ANALGESICS

Opioid Analgesics

Opioid is any substance that can produce morphine like effects. Opium is an extract of the juice of the poppy Papaver somniferum. Opium contains many alkaloids related to morphine. The main group of drugs that are discussed in section are divided into two; morphine analogues and synthetic derivatives.

Morphine analogues. Compounds closely related in structure to morphine. They may be agonist (codeine and heroin), partial agonists (nalorphine) or antagonists (naloxone).

Synthetic derivatives. Pethidine, fentanyl, methadone, pentazocine are examples of synthetic derivatives.

Opioid receptors. Three receptors mediate the main pharmacological effects of opiates. mu receptors are responsible for the analgesic and major unwanted effects (respiratory depression, sedation and dependance). Delta for analgesia and peripheral effects of opiates and kappa contribute to analgesia at spinal level and dysphoria.

Agonists and antagonists of opioid receptors

Pure agonists. They all have high affinity to mu receptors and varying affinity to delta and kappa receptors (codeine, methadone, dextropropoxyphene).

Partial antagonists and mixed agonist-antagonists: Nalorphine, and pentazocine.

Pharmacokinetics: Most opioid analgesics are well absorbed from subcutaneous and intramuscular sites as well as from the mucosal surfaces of the nose or mouth. Although absorption from the gastrointestinal tract is rapid, some opioids given by this route are subject to first-pass metabolism by glucuronidation in the liver. All opioids bind to plasma proteins with varying degrees of affinity, the drugs rapidly leave the blood and localize in highest

concentrations in tissues that are highly perfused. The opioids are converted in large part to polar metabolites, which are then readily excreted by the kidneys.

Pharmacodynamics

1. Mechanism of Action: Opioid agonists produce analgesia by binding to specific receptors, located primarily in brain and spinal cord regions involved in the transmission and modulation of pain.

Effects of morphine and its synthetic derivatives

1. Central nervous system effects-The principal effects of the opioid analgesics with affinity for mu receptors are on the central nervous system; the more important ones include analgesia, euphoria, sedation, and respiratory depression. With repeated use, a high degree of tolerance occurs to all of these effects except respiratory depression. They also cause addiction and dependence.
   1. Analgesia-Pain consists of both sensory and affective (emotional) components. Opioids can change both aspects of the pain experience. In most cases, these drugs have a relatively greater effect on the affective component.
   2. Euphoria–After a dose of morphine, a typical patient in pain experiences a pleasant floating sensation and freedom from anxiety and distress. Dysphoria is a state characterized by restlessness and a feeling of malaise.
   3. Sedation–Drowsiness and clouding of mentation are frequent concomitants of opioid action.
   4. Respiratory depression–All of the opioid analgesics can produce significant respiratory depression by inhibiting brain stem respiratory mechanisms.
   5. Cough suppression–Suppression of the cough reflex is a well-recognized action of opioids. However, cough suppression by opioids may allow accumulation of secretions and thus lead to airway obstruction and atelectasis. e.g. codeine
   6. Miosis–Constriction of the pupil is seen with virtually all opioid agonists.
   7. Nausea and vomiting–The opioid analgesics can activate the brain stem chemoreceptor trigger zone to produce nausea and vomiting.

• Peripheral effects

Cardiovascular system: Hypotension effects; has been attributed to a number of mechanisms including central depression of vasomotor-stabilizing mechanisms and release of histamine.

Gastrointestinal tract: Constipation. Opioid receptors exist in high density in the gastrointestinal tract, and the constipating effects of the opioids are mediated through an action on the local enteric nervous system as well as the central nervous system.

Biliary tract: The opioids constrict biliary smooth muscle, which may result in biliary colic. The sphincter of Oddi may constrict, resulting in reflux of biliary and pancreatic secretions and elevated plasma amylase and lipase levels.

Genitourinary tract: Renal function is depressed by opioids. It is believed that in humans this is chiefly due to decreased renal plasma flow.

Uterus: The opioid analgesics may prolong labor.

Neuroendocrine: Opioid analgesics stimulate the release of antidiuretic hormone, prolactin, and somatotropin but inhibit the release of luteinizing hormone.

Effects of mixed agonist-antagonists: Pentazocine and other opioids with agonist actions at some opioid receptors and antagonist actions at others usually produce sedation in addition to analgesia when given in therapeutic doses. At higher doses, sweating, dizziness, and nausea are common, but severe respiratory depression may be less common than with pure agonists.

Clinical use of opioid analgesics

Opioids are used in severe, constant pain, acute pulmonary edema (pulmonary edema associated with left ventricular failure), cough suppression, diarrhea, and preanaesthetic medication.