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 post-

synapse 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 Sedative- Hypnotic 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

• 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

• 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 CNSStage 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

• VascularDecreased sympathetic tone causes vasodilation & hypotension

• CardiacMyocardial 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 aftersurgery to reduce anxiety, counteract theside effects of general anesthetics, andimprove 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 InteractionsResidual 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, heroincodeine, 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 includedin 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 byselectively acting on receptors within theCNS (rather than on peripheral nerveendings) to

• 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

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

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 ActivityNatural 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• Mental confusion• Sedation• Headache• Nausea• Vomiting• Dry mouth• Constipation • Urinary retention• Itching, rash, anaphylaxis • Orthostatic hypotension • Physical dependence

Acute Opioid PoisoningAccidental ingestion of a large dose by

children or attempted suicide may produce» Coma» Decreased respiration» Cyanosis» Hypotension» Drop in body temperature» Death

Opioid AntagonistsA pure opioid antagonist fits the opiatereceptor, cannot stimulate the receptor, andblocks the opioid analgesic from attachingto the receptor.• naloxone, naltrexone

A partial antagonist fits the opiate receptor andweakly stimulates the receptor while it blocks theopioid analgesic from attaching to the receptor• butorphanol, nalbufene

Cautions and ContraindicationsOpioid analgesics should not be used in patientswith• 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 InteractionsPotentiate CNS depression of all Opioids• sedatives, hypnotics, general anesthetics,

alcohol

Meperidine or dextromethorphan • MAO inhibitors- sweating, hypotension, hypertension

Methadone• Reduced plasma levels of methadone-

rifampin, phenytoin