Transcript 10-03-04 Central Nervous Sysem No1

Drugs Affecting the Central
Nervous System
Disease states of Central Nervous
System
• Typically caused by too much, or too little
neurotransmission
• Too much
– Hyperexcitable neurons fire in absence of
stimuli (e.g. seizure disorders)
– Too many neurotransmitter molecules binding
to post-synapse receptors
• psychoses
• Too little
– Too few neurotransmitters binding to postsynapse receptors
Major Parts of the Brain
• Cerebrum
• Brainstem
• Cerebellum
Cerebrum
• Largest and uppermost part of the brain
• Divided into right and left hemispheres
• Controls all the higher intellectual and
motor functions of the body
• Cerebrum composed of an outer cortex and
an inner medulla
Cerebral Cortex
• Contains neuronal cell bodies (gray matter)
that control all voluntary activities of the
body
• Divided up into 4 lobes: frontal, parietal,
temporal, and occipital, each controlling
specific brain functions
• Electroencephalogram (EEG) is a recording
of the electrical activity of the cortex
Cerebral Medulla
• Referred to as the “white matter” and is
composed of myelinated nerve axons
• Functions to conduct nerve impulses to and
from different parts of the nervous system
• Basal ganglia are neuronal cell bodies (gray
matter) located within the cerebral medulla
that function in the regulation of motor
activity
Brainstem and Spinal Cord
• Located below the cerebrum and is
continuous with the spinal cord
• Brainstem divided into the thalamus,
hypothalamus, pons, and medulla oblongata
• Spinal cord is a collection of all the sensory
and motor nerves going to and from the
brain
Reticular Formation
• A network of nerves and brain areas involved in
regulating alertness, wakefulness, and sleep
• Composed of both inhibitory and excitatory nerves
• Excitatory nerves collectively referred to as the
reticular activating system (RAS)
• Many stimulants (amphetamines) and depressants
(alcohol, barbiturates) affect the RAS
Limbic System
• Network of nerves and brain areas involved
in emotional and behavioral responses
• Associated with emotional responses to
fear, anger, anxiety, sexual behavior, and
reward and punishment
• Affected by drugs of abuse and involved in
the development of drug dependency
Neurotransmitters
Norepinephrine
• Adrenergic hormone released at the effector
organ by sympathetic neurons
– Monamine
• Depression thought be caused by impaired
monoamine transmission
• Drugs that stimulate monoamine release are
indicated for ADD or narcolepsy
Dopamine
• Another monoamine derived from the
amino acid tyrosine
• Binds dopamine receptors (D1 or D2)
• Antipsychotics prevent signals activated by
dopamine binding
• Parkinson’s disease also caused by altered
dopamine binding
Serotonin (5-HT)
• Monoamine hormone derived from the
amino acid tryptophan
• Typically released by inhibitory neurons
• Lysergic acid diethylamide binds to
serotonin receptors
• Depression, ADD and headaches associated
with serotonin imbalance
Gamma-amino butyric acid (GABA)
• Inhibitory neurotransmitter of the brain and
central nervous system
• Synthesized from the amino acid glutamate
• Cause Ca2+ influx into the neuron resulting
in hyperpolarization
– More difficult to excite
• Benzodiazepines and barbituates enhance
GABA effects
Excitatory Amino Acids
• Amino acid glutamate or structurally related
chemicals
• Important for learning and memory
• Abnormal increased activity will result in
toxicity
– Alzheimers, ALS, stroke, Huntington’s
Antidepressants
Mental Depression
• Exogenous or reactive depression usually
occurs in response to some external factor
or adverse life event
• Endogenous depression usually originates
from within the psyche of the individual and
the causes are less well understood
• Bipolar mood disorder involves alternating
cycles of depression and mania
Causes of Mental Depression
• Exact causes not well understood
• Mental depression appears to involve the
development of low levels of the brain
monoamine neurotransmitters, serotonin
(SER) and norepinephrine (NE)
• This explanation is referred to as the
“Monoamine Theory of Mental Depression”
Treatment of Depression
• Treatment involves a combination of
psychotherapy and antidepressant drugs
• Antidepressant drugs act to increase NE and SER
levels in the brain
• Tricyclic antidepressants (TCA) and selective
serotonin reuptake inhibitors (SSRI) are the two
most important antidepressant drug classes
• Monoamine oxidase inhibitors (MAOI) are less
frequently used and require dietary restriction
Monoamine Oxidase Inhibitors
(MAOI)
• Monoamine oxidase is the enzyme that metabolizes
the monoamines NE and SER
• Inhibition of MAO increases SER and NE levels and
functional activity in the brain
• Requires 2–4 weeks for maximum effects
• Foods containing tyramine must be avoided
• Tyramine stimulates the release of NE and may cause
a hypertensive crisis
• MAOIs are indicated for patients who cannot tolerate
TCAs and SSRIs
Tricyclic Antidepressants (TCA)
• Mechanism of action of TCAs is to block reuptake
of NE and SER into nerve endings
• Blockage of reuptake increases NE and SER
levels and stimulation of NE and SER receptors
• Requires 2–4 weeks for maximum effect
• TCAs are divided into secondary amines which
increase NE more than SER and are less sedating
than tertiary amines which increase SER more
than NE
Autonomic Effects of TCAs
• TCAs possess anticholinergic activity which
can cause dry mouth, visual disturbances,
constipation, and urinary retention
• TCAs also possess alpha blocking activity
that can lower blood pressure
• TCAs can also affect cardiac rhythm and
may cause cardiac arrhythmias
Selective Serotonin Reuptake
Inhibitors (SSRI)
• Selectively block the reuptake of SER
• Cause little if any anticholinergic and alpha
blocking effects
• Are generally not sedating, and in some cases
cause CNS stimulation
• Common adverse effects include nausea,
agitation, restlessness, and less frequently
seizures
Psychomotor Stimulants
• Generally referred to as the amphetamines
• Produce CNS stimulation more than an
antidepressant effect, little used for depression
• Act by increasing NE and DA activity
• Clinical use for narcolepsy and treatment of
hyperkinetic children
• Amphetamines have a high abuse potential
• Adverse effects due to excessive CNS and
autonomic stimulation
Lithium
• Lithium is an elemental ion similar to sodium
• Acts to depress nerve excitability that helps
prevent mood swings and manic behavior
• Common adverse effects include nausea, diarrhea,
tremors, increased thirst, ringing in the ears
(tinnitis), and more seriously kidney and heart
damage
• Periodic blood levels to prevent overdosage
Sedatives and Hypnotics
• Sedatives are drugs used to induce a mild
state of CNS depression characterized by
both mental and physical calmness
• Hypnotics are drugs used to induce and
maintain sleep
• The same drugs are used to induce both
sedation and hypnosis; however, the dosage
for inducing sedation is lower
Classification of SedativeHypnotic Drugs
• Barbiturates – a drug family of chemically similar
drugs with similar actions and features
• Benzodiazepines – a drug family of chemically
similar drugs with similar actions and features
• Miscellaneous nonbarbiturates – a group of drugs
with dissimilar chemical structures and
pharmacologic features
Pharmacology of Barbiturates
• Drugs classified as short, intermediate, and
long-acting sedative-hypnotics
• At low doses they increase the inhibitory
effects of GABA
• At high doses they act like general
anesthetics, and can cause profound CNS
depression and death in overdosage
• Barbiturates are also anticonvulsants
Effects of Barbiturates
on the Sleep Cycle
• Decrease stage 1, falling asleep
• Increase stage 2, a lighter stage of sleep
• Decrease stages 3 and 4 referred to as deep
sleep or slow-wave sleep
• Decrease REM sleep, and may cause REM
rebound
Adverse Features
of Barbiturates
• Cause drug tolerance with chronic use and drug
dependency with abuse
• Can cause a severe type of physical drug addiction
when chronically abused
• The withdrawal reaction from barbiturates can be
serious, resulting in convulsions and death
• Drug interactions, induce microsomal enzymes to
increase the rate of drug metabolism of all drugs
metabolized by the microsomal enzymes
Pharmacology of
Benzodiazepines
• Drugs classified as short, intermediate, and
long-acting sedative-hypnotics
• Drugs also produce antianxiety, skeletal
muscle relaxing, and anticonvulsant effects
• Act by increasing the inhibitory effects of
GABA
• Drugs do not induce the drug metabolizing
microsomal enzymes
Effect of Benzodiazepines
on the Sleep Cycle
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Decrease stage 1, falling asleep
Increase stage 2
Decrease stages 3 and 4
Do not significantly decrease REM sleep
Benzodiazepines are considered safer drugs
than the barbiturates, especially in
overdosage
Miscellaneous Nonbarbiturates
• Zolpidem and zaleplon are short-acting
hypnotics that do not disrupt the sleep cycle
• These drugs increase the inhibitory effects of
GABA but differently than other drugs
• Both drugs are considered to be safer than
other hypnotics and are at low risk for abuse
• Side effects include dizziness, headache, GI
disturbances, and mental confusion
Alcohol
• Classified as a CNS depressant drug
• Unlike other drugs, alcohol provides nutritional
calories
• Like other drugs of abuse, alcohol causes
development of drug tolerance, dependency, and
withdrawal reactions
• Most of the pharmacology of alcohol centers around
its chronic use, abuse, and toxicology
Disulfiram
• Used to treat alcoholism and deter drinking
• Disulfiram inhibits metabolism of alcohol,
allowing acetaldehyde to accumulate
• Increased acetaldehyde produces severe nausea,
vomiting, headache, and hypotension
• Alcoholics take the drug on a daily basis, knowing
that if they drink any alcohol they will become
violently ill
Parkinson’s Disease
• A neurological movement disorder of the
brain involving the basal ganglia
• Symptoms include tremor, muscular
rigidity, and disturbances of movement
• Major cause is a deficiency of the inhibitory
neurotransmitter dopamine (DA) and the
resulting excessive activity of the excitatory
neurotransmitter acetylcholine (ACH)
Drug Therapy
• Primary therapy is the administration of
drugs that increase the levels of DA in the
basal ganglia
• Secondary therapy is the administration of
anticholinergic drugs that decrease ACH
activity in the basal ganglia
• Goal is to restore the balance between DA
and ACH activity
Drugs that Increase Dopamine
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Levodopa
Dopamine agonists
Amantadine
Enzyme inhibiting drugs that slow the
metabolic breakdown of dopamine
Levodopa
• The precursor of DA that is taken orally and
converted into DA in the basal ganglia
• Administered in combination with carbidopa that
increases the amount of DA that enters the brain
• Levodopa and carbidopa drug combination known
as Sinemet
• Levodopa is considered the most effective drug for
the treatment of Parkinson’s disease
Adverse Effects of Levodopa
• Nausea, vomiting, and loss of appetite
• Hypotension, and rapid/irregular heart rate
• Dystonias, slow or weak movements that usually
occur when levels of DA are low
• Dyskinesias, uncontrolled or involuntary
movements when DA levels are too high
• “On-off” phenomenon when drug effects suddenly
increase or decrease due to fluctuating levels of
DA in the basal ganglia
• Behavioral and mental disturbances
Dopamine Agonists
• Drugs: bromocriptine, pergolide,
pramipexole, and ropinirole
• Stimulate DA receptors in the basal ganglia
• Used alone or in combination with levodopa
• Adverse effects similar to levodopa: nausea,
hypotension, dyskinesias, and mental
disturbances
Amantadine (Symmetrel)
• An antiviral drug that additionally increases the
release of DA in the brain
• Used in early stages of treatment and in combination
with other drugs
• Effectiveness usually decreases in 6–12 months
• Adverse effects include nausea, mental disturbances,
and occasionally skin discoloration
Enzyme Inhibitors
• Selegiline (Eldepryl) inhibits MAO-B
enzyme that slows metabolism of DA in the
brain, increases DA levels; used alone or
with levodopa
• Tolcapone (Tasmar) and entacapone
(Comtan) inhibit another enzyme, COMT,
that also slows metabolism of DA; usually
used with levodopa
Anticholinergic Drugs
• Used to decrease the activity of ACH and restore
the normal balance between DA and ACH
• Benztropine (Cogentin)and trihexyphenidyl
(Artane) most widely used drugs
• Antihistamine drugs, diphenhydramine
(Benadryl), with high anticholinergic activity
occasionally used
• Used alone early in treatment or in combination
with other drugs
Central Analgesics
Clinical Indication
Produce a state of unconsciousness to
prevent painful stimulation during surgical
and dental procedures
Types of anesthetics
• Inhalation gases & volatile liquids:
chloroform, halothane, nitrous oxide
• Injectable:
fentanyl, ketamine, midazolam, propofol
Signs & Stages
of General Anesthetics
General anesthetics gradually depress the CNS
Stage I
Depression of the cerebral cortex produces analgesia
euphoria and sleep
Stage II Excitement phase with increased sympathetic tone
produces increase in blood pressure, heart rate,
respiration, and muscle tone
Stage III Surgical anesthesia because blood pressure and
respiration return to normal, spinal reflexes are
inhibited and skeletal muscles relaxed
Stage IV Medullary paralysis, paralysis of the diaphragm
circulatory collapse leading to death
Action of General Anesthetics
Induction of anesthesia: time required to bring
the patient from consciousness to Stage III
Maintainance of anesthesia: ability to keep the
patient safely in Stage III
Dissociative anesthesia: anesthesia and loss
of memory without skeletal muscle relaxation
Neuroleptanalgesia: inhibition of pain while
conscious from combination of a narcotic and a
tranquilizer
Other Effects
• CNS
Depression of voluntary (motor) and involuntary (autonomic)
systems. Secretion of antidiuretic hormone causes postop urinary
retention
• Vascular
Decreased sympathetic tone causes vasodilation & hypotension
• Cardiac
Myocardial depression, ventricular arrhythmias
• Salivary and bronchial secretions
• Skeletal muscle relaxation
• Gastrointestinal
Nausea and vomiting during recovery. Decreased intestinal motility
causes constipation
• Hepatotoxicity
Jaundice, elevated serum liver enzymes, necrosis
Adjuncts to
General Anesthesia
Drugs routinely used before and after
surgery to reduce anxiety, counteract the
side effects of general anesthetics, and
improve patient recovery.
• Analgesics-relieve pain, produce sedation
• Antianxiety drugs-relieve apprehension
• Antiarrhythmics-control arrhythmias
• Anticholinergics-decrease secretions
• Cholinergics-decrease urinary retention
• Tranquilizers-control nausea & vomiting
Drug Interactions
Residual depression of the CNS
• narcotic (opiate) analgesics
• muscle relaxants
• tranquilizers
Potentiate skeletal muscle relaxation, weakness
and fatigue
• antibiotics that promote potassium loss
streptomycin, kanamycin, erythromycin
The Opioid System
Clinical Indication
• Prevent or interrupt moderate to severe pain of
any origin without a loss of consciousness
• Acute pain-during or after surgical procedures
• Chronic pain-of any etiology from back pain to
cancer pain
Source of Opioid Analgesics
Opioid analgesics are derivatives of the
• naturally occurring plant substance opium
OR
• synthetic substances that produce the same
pharmacologic effects as opium
Types of Analgesics
Opiates-opium, heroin
codeine, morphine, hydromorphone,
oxycodone, oxymorphone
Opioids-synthetic
butorphanol, fentanyl, levorphanol,
meperidine, methadone, propoxyphene
Central analgesics (nonopioid)-tramadol
Drug Schedule Federal Comprehensive Drug
Abuse Prevention and Control Act
Because of their liability to produce physical
dependence, opioid analgesics are included
in the class of controlled substances as Schedule II
drugs
• Restricted to prescription use
• No refill without new written prescription
• Regulated by the FDA (Food and Drug
Administration) and DEA (Drug Enforcement
Agency)
Sensation of Pain
Pain is composed of at least two elements
• localized stimulation of peripheral nerves
through damage or inflammation
• recognition of pain within the CNS that
can intensify the reaction to pain
Mechanism of Action
Opioid analgesics relieve pain by
selectively acting on receptors within the
CNS (rather than on peripheral nerve
endings) to
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decrease anxiety
reduce the reaction to pain
interrupt pain signal transmission within
the spinal cord
Mechanism of Action (continued)
Opioid analgesics mimic the action of endorphins
produced in the brain and spinal cord by
selectively stimulating receptors
• mu (µ) receptors mediate analgesia, euphoria, and
respiratory depression
• kappa (κ) receptors mediate sedation, dysphoria
• delta (δ) receptors mediate, hallucinations, and
increased respiration and blood pressure
Pharmacological Effects
CNS
• Change in mental alertness, sedation (μ, κ)
• Change mood, euphoria (µ) or dysphoria (κ)
• Stimulation of chemoreceptor trigger zone
initiating nausea and vomiting
• Dose dependent depression of the vomiting center
• Depression of respiratory centers (µ)
• Headache
• Cough suppressant (antitussive)
• Secretion of antidiuretic hormone
Pharmacological Effects (continued)
• Tolerance
– Decreased response to euphoria, sedation, respiratory
depression and analgesia with chronic daily use
– Response returns when the dose is increased
• Physical dependence
– Chronic use establishes an internal expectation within
the body of receiving receptor activiation
– Withdrawal symptoms (abstinence syndrome) occur
when the drug is abruptly discontinued. (This can be
minimized by gradual taper down)
Pharmacological Effects (continued)
Smooth Muscle (μ receptor mediated)
• Spasmogenic
– Intestine- constipation
– Gall bladder common bile duct- increase
pressure, pain
– Bronchial constriction
– Urinary sphincters- oliguria
• Histamine release
– Bronchial constriction
– Vasodilation-orthostatic hypotension
Antitussive Activity
Natural opiates such as codeine, hydrocodone,
and hydromorphone suppress coughs by
inhibiting centers in the brain
At present, dextromethorphan is the only opioid
that is used in commercial over-the-counter
cough suppressant products
Usually OTC products include additional active
ingredients that treat other symptoms of cold & flu
Adverse Effects
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Mental confusion
Sedation
Headache
Nausea
Vomiting
Dry mouth
Constipation
Urinary retention
Itching, rash, anaphylaxis
Orthostatic hypotension
Physical dependence
Acute Opioid Poisoning
Accidental ingestion of a large dose by
children or attempted suicide may produce
» Coma
» Decreased respiration
» Cyanosis
» Hypotension
» Drop in body temperature
» Death
Opioid
Antagonists
A pure opioid antagonist fits the opiate
receptor, cannot stimulate the receptor, and
blocks the opioid analgesic from attaching
to the receptor.
• naloxone, naltrexone
A partial antagonist fits the opiate receptor and
weakly stimulates the receptor while it blocks the
opioid analgesic from attaching to the receptor
• butorphanol, nalbufene
Cautions and Contraindications
Opioid analgesics should not be used in patients
with
• Bronchial asthma
• Heavy pulmonary secretions
• Convulsive disorders
• Biliary obstruction
• Head injuries
• A history of allergy or sensitivity to this class
Used with caution in
• Elderly patients
• Pregnant women
Drug
Interactions
Potentiate CNS depression of all Opioids
• sedatives, hypnotics, general anesthetics,
alcohol
Meperidine or dextromethorphan
• MAO inhibitors- sweating, hypotension, hypertension
Methadone
• Reduced plasma levels of methadonerifampin, phenytoin