Analgesic Agents and Opioids

Analgesic Agents

• Morphine metabolites (morphine 3-glucuronide and morphine 6-glucuronide) in kidney failure can cause narcosis and ventilatory depression.
• Rapid administration of large opioid doses (fentanyl, sufentanil, remifentanil, alfentanil) can induce chest wall rigidity, making ventilation difficult.
• Prolonged opioid use can cause opioid-induced hyperalgesia, increasing pain sensitivity. General anesthesia with high doses of remifentanil can lead to tolerance, needing higher doses for post-operative analgesia.
• The neuroendocrine response to surgery (measured by hormones like catecholamines, antidiuretic hormone, and cortisol) is inhibited more by opioids than by volatile anesthetics.
• Aspirin irreversibly inhibits COX-1, leading to a nearly one-week duration of clinical effects, including inhibiting platelet aggregation.

Opioids

• Opioids bind to specific opioid receptors (mu, kappa, delta, sigma) throughout the CNS and other tissues, which are coupled to G proteins.
• Opioid receptors' binding of agonists induces effects like membrane hyperpolarisation, inhibiting adenylyl cyclase, activating phospholipase C, inhibiting voltage-gated calcium channels, and activating inwardly rectifying potassium channels.
• Opioid effects vary depending on exposure duration, and tolerance develops impacting opioid responses.
• Opioid receptor types (μ, κ, δ, σ) mediate varied effects (e.g., analgesia, sedation, respiratory depression). Specific agonists bind to specific receptors.
• Opioid receptor activation inhibits presynaptic release and postsynaptic response to excitatory neurotransmitters (like acetylcholine, substance P).

Pharmacokinetics

• Opioids have rapid and complete absorption after intramuscular or subcutaneous injection.
• Fentanyl's low molecular weight and high lipid solubility favor transdermal absorption via patches. Patch absorption is influenced by skin conditions.
• Fentanyl's serum concentration plateaus after 14-24 hours.
• Remifentanil has a very short half-life due to rapid hydrolysis by nonspecific esterases.
• Many opioid metabolites are eliminated by the kidneys.
• Significant amounts of lipid-soluble opioids can be retained in the lungs (first-pass uptake).

Structure-Activity Relationships

• Opioid agonists and antagonists share common structural features.
• Small molecular modifications can convert an agonist into an antagonist.
• Levorotatory (left-handed) opioid isomers are usually more potent than their dextrorotatory (right-handed) counterparts.

Biotransformation

• Opioids are primarily metabolized by the liver's cytochrome P450 system, conjugated via glucuronidation or other metabolic pathways.
• Codeine is a prodrug, activated in the liver to morphine, via CYP2D6.
• Remifentanil is hydrolyzed in the red blood cells by nonspecific esterases

Excretion

• Opioids metabolites are mainly excreted through the kidneys.
• Morphine metabolites (morphine-3-glucuronide, morphine-6-glucuronide) accumulation can be significant with impaired renal function.

Effects on Organ Systems

• Cardiovascular: Opioids can have minimal direct effects on the heart, but higher doses can lead to bradycardia. Histamine release can decrease systemic vascular resistance and blood pressure.
• Respiratory: Opioids significantly depress respiration by altering the respiratory centers, affecting CO2 response and potentially causing apneic periods.
• Cerebral: Opioids influence cerebral oxygen consumption, blood flow, and volume, although effects on ICP are minimal compared to other anesthetics.
• Gastrointestinal: Opioids slow GI motility and may cause constipation, biliary spasm, or sphincter of Oddi contraction.
• Endocrine: Opioids can inhibit hormone release like norepinephrine, antidiuretic hormone and cortisol, in response to surgery.
• Renal: Opioid metabolism and elimination depends on renal function, affecting duration of action for certain opioids.