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BIOC 309 - Pharmacology Poster Project

Chelsea Vandenberg

on 2 March 2011

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Transcript of Codeine

Introduction Codeine, also known as methylmorphine, is a naturally occurring alkaloid of opium. It is used in medicine for its analgesic, antitussive and anti-diarrheal properties. It was first isolated in 1832 by French chemist Pierre-Jean Robiquet. Codeine is classified as a narcotic and it shares many of its pharmacological characteristics with morphine. However, codeine has one sixth the potency and is far less addictive than morphine. Codeine is rapidly and extensively metabolized in the liver where approximately 5-10% of it undergoes O-demethylation by CYP2D6 enzymes to form morphine. This minor metabolic pathway as well as codeine's conversion to codeine-6-glucuronide contribute to codeine’s analgesic activity. Since codeine itself is not an adequate analgesic, people with dysfunctional or inactive CYP2D6 enzymes have a poor response to codeine’s therapeutic effects. Conversely some individuals can metabolize CYP2D6 rapidly and produce unexpectedly large amounts of morphine following small doses of codeine; this can lead to life-threatening opioid toxicity. When codeine and other opioids bind to specific opioid receptors (i.e. μ, δ, Κ) a cascade of events is set off that modulates the release of neurotransmitters involved in pain signaling. A multitude of responses such as analgesia, respiratory depression, euphoria, miosis, and altered gastrointestinal motility can occur. Codeine’s metabolite morphine mainly binds to μ1 opioid receptors blocking pain signals in the CNS, but some studies suggest the metabolite codeine-6-glucuronide causes the analgesic effect. The cough suppressing action of codeine is unrelated to its analgesic effects and, although not well understood, it is believed that unaltered codeine binds to receptors and depresses the cough center in the medulla. Codeine is extremely effective as an antitussive and, until similar-acting synthetic compounds were identified, codeine was a very common ingredient in nonprescription cough medications. Codeine-containing cough syrup such as Robitussin is a Schedule V drug and potential abuse is considered to be minor. Codeine is a Schedule II drug when taken in tablet form with no other analgesic compound, and a Schedule III drug when taken in tablet form combined with analgesics such as aspirin or acetaminophen. When prescribed to treat pain, codeine is usually combined with either a salicylate (i.e. aspirin) or acetaminophen (i.e. Tylenol) because opiate narcotics and aspirin-like drugs interact in a synergistic fashion to give an analgesic equivalence greater than what can be achieved by aspirin or codeine alone. Although not especially powerful, codeine can still be abused. Codeine dependence is possible, but not very common. Many people who abuse codeine generally have previous experience with the more potent opioids. Codeine is not commonly marketed illegally on the streets because a large quantity is usually required to satisfy a narcotic addiction. Major Treatment of mild to moderate pain (analgesic) Minor Antitussive (cough suppressant)
Treats diarrhea (constipating side effect) Indications Codeine is a weak narcotic used as an antitussive and analgesic to relieve mild to moderate pain. It resembles morphine pharmacologically but has milder actions and a higher oral effectiveness. There are three main opioid receptors (μ, δ, Κ) that all belong to the superfamily of G-protein coupled receptors. Codeine functions primarily as a partial μ-opioid receptor agonist. Opioid agonists produce analgesia by binding to opioid receptors in the CNS, spinal cord, and gastrointestinal tract where they mimic the effects of endorphins. Codeine undergoes metabolism in the liver by the P450 enzymes CYP2D6 and CYP3A4, which convert it into morphine (an active metabolite with a greater potency than codeine itself) and codeine-6-glucuronide respectively. The therapeutic effects of codeine as a cough suppressant occur at lower doses than those required for analgesia. At the generally prescribed doses, codeine has a lower potential for abuse than morphine and rarely leads to dependence. Some of codeine’s common side effects are constipation, nausea, and drowsiness. The most common drugs mixed with codeine are aspirin and acetaminophen to provide a synergistic analgesic effect. Abstract 3-O-methylmorphine Monohydrate
Codalgin Forte Codate
Codeine acetate
Codeine anhydrous
Codeine bitartrate
Codeine citrate
Codeine hydrobromide
Codeine hydrocholide
Codeine hydroiodide
Codeine meconate
Codeine nitrate
Codeine pectinate
Codeine phosphate
Codeine picrate
Codeine sulphate
Codeine tartrate
Methyl morphine monohydrate
Morphine-3-methyl ester
Morphine 3-methyl ether
Morphine monomethyl ether
N-Methyl Norcodine
Fig 5. Chemical structure of codeine:
7,8-Didehydro-4,5-epoxy-3-methoxy- 17-methyl-(5alpha, 6alpha)-morphinan 6-ol Other Names There are 3 types of opioid receptors: µ, κ, and δ. Codeine and its metabolites primarily bind to the µ-receptor.
also induce some analgesia by binding to κ and δ receptors
Opioid receptor agonist – analgesic (painkilling) and other effects by acting on µ-opioid receptors in CNS

. – controversy as to whether this is due to the action of morphine or codeine-6-glucuronide

. – believed to occur due to unaltered codeine binding to receptors

Codeine has a weaker affinity than morphine for opioid receptors
Codeine-6-glucuronide, norcodeine, and codeine have a similar affinity to µ-opioid receptor
Codeine has one-sixth the analgesic activity of morphine
Sites of analgesic effects – brain, brain stem, spinal cord, GI tract, and primary afferent peripheral terminals

direct central action in the cough center of medulla Gi/o protein coupled receptor
Activation of presynaptic and postsynaptic µ-opioid receptor

Penetrates blood brain barrier (faster than morphine)
O-methylation of codeine in brain may occur in close proximity to opioid receptors Presynaptic receptor activation - inhibits Ca influx that would otherwise occur during the propagation of an action potential
inhibits neurotransmitter vesicle release in the dorsal horn of the spinal cord
Postsynaptic receptor activation – open K channels and K flows out of post-synaptic neuron (increases K conductance)
results in postsynaptic hyperpolarization, and decreased action potential generation Mechanism of Action Dosing adjustment in renal impairment:
ClCR: 10-50mL/min then use 75% of original dose
ClCR: <10mL/min then use 50% of original dose
ClCR = Creatinine Clearance
IM = Intramuscular
SubQ = Subcutaneous Table 4. Dosage of codeine required for different age groups depending on what the drug has been prescribed for. The dose required for cough suppression is less than the dose required for pain. Dosage
Opioid toxicity characteristics: depressed level of consciousness, CNS depression, respiratory depression, and pupillary miosis.
The adult lethal dose is 0.5 to 1.0 g for an average person. This dose may cause convulsions and unconsciousness; death from respiratory failure may result within 4 hours
Minimum lethal adult dose = 800 mg (about 12mg/kg body weight).
Serum concentrations over 5 mg/L were detected in an adult who had self-administered 900 mg of codeine intravenously; he regained consciousness only after 3 days when serum levels reached 1.3 mg/L
Drug concentrations in codeine fatalities are approximately 2.8 mg/L in blood and 103.8 mg/L in urine
Tolerance to codeine increases the potentially toxic doses. Studies of tolerance show that individuals could tolerate up to 240 mg by mouth, 4 times daily.

Doses over 5 mg/kg may cause serious respiratory depression.
Children may display signs of toxicity at 1/20 th of the minimum lethal dose of 800mg
A cough syrup which contained 10 mg of codeine/5 mL, produced severe poisoning after two 5 mL doses in a prematurely born 3 month old baby. Adults Children Toxicity Pharmacokinetics Comes as tablet, capsule, or solution
Oral administration: almost complete absorption through gastrointestinal tract
Potency is about 60% of the intramuscular form
Higher oral : parenteral potency ratio than in morphine

High ratio due to lower first pass metabolism in liver Into bloodstream
Protein binding is approximately 7-25% in human serum
Slightly lipid soluble
enough to cross placenta, enter breast milk, and slowly

Does not accumulate in body tissue

Major pathway: mainly metabolized in liver by glucuronidation
Metabolised by CYP 3A4 to codeine-6-gluronide (active metabolite)
Minor pathways: metabolized in liver to active metabolite (morphine) and inactive metabolite (norcodeine)
Codeine is metabolized to morphine by CYP 2D6 through the process of O-demethylation to morphine
Codeine is metabolized to norcodeine by CYP 3A4 through the process of N-demethylation
Half-life: 2-6 hours
Some metabolism occurs in GI tract and brain
GI tract - enzyme CYP 3A4, Brain - enzymes CYP 3A4 and CYP 2D6
Metabolism rate: 30mg/hour
People who are poor metabolizers of codeine receive reduced benefit due to reduced metabolite formation

Excreted in urine
About 10% as unchanged drug
Mainly eliminated by metabolism
5-13% norcodeine
~80% free and conjugated forms of codeine (codeine-6-glucuronide)
5-10% morphine
Remainder of dose excreted in feces (small amount)
95% recovered in urine within 48 hours after ingestion Excretion Absorption Distribution Metabolism Ardinex = Codeine Phosphate and Ibuprofin
Calcidrine = Calcium Iodide and Codeine
Codalgin Forte Codate = Paracetamol and Codeine phosphate
Novahistine DH = Chlorpheniramine/Codeine/Pseudoephedrine
Nucofed = Codeine Phosphate, Pseudoephedrine Hydrochloride
Robitussin AC = Codeine, Pheniramine, and Guaifenesin
Tussar-2 = Codeine Phosphate, Guaifenesin, and Drugs Containing Codeine Non-steroidal anti-inflammatory drugs (NSAIDS) – effective in managing mild to moderate pain i.e. Ibuprofen and aspirin
Acetaminophen – non-narcotic analgesic, effective in treating minor aches and pains on its own, but when in combination with opioid analgesics it can be used to manage more severe pain
Semi-synthetic opioids – derived from natural opiates and share a similar chemical structure. Used for their analgesic properties. Examples: hydrocodone, oxymorphone, hydromorphone, oxycodone.
Synthetic opioids – artificially manufactured and produce many of the same effects as morphine by activating opioid receptors. Examples: methadone, merperidine, pentazocine, butorphanol, fentanyl.

Dextromethorphan (DM on cough syrup labels) - non-narcotic antitussive used to treat non-productive cough, it is less effective than narcotic agents such as codeine, but it has few side effects. It is found in many over the counter cough medicines such as Benylin, Delsym, Buckleys, and Contac.
Benzonatate - a prescribed non-opioid antitussive that operates by anesthetizing the respiratory tract. It is generally regarded as a safer alternative to codeine. It is sold in the US under the brand name Tessalon.
Non-pharmacological antitussive treatments- Traditional Chinese medicine: includes acupuncture and herbal products for asthma and bronchitis Alternative Treatments Pain Cough Codeine is contraindicated in patients:
With hypersensitivity or allergic reaction to codeine
With acute respiratory depression
With chronic constipation
During labour (may produce codeine withdrawal symptoms in neonate)
Use precautionary measures in patients with:
Asthma or COPD (Chronic obstructive pulmonary disease)
Hepatic or renal impairment

CNS depressants (ex. alcohol, and barbiturates)
Antiperistaltic antidiarrhoeals (ex. kaolin, and pectin)
Substances that inhibit CYP2D6 (ex. quinidine, and antipsychotic agents)
Tranquillisers, sedatives and hypnotics Contraindications Side Effects Group 5:
Jenelle Corkill, Katrina Hill, Stephanie Ruscheinsky, Alysha Rusk, Chelsea Vandenberg Codeine makes up 0.7-2.5% of opium from Papaver somniferum (poppy seed) and is the main source for codeine production
Codeine was isolated from opium about 150 years ago and was recognized for pain relieving effects
Codeine has not been tested on pregnant animals; therefore, extreme caution must be used when administered to pregnant women
About 7% of Caucasians are poor metabolizers of codeine: CYP2D6 is not expressed due to inactivating mutations in the CYP2D6 gene
Recreational drug – cough syrups/tablets containing codeine are available without prescription; users reported that they purchased codeine from multiple pharmacies so as not the arouse suspicion
Heroin addicts may use codeine to ward off withdrawal effects
Available in conjunction with promethazine (anti-nausea medicine)

Regulated under various narcotic control laws in Australia, Canada, USA, UK, and many other countries
Is banned in Greece, and United Arab Emirates (includes places such as Dubai, and Abu Dhabi). Travellers must have a notarized and authenticated doctor’s prescription for UAE; however, for Greece this may not be sufficient and could result in jail time Becoming one of the most abused codeine preparations Interesting Facts “Anesthesia Assisted Medical Opiate Detoxification.” Codeine Side Effects, Overuse. Retrieved: 21 Jan. 2011. <http://www.codeineaddiction.biz/codeinesideeffects.html>
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derived from the Greek word opion meaning “poppy juice” as a reference to the substance from the seed capsules. The dried milky juice is obtained from the unripe capsules of the poppy plant (Papaver somniferum) and is used to prepare many addictive narcotic drugs such as morphine, codeine, and papaverine.

refers to any of the drugs that are derived from opium. Opiates include such drugs as codeine, morphine, and papaverine. They are primarily central nervous system depressants and narcotic analgesics.

refers to any compound that acts like morphine, the most abundant alkaloid compound in opium. Opioids include substances that are derived from plants such as morphine and codeine, those that occur naturally in the body such as endorphins and enkephalins, and synthesized compounds such as heroin and fentanyl. Terminology Opium Opiate Opioid Fig 1. A person scoring the poppy pod to obtain opium. Fig 3. Synthesis of opiates (such as morphine and codeine) by scoring the heads of poppies and preparing the extracted opium. Fig 4. Chemical structures of morphine and codeine. Methylated Table 1. Physical properties of codeine and morphine. Fig 2. Head of an opium poppy with milky residue. Table 2. Different uses of codeine in combination with other drugs. Fig 7. Structure of mu-opioid receptors in the brain: 7 membrane-spanning domains coupled to a G-protein. Extracellular N domain is the binding site for morphine and codeine. Fig 8. Main metabolic pathways in the liver for the conversion of codeine to its metabolites. Codeine is metabolized by cytochrome P450 enzymes to form morphine, codeine-6-glucuronide, and norcodeine. Drug Interactions Pseudoephedrine Hydrochloride 2+ Table 3. Time to onset of drug action and peak action for different routes of administration. + + + Codeine Analgesic effect Antitussive effect µ-Opioid Receptor Agonist or Codeine cross blood brain barrier
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