19 - CNS Pharmacology (Complete File).pdf

Prepared by: Renz Victor T. Guangco, M.D.
NCM 106: PHARMACOLOGY
CENTRAL NERVOUS SYSTEM
PHARMACOLOGY
SEDATIVE-HYPNOTICS, ANTISEIZURE DRUGS, ANTIDEPRESSANTS, ANTIPSYCHOTICS,
MOOD STABILIZERS AND DRUGS FOR PARKINSONISM

• Sedative-hypnotics are commonly ordered for
treatment of sleep disorders.
• The mildest form of CNS depression is sedation,
which diminishes physical and mental responses at
lower dosages of certain CNS depressants but does
not a
ff
ect consciousness.
• Sedatives are used mostly during the daytime.
• Increasing the drug dose can produce a hypnotic
e
ff
ect—not hypnosis but a form of “natural” sleep.
THE SEDATIVE-HYPNOTIC DRUGS
INTRODUCTION AND GENERAL PROFILE

• Sedative-hypnotic drugs are sometimes the same drug;
however, certain drugs are used more often for their
hypnotic e
ff
ect.
• With very high doses of sedative-hypnotic drugs,
anesthesia may be achieved
• Sedatives were
fi
rst prescribed to reduce tension and
anxiety.
• Barbiturates were initially used for their antianxiety e
ff
ect
• Because of the many side e
ff
ects of barbiturates and
their potential for physical and mental dependency, they
are now less frequently prescribed.

• Hypnotic drug therapy should usually be short term to
prevent drug dependence and tolerance.
• Interrupting hypnotic therapy can decrease drug
tolerance
• Abruptly discontinuing a high dose of hypnotic taken
over a long period can cause withdrawal symptoms.
• In such cases the dose should be tapered to avoid
withdrawal symptoms

• Hypnotic drug therapy should usually be short term to
prevent drug dependence and tolerance.
• Interrupting hypnotic therapy can decrease drug
tolerance
• Abruptly discontinuing a high dose of hypnotic taken
over a long period can cause withdrawal symptoms.
• In such cases the dose should be tapered to avoid
withdrawal symptoms
• As a general rule, the lowest dose should be
taken to achieve sleep.

COMMON SIDE EFFECTS AND ADVERSE REACTIONS

• The long-acting group includes phenobarbital,
which is used to control seizures in epilepsy.
• The intermediate-acting barbiturates, such as
butabarbital, are useful as sleep sustainers for
maintaining long periods of sleep.
• Because these drugs take approximately 1
hour for the onset of sleep, they are not
prescribed for those who have trouble getting
to sleep.
• The short-acting barbiturate secobarbital may be
used for procedure sedation.
BARBITURATES
GENERAL PROFILE

• Increase duration of the GABA-gated
channels opening
• GABAmimetic, directly activating
Cl channels
• Depresses excitatory
neurotransmitters & exert non-
synaptic membrane e
ff
ects
• Can induce full surgical anesthesia
BARBITURATES
MECHANISM OF ACTION

• Phenobarbital: oral and IV
• Excreted unchanged in the urine (20-30%)
• Elimination rate is increased by alkalization of
the urine.
• Thiopental: IV
• Undergo redistribution
BARBITURATES
PHARMACOKINETICS

• Pentobarbital and secobarbital are used
primarily for short-term treatment of insomnia.
• Other uses include control of seizures,
preoperative anxiety, and sedation induction.
• They have a rapid onset with a short duration
of action
• Considered short-acting barbiturates.
BARBITURATES
PHARMACODYNAMICS

• Pentobarbital and secobarbital are used
primarily for short-term treatment of insomnia.
• Phenobarbital – Seizure disorder
• Metharbital – converted to Phenobarbital in
the body
• Thiopental & Methohexital – IV anesthetic
BARBITURATES
CLINICAL USES

• Potent inducer of hepatic microsomal enzymes
• Tolerance and dependence
• ABSOLUTE CONTRAINDICATIONS: patients
w/ history of hereditary coproporphyria, acute
intermittent porphyria, variegate porphyria, or
symptomatic porphyria
BARBITURATES
SIDE EFFECTS AND ADVERSE REACTIONS

• Alcohol, opioids, and other sedative-hypnotics
used in combination- further depress the CNS.
• Pentobarbital increases hepatic enzyme action
(potent cytochrome inducer)
• Increased metabolism and decreased e
ff
ect of
drugs such as oral anticoagulants,
glucocorticoids, tricyclic antidepressants, and
quinidine.
• Pentobarbital may cause hepatotoxicity if taken
with large doses of acetaminophen.
BARBITURATES
DRUG INTERACTIONS

• This drug group is ordered as sedative-
hypnotics for inducing sleep.
• Several benzodiazepines marketed as
hypnotics include
fl
urazepam, alprazolam,
temazepam, triazolam, estazolam, and
quazepam.
• Increased anxiety might be the cause of
insomnia for some patients, so lorazepam and
diazepam can be used to alleviate the anxiety.
BENZODIAZEPINES
GENERAL PROFILE

• Bind to speci
fi
c GABA A receptor
subunits at CNS neuronal synapses
facilitating frequency of GABA-
mediated chloride ion channel opening
—enhance membrane hyperpolarization.
BENZODIAZEPINES
MECHANISM OF ACTION

• Benzodiazepines are well absorbed through the
gastrointestinal (GI) mucosa.
• They are rapidly metabolized in the liver to
active metabolites.
• Benzodiazepines usually have an intermediate
half-life of usually 8 to 24 hours and are highly
protein bound.
• When taken with other highly protein-bound
drugs, more free (or unbound) drug is available,
resulting in an increased risk for adverse e
ff
ects
BENZODIAZEPINES
PHARMACOKINETICS

• Oral absorption di
ff
er in lipophilicity
• Diazepam and Triazolam more lipid soluble
• IM absorption is erratic
• All cross the placental barrier during pregnancy
• Detectable in breast milk
• Displacement of Warfarin from the binding site
BENZODIAZEPINES
PHARMACOKINETICS

BENZODIAZEPINES
DRUG CLASSES BASED ON DURATION OF ACTION

BENZODIAZEPINES
PHARMACOKINETICS

• Benzodiazepines are used to treat insomnia by
inducing and sustaining sleep.
• They have a rapid onset of action and
intermediate- to long-acting e
ff
ects.
• The normal recommended dose of a
benzodiazepine may be too much for the older
adult, so half the dose is recommended initially
to prevent overdosing
BENZODIAZEPINES
CLINICAL USES

• Alprazolam – Anxiety and Agoraphobia
• Triazolam, Quazepam, Temazepam, Flurazepam, Estazolam
– Insomnia
• Diazepam - Anxiety, status epilepticus, anesthetic premed,
muscle relaxation
• Lorazepam - Anxiety, anesthetic premedication, symptomatic
alcohol withdrawal
• Midazolam - Pre-anesthetic & intraoperative medication
• Diazepam, Lorazepam, Midazolam – for Anesthesia
• Clonazepam - Seizure, acute mania, movement disorder
• Clonazepam, Nitrazepam, Lorazepam, and Diazepam -
Seizures
BENZODIAZEPINES
CLINICAL USES

• Tolerance, Dependence
• Prolonged Sleep, Ataxia, Lethargy, Drowsiness
• Impaired Judgement, Impaired Motor Skill,
Confusional State
• Anterograde Amnesia
• DISADVANTAGES: interaction w/ alcohol will
lead to long-lasting hang-over e
ff
ects
BENZODIAZEPINES

• Additive e
ff
ect: alcohol, other CNS
depressants, opioid analgesics,
anticonvulsants, phenothiazenes, anti-
histamine, anti-HPN, and antidepressants
• CYP450 inhibitor: Cimetidine, OCP, prolong
BZD half-life
BENZODIAZEPINES
DRUG INTERACTIONS

• Benzodiazepine antagonist
• Blocks many of the actions of benzodiazepines, zolpidem,
zaleplon, and eszopiclone
• It does not antagonize the central nervous system e
ff
ects of
other sedative-hypnotics, ethanol, opioids, or general
anesthetics.
• Approved for use in reversing the central nervous system
depressant e
ff
ects of benzodiazepine overdose and to hasten
recovery following use of these drugs in anesthetic and
diagnostic procedures.
BENZODIAZEPINE ANTIDOTE: FLUMAZENIL
GENERAL PROFILE

• IV; acts rapidly but short half-life (0.7-1.3 hours) due to rapid
hepatic clearance
• AE: agitation, confusion, dizziness, dyspnea, and nausea
• Patients who have ingested benzodiazepines with tricyclic
antidepressants, seizures and cardiac arrhythmias may follow
fl
umazenil administration
BENZODIAZEPINE ANTIDOTE: FLUMAZENIL
GENERAL PROFILE

• Similar to benzodiazepines
• Binds to BZ 1 (omega receptor)
• Minor e
ff
ects on sleep architecture. Less tolerance and
dependence.
• T ½: 1.5-3.5 hours
• AE: headache, dizziness, confusion, ataxia
• Rifampin decreases half-life
OTHER SEDATIVE HYPNOTIC DRUGS
ZOLPIDEM

• Agonist at MT1 & MT2 receptors at the
suprachiasmatic nuclei of the brain
• → No direct e
ff
ects on GABAergic
neurotransmission in the central nervous system.
• Ramelteon reduced the latency of persistent sleep
with no e
ff
ects on sleep architecture and no
rebound insomnia or signi
fi
cant withdrawal
symptoms.
• AE: dizziness, somnolence, fatigue, endocrine
changes, ↓ testosterone, ↑ prolactin
RAMELTEON

• DRUG INTERACTIONS:
• CYP1A2: Cipro
fl
oxacin, Fluvoxamine, Tacrine,
Zileuton
• CYP2C9: Fluconazole
• Rifampicin induces its metabolism
• Used with caution in liver dysfunction
RAMELTEON

• 5-HT1A agonist
• Has a
ffi
nity for D2 receptors
• Used in generalized anxiety disorder
• Buspirone treated patients show no
rebound anxiety or withdrawal signs on
abrupt discontinuance.
• Not e
ff
ective in blocking the acute
withdrawal syndrome resulting from abrupt
cessation of use of benzodiazepines or
other sedative-hypnotics.
BUSPIRONE

• No sedation, no motor incoordination, no
withdrawal e
ff
ects
• Rapidly absorbed orally but undergoes
extensive
fi
rst-pass metabolism via
hydroxylation and dealkylation reactions to
form several active metabolites.
• AE: nausea, dizziness, headache,
restlessness
• Rifampin ↓ half-life of Buspirone
• Ketoconazole & Erythromycin ↑ half-life of
Buspirone
BUSPIRONE

• A seizure disorder results from abnormal electric
discharges from the cerebral neurons
• It is characterized by a loss or disturbance of
consciousness and usually involuntary, uncontrolled
movements.
• Seizures occur when there is a disruption in the
electrical functioning of the brain due to an
imbalance in the excitation and inhibition of electrical
impulses.
AN OVERVIEW OF SEIZURES

• An excessive amount of excitation discharges could be
due to several reasons:
• A defect in the neuronal membrane (organic brain
injury)
• Electrolyte imbalance
• Decrease in the gamma-aminobutyric acid (GABA)
inhibitory action.

• The EEG records abnormal electric discharges of the
cerebral cortex.
• Of all seizure cases, 75% are considered to be
primary, or idiopathic (of unknown cause)
• The remainder are secondary to brain trauma, brain
anoxia (absence of oxygen), infection, or
cerebrovasculardisorders (e.g., cerebrovascular
accident [CVA], stroke).
• Epilepsy is a chronic, usually lifelong disorder.
• The majority of persons with seizure disorder had
their
fi
rst seizure before 20 years of age.

ACTION POTENTIAL FIRING: A SCHEMA

THE TARGETS OF THE DIFFERENT ANTI-SEIZURE DRUGS

THE ANTISEIZURE DRUGS
OVERVIEW OF THE ANTISEIZURE DRUGS AND THEIR RESPECTIVE CLASSES

THE ANTISEIZURE DRUGS
OVERVIEW OF THE DRUGS AND THEIR INDICATIONS

• Blocks sustained high-frequency repetitive
fi
ring of
action potential
• Prolonging the inactivated state of Na channels
• Decreases the synaptic release of glutamate &
enhances the release of GABA
• Alters Na, K, & Ca conductance, membrane
potentials & the concentrations of amino acids &
the neurotransmitters NE, Ach, & GABA.
• USE: partial seizures / generalized tonic-clonic
seizures
PHENYTOIN
MECHANISM OF ACTION

• Oral, IM (Fosphenytoin – well absorbed after IM
admin)
• Highly bound to plasma proteins; T ½: 12-36 hours
• Accumulates in brain, liver, muscle, and fat
• Metabolized to inactive metabolites that are
excreted in the urine.
• Elimination is dose-dependent
PHENYTOIN
PHARMACOKINETICS

• Nystagmus, diplopia, ataxia, sedation, gingival
hyperplasia, hirsutism, coarsening of facial
features, fetal hydantoin syndrome
• Mild peripheral neuropathy, megaloblastic anemia,
fever, skin rash
PHENYTOIN

PHENYTOIN

• Displace Phenytoin from binding site –
Sulfonamides, Valproate, Phenylbutazone
• Inhibit Phenytoin metabolism – Cimetidine,
Disul
fi
ram, Doxycycline, INH, Phenylbutazone,
Sulfa, Warfarin, Chloramphenicol
• Enhance Phenytoin metabolism – Barbiturates,
Carbamazeine, Pyridoxine, Theophylline
• Phenytoin decreases serum levels of:
Carbamazepine, Chloramphenicol, Corticosteroids,
Haloperidol, Quinidine, Theophylline, OCP
PHENYTOIN
DRUG INTERACTIONS

• Blocks Na channels
• Decrease synaptic transmission
• Potentiation of K currents
• USE: DOC for partial seizures & generalized
tonic-clonic seizures / Trigeminal neuralgia.
• Also used for mania (bipolar disorder)
CARBAMAZEPINE
MECHANISM OF ACTION

• Slowing absorption by giving the drug after meals
helps the patient tolerate larger total daily doses.
• 70% bound to plasma proteins; no displacement of
other drugs from protein binding sites
• Ability to induce microsomal enzymes
• Completely metabolized
PHARMACOKINETICS
CARBAMAZEPINE

• Diplopia
• Ataxia
• Idiosyncratic blood dyscrasia
• Aplastic anemia
• Agranylocytosis
• Leukopenia
CARBAMAZEPINE

• Increase Carbamazepine via metabolism:
Cimetidine, Erythromycin, INH
• Decrease Carbamazepine via increase
metabolism: Phenytoin, Valproic acid
• Carbamazepine decreases levels: Warfarin, OCP,
Doxycyline, Phenytoin, Haloperidol
• Carbamazepine increases levels: Cimetidine, INH
• Lithium induces Carbamazepine toxicity
DRUG INTERACTIONS
CARBAMAZEPINE

GENERAL PROFILE AND MECHANISM OF ACTION
VIGABATRIN

• Irreversible inhibitor of GABA aminotransferase (GABA-T)
• This paradoxically leads to inhibition of synaptic GABA-A
receptor responses, but also prolongs the activation of
extra synaptic GABA-A receptors that mediate tonic
inhibition
• Also inhibit the vesicular GABA transporter
VIGABATRIN

• Rapidly absorbed in the GI tract
• Plasma ½ life: 6-8 hours
PHARMACOKINETICS
VIGABATRIN

• USE: treatment of partial seizures and infantile spasms
(WEST syndrome).
• Used in patients unresponsive to conventional drugs.
CLINICAL USES
VIGABATRIN

• Most important adverse e
ff
ect: Irreversible retinal
dysfunction
• Drowsiness, behavioral & mood changes, weight gain,
visual
fi
eld defect
• Less common but more troublesome: agitation,
confusion, and psychosis
• BUT a preexisting mental illness is just a relative
contraindication to drug use.
VIGABATRIN

• Adjunctive treatment for partial seizures
• Inhibitor of GABA uptake in both neurons and glia.
(GAT 1)
• Increases extracellular GABA levels in the forebrain
and hippocampus where GAT-1 is preferentially
expressed
• Potentiation of tonic inhibition
TIAGABINE

• Tiagabine is 90–100% bioavailable, has linear
kinetics, and is highly protein bound.
• Half-life: 5–8 hours
• Food decreases the peak plasma concentration
BUT to avoid adverse e
ff
ects, the drug should be
taken with food
• The drug is metabolized in the liver by oxidation
• Elimination is primarily in the feces (60–65%) and
urine (25%)
TIAGABINE

• Nervousness, dizziness, tremor, di
ffi
culty in
concentrating, and depression.
• Excessive confusion, somnolence, or ataxia may
require discontinuation.
• Can cause seizures in some patients
TIAGABINE

• Used for partial seizures
• Blocks glutamate NMDA receptors
• Potentiates GABA A receptors
GENERAL PROFILE
FELBAMATE

• Half-life: 20 hours
• Metabolized by hydroxylation and conjugation
• A signi
fi
cant percentage of the drug is excreted
unchanged in the urine.
PHARMACOKINETICS
FELBAMATE

• Aplastic anemia
• Hypersensitivity reactions
• Severe hepatitis
FELBAMATE

• Blocks voltage-dependent Na & Ca channels (L-
type)
• Depresses the excitatory action of kainate on
glutamate receptors
• Potentiates inhibitory e
ff
ect of GABA
• Multiple e
ff
ects of Topiramate may arise through a
primary action on kinases altering the
phosphorylation of voltage-gated and ligand-gated
ion channels
TOPIRAMATE
MECHANISM OF ACTION

• Monotherapy demonstrated e
ffi
cacy against partial
and generalized tonic-clonic seizures.
• The drug is also approved for the Lennox-Gastaut
syndrome, and may be e
ff
ective in infantile spasms
and even absence seizures.
• Also approved for the treatment of migraine
headaches.
GENERAL USES
TOPIRAMATE

• MOST COMMON: Cognitive side e
ff
ects – May
prompt drug discontinuance
• Paresthesia
• First few days of treatment: Somnolence, fatigue,
dizziness, nervousness, and confusion
• In children: Decreased sweating (oligohydrosis) and
an elevation in body temperature
• Long term SE: Weight loss
TOPIRAMATE

• Acute myopia and glaucoma
• May require prompt drug withdrawal
• Teratogenesis (hypospadias), sedation, mental
dulling, renal stones, weight loss
TOPIRAMATE

• Inhibits voltage-gated sodium channels
• Also inhibits voltage-gated Ca channels (N- and P/Q-
type channels), which would account for its e
ffi
cacy in
primary generalized seizures in childhood, including
absence attacks
• Decreases the synaptic release of glutamate
MECHANISM OF ACTION
LAMOTRIGINE

• Monotherapy for partial seizures.
• Also active against absence and myoclonic seizures
in children and is approved for seizure control in the
Lennox-Gastaut syndrome.
• Also e
ff
ective for bipolar disorder.
CLINICAL USES
LAMOTRIGINE

• Completely absorbed; T ½: 24 hours
• Has linear kinetics and is metabolized primarily by
glucuronidation to the 2- N -glucuronide, which is
excreted in the urine.
PHARMACOKINETICS
LAMOTRIGINE

• MOST COMMON: Hypersensitivity reaction
• Diplopia, ataxia, headache, dizziness
• Life-threatening skin disorders: It can produce a
potentially fatal rash (Stevens-Johnson syndrome)
• Blood dyscrasias
LAMOTRIGINE

• Hypersensitivity reactions
• Diplopia
• Ataxia
• Headache
• Dizziness
• Life-threatening skin disorders
• Hematotoxicity
LAMOTRIGINE

LAMOTRIGINE

• Blocks sustained high-frequency repetitive
fi
ring of neurons
(Na channel blockade).
• Blocks NMDA receptor-mediated excitation
• Increased levels of GABA in the brain after administration of
Valproate
• Facilitate glutamic acid decarboxylase (GAD) - enzyme
responsible for GABA synthesis
• Inhibitory e
ff
ect on GAT 1
• At very high concentrations, Valproate inhibits GABA
transaminase in the brain, thus blocking degradation of
GABA.
MECHANISMS OF ACTION
VALPROIC ACID

• Well-absorbed after oral dose; BA >80%; T ½: 9-18
hours
• Food may delay absorption, and decreased toxicity
may result if the drug is given after meals.
PHARMACOKINETICS
VALPROIC ACID

• MOST COMMON: nausea, vomiting, and other gastrointestinal
complaints such as abdominal pain and heartburn
• Fine tremors
• Weight gain, increase appetite
• Hair loss
• Hepatotoxicity
• Thrombocytopenia
• Contraindicated in Pregnancy: May cause NTD - Spina bi
fi
da
• Sedation (uncommon)
VALPROIC ACID

• Nausea and vomiting
• GIT discomfort (pain & heartburn)
• Fine tremors
• Weight gain
• Increase appetite
VALPROIC ACID
• Hair loss
• Hepatotoxicity
• Thrombocytopenia
• Spina bi
fi
da
• Sedation

• Decrease Valproate from increase metabolism:
Carbamazepine
• Increase Valproate levels w/ antacid (↑ absorption)
• Salicylates (displace from binding site)
• When used with Clonazepam, may precipitate
absence seizures
DRUG INTERACTIONS
VALPROIC ACID

• Modify the synaptic or non-synaptic
release of GABA
• Binds to the a2δ subunit voltage sensitive
Ca channels
• Decease Ca entry w/ predominant e
ff
ect
on presynaptic N-type channels
• Decrease in the synaptic release of
glutamate
GABAPENTIN & PREGABALIN: GENERAL PROFILE AND MECHANISM OF ACTIONS
GABAPENTINOIDS

• Pregabalin is rapidly and completely
absorbed as compared to gabapentin.
• Peak plasma concentrations: pregabalin
> gabapentin
• Transported in the bloodstream as a free
drug and is actively transported in the
blood-brain barrier
GABAPENTIN & PREGABALIN: PHARMACOKINETICS
GABAPENTINOIDS

• Oral bioavailability: Pregabalin = 90%
Gabapentin = 30–60%
• Food has only a slight e
ff
ect on the rate
and extent of absorption of gabapentin but
can substantially delay the absorption of
pregabalin without a
ff
ecting the
bioavailability.
• Excreted unchanged in the kidneys
GABAPENTIN & PREGABALIN: GENERAL PROFILE AND MECHANISM OF ACTIONS
GABAPENTINOIDS

• GABAPENTIN - adjunct against partial
and generalized seizures
• PREGABALIN - adjunctive treatment of
partial seizures, with or without
secondary generalization. Also approved
for use in neuropathic pain, including
painful diabetic peripheral neuropathy
and post-herpetic neuralgia
GABAPENTIN & PREGABALIN: CLINICAL USES
GABAPENTINOIDS

• Somnolence
• Dizziness
• Ataxia
• Headache
• Tremor
GABAPENTIN & PREGABALIN: SIDE EFFECTS AND ADVERSE REACTIONS
GABAPENTINOIDS

• Decrease Ca channel (T-type) current
• Inhibits Na-K-ATPase
• Depresses the cerebral metabolic rate
• Inhibits GABA aminotransferase
• DRUG OF CHOICE FOR ABSENCE SEIZURES
MECHANISM OF ACTION
ETHOSUXAMIDE

• Absorbed completely
• Completely metabolized, principally by hydroxylation, to
inactive metabolites.
PHARMACOKINETICS
ETHOSUXAMIDE

• ADVERSE EFFECTS: gastric distress, lethargy,
headache
• DRUG INTERACTION: Administration of Ethosuximide
with Valproic acid results in a decrease in Ethosuximide
clearance and higher steady-state concentrations owing
to inhibition of metabolism.
SIDE EFFECTS AND DRUG INTERACTIONS
ETHOSUXAMIDE

• Binds selectively to the synaptic vesicular protein SV2A.
• Modi
fi
es the synaptic release of glutamate and GABA
through an action on vesicular function
MECHANISM OF ACTION
LEVETERACETAM

• Adjunctive treatment of partial seizures in adults and
children for primary generalized tonic-clonic seizures
and for the myoclonic seizures of juvenile myoclonic
epilepsy.
CLINICAL USES
LEVETERACETAM

• Somnolence
• Asthenia
• Ataxia
• Dizziness
LEVETERACETAM

COMMONLY USED BENZODIAZEPINES FOR SEIZURE DISORDERS
THE BENZODIAZEPINES

denotes a variety of mental disorders: the presence of delusions (false
beliefs), various types of hallucinations, usually auditory or visual, but
sometimes tactile or olfactory, and grossly disorganized thinking in a clear
sensorium
GENERAL DEFINITION
PSYCHOSIS

A GENERAL OVERVIEW
THE DOPAMINERGIC SYSTEMS

1. Mesolimbic-mesocortical: behavior and psychosis
2. Nigrostriatal – coordination and smoothness of voluntary movements
3. Tuberoinfundibular – inhibition of anterior pituitary secretion of prolactin
4. Medullary-periventricular: eating behavior
5. Incertohypothalamic – regulation of motivation of copulatory behavior
THE DOPAMINERGIC SYSTEMS

• It is a particular kind of psychosis
characterized mainly by a clear sensorium
but a marked thinking disturbance.
• Considered to be a neurodevelopmental
disorder.
• This implies that structural and functional
changes in the brain are present even in
utero in some patients, or that they
develop during childhood and
adolescence, or both
A GENERAL OVERVIEW
SCHIZOPHRENIA

THE POSITIVE & NEGATIVE SYMPTOMS
SCHIZOPHRENIA

THE PATHOPHYSIOLOGY OF PSYCHOSIS
ANTIPSYCHOTIC DRUGS

• A group of agents that lessen delusions, hallucinations,
and disordered thinking as well as improve mood,
produce anxiolysis, and resolve sleep problems in
patients a
ffl
icted w/ schizophrenia, bipolar disorder,
psychotic depression, senile psychosis, drug-induced
psychosis, and other types of psychosis.
• Neuropleptics are antipsychotics associated w/ high
incidence of EPS even in therapeutic doses.
• The relatively newer atypical agents are more often used
currently because they do not produce much EPS.
A GENERAL OVERVIEW
ANTIPSYCHOTIC DRUGS

• An INVERSE AGONIST is an agent that binds to the
same receptor as an agonist but induces the opposite
pharmacologic response.
• Prerequisite for response is that the receptor must
have a constitutive/intrinsic/basal level activity in the
absence of any ligand.
• An inverse agonist decreases activity below this level.
A GENERAL OVERVIEW
ANTIPSYCHOTIC DRUGS

COMPARISON BETWEEN THE TYPICAL & ATYPICAL ANTIPSYCHOTIC DRUGS
ANTIPSYCHOTIC DRUGS

• ALIPHATICS:
• Chlorpromazine
• Thioridazine
• Previously the most widely used
agents but produce more sedation and
weight gain
PHENOTHAZINE DERIVATIVES
ANTIPSYCHOTIC DRUGS
• PIPERAZINE:
• Fluphenazine
• Perphenazine
• More potent and more selective

• Haloperidol
• Most widely used typical or classical agent.
• More EPS than atypical drugs and phenothiazines.
• More potent, fewer autonomic e
ff
ects than phenothiazines
BUTYROPHENONES
ANTIPSYCHOTIC DRUGS

• Clozapine
• Asenapine
• Alanzapine
• Quetiapine
• Paliperidone
ATYPICAL ANTIPSYCHOTICS
ANTIPSYCHOTIC DRUGS
• Risperidone
• Sertindole
• Ziprasidone
• Zotepine
• Aripiprazole
Greater antagonist e
ff
ects on 5HT2A receptor, activity on D2 receptors. Acts
as partial agonists at 5HT1A receptors, synergistic on 5HT2A. Most are 5HT6
and 5HT7 antagonist

OTHER DRUGS
ANTIPSYCHOTIC DRUGS

• Most have incomplete absorption w/
signi
fi
cant
fi
rst-pass e
ff
ect, so BA is
relatively low
• Oral Chlorpromazine, Thioridazine –
25-35%
• Haloperidol – 65%
• Highly lipid soluble w/ 92-99% protein
binding
• Volume of distribution is large, >7L/kg
PHARMACOKINETICS
ANTIPSYCHOTIC DRUGS

• Clinical e
ff
ects are longer than what would be
expected from the plasma half-lives
• For typical antipsychotics, this is associated w/
prolonged D2-receptor occupancy in the CNS.
• Therefore, in most cases, recurrence of
psychotic symptoms, although variable, take
an average of 6 months, especially with long-
acting formulations.
• Exception: Clozapine, in w/c recurrence of
schizophrenia symptoms is rapid and often
serious, It is never abruptly discontinued
unless an emergency AE (myocarditis or
agranulocytosis) sets in.
PHARMACOKINETICS
ANTIPSYCHOTIC DRUGS

• At therapeutic doses, antipsychotics do
not a
ff
ect metabolism of other
medications.
• Undergo phase 1 metabolism via oxidation
or demethylation by CYP2D6, CYP1A2, and
CYP3A4.
• Potential drug interactions can occur
when taken w/ other inhibitors of the
CYP450 enzymes (Cimetidine or
Ketoconazole).
PHARMACOKINETICS
ANTIPSYCHOTIC DRUGS

• Phenothiazines which where developed
earlier produce many CNS, autonomic, and
endocrine e
ff
ects.
• Because they also block α-
adrenoceptors, muscarinic, H1-receptors,
and 5HT2 receptors.
PHARMACODYNAMICS
ANTIPSYCHOTIC DRUGS

• The antipsychotic e
ff
ects of earlier developed
agents (typical agents are considered as
dopamine-receptor antagonists) is partly due to
their blockade of dopamine’s e
ff
ect in inhibiting
adenylyl cyclase activity in the mesolimbic
system.
PHARMACODYNAMICS
ANTIPSYCHOTIC DRUGS

• DOPAMINERGIC SYSTEMS
1. Mesolimbic-mesocortical - behavior and
psychosis
2. Nigrostriatal – coordination and
smoothness of voluntary movements
3. Tuberoinfundibular – inhibition of anterior
pituitary secretion of prolactin
4. Medullary-periventricular - eating behavior
5. Incertohypothalamic – regulation of
motivation of copulatory behavior
PHARMACODYNAMICS
ANTIPSYCHOTIC DRUGS

• Most of the atypical and some of the typical
drugs ae potent in blocking both 5HT2A and D2-
receptors.
• Aripiprazole, appears to be a partial agonist of
D2-receptors.
• Most atypical agents also block a1-
adrenoceptors in varying degrees.
• EPS is linked closely to agents with high D2
potency.
PHARMACODYNAMICS
ANTIPSYCHOTIC DRUGS

PHARMACODYNAMICS
ANTIPSYCHOTIC DRUGS

• Antipsychotics have not been shown to be
e
ff
ective in treating behavior abnormalities in
dementia and may be associated w/ higher
mortality.
• Antipsychotics are not used in withdrawal
syndromes from substance abuse or in mild
anxiety due to less favorable safety pro
fi
les
than BZDs.
CLINICAL INDICATIONS
ANTIPSYCHOTIC DRUGS

• Anti-emesis – most typical agents except
Thioridazine (Prochlorperazine,
Benzquinamide)
• Relief of pruritus – Phenothiazines
• Preoperative sedatives – Promethazine
• Neuroleptanesthesia – Droperidol + general
anesthesia (controlled loss of consciousness)
CLINICAL INDICATIONS
ANTIPSYCHOTIC DRUGS

• BEHAVIORAL EFFECTS:
• “Pseudodepression” that may be due to drug-
induced akinesia or may be due to higher doses
than needed in a partially remitted patient.
• Toxic-confusional states may occur with very
high doses of drugs that have prominent
antimuscarinic actions.
SIDE EFFECTS & ADVERSE REACTIONS
ANTIPSYCHOTIC DRUGS

• NEUROLOGIC EFFECTS:
• Extrapyramidal reactions occurring early during
treatment with older agents include typical
Parkinson’s syndrome, akathisia, and acute
dystonic reactions (spastic retrocollis or
torticollis).
• Seizures, recognized as a complication of
chlorpromazine treatment.
ANTIPSYCHOTIC DRUGS

• ANS EFFECTS:
• Orthostatic hypotension or impaired ejaculation
• Common complications of therapy with
chlorpromazine or mesoridazine
ANTIPSYCHOTIC DRUGS

• METABOLIC AND ENDOCRINE EFFECTS:
• Weight gain is very common, especially with clozapine
and olanzapine.
• Hyperglycemia may develop.
• Hyperlipidemia may occur.
• Hyperprolactinemia in women results in the
amenorrhea- galactorrhea syndrome and infertility; in
men, loss of libido, impotence, and infertility may
result.
• Hyperprolactinemia may cause osteoporosis,
particularly in women.
ANTIPSYCHOTIC DRUGS

• TOXIC/ALLERGIC REACTIONS:
• Agranulocytosis.
• Clozapine causes fatal agranulocytosis (1-2%).
• Clozapine is the DOC if there is a suicide
attempt.
ANTIPSYCHOTIC DRUGS

• OCULAR COMPLICATIONS:
• Deposits in the anterior portions of the eye
(cornea and lens) are a common complication of
chlorpromazine therapy.
• Thioridazine is the only antipsychotic drug that
causes retinal deposits, which in advanced cases
may resemble retinitis pigmentosa.
• The deposits are usually associated with
“browning” of vision.
ANTIPSYCHOTIC DRUGS

• CARDIAC TOXICITY:
• Ziprasidone carries the greatest risk of QT
prolongation and therefore should not be
combined with other drugs that prolong the QT
interval, including thioridazine, pimozide, and
group 1A or 3 antiarrhythmic drugs.
• Clozapine is sometimes associated with
myocarditis.
• Thioridazine and Mesoridazone both can cause
serious ventricular arrhythmias.
ANTIPSYCHOTIC DRUGS

• NEUROPLEPTIC MALIGNANT SYNDROME:
• This life-threatening disorder occurs in patients who are
extremely sensitive to the extrapyramidal e
ff
ects of
antipsychotic agents.
• The initial symptom is marked muscle rigidity.
• There is also stress leukocytosis and high fever.
• Autonomic instability, with ↑ blood pressure and pulse rate,
is often present.
• Elevated creatinine kinase.
• Treatment: antiparkinson’s drugs, muscle relaxants or
diazepam, antipyretics, cooling, or change of antipsychotics
ANTIPSYCHOTIC DRUGS

• THE EXTRAPYRAMIDAL SIGNS
• AKATHISIA – motor disorder characterized by
restlessness and inability to stay still w/
compelling urge to move.
• DYSTONIA – neurological condition in w/c
there is sustained muscle contractions causing
twisting, repetitive and spastic movements,
and abnormal posture.
ANTIPSYCHOTIC DRUGS

• THE EXTRAPYRAMIDAL SIGNS
• TARDIVE DYSKINESIA – most unwanted e
ff
ect.
• Late onset, irreversible neurologic abnormality in w/
c there is repetitive, purposeless, involuntary,
choreoathetoid (worm-like) movements often due to
long-term use.
• May be self-limiting in some.
• Maybe irreversible in the late stages.
• Treatment: reduce dosage or change to newer
atypical drug, all other meds w/ central anticholinergic
e
ff
ects should be stopped, and Diazepam
ANTIPSYCHOTIC DRUGS

DISEASE CHARACTERISTICS
MAJOR DEPRESSIVE DISORDER

THE DSM-5 DEFINITION
MAJOR DEPRESSIVE DISORDER

MONOAMINE SYNTHESIS AND RELEASE
CENTRAL TO THE PATHOPHYSIOLOGIC MECHANISM OF MDD

• Therapeutic lag (3-4 weeks) – before a measurable
therapeutic response becomes evident
• 8 weeks - time it takes to reduce depressive
symptoms by 50%
• If no response by this time, change drug
• If partial response only, add another drug
• 6-12 months – maintenance phase
CLINICAL CONSIDERATIONS FOR THE THERAPEUTIC EFFECTS OF ANTIDEPRESSANTS
ANTIDEPRESSANT DRUGS

CLINICAL CONSIDERATIONS FOR THE THERAPEUTIC EFFECTS OF ANTIDEPRESSANTS

GENERAL DRUG CLASSES

• Powerful antidepressant
• Block the enzyme that destroys the
monoamine neurotransmitters
• Boosts neurotransmitters in the brain
• Original MAOI – irreversible enzyme activity
returns to normal only when new enzymes
are synthesized
• Also called “suicide inhibitors” (destroys
the enzyme)
GENERAL PROFILE
THE MONOAMINE OXIDASE INHIBITORS

• Inhibits MAO A and MAO B
• MAO B inhibition - linked to prevention
of neurodegenerative processes
(Parkinson’s disease)
• MAO A inhibition – linked to
antidepressant action and the
troublesome HTN side e
ff
ects
MECHANISM OF ACTION

• Cause “cheese reaction”
• Diet restrictions are required
• cIrreversible and non-selective
• Second line treatment for anxiety disorders
(panic disorder and social phobia)
• Phenelzine, Tranylcypromine,
Isocarboxazid
CLASSICAL MAOI

• Same therapeutic e
ff
ects of MAOI
• Less HTN e
ff
ect
• No cheese reaction
• Moclobemide
REVERSIBLE INHIBITORS OF MONOAMINE OXIDASE - A (RIMA)

• Treatment of Parkinson’s disease
• Selegiline
SELECTIVE INHIBITORS OF MAO-B

• Block the reuptake pumps of 5-HT, NE, and dopamine
• Negative allosteric modulator of the
neurotransmitter reuptake process
• Some are more potent in inhibition of the 5-HT
reuptake pump (Clomipramine)
• More selective for NE over 5-HT (Desipramine,
Maprotilene, Nortriptyline, Protriptyline)
• Most block both NE and 5-HT reuptake
GENERAL PROFILE & MECHANISM OF ACTION
TRICYCLIC ANTIDEPRESSANTS

• Orthostatic hypotension, dizziness (a1
blockade)
• Dry mouth, blurred vision, urinary retention,
constipation, memory disturbances (anti-
muscarinic e
ff
ect)
• Sedation, somnolence, weight gain (H1
receptor blockade)
TRICYCLIC ANTIDEPRESSANTS

• Selective and potent inhibition of serotonin uptake
• Act on presynaptic axon terminal initially
• Does not relieve depression immediately
• Starting dose – same as maintenance dose
• Onset – usually 3-8 weeks
• Response – complete remission of symptoms
• Target symptoms do not worsen when treatment
initiated
• Not given alone during initial therapy. May add
benzodiazepines to lessen side e
ff
ects.
GENERAL PROFILE
SELECTIVE SEROTONIN REUPTAKE INHIBITORS

• Blocks 5HT reuptake both in the dendrite
and the axon
• Desensitization/down-regulation of
autoreceptors
• Increased release of 5HT at the axon
MECHANISM OF ACTION

SIDE EFFECT AND ADVERSE REACTIONS

• Reboxetine – the
fi
rst truly selective noradrenergic
reuptake inhibitor
• Therapeutic pro
fi
le:
• Depression
• Apathy
• Fatigue
• Psychomotor retardation
• Attention de
fi
cit and impaired concentration
• Disorders (not limited to depression) characterized
by cognitive slowing, especially de
fi
ciencies in
working memory and in the speed of information
processing
GENERAL PROFILE & MECHANISM OF ACTION
SELECTIVE NOREPINEPHRINE REUPTAKE INHIBITORS

SELECTIVE NOREPINEPHRINE REUPTAKE INHIBITORS

• Buproprion – prototype
• Prodrug
• Active metabolite is more powerful NE reuptake blocker
in the brain
• Not associated w/ sexual dysfunction
• Lack a signi
fi
cant serotonergic component to its MOA
• Useful antidepressant for patients who cannot tolerate the
serotonergic SE of SSRIs
• ↓ the craving for smoking
DOPAMINE & NOREPINEPRHINE REUPTAKE INHIBITORS

Venlafaxine – the prototypical and only SNRI
→ Metabolized by CYP2D6
o Active metabolite: desvenlafaxine
o Short T ½
o 45% - excreted unchanged in the urine

Dual reuptake inhibitor

How does it di
ff
er from TCA? **TCA w/o adverse e
ff
ects
o No a1 blockade
o No cholinergic blockade
o No histamine blockade

Di
ff
erent degrees of inhibition:
o Most potent vs SERT
o Moderately potent vs NET
o Least potent vs dopamine reuptake
SEROTONIN NOREPINEPRHINE REUPTAKE INHIBITORS

• Venlafaxine – the prototype
• Metabolized by CYP2D6
• Active metabolite: desvenlafaxine
• Short T ½
• 45% - excreted unchanged in the
urine

• How does it di
ff
er from TCA?
• No a1 blockade
• No cholinergic blockade
• No histamine blockade

• Di
ff
erent degrees of inhibition:
• Most potent vs SERT
• Moderately potent vs NET
• Least potent vs dopamine reuptake

• Mirtazapine
• Potent antagonist actions on a2-receptors
• With antagonist action at 5HT 2A, 2C, and 3
receptors and Histamine 1 receptors
• has 5HT2A antagonist properties
contributing to its antidepressant actions
• 5HT2A, 2C, and H1 blocking contribute to its
anxiolytic and sedative-hypnotic properties
• Blocking H1 – sedation
• Blocking 5HT2C and H1 – weight gain
ALPHA-2 ANTAGONIST

• NE can no longer turn o
ff
its own release
• Noradrenergic neurons are disinhibited
• Prevent NE from turning o
ff
5HT release
• Serotonergic neurons become
disinhibited
• NE release in the raphe nucleus will
increase and cause a1-receptors to be
stimulated, provoking more 5HT release
ALPHA-2 ANTAGONIST

• Drowsiness, lightheadedness
• Weight gain & increase in appetite
• Dry mouth
• Constipation
ALPHA-2 ANTAGONIST

• Phenylpiperazine, Nafazodone, Trazodone
• Act by potent blockade of 5HT2A
• 5HT2A receptors, combined w/ less potent serotonin reuptake inhibitor actions
SEROTONIN 2A REUPTAKE INHIBITORS

• Seen in 2% of adult population, usually
diagnosed in their 20’s or 30’s.
• Main phasic is characterized by hyperactivity,
irritability, lessened impulse control, lack of
inhibition, rapid thought processes, lessened
need for sleep, and for some, even psychotic
symptoms and lower cognitive performance.
• Depression is similar to that seen in major
depressive disorder w/ main features being
depression, mood changes during the day, sleep
abnormalities, anxiety, and for some, psychosis.
GENERAL OVERVIEW OF BIPOLAR DISORDER
BIPOLAR DISORDER

• A
ff
ected people are at risk for suicide.
• What triggers the mood swings are largely
unknown, although ↑ catecholamine-related
activity is thought to be a predisposing factor.
• Medications or substances exacerbating mania ↓
dopamine or NE.
• There may also be involvement of glutamate or Ach.
• BPD appears to be inherited or genetically
determined and many genes are shared w/
schizophrenia
BIPOLAR DISORDER

BIPOLAR DISORDER

• Inhibit inositol monophosphatase (IMPase)
• Inhibit GSK-3
• A constitutively active enzyme that counteracts
neurotrophic and neuroprotective processes,
energy metabolism in brain tissues, and
neuroplasticity.
• Also a
ff
ect signaling in protein-kinase C w/c is
involved in synthesis of proteins in
neuroplasticity and mood stabilization.
LITHIUM: GENERAL PROFILE & MECHANISM OF ACTION
MOOD STABILIZERS

LITHIUM: GENERAL PROFILE & MECHANISM OF ACTION
MOOD STABILIZERS

LITHIUM: PHARMACOKINETICS
MOOD STABILIZERS

• Bipolar a
ff
ective disorder
• Use for manic phase of BPD is currently being replaced
by Valproate and atypical antipsychotics.
• Due to the slow onset of action of Lithium, which proves
to be disadvantageous in severe manic disorders.
• Antipsychotics + long acting BZDs are used.
• Depression component of BPD is treated w/ atypical
antipsychotics (Quetiapine)
• This phase can be managed with antidepressants,
but evidence shows these may lead to more cycling
and swinging to manic phase
LITHIUM: DRUG INDICATIONS
MOOD STABILIZERS

• Bipolar a
ff
ective disorder
• In therapeutic doses, Lithium does not cause any
adrenoceptor blockade, activation, or sedation
e
ff
ects.
• Nausea and tremor can manifest.
• E
ff
ective as prophylactic agent against both mania
and depression.
MOOD STABILIZERS

• Recurrent depression with cyclic pattern
• Acute major depression – adjunct to standard
antidepressant
• Schizoa
ff
ective disorder – adjunct to
antipsychotics
• Schizophrenia – adjunct to antipsychotics in
treatment-resistant patients.
MOOD STABILIZERS

• Done for individualized dosing in treatment of acute
episode and for maintenance.
• Started about 5 days after starting the medications
and serum levels are obtained 10-12 hours after the
last dose.
• Dose adjustments are done as needed
LITHIUM: TREATMENT MONITORING
MOOD STABILIZERS

• Factors that in
fl
uence choice of prophylactic
Lithium are:
• Severity and frequency of attacks
• Progressive disease
• Compliance to maintenance therapy
LITHIUM: TREATMENT MONITORING
MOOD STABILIZERS

• Those who have had at least 2 mood cycles or those
with a
fi
rmly established diagnosis of bipolar I
• Maintenance treatment is best initiated as early as
possible for lesser relapses.
LITHIUM: DRUG INTERACTION
MOOD STABILIZERS

• Diuretics and newer NSAIDs reduce clearance of Li
by 25%
• Neuroleptic use (except for clozapine and newer
atypical antipsychotics) along with Lithium is
associated with more EPS.
LITHIUM: DRUG INTERACTIONS
MOOD STABILIZERS

• More often therapeutic use rather than accidental or
suicidal ingestion
• Because of accumulation of levels due to low serum
sodium, diuretic use, poor renal function, or severe
dehydration from any cause.
• Toxic levels >2mEq/L
• Treatment is dialysis
LITHIUM: OVERDOSAGE
MOOD STABILIZERS

LITHIUM: SIDE EFFECTS AND ADVERSE REACTIONS
MOOD STABILIZERS

• ↑ GFR in pregnancy → ↑ renal clearance of Lithium
• Pre-pregnancy clearance rates are rapidly resumed after
delivery.
• Toxic levels can raise right after delivery despite
therapeutic levels.
• Careful monitoring should be done.
• Lithium can be excreted in breast milk.
• Neonatal Lithium toxicity is characterized by lethargy, poor
suck, weak moro re
fl
ex, hepatomegaly.
• Low teratogenic potential but further studies are needed
LITHIUM: PREGNANCY AND LACTATION
MOOD STABILIZERS

• Anti-epileptic that is as e
ff
ective as Lithium in the early stages of treatment of BPD.
• Used successfully in Lithium non-responders.
• Because of its more favorable safety pro
fi
le, this has been used instead of Lithium,
as levels can be quickly increased over several days to achieve desired
therapeutic range.
• Combination with other psychotropic agents is often better tolerated.
• 1st line drug for mania
• May be combined with Lithium for mono-therapy non-responders
OTHER RECOMMENDED DRUGS: VALPROIC ACID
MOOD STABILIZERS

• Acceptable option when Lithium response is unsatisfactory.
• Main limitation is that it is a CYP3A4 inducer, and therefore has potential
undesirable drug interactions.
• Used for acute mania and prophylaxis
• Can be used as monotherapy or in combination with Lithium.
• Blood dyscrasias has not been demonstrated in doses used for BPD
OTHER RECOMMENDED DRUGS: CARBAMAZEPINE
MOOD STABILIZERS

• Used in reducing episodes of depression cycles in BPD and for maintenance.
• NOT used for acute manic episodes.
OTHER RECOMMENDED DRUGS: LAMOTRIGINE
MOOD STABILIZERS

• “Paralysis agitans” or Shaking palsy
• Resting tremor
• Muscular rigidity
• Increased tone or sti
ff
ness in the muscles
• Mask-like face and clog-like release of
muscles
PARKINSONISM: AN OVERVIEW

• Bradykinesia
• Di
ffi
culty initiating and continuing movement
• Postural instability
• Forward
fl
exion of neck, hips, knees, and
elbows leads to poor balance.
• Gait disorders
• Shu
ffl
ing, small steps described as
festination, reduced arm swing, and sudden
freezing spells lead to problems in walking.
• Handwriting – micrographia

MOTOR SYMPTOMS

NON-MOTOR SYMPTOMS

• Genetic, <50 y/o in 10-15% of cases
• Mutation of α-synuclein gene at 4q21 → Sucleinopathy
• Environmental or endogenous toxins
• Increase risk in health care, teaching, farming, Pb & Mg
exposure, and Vitamin D de
fi
ciency
• Drug induced: antipsychotics and MPTP
• Reduced level of Dopamine in the basal ganglia
PARKINSONISM: PATHOGENESIS

• The main pathological feature of
Parkinson’s disease is the loss of the
dopaminergic nigrostriatal pathway.
• Dopaminergic neurons in the substantia
nigra that normally inhibit the output of
GABAergic cells in the striatum are lost.
• 80% of the Dopamine producing cells must
be lost before symptoms begin to show
PARKINSONISM: PATHOGENESIS

THE BIOCHEMICAL SYNTHESIS &
DEGRADATION OF DOPAMINE

• Pharmacologic attempt to restore dopaminergic activity with Levodopa and
dopamine agonists.
• Restore normal balance of cholinergic & dopaminergic in
fl
uences on the basal
ganglia
PARKINSONISM: TREATMENT GOALS

DRUGS FOR PARKINSONISM
GENERAL OVERVIEW

DRUGS FOR PARKINSONISM
SCHEMATIC REPRESENTATION OF THEIR RESPECTIVE MECHANISMS

• (-)-3-(3-4 dihydroxyphenyl) L-alanine
• Immediate precursor of dopamine
• Levotatory stereoisomer of dopa
• Dopa: amino acid precursor of Dopamine & NE.
GENERAL PROFILE
DOPAMINE REPLACEMENT: LEVODOPA

• Rapidly absorbed from the small intestine
• Food delays absorption
• Amino acids in the food compete with the
drug
• Peak plasma concentration: 1-2 hours
• Plasma T ½: 1-3 hours
PHARMACOKINETICS

• Rapidly absorbed from the small intestine
• Food delays absorption
• Amino acids in the food compete with the drug
• Peak plasma concentration: 1-2 hours
• HVA, DOPAC (dihydroxyphenylacetic acid) are
the main metabolites
• Only 1-3% enters the brain
PHARMACOKINETICS

PHARMACOKINETICS

• Early use lowers mortality rate
• Responsiveness may be lost secondary to
disappearance of dopaminergic nerve
terminals
• Combined w/ Carbidopa or Benzeraside
• Sinemet – preparation containing Levodopa in
fi
xed proportion (1:10 or 1:4)
• Sinemet 25/100 TID
• 30-60 minutes before meals
CLINICAL USES

• GIT e
ff
ects: vomiting (CTZ)
• Reduced by Carbidopa
• Phenothiazenes are contraindicated
• CVS: tachycardia, ventricular extrasystole, atrial
fi
brillation, postural hypotension
• Dyskinesia
• Choreoathethosis of the face and distal extremities is
the most common presentation
• Dose related
• Fluctuations in clinical respon

• Wearing-o
ff
reactions or end-of-dose akinesia
(timing of levodopa intake)
• On-o
ff
phenomenon (unrelated to the timing of
doses)
• Behavioral e
ff
ects:
• Depression, anxiety, agitation, insomnia,
somnolence, confusion, delusions,
hallucinations, nightmares, euphoria
• Controlled by Clozapine, Olanzapine, and
Risperidone

• Mydriasis
• Blood dyscrasias
• Hot
fl
ushes
• Gout
• Brownish discoloration of the urine
• Abnormal smell
• Priapism
• Transient elevations of transaminases and BUN

• Vitamin B6 (Pyridoxine)
• Enhance extracerebral metabolism of
Levodopa
• Prevented by decarboxylase inhibitor
• MAO-A inhibitors
• HTN crisis
DRUG INTERACTIONS

• Psychoses
• Angle-closure glaucoma
• Cardiac dysrhythmia (less incidence in
combination w/ Carbidopa)
• PUD
• Melanoma or suspicious undiagnosed skin
lesion
CONTRAINDICATIONS

• Does no penetrate the BBB
• Reduces the peripheral metabolism of
Levodopa
• Increases plasma levels of Levodopa
• Prolongs the plasma T ½ of Levodopa
• Increase available amounts of dopa for
entry into the brain.
• Reduce the daily requirement of Levodopa
by 75%
CARBIDOPA & BENZERASIDE
PERIPHERAL DECARBOXYLASE INHIBITORS

• Do not require enzymatic conversion for an
active metabolite
• Not potential toxic metabolites
• Do not compete w/ other substances for an
active transport
• First line drugs in Parkinsonism
• End of dose akinesia to Levodopa
• On-o
ff
phenomenon refractory to Levodopa
GENERAL PROFILE
DOPAMINE AGONISTS

• GIT: anorexia, N&V, bleeding PUD, re
fl
ux
esophagitis
• CVS: postural hypotension, painless digital
vasospasm
• Dyskinesia, mental disturbances, erythromelalgia
DOPAMINE AGONISTS

• History of psychotic illness
• Recent MI
• Peripheral vascular disease
• Peptic ulcer disease (PUD)
CONTRAINDICATIONS
DOPAMINE AGONISTS

• MAO-A: metabolizes NE & Serotonin
• MAO-B: metabolizes dopamine
GENERAL PROFILE
MONOAMINE OXIDASE INHIBITORS

• Selective irreversible inhibitor of MAO-B at normal
doses
• Inhibits MAO-A at higher doses
• Retards breakdown of dopamine
• In consequence, it enhances and prolongs the anti-
parkinsonism e
ff
ect of levodopa and may reduce
mild on-o
ff
or wearing-o
ff
phenomena.
• It is therefore used as adjunctive therapy for patients
with a declining or
fl
uctuating response to levodopa.
• Taken 5mg w/ breakfast and lunch
• May cause insomnia when taken later during the day
SELEGILINE

• More potent than Selegiline in preventing
MPTP-induced Parkinsonism and is being
used for early symptomatic treatment.
• Also used as adjunctive therapy at a dosage
of 0.5 or 1 mg/d to prolong the e
ff
ects of
levodopa-carbidopa in patients with
advanced disease.
RASAGILINE

• Neither Selegiline nor Rasagiline should be taken by patients receiving
meperidine, tramadol, methadone, propoxyphene, cyclobenzaprine, or St. John’s
wort.
• Should be used with care in patients receiving TCA or SSRI because of the
theoretical risk of acute toxic interactions of the serotonin syndrome type.
• The combined administration of levodopa and a nonselective inhibitor must be
avoided, because it may lead to hypertensive crises.
NOTES

• Central and peripheral metabolism
• Slightly more potent and has a longer
duration of action
TOLCAPONE
CATHECOL-O-METHYLTRANSFERASE INHIBITORS

• Peripheral metabolism
• Prolongs the duration of Levodopa by
decreasing its peripheral metabolism
• Helpful in patients receiving Levodopa
who have
fl
uctuations
• T ½: 2 hours
ENTACAPONE

• Combination of Levodopa w/ both
Carbidopa and Entacapone
• Simpli
fi
es drug regimen
• Requires consumption of lesser # of
tablets
• Use of Stalevo has been associated
with earlier occurrence and increased
frequency of dyskinesia.
STALEVO

• Due to increased levodopa exposure
and include dyskinesias, nausea, and
confusion.
• Other adverse e
ff
ects include postural
hypotension, fatigue, somnolence,
peripheral edema, and constipation.
• Tolcapone may cause an increase in
liver enzyme levels and has been
associated rarely with death from acute
hepatic failure.

• An antiviral agent
• Potentiate dopaminergic function by
in
fl
uencing the synthesis, release, or
reuptake of dopamine.
GENERAL PROFILE
ANTIVIRAL DRUG: AMANTADINE

• Peak plasma concentration: 1-4 hours after
oral dose
PHARMACOKINETICS

• Less potent than Levodopa and bene
fi
ts are
short-lived.
• During that time it may favorably in
fl
uence
the bradykinesia, rigidity, and tremor of
Parkinsonism
CLINICAL USE

• Restlessness, depression, irritability,
insomnia, agitation, excitement,
hallucinations, and confusion.
• Livedo reticularis (dermal lesions / erythema
on extremities) – clears within a month after
drug withdrawal

• History of seizures and heart failure
CONTRAINDICATION

• Benztropine mesylate, Biperiden,
Orphenadrine, Procyclidine,
Trihexyphenidyl
• Improve tremor & rigidity of
Parkinsonism but have little e
ff
ect in
bradykinesia.
GENERAL PROFILE
ACETYLCHOLINE BLOCKING AGENTS

• CNS
• Mydriasis, urinary retention,
constipation, tachycardia, tachypnea,
increase IOP, palpitations, cardiac
arrhythmia, dryness of the mouth
• Acute suppurative parotitis

• With Benztropine:
• Prostatic hyperplasia, obstructive GI
diseases, angle-closure glaucoma
CONTRAINDICATIONS

END
Sources:
•Pharmacology, A Patient-Centered Nursing Process Approach, 11th Ed. by Mcquiston et. al.
•Katzung Basic & Clinical Pharmacology, 16th Ed.

19 - CNS Pharmacology (Complete File).pdf

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19 - CNS Pharmacology (Complete File).pdf