PHARMACOLOGY OF THE CENTRAL NERVOUS

SYSTEM

TERMS TO LEARN

Akathisia An inner sense of restlessness (motor

restlessness)
Central Serotonin Caused by over activation of central 5-HT receptors.
Syndrome Symptoms include abdominal pain, diarrhea, sweating, fever,
and tachycardia. Hypertension, delirium, myoclonus; can
induce cardiovascular shock and death.
Delirium Tremors Autonomic instability, hallucinations, tremor, hypertension,
(DTs) tachycardia, and risk of seizures associated with cessation of
alcohol ingestion.
Dyskinesias Abnormal involuntary movement
Extrapyramidal Parkinson-like syndrome (Tremors Rigidity
Syndrome Akathisia, Postrual instability), akathisias, and
(EPS) dystonias (Protruding of tongue)
Neuroleptic Characterized by muscular rigidity, fever, and automatic
Malignant instability; associated with the use of neuroleptic medications
Syndrome (eg, haloperidol)
Tardive Dyskinesia Syndrome of involuntary movements typically involves
(TD) mouth, face, limbs., and trunk
Trigeminal Sharp, stabbing pain that occurs in one or more
Neuralgia divisions of the trigeminal nerve.
Wernicke- Neurologic disorder caused by thiamine deficiency; often
Korsakoff seen in chronic alcoholic patients; symptoms include
Syndrome confusion, ataxia, and memory impairment.

Anxiety disorder DOC Alternate

Panic Disorder (PD) Benzodiazepines (BDZs) (SSRIs) fluoxetine,
Alprazolam 0.25mg TID or QID fluvoxamine, paroxetine,

Panic Disorder with
Agoraphobia (PDA)
Social Phobia (Social
Anxiety Disorder (SAD)-
stage fear or public
speaking fear
Obsessive-Compulsive
Disorder (OCD)
Post-traumatic Stress
Disorder (PTSD)
Generalized Anxiety
Disorder (GAD)
Attention Deficit
Hyperactivity Disorder
or clonazepam 0.25 to 0.5mg BID sertraline and citalopram
Behaviourally changes
Low-dose propranolol (10mg) MAOIs can be used;
taken 30 minutes before the event. moclobemide (in
antidepressant doses)
Clomipramine (TCA) SSRI
Paroxetine is the only agent Citalopram
specifically approved for
treatment of PTSD in Canada
All SSRI’s
Methylphenidate @ or
dexamphetamine are each
effective in over 80% of
accurately diagnosed ADHD

ANALGESICS

What are NSAIDS?

A group of dissimilar drugs with the same mechanism of action, that is
inhibition of cycloxygenase with subsequent inhibition of prostaglandin
synthesis.

Name four groups of NSAIDS?

Salicylates, indoleacetic acids, propionic acids, oxicams, fenamates and
pyrazolones.

What is the mechanism of action of the salicylates?

Inhibition of cyclooxygenase by acetylation. Cyclooxygenase is required for
the synthesis of prostaglandins and leukotrienes.

How does the mechanism of action of aspirin differ from the other
NSAIDS?
The effect of aspirin is irreversible, all the others are reversible inhibitors of
cyclooxygenase.

What are the main therapeutic uses of the nonsteroidal anti-

inflammatory agents?
Anti-inflammatory agents, analgesics, antipyretics and antiplatelet agents.

Why does blockade of prostaglandin synthesis relieve pain?

Prostaglandins convert pain receptors into a more sensitized form.

What is the difference between COX-1 and COX-2 inhibitors?

COX-1 is constitutively expressed in most tissues and is thought to protect
the gastric mucosa while COX-2 is expressed constitutively in the kidney
and brain and can be induced at sites of inflammation. Thus inhibition of
COX-2 may explain anti-inflammatory activity.

Aspirin and the salicylates are primarily inhibitors of which isozymes?

COX-1 and COX-2 (at high concentration).

How is aspirin metabolized?

It is converted to salicylate and then conjugated to glycine and glucuronides.

What is the difference in aspirin metabolism between analgesic and

anti-inflammatory doses?
Conjugation occurs primarily at analgesic and antipyretic doses, while at
anti-inflammatory doses it is primarily excreted as salicylate. Excretion
follows zero order kinetics.

What are the main pharmacological actions of aspirin?

Analgesia, anti-inflammatory action, antipyresis and prevention of thrombus
formation and prolongation of bleeding time.

How does aspirin prevent thrombus formation and prolong bleeding

times?
Aspirin shifts the balance between inhibition of prostacyclin formation in the
vasculature and inhibition of aggregation of platelets to inhibition of
aggregation thus increasing the bleeding time.

What are the therapeutic uses of Aspirin?

Analgesia, antipyresis, anti-inflammation, acute rheumatic fever, and
rheumatoid arthritis.

What are the adverse effects of aspirin on the GI tract?

GI irritation and bleeding, gastric ulceration and hemorrhage and
exacerbation of peptic ulcers.

Does aspirin have effects on the cardiovascular system?

Not at therapeutic doses but at large doses there is dilation of peripheral
vessels and toxic amounts cause central vasomotor paralysis.

What are the effects of aspirin on the respiratory system?

Low doses increase oxygen consumption and CO2 production, higher doses
stimulate the respiratory center directly resulting in respiratory alkalosis and
then eventually respiratory paralysis and acidosis occur.

How does aspirin effect acid-base balance?

There effects are related to the respiratory effects. Low doses increase CO2
production. At higher doses there is compensation for respiratory alkalosis
and at toxic doses there is metabolic acidosis. Also at toxic doses there are
additional disturbances in potassium balance.

What is salicylism?
Mild aspirin toxicity. It is characterized by ringing in the ears, dizziness,
headache, mental confusion, deafness etc.

What toxicities doses aspirin have at very high doses?

CNS disturbances, GI disturbances, respiratory and acid-base balance
disturbances.

How do you treat overdose toxicity of aspirin?

Maintain respiration and circulation, minimize the amount of drug absorbed
through gastric lavage and increase aspirin elimination by forced diuresis
and alkalinization of the urine.
Are allergic reactions common with aspirin?
They occur in about 1% of patients, with an increased incidence in
asthmatics especially those with nasal polyps.

What kind of drug interactions are associated with aspirin use?

It displaces other drugs from plasma protein binding sites thus increasing the
effects of many drugs.

Name two cox-2 inhibitors?

Celexoxib and rofexcoxib.

What is the advantage of the COX-2 inhibitors over the salicylates?

They have fewer GI effects than the salicylates.

What are the therapeutic uses of the COX-2 inhibitors?

Osteoarthritis, rheumatoid arthritis.

What are the toxicities associated with the COX-2 inhibitors?

Abdominal pain, diarrhea, dyspepsia, edema in the lower extremities.

What effect do the COX-2 inhibitors have on bleeding time?

They have little or no effect.

What is the mechanism of action of the propionic acid derivatives?

They work the same as aspirin.

How do the propionic acid inhibitors differ from aspirin in their GI

effects?
They produce the same GI effects but to a lesser extent.

What type of pain are the propionic acid inhibitors better used for than
aspirin?
Dysmenorrheal.

Do the propionic acid inhibitors show cross-sensitivity to aspirin?

Yes they do.

What is the advantage if any of naproxen over ibuprofen?

Naproxen is long acting and can be given twice daily.
How does acetaminophen differ from aspirin in its pharmacological
actions?
It has little or no anti-inflammatory action.

What is the mechanism of action of acetaminophen?

Inhibition of prostaglandin synthesis. It inhibits COX-1 and not COX-2. It
may also possibly inhibit other isozymes of COX.

How is acetaminophen metabolized?

By conjugation and oxidation by cytochrome P450 enzymes.

How does acetaminophen effect the GI Tract?

It has little or no effect.

How does acetaminophen effect respiration or the acid base balance?

It has little effect.

What are the therapeutic uses of acetaminophen?

It is used for analgesia and antipyresis, like aspirin.

What are the adverse effects of acetaminophen?

They are generally mild and include skin rash, drug fever, and mucosal
lesions.

What types of long-term toxicity can occur with acetaminophen?

Hepatic damage.

What is the mechanism of the acetaminophen hepatotoxicity?

Certain metabolites of acetaminophen bind to hepatic proteins and cause
necrosis.

What agent is used to treat acetaminophen overdose toxicity?

Sulfhydryl compounds such as N-acetylcysteine.

What drugs are considered opioid analgesics?

Purified alkaloids from the poppy, semisynthetic derivatives of these
alkaloids and a group of synthetic compounds with actions similar to the
opiates.
What are the general features of the opioids?
They have certain common structural features, they are stereospecific and
they act at specific receptor sites.

Which drug is considered the prototype and standard for the opioid
drugs?
Morphine.

What is the mechanism of action of morphine?

It is an agonist at specific receptors termed opiate receptors.

What are the main pharmacological effects of morphine?

Analgesia, respiratory depression, drowsiness and sedation, euphoria and
tranquility, papillary constriction, nausea and vomiting, and GI effects.

What type of analgesia does morphine produce?

It produces analgesia without loss of consiousness, it is more effective
against continuous dull pain than sharp intermittent pain, and it acts at both
the spinal level and at higher levels.

What effect does morphine have on respiration?

It produces respiratory depression primarily due to a decrease in sensitivity
in the chemoreceptor centers to plasma CO2.

What effect does morphine have on the eye?

It causes papillary constriction.

What effect does morphine have on the GI system?

Constipation is produced.

Does morphine affect the cardiovascular system?

It has mild effects there such as orthostatic hypotension.

Name the routes of administration for morphine?

PO, IV, SC, IM.

Why are higher doses of morphine required orally?

Due to first pass metabolism

How morphine metabolized?

It is mainly glucuronidated.

Name two other important uses of morphines besides analgesia?

Sickle cell crisis and pulmonary edema due to acute left ventricular failure-
dyspnea.

What are the side effects of morphine use?

Dependence, increased pressure in the biliary tract, dysphoria and
excitement, allergic reactions.

What type of withdrawal symptoms are seen with use of the opiates?
It reflects an exaggerated rebound from the acute pharmacologic effects of
the drug. The signs of withdrawal include rhinorrhea, lacrimation, yawning,
chills, gooseflesh, hyperventilation, hyperthermia, mydriasis, muscular
aches, vomiting, diarrhea, anxiety and hostility.

What are the major drug-drug interactions of morphine?

It can interact with CNS depressants, antipsychotic agents and MAO
inhibitors (antidepressants).
What are the contraindications for morphine use?
Head injuries, decreased pulmonary function, pregnancy and urinary tract
obstruction.

What are the two naturally occurring opiate alkaloids?

Morphine and codeine.

Name two drugs that are opiate antagonists?

Naltrexone and naloxone.

What types of drugs are pentzocine, buprenorphine, and butorphanol?

Mixed opiate agonists/antagonists.

What two physiologic effects of morphine are not affected by tolerance?

GI effects and papillary constriction.

How does the potency of codeine compare to morphine?

Codeine is about 1/10 as potent.

Is the abuse of potential for codeine less or more than for morphine?
Codeine has less abuse potential than morphine.

How do the effects of meperidine on the CNS compare with those of

morphine?
Meperidine may be excitatory at toxic doses or with chronic use.

How do the effects of meperidine on the GI tract compare with morphine?

There is less constipation and less spasm of the biliary tract.

What effect does meperidine have on the eyes?

Unlike most opiates it causes the pupils to dilate rather than constrict. This is
related to its anticholinergic activity.

How is meperidine used clinically?

It is used to produce analgesia.