Opioids - an introduction Dr. S. Parthasarathy MD., DA., DNB, MD (Acu), Dip. Diab. DCA, Dip. Software statistics- PhD ( physiology), IDRA

History Opium was first mentioned in Eber’s papyrus (1500 BC) and in the writing of Theophrastus (300 BC) It was used throughout the middle ages in Europe as the preparation, named ‘laudanum’. Tincture !! Crude opium is a dark brown and resinous material which is obtained from poppy (papaver somniferum) capsule. Opos – juice of poppy

Originally meconium

In 1806, Sertürner reported the isolation of a pure substance in opium that he named morphine after Morpheus, the Greek god of dreams. It contains two types of alkaloids: (i) alkaloid of phenanthrene derivatives–morphine (10%), codeine (5%), thebaine (0.2%), (ii) alkaloid of benzoisoquinoline derivatives – papaverine (1%), noscapine (6%).

1840 – oral morphine – went on 1860 – 70 – hypodermic- morphine – used 1900 – more side effects 1914 – thio Concept of balanced analgesia More uses 1939 – pethidine 1960-70 – fentanyl

Some terms- opioid , opiate , narcotic opioid is defined as a natural, semisynthetic or synthetic compound that acts at opioid receptors. May be antagonist! Opiate is a specific term to describe drugs derived from the opium poppy (Papaver somniferum). Narcotic Greek word for stupor. At one time the term ‘narcotic’ was referred to any drug that induced sleep and then it became associated with opioids. But now it is often used in legal context

Receptors Four broad classes of opioid receptors are currently accepted. Mu (MOP) – morphine Kappa (KOP) - ketocyclazocine Delta (DOP) – vas deferens Nociceptin receptor (NOP)

MOP DOP KOP NOP analgesia, sedation, respiratory depression, bradycardia, nausea vomiting reduction in gastric motility spinal and supraspinal analgesia and reduce gastric motility spinal analgesia, diuresis and dysphoria. Analgesia Hyperalgesia Allodynia

Where are mu receptors cerebral cortex basal ganglia presynaptic primary afferent neurones in dorsal horn periaquaductal grey µ2 receptor has lower affinity for morphine. It mediates spinal analgesia, respiratory depression and constipation

DOP Found in midbrain nucleus raphe magnus part of descending inhibitory control pathway Limited clinical use as produces side effects at doses lower than those required for analgesia Side effects include diuresis, sedation, dizziness, confusion and dysphoria

KOP Nucleus raphe magnus (midbrain), hypothalamus, spinal cord Analgesia Dysphoria Sedation Dependence Miosis

NOP . Spinally, has been shown to produce analgesia and hyperalgesia, dependent upon the administered concentration, and allodynia. Supraspinally, when administered intra cerebrovascularly it is thought to produce a pro-nociceptive anti-analgesic effect, owing to an inhibition of endogenous opioid tone

A μ3 receptor is found in vascular tissue and in leukocytes, and it may have roles in vascular control and immunomodulation The κ1 receptor mediates spinal analgesia, whereas activation of the κ3 receptor results in supraspinal analgesia, sedation, and ventilatory depression The majority of opioid receptors in myocardium appear to be δ, and this receptor may play a role in the phenomenon of ischemic preconditioning

In short what ? Mu 1 and 2 Delta Kappa Nociceptin

Mechanism of action ?? Inhibition of calcium entry into the cell closes voltage sensitive calcium channels Potassium efflux resulting in hyperpolarisation Inhibition of adenylyl cyclase reduces cAMP levels Overall result is reduced neuronal cell excitability with a reduction in nerve impulse transmission and inhibition of neurotransmitter release

Classification of opioids According to chemistry Natural Semisynthetic Synthetic According to Pharmacodynamics Agonists Partial agonists Agonists antagonists Antagonists

Morphine and pethidine Naturally occurring Morphine, Codeine, Papaverine, Thebaine. Morphine and pethidine

Semisynthetic Morphine Diacetyl morphine Hydromorphone Hydrocodone Oxycodone Thebaine derivative – etorphine - wild life

Synthetic 1. Morphinan series: Levorphanol, butorphanol. 2. Diphenylpropylamine series: Methadone. 3. Benzomorphinan series: Pentazocine. 4. Phenylpiperidine series: Meperidine, fentanyl, sufentanil, alfentanil.

Agonists : morphine, pethidine fentanyl etc.. Partial agonists – buprenorphine agonist- antagonists – pentazocine, butorphanol , nalbuphine Pure antagonists – naloxone , naltrexone , nalmefene

Pharmacodynamics

Analgesia Relief of almost any pain Acute burning severe pain – more effective Neuropathic pain less First pain ? √ Second pain !! Blunt reflexes Perception of pain- it acts Descending pathways and spinal cord Don’t put to sleep always and don’t numb Euphoria - yes

Does it affect touch ?? No

CNS effects – euphoria Dysphoria and agitation rare with analgesic doses Hypnosis and sedation will occur with high doses No amnesia Elevate ICP with PaCO2 only Seizures with norpethidine

Ventilation Opioids produce a dose-related depression of the ventilatory response to CO2 by a direct effect on ventilatory centers in the medulla. Morphine also blunts the response to hypoxia Sleep will increase blunting Difficult to reverse without reversing analgesia Extremes of age , other potent depressants- danger

Respiratory system

Skeletal muscle rigidity Generalized hypertonus of skeletal muscle can be produced by large IV doses of most opioid agonists. Common with fentanyl, alfentanil, sufentanil, severe form, “lead pipe” muscle rigidity very little loss of compliance when opioids are given to patients with tracheotomies, suggesting that the primary etiology is supraglottic obstruction from constriction of laryngeal and pharyngeal muscles.

Antitussive Suppression of cough centres in medulla Codeine Dextromethorphan ( dextro isomers - better antitussive ) Heroin Antitussive activity – in fibreoptic intubation - Less analgesia with codeine – different mechanism

Miosis Opioids stimulate the Edinger-Westphal nucleus of the oculomotor nerve to produce miosis Hypoxia – mydriasis – beware Small doses – maximal effect Qualitative but not quantitative

CVS effects Bradycardia and peripheral vasodilatation are seen at higher doses and when opioids are combined with other anesthetic drugs. No myocardial depression, no autonomic activity – Ideal for cardiac anesthesia Fentanyl – brady , pethidine and pentazocine – tachycardia and hypertension Reduces the size of infarct

Histamine release Some opioids, particularly morphine and meperidine, produce a nonimmunologic release of histamine from circulating basophils and tissue mast cells. most often seen as local itching, redness, or urticaria near the site of intravenous injection, often mistake for true allergy. Anti H1 and anti H2 drugs as prevention Perioral itch by fentanyl – no histamine – naloxone ok but antihistaminics ?

Naloxone may increase vomiting

GI and smooth muscle Opioids decrease the passage of fluids and solids at every level of the GI tract—so-called opioid bowel dysfunction (OBD). They delay gastric emptying and increase antral tone. Opioids cause contraction of smooth muscle in the gall bladder and spasm of the sphincter of Oddi. biliary colic -? Intra op cholangiogram - ?

Opioid receptors are found throughout the enteric plexus of the bowel; their activation or stimulation causes tonic contraction of gastrointestinal smooth muscle, thereby decreasing coordinated, peristaltic contractions.

Smooth Muscle Effects increase the contractions of the ureter although they relieve the pain caused by ureteral stones. They also decrease detrusor contraction in response to bladder distension (the voiding reflex) and increase the tone of the urinary sphincter by both central and peripheral mechanisms.

Pregnancy and fetus Opioids have no specific teratogenic effects, but chronic opioid use by the mother can lead to physical dependence by the fetus. Neonatal withdrawal may occur shortly after delivery and in some instances may be life-threatening.

When tolerance to an opioid occurs, there is simultaneous development of cross-tolerance to all other opioid agonists. In general, tolerance develops to depressant effects (analgesia, ventilatory depression, euphoria), less tolerance to some of the stimulant effects, like constipation or pupillary constriction.

Hormonal effects = ? Use in the perioperative scenario OPIOIDS MODULATE ANGIOGENESIS OPIOIDS ARE IMMUNOSUPPRESSIVE Cardiac protective Neuro protective Meperidine and shivering why ??

Pictures from the net / journals for closed academic purpose only

May be next time individual drugs History Receptors Classification – two types CNS CVS RS GUT Smooth muscles Thank you all