Lecture 33 - 3rd Asessment - Opioid Drugs

Pharmacology & Toxicology Dept Dr. Mariam Yousif 19/12/2006

OBJECTIVES After studying this material you should know the:

• Classification of narcotic agonists, antagonists and prototype agents for each class. • Main opioid receptor subtypes and mechanism by which the narcotic agonists produce their pharmacological effects. • Pharmacokinetics of opioid agonists. • Pharmacological actions and adverse effects of opioid analgesics on various organ systems • Clinical uses of analgesics.

Narcotic Analgesics? Narcotic refers to any derivative of the opium plant or any synthetic drug that imitates natural narcotics.

Narcotic agonists (narcotic analgesics) include opium derivatives and synthetic drugs with similar properties.

They are used to relieve or decrease pain without causing the person to lose consciousness.

Opioid Peptides Endogenous analgesic compounds, endorphins, are released in response to pain in certain parts of the CNS.

Many endorphins have been identified, they are all peptides (opioid peptides), defined as peptides with opiate-like pharmacological effects. e.g. β-endorphin, met-enkephalin, nociceptin

Opioid Analgesics Opioid analgesics are agonists at endorphin receptors. The actions of opioid analgesics stem from their ability to mimic the actions of endogenous mediators, the opioid peptides.

Morphine-Like Drugs The term opioid applies to any substance, that produces morphine-like effects that are blocked by antagonists like naloxone.

Opium is an extract of the juice of the poppy Papaver somniferum, which has been used to produce euphoria, analgesia and sleep.

Opium contains many alkaloids related to morphine.

Analgesic Drugs # Phenanthrene derivatives (Morphine analogues): closely related in structure to morphine. Can be agonists (e.g. diamorphine (heroin) and codeine), partial agonists (e.g. nalorphine) or antagonists (e.g. naloxone).

# Synthetic derivatives with structures unrelated to morphine but similar pharmacological effects. Piperidines ( e.g. pethidine, known as meperidine in USA, fentanyl) Methadone, pentazocine

Opioid Receptors All opioid drugs, whether naturally occurring such as morphine, or chemically synthesized, interact with specific opioid receptors to produce their pharmacologic effects.

Three types of opioid receptors, termed µ, δ and к, mediate the main pharmacological effects of opiates.

Opioid Agonists and Antagonists # Full agonists e.g. morphine, methadone, codeine High affinity for µ-receptors and lower affinity for δ- and к-receptors.

# Partial agonists (mixed agonists-antagonists) Combined degree of agonist and antagonist activity at different receptors e.g. pentazocine, nalorphine

# Antagonists e.g. naloxone, naltrexone.

Pharmacokinetics Opioid analgesics may be given orally, by injection or intrathecally to produce analgesia

Morphine is metabolized to morphine 6-glucoronide (M6G), which is more potent as an analgesic. Morphine and M6G are the active metabolites of diamorphine and codeine.

Acute overdosage with morphine produces coma and respiratory depression.

Mechanism of action of opioids All opioid receptors are linked through Gproteins to inhibition of adenylate cyclase, thus, reducing cAMP content. All three receptor subtypes exert this effect, and they also exert effects on ion channels.

Mechanism of action of opioids Opioids promote the opening of potassium channels (causing hyperpolarization) and inhibit the opening of voltage-gated calcium channels.

Narcotic analgesics inhibit pain transmission by inhibiting the release of substance P (a pain neurotransmitter).

Pharmacological Actions Morphine is typical of many opioid analgesics and will be taken as the reference compound

Effects on the CNS Analgesia

Euphoria and sedation

Respiratory depression: Commonest cause of death in acute opioid poisoning.

Pharmacological Actions Effects on the CNS Depression of cough reflex : Codeine suppresses cough in sub-analgesic doses and is often used in cough medicines.

Pupillary constriction: Pinpoint pupils are important diagnostic feature in overdosage with morphine.

Nausea and vomiting

Effects on GIT Morphine reduces gastrointestinal motility causing constipation.

The resulting delay in gastric emptying can retard the absorption of other drugs.

Opiates should be avoided in patients suffering from biliary colic caused by gallstones. Pressure in the biliary tract increases because of contraction of the gall bladder and constriction of the biliary sphincter.

Other Actions of Opioids Histamine Release Morphine releases histamine from mast cells. Morphine should not be given to asthmatic patients, as the bronchoconstriction effect can have serious consequences.

Pethidine does not produce this effect.

Tolerance and Dependence Tolerance to the analgesic effect of opioids develops rapidly and can often be detected within 12-24 hrs of administration.

As a result, larger and larger doses of the drug are needed to achieve the same clinical effect, leading to an increased severity and incidence of adverse effects.

Tolerance and Dependence Physical dependence develops rapidly, accompanied by physical withdrawal syndrome.

This syndrome comprises a complex mixture of irritable and sometimes aggressive behavior coupled with extremely unpleasant autonomic symptoms.

Tolerance and Dependence Weak, long acting µ-receptor agonists, such as methadone, may be used to relieve withdrawal symptoms.

Certain opioid analgesics, such as codeine and pentazocine, are much less likely to cause physical or psychological dependence.

Adverse Effects of Opioids The adverse effects limit the dose that can be given and the analgesia that can be maintained.

All are direct consequences of opioid receptor activation. They can be inhibited by opioid receptor antagonists such as naloxone.

Adverse Effects of Opioids Respiratory depression: The most serious side effect, the most common cause of death from opioid overdose.

Constipation

Pupillary constriction (miosis)

Vomiting

Other Opioid Analgesics Drugs as nalorphine and pentazocine, produce a mixture of agonist and antagonist effects (partial agonists).

READING ASSIGNMENT FROM PHARMACOLOGY TEXTBOOK, RANG ET AL 5TH ED. PAGES 581-582.

Other Opioid Analgesics Diamorphine (Heroin), Codeine, Pethidine (meperidine), Fentanyl, Methadone, Pentazocine

Clinical Uses of Analgesics # Analgesics are used to treat and prevent pain, such as: Pre- and postoperative pain. Common painful conditions including headache, dysmenorrhea, labour, trauma and burns. Many medical and surgical emergencies (e.g. myocardial infarction). Terminal disease (especially metatastic cancer)

Clinical Uses of Analgesics The choice and route of administration of analgesic drugs depends on the nature and duration of the pain.

A progressive approach is often used, starting with NSAIDs, supplemented first by weak opioid analgesics and then by strong opioids.

Clinical Uses of Analgesics In general, severe acute pain is treated with strong opioids (e.g. morphine, fentanyl) given by injection.

Mild inflammatory pain is treated with NSAIDs supplemented by weak opioids (e.g. codeine).

Severe pain (e.g. cancer pain) is treated with strong opioid given orally, intrathecally, epidurally or by subcutaneous injection.

Opioid Antagonists Pure antagonists include naloxone (short acting) and naltrexone (long acting).

Naloxone Main clinical uses in treatment of respiratory depression caused by opioid overdose & to improve breathing in newborn babies affected by opioid analgesics given to their mother during labour.

Opioid Antagonists Naltrexone

Very similar to naloxone but with the advantage of a much longer duration of action. It may be given to addicts.

DRUG LIST Morphine Diamorphine (heroin) Codeine Methadone Fentanyl Pethidine (Meperidine) Pentazocine Nalorphine Naloxone Naltrexone