Pharm 100 - Lesson B.4
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The term “opioid” refers to any natural or synthetic substance which exerts actions on the body thatare similar to those induced by morphine and that are antagonized (blocked) by the drug naloxone.
- 1. Opiate narcotics (analgesic agents obtained from the opium poppy).
- 2. Substances structurally related to morphine
- 3. Synthetic drugs with structures different from that of morphine.
- 4. Endogenous brain peptides that exert analgesic actions (opioid peptides- enkephalins andendorphins).
Concept of Opioid Receptors
In the 1970’s, specific receptor sites for opioid molecules were found in the brains of experimentalanimals and humans. The questions was: Why did these receptors exist and was there an endogenoussubstance that interacted with these receptors? In 1975, endogenous substances were isolated thatinteracted with these receptors. These substances, which were peptides, are known collectively as endorphins. There are now at least three known families of endorphins; these are: enkephalins,dynorphins and $-endorphins. The endorphins are able to act as neurotransmitters and neuromodulators. They affect the perception of pain and emotional response to pain. They may influence mood and areassociated with the reward pathways in the brain.
types of opioid receptors
- Mu (µ) receptors are resent in all structures in the brain and spinal cord. They mediate analgesia. They also mediate morphine mediated depression of respiration in the brain stem. Thus, analgesia anddepression of respiration are linked. If they are mediated by the same receptor subtype, it is difficult toobtain drugs where there is separation in the two responses. These receptors are also involved in the compulsive abuse behaviour demonstrated by opiate users.
- Kappa (k) receptors are involved in analgesia, dysphoria and miosis (pin-point pupils). The mixed agonist/antagonists, e.g. pentazocine, act predominantly on these receptors. The endogenous ligand arethe dynorphins, although the endorphins have some activity at these receptors.
- Delta (*) receptors have as their endogenous ligand, the enkephalins. These receptors are involved in analgesia at the level of the spinal cord and brain. They may also modulate the emotional response to opioids.
- Opioid receptors are located in the peripheral as well as the central nervous system. These arelocated in the gastrointestinal tract and are responsible for the constipation caused by opiates.
- Illicit a full response.
- Natural – morphine and codeine
- Semi-synthetic – heroin
- Synthetic – meperidine and methadone
Pentazocine is the best example of this group. This group can illicit a response when given alone, but can block part of theresponse to morphine, when given together with morphine.
- These agents block the response to morphine, heroin and other opiates atthe respective receptor. Administration of an antagonist to an addict willprecipitate “withdrawal”. The prototype antagonist is naloxone. It has no analgesic activity and is used in:
- (a) Reversal of opioids overdose.
- (b) Treatment of opioid dependence.
- (c) Diagnosis of opioid physical dependence.
- (d) Naltrexone – an opioid antagonist is used to treat alcohol dependence.
Therapeutic Uses of Opioid Drug
- Relief of severe pain (e.g. post-surgical pain and pain experienced by some terminally ill patients). Analgesia is the major use for the opiates
- Treatment of diarrhea. Opioid receptors in the neural plexus of the gastrointestinal tract mediate opiate-induced inhibition of gastrointestinal motility. Thus, opiates are used to treat diarrhea, butc onstipation is a problem when the drugs are used as analgesics. Diphenoxylate (Lomotil) is an opiatewhich is not an analgesic, does not produce dependence, but is useful in controlling diarrhea. It is sold asan over-the-counter drug.
Pharmacological Effects of Opioid Agonists
- 1. Analgesia. Morphine is the most effective analgesic available. There is no ceiling to the intensityof pain which can be relieved. Respiratory depression is the limiting factor.
- 2. Euphoria (feeling of well being, energetic). In some individuals, dysphoria (fear, anxiety, lethargy,apathy) may occur.
- 3. Sedation. All opiates/opioids produce sedation, at least those that are analgesics.
- 4. Hypnosis/sleep (narcotic effect). Morphine produces sedation and hypnosis, but not as intense asthat produced by the CNS depressants. The patient is usually arousable. There is reducedmentation and lack of concentration and apathy
- 5. Relief or prevention of cough.
- 6. Respiratory depression (basis of toxicity) ÷ respiratory arrest.
- 7. Decreased gastrointestinal motility (constipation).
- 8. Constriction of the pupils of the eyes (miosis). All opiates/opioids which gain access to the centralnervous system will cause pin-point pupils. A sign of the user.
- 9. Nausea, vomiting. Morphine stimulates the vomiting centre (chemotrigger zone) in the medulla. Vomiting is an unpleasant but not life-threatening side effect.
- 10. Drug dependence. Develops to all opiate analgesics.
Mechanism of Action
- Morphine and related opioids act on specific receptors on neurons – the opioid receptors. Responses are elicited when these receptors are activated. Naloxone does not activate these receptors. However, it occupies and blocks the opioid receptors.
- Inhibition of pain response by:
- 1) reduced presynaptic release of chemical transmitters that are mobilized by pain impluse.
- 2) blockade of post synaptic effect of these transmitters.
- 3) activation of descending inhibitory pathways to block pain input.
- 4) reduced emotional reactionto pain by acting on limbic brain
Narcotic (Opioid) Drug Dependence
- 1. Tolerance: Loss of effectiveness with repeated administration. Tolerance to most, but not all,pharmacological effects occurs; the exceptions are constriction of the pupils and the constipating effect
- Cross-tolerance between all narcotic (opioid) analgesics occurs providing they act on the samereceptor. Tolerance is reversible in a few days after the opioid is discontinued.
- 2. Physical dependence: Develops after repeated administration. A pronounced withdrawalsyndrome can occur and is an indicator of physical dependence. It is not life threatening. Awithdrawal syndrome can occur after discontinuing the drug or after administration of Naloxone. The withdrawal syndrome is manifested as
- (a) Restlessness, anxiety, insomnia.
- (b) Sweating, fever, chills
- (c) Increased respiratory rate
- (d) Retching and vomiting
- (e) Cramping
- (f) Explosive diarrhea
- The kinds of symptoms, as well as their severity and duration, are determined by the particular drug,the chronicity and pattern of use, the typical daily dose, concurrent use of other drugs, the route ofadministration, and the health of the user.
- 3. Psychological dependence: (addiction) Pronounced craving and compulsion for narcotic (opioid)analgesics can develop. Use of narcotic analgesics with other psychoactive drugs (e.g. cocaine) canoccur. The basis for the psychic dependence is the euphoric action of the opioids which serves as avery powerful reinforcing factor in the drug-seeking behaviour.
Neonatal Drug Dependence
A mother physically dependent on opioid analgesics during pregnancy faces an increased risk ofpremature delivery and a low birth weight infant. At birth, the infant undergoes an abrupt termination ofdrug supply resulting in a withdrawal reaction (irritability, sleep disturbances, poor feeding andoccasionally seizures). The withdrawal may last weeks to months.
Opioid overdose is a medical emergency. Overdose of all opioid drugs can produce profound respiratory depression which is the cause of death. Treatment consists of opioid antagonists such as naloxone and support of respiration and other vital functions.
Factors which determine abuse of opioids are:
- Inherent properties of the compound. How much euphoria and reinforcement does it produce?
- The size of the dose. The greater the dose the greater the euphoria.
- The route of administration. The euphoria is rapid in onset and intense following intravenousadministration as compared to oral doses.
- The use of opioids in combination with other drugs. The euphoria of two drugs is usually greaterthan one drug, e.g. heroin and cocaine or methamphetamine (the mixture is called a “speed ball”).
Effects of opioid abuse:
- A large number of intravenous drug users suffer deleterious effects of chronic needle use. Abscesses and infections at the site of administration. The major concern is the spread of diseasethrough contaminated needles (hepatitis and AIDS).
- Lifestyle of the user is often aberrant. They may need to resort to crime or prostitution to obtainmoney for drugs. They spend all their money on drugs and leave very little for nutrition, etc. Theydo not seek medical help when ill as their use of drugs will be detected and thus they are often in poor health. They may abandon friends and family.
Treatment of Opioid Dependence
- Some European countries allow a physician to provide morphine, and in some cases heroin, toindividuals dependent on these drugs. Canada does not. In Canada, methadone is the drug used to treatopioid dependence. It is used in two different modalities:
- 1. Cessation of drug use. Oral methadone replaces the drug of dependence and the dose of methadoneis slowly reduced over time. Other pharmacological agents may be added to the program andshould be accompanied by counselling and rehabilitation.
- 2. Methadone maintenance. This is a method where methadone replaces the drug of dependence butthe dose is not reduced. The individual substitutes methadone dependence for street heroin or otherdrug dependence. The advantages are that methadone is available and is effective orally, and theaddict has a ready supply of drug and does not need to resort to crime to fulfill their need. Thesubstitution of a long acting oral drug in place of an intravenous drug also removes the person fromthe circumstances of administering the drug. no needles. The health risks to the addict are less. In short, this isa risk-reduction method.
- The street names for morphine are “M”, Morph or Miss Emma. Morphine is usually used alone, butmay be found in combination with cocaine and methamphetamine.
- Morphine may be taken orally intablet form, smoked, sniffed and injected.
Effects of Short-Term Use – Low Doses - Morphine
- CNS: Effects or morphine use include suppression of the sensation of pain and emotional responseto it, euphoria, drowsiness, lethargy, relaxation, difficulty in concentrating, decreased physical activity insome users, and increased physical activity in others, mild anxiety or fear, pupillary constriction, blurred vision, impaired night vision, and suppression of cough reflex.
- Respiratory: slightly reduced respiratory rate.
- Gastrointestinal: nausea and vomiting, constipation, loss of appetite, decreased gastric motility.
Effects of Short-Term Use – Higher Doses - Morphine
Intensification of morphine’s low-dose effects may occur with administration of higher doses. Duration of effects also increases with increased dosage. As the dose increases, sensitivity and emotionalresponse to painful stimuli decrease, probability of sleep increases, ability to concentrate is increasinglyimpaired, breathing becomes progressively slower and more shallow, heart rate gradually slows andblood pressure decreases. The rush also increases in intensity. In very high doses, the CNS depressioncan be profound resulting in coma. The heart rate is irregular and respiration is shallow. The bodytemperature is low. The skin is cold and clammy, and the pupils are constricted.
Effects of Long-Term Us - Morphine
There does not appear to be marked physiological deterioration or psychological impairment onlong-term use. Adverse effects of long-term use include mood instability, pupillary constriction (impairsnight vision), constipation, reduced libido, menstrual irregularity, and respiratory impairment.
Potential for Abuse - Morphine
- The dependence liability of morphine exceeds that of all other opioids in common use except heroin. This reflects its powerful euphoric and analgesic properties.
- The inherent harmfulness of morphine is not high with low to moderate doses. Nausea andvomiting are common. Lethality with high doses can occur.
- Morphine is available by prescription and its importation and sale are controlled by the NarcoticControl Act. The strict control on the prescribing of morphine reduces its potential for abuse.
- It isavailable as a street drug.
- Heroin is diacetylmorphine. It is produced synthetically from morphine. Heroin was used in theearly 1900’s for medical purposes as an analgesic. The high dependence liability led to the abandonment of the drug and a change in laws to prohibit its importation, manufacture and sale. In the mid 1980’s,Canadian physicians and the public lobbied to have the drug available for medical purposes and the lawswere changed to allow the drug to be imported from the United Kingdom. The legitimate medical uses are extremely low. Heroin is more potent than morphine, but between the two drugs, it is not more efficacious. Double-blind studies do not detect any differences in analgesic efficacy. It should be noted that heroin is rapidly converted to morphine in the body.
- The street names for heroin are Dust, “H”, Horse, Junk, Smack, Scag and Black Tar. Heroin issometimes encountered on the illicit market in combination with amphetamines (bombitas) or with cocaine (dynamite, speed ball, whiz bang). The concentration of heroin in a street sample can very from3% to 20% and in rare cases 90%. The heroin powder and the cutting or diluting material, are usually dissolved in water and injected either subcutaneously (skin popping), intramuscularly or intravenously(mainlining). The latter is the preferred route by most addicts. Occasionally, heroin can be sniffed(snorted) or smoked (chasing the dragon). Smoking of heroin was evidently very popular among militarypersonnel during the Vietnam war. The drug was readily available and cheap, at least by westernstandards.
Effects of Short-Term Use – Low Dose - Heroin
- CNS: Effects of heroin use include suppression of the sensation of pain, euphoria, mental clouding, heightened feelings of well-being, relaxation and drowsiness in some, and in others talkativeness andactivity. After dosing, users experience a drowsy, dreamy, mild dozing state referred to as a “nod”(owing to the characteristic lolling of the head). Users may experience decreased physical activity,inability to concentrate, apathy, pupillary constriction, droopy eyelids, and impaired night vision. Noviceusers may react with giddiness and dizziness or fearfulness and anxiety.
- Respiratory: Decreased respiratory rate; at high doses this is the major cause of death.
- Gastrointestinal: Nausea and vomiting are common among new users; reduced appetite, decreasedgastric motility, and constipatio
Effects of Short-Term Use – Higher doses - Heroin
- As the dose is increased, the magnitude and duration of the response also increase. The response to painful stimuli is blunted further. The individual becomes less able to concentrate, and wishes to sleep. Respiration may be depressed, heart rate slows, and blood pressure decreases.
- In very high doses, heroin will induce deep sleep, low blood pressure, slow and irregular heart rate,with shallow and depressed respiration. The body temperature is lowered and the skin is cold andclammy.
Effects of Long-Term Use - Heroin
As with morphine, heroin, when administered under medical supervision, does not result in markedphysiological or psychological impairment. Use of street heroin is associated with that lifestyle and theuse of contaminated needles and impure drugs. Long-term use of heroin can lead to mood swings,reduced libido, menstrual irregularities, and certain types of respiratory impairment.
Heroin and Pregnancy - Heroin
Pregnant heroin-dependent women have a high neonatal mortality rate. The infant is often bornpremature and of low birth weight. This effect is due to heroin, but also to lack of proper nutrition.
Tolerance and Dependence - Heroin
Tolerance develops to heroin with chronic use as it does to all other opiates. Powerful physical andpsychological dependence develops rapidly upon regular high dose use. These phenomena are describedabove.
Potential for Abuse - Heroin
- The dependence liability of heroin is the greatest of the opioids in common use, includingmorphine. This is due to its extremely powerful euphoric and analgesic effects and its solubility. Thedrug enters the brain quickly after intravenous administration and there is immediate and intensegratification.
- The inherent harmfulness in low to moderate doses is low. Nausea and vomiting are unpleasantadverse effects. However, higher doses of heroin, especially those greater than those to which the user istolerant, can be life-threatening. Users of street heroin are at risk as they are not sure of the dose andthey can easily administer a lethal dose. Street users know the risks, but accept them as the pleasure ofthe drug is intense.
- The availability of heroin is controlled by law. There has been an international effort to curtail trafficking in heroin and all other illicit drugs. Despite all these efforts, the drug is widely available onthe streets of most major cities.
A number of narcotic analgesics have become problematic in terms of producing drug dependence whenused clinically, probably more correct to state over-used. Thus oxycodone, and hydrocodone havebecome drugs which are sought after by those dependent on narcotic analgesics. The source for the illicitmarket is diversion from legal sources.
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