Opioids Pharmacology Lecture Notes PDF

1 PM 719 Pharmacology II Lecture Notes (LN) Chapter 31 Opioids Origin The poppy plant (Papaver somniferum) produces a brown resin that is called crude opium. The principle alkaloid (active ingredient) in opium is morphine. So, opium ingesti...

1 PM 719 Pharmacology II Lecture Notes (LN) Chapter 31 Opioids Origin The poppy plant (Papaver somniferum) produces a brown resin that is called crude opium. The principle alkaloid (active ingredient) in opium is morphine. So, opium ingestion po, smoking, dissolve in ethanol and drink are simply ways to get morphine into the body. Many drugs are synthesized from the starting material morphine including heroin which ois diacetylmorphine. Add two acetyl groups to morphine and the drug enters the brain much faster, hence the “rush.” Codeine is the second most important opioid drug found in opium. Codeine is a prodrug of morphine. Codeine is actually methyl morphine. Over 80% of the world’s supply of opium (from which morphine and codeine are extracted) comes from Afghanistan. Opium is still the source of morphine and codeine because they are still too difficult and expensive to synthesize in the laboratory opium = a mixture of many active and non-active alkaloid drugs including morphine and codeine morphine = morphine codeine = methylmorphine Heroin =. diacetylmorphine (spelling Heroin with a capital first letter is an old habit of mine. Heroin is trademark name for diacetyl morphine. When first invented in 1890 it made the persons at Merck who first tried it feel “heroic.” (It’s all about morphine) Terms: Distinguish and define each term opium raw gum collected from the ripe pod of the poppy plant opiate any drug derived directly from the opium poppy plant but mostly two, moprhine and codeine. Heroin is a semisynthertic. opioid the modern term that describes any drug from any source that binds to the receptors listed below and acts like morphine. So, morphine is an opiate because it comes from the poppy plant and it is an opioid because it binds to the  2 receptors below. Fentanyl is made in the lab, a total synthetic. Nobody uses the term opiate anymore. Opioid Receptors mu receptor major analgesic receptor morphine is a full agonist codeine is a partial (weak) agonist at these receptors naloxone is a strong mu receptor antagonist delta See Katzung Table 31-1, pg 574 kappa See Katzung Table 31-1, pg 574 Endogenous Opioid Peptides (EOP) This is the general term used to describe the natural opioids produced by the brain. Yes, we are all making opioids in our brains all the time. EOPs include endorphins, enkephalins, and dynorphins EOPs are small peptides and they bind to the various opioid receptors with variable affinities. See Table 31-1 pg 583 Pharmacokinetics of the Opioid Drugs Absorption major first pass effect for morphine, best im or iv, po requires higher doses to reduce loss from first pass effect, typical IV dose is 10 mg, PO dose is 30 mg. some available as patches, provides for long term use, avoids first pass Distribution some storage depot effect in fat tissues rapid distribution into muscle, brain and other highly perfused organs Metabolism mostly polar water soluble glucuronide conjugates (Phase II) morphine converted to active metabolite, morphine-3-glucuronide (M3G) which blocks GABA and glycine receptors but it poorly crosses the BBB, can produce seizures with high dose morphine morphine converted to active metabolite, morphine-6-glucuronide (M6G) which is 4-6 times more potent analgesic than morphine, can  3 induce overdose if not cleared by the kidney M3G and M6G can accumulate with renal failure (water soluble active metabolites that can not be removed) fentanyl has no active metabolites codeine is demethylated in the liver to morphine by CYP 2D6 which means that codeine is a prodrug (covered also in the Pharmacogenomics Chapter 5). polymorphisms (increased activity) results in poor response in some individuals Excretion mostly through the urine (water soluble glucuronide metabolites) Pharmacodynamics Mechanism of Action (a) bind to and activate G-protein coupled receptors (mu, kappa, delta, Table 31-1, pg 583) (b) major receptor level actions through G-protein coupled actions are to open Ca gates and phosphorylate proteins but opioids close this gate. (c) Major actions of opioids (1) close voltage gated Ca channels on pre-synaptic terminals and reduce (stop) neurotransmitter release (2) open K channels and hyperpolarize postsynaptic neurons (d) among the neurotransmitters that are inhibited from being released include glutamate (excitatory NT), Ach, NE, 5HT and substance P Receptor Type and Physiologic Effect (a) most analgesics act on mu receptors (b) morphine’s drug dependency, euphoria, respiratory depression, and analgesia (mostly) through mu receptor actions Receptor Distribution and Mechanism of Analgesia (a) receptors widely distributed in spinal cord, stop pain signal transmission by blocking excitation NTs (b) binding of morphine and other opioids induces the release of natural endogenous peptides (endorphins) which act on other opioid receptors (c) mu receptors are found on PNS peripheral terminals of sensory  4 neurons and helps explain PNS actions of opioids Tolerance and Physical Dependence (a) tolerance = loss of response after repeated use, higher doses required to achieve the same clinical effects as once lower doses achieved (b) physical dependence = withdrawal or abstinence syndrome (c) mechanism of tolerance and dependence not well understood (d) receptor recycling = morphine blocks receptor endocytosis of mu receptor which is normally required to reactivate receptor (e) receptor uncoupling = opioid receptor uncouples from G-protein component and dysfunction occurs (f) both (d) and (e) are hypotheses to explain tolerance and dependence, pick one, neither answers all the questions (g) persistent administration of morphine, fentanyl and others can lead to increased pain sensation (go figure) Organ System Effects of Morphine and Others (a) How do I say this part is important? (b) CNS (mostly through mu receptor interactions) (c) Analgesia (1) effect both sensory and affective (emotional) aspect to pain (2) opioids but not NSAIDs effect both, NSAIDs only effect sensory (d) Europhoria (1) the pleasant floating sensation following iv admistration (e) Sedation (1) drowsiness and clouding of mentation with no amnesia (2) marked sedation less frequent with synthetics (meperidine, fentanyl) (f) Respiratory Depression (1) all opioids can depress respiratory depression by inhibiting brainstem respiratory mechanisms (2) depressed response to CO2 challenge (g) Cough Suppression (1) may lead to airway obstruction from inability to remove secretions (h) Miosis (1) pupil constriction, no tolerance develops (2) a valuable sign in diagnosis of overdose (i) Truncal rigidity (1) intensification of tone in large trunk muscles (2) reduces thoracic compliance (j) Nausea and vomiting (1) activate brainstem chemoreceptor trigger zone (k) Temperature (1) endogenous peptides contribute to temperature regulation  5 (2) mu receptor agonists produce hyperthermia (3) kappa receptor agonists produce hypothermia (l) PNS effects (1) Cardiovascular system, mostly no effects except for meperidine which has major antimuscarinic effects that induces tachycardia (2) GI, constipation is common ADR of opioids, no tolerance to this effect is seen with continued use (3) Sphincter of Oddimay constricts with reflux pancreatic secretions,elevations of serum amylase and lipase two blood test markers of psncreas function (4) Renal function depressed (5) Pruritis, produce flushing, warming of the skin, histamine mediated (j) Mixed Agonist and Antagonist Function Opioids (1) Agonist at one type of opioid receptor and antagonist at other type or types (2) Actions at delta and kappa (agonist) can antagonize actions of morphine at mu receptors (3) mixed agonist-antagonist drugs include buprenorphine pentazocine nalbuphine Clinical Pharmacology of the Opioids Analgesia (a) severe constant pain well treated with opioids, sharp, intermittent pain they do not work as well (b) acute pulmonary edema (dyspnea) iv morphine often used (perception and anxiety of shortness of breath is reduced) (c) cough reduced at doses lower than required for analgesia (d) diarrhea reduced (but if bacterial in origin, then chemotherapy required) some opioids have little or no CNS effects (diphenoxylate, loperamide) (e) Shivering, meperidine has most pronounced effect in reducing shivering (drug blocks alpha2 receptors) (f) Use in Anesthesia, used as premedication (sedative, anxiolytic, and analgesic properties) Alternative Routes of Administration (1) rectal suppositories, transdermal patches, intranasal, buccal transmucosal (fentanyl lollipop) (2) Patient controlled analgesia (PCA), patient pushes a button to receive  6 a iv (usually) dose of a drug. Toxicity and ADRs (1) Tolerance (a) effects vary with type of binding (strong vs weak agonist) (b) tolerance occurs most often after 2-3 weeks of continuous use (c) with more potent drug (remifentanil) tolerance can occur within hours (d) a patient never exposed to opioids may develop respiratory depression with a dose of 60 mg of morphine but an addict can tolerate up to 2000 mg with little to no respiratory depression (e) drugs that are mixed agonist-antagonists or pure antagonists do not develop tolerance (f) cross-tolerance = tolerance with morphine, then patient is tolersnt to other opioids (g) “opioid rotation” helps reduce tolerance, change from morphine to hydromorphone (2) Physical Dependence (a) mostly seen with opioids of the mu type (b) signs of withdrawal include rhinorrhea, lacrimation, yawning, chills, gooseflesh (piloerection), hyperventilation, hyperthermia, mydriasis, muscular aches, vomiting, diarrhea, anxiety, and hostility. (c) withdrawal signs start at 6-10 hrs for morphine addicted patients (3) Psychological Dependence (a) the effects of the opioids (euphoria, sedation etc) help promote compulsive use Drug Interactions summarized very well in Table 31-5, pg 597 and in the Chapter itself. Good to understand the major effects of three different important classes of drugs and their effects on the opioids. Specific Agents Strong Agonists (strong mu agonists) (a) morphine, hydromorphine, oxymorphone, diacetylmorphine (Heroin) (b) methadone, may be useful for neuropathic pain not treated well by those in (a) above because methadone acts on NMDA receptors and blocks monoaminergic reuptake  7 (c) methadone, used to treat opioid withdrawal, tolerance and withdrawal develops more slowly (d) fentanyl, sufentanil, alfentanil, remifentanil (widely used) (e) meperidine has significant antimuscarinic ADRs (tachycardia), not often used (f) levorphanol, synthetic resembling morphine Mild to Moderate Agonists (a) codeine, oxycodone, dihydrocodeine, hydrocodone (b) often used in combination with aspirin or acetaminophen (c) propoxyphene, low analgesic activity, 120 mg propoxyphene = 60 mg codeine (d) this above equivalency as in (c) above is a common issue in opioid therapy, these drugs are always being compared on a scale of comparison based usually to the gold standard, morphine Apps carried by residents will show tables of equivalence. For example what dose of opioid X PO will provide the same relief as the gold standard, 10 mg morpine IV. (e) diphenoxylate, difenoxin, loperamide used for diarrhea, low potential for abuse (low solubility after iv dose and/or low penetration into the brain) but they work because the GI has opioid mu receptors. Mixed Receptor Actions (a) nalbuphine, strong kappa agonist, mu receptor antagonist (b) buprenorphine, partial mu agonist, kappa antagonist, also available combined with a pure mu antagonist to prevent illicit use (drug is given po but can be injected) (c) butorphanol, mostly kappa agonist (d) pentazocine, weak mu, but kappa agonist Miscellaneous (a) tramadol blocks 5HT reuptake, weak mu agonist, (b) tapentadol, modest mu, significant NE reuptake inhibitor Antitussives (a) work at doses lower than required for analgesia (b) dextromethorphan (OTC drug), codeine (c) levopropoxyphene The Opioid Antagonists (a) naloxone, naltrexone, nalmefene  8 (b) morphine derivatives with high affinity for mu receptors (c) some reversing action at kappa and delta receptors (d) drugs have no effect if given to patient with no opioids in their system (e) no tolerance develops (f) opioid overdose treated with these antagonists reverses the symptoms of overdose within minutes (g) clinical uses include (1) treat acute opioid overdose (2) also used in low dose as maintenance drug for drug addiction treatment The Required Drugs are in Bold and covered in the above Lecture Notes. Opioid Agonists morphine methadone fentanyl meperidine (with some anticholinergic actions) oxycodone sufentanil codeine hydrocodone Mixed Agonist-Antagonist buprenorphine nalbuphine Antitussives dextromethorphan codeine Opioid Antgonist naloxone naltrexone Drugs for Moderate Pain tapentadol tramadol Misc Drugs All covered sufficiently in the shaded box on page 580 in Katzng. Simply be aware of and remember these. Some have major importance in podiatry. ziconotide (snail cone, check this one out). gabapentin  9 pregbalin THC Pharmacology of Drugs of Abuse (a) all addictive drugs increase DA levels in the mesolimbic projections (b) addictive drugs put into three grpups (1) Act through G-protein coupled receptors opioids GHB hallucinogens (LSD, PCP) (2) Act through inotropic receptors or ion channels nicotine alcohol benzodiazepines dissociative anesthetics some inhalants (3) Bind to monoamone transporters cocaine amphetamines ecstasy Another Way of Listing the Required Drugs: Strong Opioid Agonists morphine methadone fentanyl hydromorphone levorphanol oxymorphone meperidine oxycodone sufentanil alfentanil remifentanil Partial Agonists codeine hydrocodone  10 Mixed Opioid Agonist-Antagonist buprenorphine nalbuphine pentazocine butorphanol Antitussives dextromethorphan codeine Opioid Antagonists naloxone naltrexone nalmefene alvimopan methylnaltrexone Other Analgesics Used In Moderate Pain tapentadol tramadol ziconotide Analgesic Combinations codeine/acetaminophen codeine/aspirin hydrocodone/acetaminophene hydrocodone/ibuprofen oxycodone/acetaminophen oxycodone/aspirin  11 So what does the AACPM Currcular Guide (2023) list for the required Opioid drugs? See below (the whole document is on Canvas for this course). 12