and metharbital (converted to phenobarbital in the body) are effective
in the treatment of generalized tonic-clonic seizures.
- anticonvulsant actions
Some sedative-hypnotics, particularly members of the carbamate and benzodiazepine groups,
exert inhibitory effects on polysynaptic reflexes and internuncial transmission and at high doses
may also depress transmission at the skeletal neuromuscular junction. Somewhat selective
actions of this type that lead to muscle relaxation can be readily demonstrated in animals and
have led to claims of usefulness for relaxing contracted voluntary muscle in joint disease or
muscle spasm .
- antihistaminic effect.
Effects on Respiration and Cardiovascular Function
At hypnotic doses in healthy patients, the effects of sedative-hypnotics on respiration are
4

comparable to changes during natural sleep. However, even at therapeutic doses, sedativehypnotics can produce significant respiratory depression in patients with pulmonary disease.
Effects on respiration are dose-related, and depression of the medullary respiratory center is the
usual cause of death due to overdose of sedative-hypnotics.
At doses up to those causing hypnosis, no significant effects on the cardiovascular system are
observed in healthy patients. However, in hypovolemic states, heart failure, and other diseases
that impair cardiovascular function, normal doses of sedative-hypnotics may cause
cardiovascular depression, probably as a result of actions on the medullary vasomotor centers. At
toxic doses, myocardial contractility and vascular tone may both be depressed by central and
peripheral effects, leading to circulatory collapse. Respiratory and cardiovascular effects are
more marked when sedative-hypnotics are given intravenously.
Pharmacokinetics
Absorption and Distribution
The rates of oral absorption of benzodiazepines differ depending on a number of factors,
including lipophilicity. Oral absorption of triazolam is extremely rapid, and that of diazepam and
the active metabolite of clorazepate is more rapid than other commonly used benzodiazepines.
Clorazepate is converted to its active form, desmethyldiazepam (nordiazepam), by acid
hydrolysis in the stomach.
Oxazepam, lorazepam, and temazepam are absorbed from the gut at slower rates than
other benzodiazepines. The bioavailability of several benzodiazepines, including
chlordiazepoxide and diazepam, may be unreliable after intramuscular injection. Most of the
barbiturates and other older sedative-hypnotics are absorbed rapidly into the blood following
their oral administration.
Lipid solubility plays a major role in determining the rate at which a particular sedative-hypnotic
enters the central nervous system. For example, diazepam and triazolam are more lipid-soluble
than chlordiazepoxide and lorazepam; thus, the central nervous system actions of the former
drugs are more rapid in onset. The thiobarbiturates (eg, thiopental), in which the oxygen on C 2 is
replaced by sulfur, are very lipid-soluble, and a high rate of entry into the central nervous system
contributes to the rapid onset of their central effects (see Chapter 25: General Anesthetics). In
contrast, phenobarbital and meprobamate have quite low lipid solubility and penetrate the brain
slowly. All sedative-hypnotics cross the placental barrier during pregnancy. If sedative-hypnotics
are given in the predelivery period, they may contribute to the depression of neonatal vital
functions. Sedative-hypnotics are detectable in breast milk and may exert depressant effects in
the nursing infant. Although sedative-hypnotic drugs, including benzodiazepines, bind to plasma
proteins, few clinically significant interactions involving these drugs appear to be based on such
protein binding. One exception is chloral hydrate, which transiently increases the anticoagulant
effects of warfarin by displacement of the anticoagulant drug from such binding sites.
Biotransformation: Metabolic transformation to more water-soluble metabolites is necessary for
clearance of sedativehypnotics from the body. The microsomal drug-metabolizing enzyme
systems of the liver are most important in this regard. Few sedative-hypnotics are excreted from
the body in unchanged form, so elimination half-life depends mainly on the rate of metabolic
transformation.
Side effects:
- toxic effects resulting from acute overdose
- tolerance (decreased responsiveness to a drug following repeated exposureis a common
feature of sedative-hypnotic use. It may result in an increase in the dose needed to maintain
symptomatic improvement or to promote sleep.)
- dependence -most sedative-hypnotics including benzodiazepinesare capable of causing
physiologic dependence when used on a chronic basis.
- medullary depression (depression of respiratory system, hypotension, and cardiovascular
collapse,bradycardia)
- amnesia, depression
5

- Rebound effect
- nausea, vomiting
- allergy
Flumazenil is antagonist of hypnotic drugs. Flumazenil is one of several 1,4-benzodiazepine
derivatives with high affinity for the benzodiazepine receptor that act as competitive antagonists.
It is the only benzodiazepine receptor antagonist available for clinical use at present. It blocks
many of the actions of benzodiazepines (and imidazopyridines) but does not antagonize the
central nervous system effects of other sedativehypnotics, ethanol, opioids, or general
anesthetics. Flumazenil is approved for use in reversing the central nervous system depressant
effects of benzodiazepine overdose and to hasten recovery following use of these drugs in
anesthetic and diagnostic procedures. While the drug reverses the sedative effects of
benzodiazepines, antagonism of benzodiazepine-induced respiratory depression is less
predictable. When given intravenously, flumazenil acts rapidly but has a short half-life (0.7 1.3
hours) due to rapid hepatic clearance. Since all benzodiazepines have a longer duration of action
than flumazenil, sedation commonly recurs, requiring repeated administration of the antagonist.
Adverse effects of flumazenil include agitation, confusion, dizziness, and nausea. Flumazenil
may cause a severe precipitated abstinence syndrome in patients who have developed
physiologic benzodiazepine dependence. In patients who have ingested benzodiazepines with
tricyclic antidepressants, seizures and cardiac arrhythmias may occur following flumazenil
administration.Transient improvement in mental status has been reported with flumazenil when
used in patients with hepatic encephalopathy.
The newer hypnotics zolpidem and zolpidem are more selective in their central actions even
though they appear to act through benzodiazepine receptors.
Buspirone has selective anxiolytic effects, and its pharmacologic characteristics are quite
different from those of other drugs described in this chapter. Buspirone relieves anxiety without
causing marked sedative or euphoric effects. Unlike benzodiazepines, the drug has no hypnotic,
anticonvulsant, or muscle relaxant properties. Buspirone does not interact directly with
GABAergic systems. It may exert its anxiolytic effects by acting as a partial agonist at brain 5HT1A receptors, but it also has affinity for brain dopamine D 2 receptors. Buspirone-treated
patients show no rebound anxiety or withdrawal signs on abrupt discontinuance.
The drug is used in generalized anxiety states but is not very effective in panic disorders.
Zolpidem The drug binds selectively to the BZ1 ( 1) subtype of benzodiazepine receptors
that contain 1 subunits and facilitates GABA-mediated neuronal inhibition. Like the
benzodiazepines, the actions of zolpidem are antagonized by flumazenil. Unlike
benzodiazepines, zolpidem has minimal muscle relaxing and anticonvulsant effects. However,
amnestic effects have been reported with use of doses greater than recommended. The drug has a
rapid onset of action, and its duration of hypnotic action is close to that of triazolam. Zolpidem
causes minor effects on sleep patterns at the recommended hypnotic dose but can suppress REM
sleep at higher doses. Rebound insomnia may occur on abrupt discontinuance of higher doses.
Respiratory depression occurs if large doses of zolpidem are ingested with other CNS
depressants, including ethanol.

Antiepileptics
Epilepsy is a chronic brain disease of diverse etiology; it is characterized by recurrent
paroxysmal episodes of uncontrolled excitation of brain neurons. Involving larger or smaller
parts of the brain, the electrical discharge is evident in the electroencephalogram (EEG) as
synchronized rhythmic activity and manifests itself in motor, sensory, psychic, and vegetative
(visceral) phenomena. Because both the affected brain region and the cause of abnormal
excitability may differ, epileptic seizures can take many forms.

Classification
I Partial convulsions
1.psychomotor crisis
- carbamazepine
- phenobarbital
- phenytoin
- lamotridgine
- hexamidine
- clobazepam
- valproic acid
II Generalized convulsions
1) Petit mal (minor crisis)
- ethosuximide
- lamotridgine
- valproic acid
- clonazepam
- thrimetadione
2) Grand mal (major crisis) ( tonic-clonic convulsions)
- phenobarbital
- phenytoin
- valproic acid
- carbamazepine
- lamotridgine
- hexamidine
3) Status epilepticus
- diazepam
- phenobarbital
- lorazepam
- general anesthetics (intravenous)
- clonazepam
4) Myoclonic syndromes
1. valproic acid
2. clonazepam
3. diazepam
4. nitrazepam
5.
III Contractures
a) GABA derivates
Phenibut
baclofen
b) non benzodiazepines
tolperyzone
mefedol
c) benzodiazepines
diazepam
fenazepam
Antiepileptics
Classification 2
I order the drugs administrated in monotherapy
Phenobarbital
Phenytoin
Trimetadione
Ethsuximide
Primidone
Clonazepam
Carbamazepine
Nitrazepam
Valproic acid
Lamotridgine
II order these drugs are associated with I order drugs
Diazepam
Bromides
Acetazolamides
7

The brief duration of a single epileptic fit makes acute drug treatment unfeasible. Instead,
antiepileptics are used to prevent seizures and therefore need to be given chronically. Only in the
case of status epilepticus (a succession of several tonic-clonic seizures) is acute anticonvulsant
therapy indicated usually with benzodiazepines given i.v. or, if needed, rectally.
The initiation of an epileptic attack involves pacemaker cells; these differ from other nerve
cells in their unstable resting membrane potential, i.e., a depolarizing membrane current persists
after the action potential terminates. Therapeutic interventions aim to stabilize neuronal resting
potential and, hence, to lower excitability. In specific forms of epilepsy, initially a single drug
is tried to achieve control of seizures, valproate usually being the drug of first choice in
generalized seizures, and carbamazepine being preferred for partial (focal), especially partial
complex, seizures. Dosage is increased until seizures are no longer present or adverse effects
become unacceptable. Only when monotherapy with different agents proves inadequate can
changeover to a second-line drug or combined use (add on) be recommended, provided
that the possible risk of pharmacokinetic interactions is taken into account. The precise mode of
action of antiepileptic drugs remains unknown. Some agents appear to lower neuronal
excitability by several mechanisms of action. In principle, responsivity can be decreased by
inhibiting excitatory or activating inhibitory neurons. Most excitatory nerve cells utilize
glutamate and most inhibitory neurons utilize -aminobutyric acid (GABA) as their transmitter
Various drugs can lower seizure threshold, notably certain neuroleptics, the tuberculostatic
isoniazid, and "-lactam antibiotics in high doses; they are, therefore, contraindicated in
seizure disorders. Glutamate receptors comprise three subtypes, of which the NMDA subtype has
the greatest therapeutic importance. (N-methyl-D-aspartate is a synthetic selective agonist.) This
receptor is a ligand-gated ion channel that, upon stimulation with glutamate, permits
entry of both Na+ and Ca2+ ions into the cell. The antiepileptics lamotrigine, phenytoin, and
phenobarbital inhibit, among other things, the release of glutamate. Felbamate is a glutamate
antagonist.
Benzodiazepines and Phenobarbital augment activation of the GABAA receptor by
physiologically released amounts of GABA. Chloride influx is increased, counteracting
depolarization.
Progabide is a direct GABA-mimetic. Tiagabin blocks removal of GABA from the synaptic cleft
by decreasing its re-uptake. Vigabatrin inhibits GABA catabolism. Gabapentin may augment the
availability of glutamate as a precursor in GABA synthesis and can also act as
a K+-channel opener.
Carbamazepine, valproate, and phenytoin enhance inactivation of voltage-gated sodium and
calcium channels and limit the spread of electrical excitation by inhibiting sustained highfrequency firing of neurons.
Ethosuximide blocks a neuronal Ttype Ca2+ channel and represents a special class because it is
effective only in absence seizures. All antiepileptics are likely, albeit to different degrees, to
produce adverse effects. Sedation, difficulty in concentrating, and slowing of psychomotor drive
encumber practically all antiepileptic therapy. Moreover, cutaneous, hematological, and hepatic
changes may necessitate a change in medication. Phenobarbital, primidone, and phenytoin may
lead to osteomalacia (vitamin D prophylaxis) or megaloblastic anemia (folate prophylaxis).
During treatment with phenytoin, gingival hyperplasia may develop in ca. 20% of patients.
Valproic acid (VPA) is gaining increasing acceptance as a first-line drug; it is less sedating than
other anticonvulsants. Tremor, gastrointestinal upset, and weight gain are frequently observed;
reversible hair loss is a rarer occurrence. Hepatotoxicity may be due to a toxic catabolite (4-en
VPA). Adverse reactions to carbamazepine include: nystagmus, ataxia, diplopia, particularly if
the dosage is raised too fast. Gastrointestinal problems and skin rashes are frequent. It exerts an
antidiuretic effect (sensitization of collecting ducts to vasopressin !water intoxication).
Carbamazepine is also used to treat trigeminal neuralgia and neuropathic pain. Valproate,
carbamazepine, and other anticonvulsants pose teratogenic risks. Despite this, treatment should

continue during pregnancy, as the potential threat to the fetus by a seizure is greater. However, it
is mandatory to administer the lowest dose affording safe and effective prophylaxis. Concurrent
high-dose administration of folate may prevent neural tube developmental defects.
Carbamazepine, phenytoin, phenobarbital, and other anticonvulsants (except for gabapentin)
induce hepatic enzymes responsible for drug biotransformation. Combinations between
anticonvulsants or with other drugs may result in clinically important interactions (plasma
level monitoring!). For the often intractable childhood epilepsies, various other agents are
used, including ACTH and the glucocorticoid, dexamethasone. Multiple (mixed) seizures
associated with the slow spike-wave (LennoxGastaut) syndrome may respond to valproate,
lamotrigine, and felbamate, the latter being restricted to drug-resistant seizures owing to its
potentially fatal liver and bone marrow toxicity. Benzodiazepines are the drugs of choice for
status epilepticus ; however, development of tolerance renders them less suitable for long-term
therapy. Clonazepam is used for myoclonic and atonic seizures. Clobazam, a 1,5-benzodiazepine
exhibiting an increased anticonvulsant/sedative activity ratio, has a similar range of clinical uses.
Personality changes and paradoxical excitement are potential side effects.
Clomethiazole can also be effective for controlling status epilepticus, but is used mainly to treat
agitated states, especially alcoholic delirium tremens and associated seizures.
Topiramate, derived from D-fructose, has complex, long-lasting anticonvulsant actions that
cooperate to limit the spread of seizure activity; it is effective in partial seizures and as an add-on
in LennoxGastaut syndrome.
Antiparkinsonian Drugs
Parkinsons disease (shaking palsy) and its syndromal forms are caused by a degeneration of
nigrostriatal dopamine neurons. The resulting striatal dopamine deficiency leads to overactivity
of cholinergic interneurons and imbalance of striopallidal output pathways, manifested by
poverty of movement (akinesia), muscle stiffness (rigidity), tremor at rest, postural instability,
and gait disturbance.
Pharmacotherapeutic measures are aimed at restoring dopaminergic function or suppressing
cholinergic hyperactivity.
Classification
1.Remedies that activated dopaminergic system
1) predecessors of dopamine
Levodopa (L Dopa)
Levodopa adjunct (mixed drugs)
- Sinement
- Nacom
- Madopar
- Entancapone
2) dopaminimimetics
- Bromocriptine
3) MAO inhibitor
- Selegeline
2. Remedies that inhibits glutamatergic system
- Amantadine
3. Remedies that inhibits cholinergic system
- Trihexyphenidyl
- Difenyltropine
- Benztropine mesilate
- Triperidine
L-Dopa. Dopamine itself cannot penetrate the blood-brain barrier; however, its natural precursor,
L-dihydroxyphenylalanine (levodopa), is effective in replenishing striatal dopamine levels,
9

because it is transported across the blood-brain barrier via an amino acid carrier and is
subsequently decarboxylated by DOPA-decarboxylase, present in striatal tissue. Decarboxylation
also takes place in peripheral organs where dopamine is not needed, likely causing undesirable
effects (tachycardia, arrhythmias resulting from activation of 1-adrenoceptors, hypotension, and
vomiting). Extracerebral production of dopamine can be prevented by inhibitors of DOPAdecarboxylase (carbidopa, benserazide) that do not penetrate the blood-brain barrier, leaving
intracerebral decarboxylation unaffected. Excessive elevation of brain dopamine levels may lead
to undesirable reactions, such as involuntary movements (dyskinesias) and mental disturbances.
Dopamine receptor agonists. Deficient dopaminergic transmission in the striatum can be
compensated by ergot derivatives (bromocriptine , lisuride, cabergoline, and pergolide) and
nonergot compounds (ropinirole, pramipexole). These agonists stimulate dopamine receptors
(D2, D3, and D1 subtypes), have lower clinical efficacy than levodopa, and share its main
adverse effects.
Inhibitors of monoamine oxidase-B (MAOB). This isoenzyme breaks down dopamine in the
corpus striatum and can be selectively inhibited by selegiline. Inactivation of norepinephrine,
epinephrine, and 5-HT via MAOA is unaffected. The antiparkinsonian effects of
selegiline may result from decreased dopamine inactivation (enhanced levodopa response) or
from neuroprotective mechanisms (decreased oxyradical formation or blocked bioactivation of
an unknown neurotoxin).
Inhibitors of catechol-O-methyltransferase (COMT). L-Dopa and dopamine become
inactivated by methylation. The responsible enzyme can be blocked by entacapone, allowing
higher levels of L-dopa and dopamine to be achieved in corpus striatum.
Anticholinergics. Antagonists at muscarinic cholinoceptors, such as benzatropine and biperiden,
suppress striatal cholinergic overactivity and thereby relieve rigidity and tremor; however,
akinesia is not reversed or is even exacerbated. Atropinelike peripheral side effects and
impairment of cognitive function limit the tolerable dosage.
Amantadine. Early or mild parkinsonian manifestations may be temporarily relieved by
amantadine. The underlying mechanism of action may involve, inter alia, blockade of
ligandgated ion channels of the glutamate/ NMDA subtype, ultimately leading to a diminished
release of acetylcholine. Administration of levodopa plus carbidopa (or benserazide) remains the
most effective treatment, but does not provide benefit beyond 35 y and is followed by gradual
loss of symptom control, on-off fluctuations, and development of orobuccofacial and limb
dyskinesias. These long-term drawbacks of levodopa therapy may be delayed by early
monotherapy with dopamine receptor agonists. Treatment of advanced disease requires the
combined administration of antiparkinsonian agents.

10