CNS Pharmacology: Blood-Brain Barrier & Analgesics

• Introduction to Central Nervous System Pharmacology: CNS/Pain

The Blood-Brain Barrier

• Entry of drugs into the brain is impeded
• Passage across the blood-brain barrier is limited to lipid-soluble drugs.
• Protein-bound or highly ionized drugs are unable to cross.

Adaptation of the CNS to Prolonged Drug Exposure

• Decreased side effects: When CNS drugs are taken chronically, the intensity of the side effects may decrease, but the therapeutic effects remain undiminished.
• With Morphine: Is taken to control pain, nausea is a common side effect early on, but treatment continues, nausea diminishes, and analgesic effects persist.
• Tolerance: Decreased response occurring during the course of prolonged drug use.
• Physical dependence: State in which abrupt discontinuation of drug use will precipitate a withdrawal syndrome.

Analgesics and Opioids

• Analgesics: Drugs that relieve pain without causing loss of consciousness.
• Opioids: The most effective pain relievers available.

Endogenous Opioid Peptides

• 3 families of peptides: enkephalins, endorphins, and dynorphins

Opioid Receptors

• Three main classes of opioid receptors as follows
• Mu receptors: Analgesia, respiratory depression, euphoria, sedation, and physical dependence
• Kappa receptors: Analgesia and sedation; kappa activation may underlie psychotomimetic effects seen with certain opioids
• Delta receptors

Classification of Drugs That Act as Opioid Receptors

• Can be an Agonist, partial agonist, or antagonist
• Pure opioid agonists
• Agonist-antagonist opioids
• Pure opioid antagonists

Pure Opioid Agonists

• Activate mu receptors and kappa receptors
• Can produce analgesia, euphoria, sedation, respiratory depression, physical dependence, constipation, and other effects
• Morphine: Strong opioid agonists and moderate to strong opioid agonists
• Codeine: Moderate to strong agonists

Agonist-Antagonist Opioids

• Pentazocine and buprenorphine are examples
• When administered alone, it produces analgesia
• If administered with a pure opioid agonist, it can antagonize analgesia caused by the pure agonist

Pure Opioid Antagonists

• Naloxone [Narcan] is a prototype of the pure opioid antagonists
• Work as antagonists at mu and kappa receptors
• Does not produce analgesia or any other effects caused by opioid agonists
• Reversal of respiratory and central nervous system (CNS) depression caused by overdose with opioid agonists

Basic Pharmacology of the Opioids

• Strong opioid agonists include Morphine, and other strong opioid agonists
• Moderate to strong opioid agonists also exist
• Agonist-antagonist opioids also are prescribed

Morphine

• Source is seedpod of the poppy plant
• Overview of pharmacologic actions include: Pain relief; Drowsiness; Mental clouding; Anxiety reduction; A sense of well-being; Respiratory depression; Constipation; Urinary retention; Orthostatic hypotension; Emesis; Miosis; Cough suppression; Biliary colic; Tolerance and physical dependence; and Euphoria/Dysphoria

Morphine: Toxicity

• Clinical manifestations: Classic triad which includes coma, respiratory depression, and pinpoint pupils
• Treatment: Ventilatory support and use antagonist naloxone [Narcan]
• General guidelines: Monitor vital signs before giving and give on a fixed schedule

Morphine: Therapeutic Use

• Relief of pain is therapeutic use
• Relieves pain without affecting other senses, i.e. sight, touch, smell, and hearing
• No loss of consciousness
• Pain is relieved by mimicking the actions of endogenous opioid peptides, primarily at mu receptors

Morphine: Pharmacokinetics

• Can be administered by several routes which includes: oral, intramuscular, intravenous, subcutaneous, epidural, and intrathecal
• Is not very lipid-soluble
• Does not cross blood-brain barrier easily
• Only a small fraction of each dose reaches site of analgesic action

Morphine: Tolerance and Physical Dependence

• Physical dependence may occur
• Abstinence syndrome with abrupt discontinuation
• About 10 hours after last dose, the initial reaction occurs and includes yawning, rhinorrhea, and sweating
• Progresses to violent sneezing, weakness, nausea, vomiting, diarrhea, abdominal cramps, bone and muscle pain, muscle spasms, and kicking movements
• Lasts 7 to 10 days if untreated
• Withdrawal is unpleasant but not lethal, as it may be with CNS depressants

Morphine: Additional Info

• Abuse liability should be considered
• Precautions include: Decreased respiratory reserve, Pregnancy, Labor and delivery, Head injury, and other precautions
• Drug interactions include: CNS depressants, Anticholinergic drugs, Hypotensive drugs, Monoamine oxidase inhibitors, Agonist-antagonist opioids, Opioid antagonists, and other interactions

Other Strong Opioid Agonists

• Fentanyl [Duragesic, Abstral, Actiq, Fentora, Onsolis, Lazanda, Subsys] is an example
• 100 times the potency of morphine
• Formulations given via three routes which include: Parenteral for surgical anesthesia; Transdermal [Duragesic] patch with heat acceleration or iontophoresis needle-free system; Transmucosal lozenge on a stick [Actiq], buccal film [Onsolis], buccal tablets [Fentora], sublingual tablets [Abstral], or sublingual spray [Subsys]

Additional Strong Opioid Agonists

• Other strong opioid agonists include: Alfentanil and sufentanil, Remifentanil, and Meperidine, Short half-life, Interacts adversely with several other drugs, Toxic metabolite accumulation
• Methadone: Treatment for pain and opioid addicts
• Hydromorphone (Dilaudid): Morphine derivative that is much more potent, relative potency of hydromorphone to morphine is 7.5:1, Given to those with severe pain, Highly addictive

Moderate to Strong Opioid Agonists

• Similar to morphine in most respects
• Produce analgesia, sedation, and euphoria
• Can cause respiratory depression, constipation, urinary retention, cough suppression, and miosis
• Can be reversed with naloxone
• Different from morphine, produce less analgesia and respiratory depression than morphine, Somewhat lower potential for abuse

Codeine

• 10% converts to morphine in liver and assists with pain and cough suppression
• Usually administered orally in a formulation along with aspirin or acetaminophen
• 30 mg produces same effect as 325 mg of acetaminophen

Oxycodone

• Analgesic actions equivalent to those of codeine
• Commonly used a long-acting analgesic like Immediate-release or Controlled-release [OxyContin]
• Crushes and snorts/injects medication when abused
• 2010 OP formulation much harder to crush and does not dissolve into an injectable solution to decrease risk of abuse

Hydrocodone

• (Vicodin)
• Most widely prescribed drug in the United States
• Combined with aspirin, acetaminophen, or ibuprofen

Agonist-Antagonist Opioids

• Pentazocine (Talwin) is an Agonist on Kappa, Antagonist on Mu, includes Limited resp. depression, and Can precipitate withdrawal in addicted patients
• Buprenorphine: 7-day patch called Butrans and in Sublingual film called Suboxone

Dosing Guidelines

• Pain status should be evaluated before opioid administration and about 1 hour after
• Opioid analgesics must be adjusted to accommodate individual variation
• As a rule, opioids should be administered on a fixed schedule
• Avoiding withdrawal necessary

Clinical Use of Opioids

• Balance the need to provide pain relief with the desire to minimize abuse
• Minimize fears about physical dependence and addiction

Patient-Controlled Analgesia

• Use patient-controlled analgesia devices, drug selection and dosage regulations
• Comparison of patient-controlled analgesia with traditional intramuscular therapy: Multiple intramuscular injections: Painful to the patient; cause negative side effects, including bruising and hematoma formation
• Patient and family education

Opioid Antagonists

• Principle uses:
  • Treatment of opioid overdose and relief of opioid-induced constipation
  • Reversal of postoperative opioid effects
  • Reversal of neonatal respiratory depression
  • Management of opioid addiction

Naloxone

• Mechanism of action: Competitive antagonist
• Pharmacologic effects determined
• Pharmacokinetics determined

Naloxone: Therapeutic Uses

• Reversal of opioid overdose, drugs of choice is pure opioid agonist overdose, titrated cautiously with physical dependence
• Reversal of postoperative opioid effects, titrated to achieve adequate ventilation and to maintain pain relief
• Reversal of neonatal respiratory depression, opioids given during labor and delivery may cause respiratory depression in neonate

Naloxone: Additional Info

• Preparations, dosage, and administration determined
• Preparations and routes determined
• Usage information for opioid overdose, postoperative opioid effects, and neonatal respiratory depression available

Nonopioid Centrally Acting Analgesics

• Relieve pain by mechanisms largely or completely unrelated to opioid receptors
• Do not cause respiratory depression, physical dependence, or abuse
• Not regulated under the Controlled Substances Act.
• Examples include: Tramadol [Ultram] which includes risk of suicide & Clonidine [Duraclon]

Tramadol (Ultram)

• Has a combination of opioid and nonopioid mechanisms
• Therapeutic use: Moderate to moderately severe pain
• Adverse effects: Sedation, dry mouth
• Drug interactions with CNS depressants
• Carries abuse liability and risk of suicide
• Immediate-release and extended-release forms available

Clonidine

• Treats hypertension and provides relief of severe pain
• Mechanism of pain relief: Alpha2-adrenergic agonist
• Used in combination with opioid analgesics
• Adverse effects: Cardiovascular which includes Severe hypotension, rebound hypertension, and bradycardia
• Specific contraindications