Chapter 11: Opioids Flashcards
What’s the plant that opiates are derived from?
Papaver somniferum
In the 1500’s in western Europe opiates were considered what?
a panacea, cure all
Used in apothecaries as?(2)
laudanum : opium + alcohol+ flavourings
paten medicines
What are the alkaloids in opium?
- morphine, codeine, papaverine (naturally occurring)
Use of opiates in the USA increase because of what?
- analgesic - civil war
- hypodermic needle
- patent medicine industry
By when was the habit forming properties discovered in the USA?
- 1870
Heroin was discovered when? marketed as what?
- 1874, non addictive drug by Bayer
Social attitudes towards opiates in the 1900s?3
- punishable loss of self control
- unearned pleasure
- repressive legislation = best way to address issue. (control laws over them)
Pure food and drug act of 1906?
- importation of dangerous substances= illegal
- labels!
- compounds had to meet standards of identity and purity
Harrison Narcotics Tax Act (1914)
- control non medical use of drugs and to monitor their legitimate medical use
- black market in narcotics occurred
- heroin was not covered by this act..remained legal until 1924
Anslinger Era (1930-1962)?
- drug abuse = immoral, requiring harsh penalties
- exaggerated drug dangers
Opiate refers to what?
- naturally occurring substances like morphine and codeine
Opioid refers to what?
- synthetic and semi-synthetic compounds….now more general seems to refer to alls rugs in this class
Narcotic?
- drug that causes sleep
Narcotic Analgesic?
- pain reduction
Narcotic has become to mean what?
- addictive…and includes non-narcotic drugs
Sap from the speed pod of Papaver somniferum contains what?
- morphine (10%)
- Codeine (.5%)
- Thebaine (0.1%)
Heroin?
- semisynthetic made by modifying morphine…ten times more lipid soluble than morphine
Canadian use for medical purposes is _____ restrictive than in the USA. example?
- less
- ex: codeine is available legally over the counter in canada
Thebaine is the source of what synthetic compounds?
Oxycodone ( Percoet, Percodan, Oxycontin trade names) , Etorphine (main ones)
- buprenorphine, nalorphine and naloxone.
OxyContin????
- high concentration ocycodone tablet in slow release form.
- crushed, dissolved, and injected the effect is powerful and highly addictive.
Synthetic opioids? Characteristics?(2)
- bear little chemical resemblance to morphine but occupy the same receptors
- some are more and some are less effective than morphine.
Synthetic opioids :
Mepridine (Demerol)
-short acting
Synthetic Opioids?
Methadone (Dolophine)
- long acting, more effective given orally
Synthetic Opioids?
Buprenorphine?
has been used in the treatment of opiate addiction - long lasting prevention of withdrawal
Synthetic opioids?
Fentanyl ( Sublimaze)
- designer drugs are based on this molecule
- MPTP : metabolized into neurotoxin that destroys the substantial nigra
Heroin ????
- invented in 1898 at Bayer co (creators of aspirin)….non addictive analgesic…haha
- causes less nausea and vomiting than morphine and is a more effective analgesic ( 10x)
- diacetylmorphine… added an acetyl group to morphine..
Administration?
Morphine
L> base…Kpa 8..most of its molecules are ionized in stomach acid, not lipid soluble
- not rapidly absorbed orally
- significant first pass metabolism in the stomach and liver
- recreational purposes: non oral routes are used
Administration?
Heroin
- can be snorted unlike morphine
- can be vaporized and the vapour inhaled..chasing the dragon
- iv injection ( still used but less common)
Distribution? (2)
heroin
codeine
- heroin (highly lipid soluble) molecule is inactive in the brain but is rapidly converted into it’s metabolites, mainly morphine but also monoacetylmorphine
- codeine, too metabolizes into morphine
After absorption occurs most opioids are highly concentrated where?
Why do opioids pass through readily via placental but not brain barrier.
- lungs, spleen, liver and proteins in the blood
- poor lipid solubility except heroin
Excretion? 3
- methadone
- naloxone
- excretion varies depending upon the opioid
- methadone metabolism and excretion is slow because of binding to plasma protein
- naloxone is very rapidly metabolized and this must be considered when the drug is used to treat an overdose
Opioid receptors? (4)
mu, kappa, delta and ORL1
What binds at the opioid receptors?
- endogenous opioids…endorphines and enkephalins
When opioid receptors are activated what occurs?
- inhibition at postsynaptic membranes
At presynaptic membranes Opioid receptors inhibit what?7
- release of several NTs
- glutamate, GABA, glycine, norepinephrine, DA, acetylcholine
The ligand receptor complex can do what to the cell and alter what?
- enter the cell via endocytosis
- alter the expression of genes
Opioid Action? What are the classification types?
- agonism, antagonism or nothing
What is a mixed agonist?
- agonistic effects at two or more receptor subtypes
Those with the weakest attraction to a receptor have what kind of affect on the receptor?
- greatest effect
- morphine binds weakly to mu receptors but has a strong effect.
- nalorphine is the opposite
Nalorphine has a strong affinity to mu therefore it has a ___ effect. It is also a partial agonist, what does this mean?
- weak
-competes for a receptor
L> will win against those with weak affinity like morphine..
Opioid antagonists will do what?
displace any other opioid from the mu receptor but have few effects of their own. (naloxone)
Naloxone??? (4)
Pure antagonist at mu, kappa and delta.
- used to treat opioid overdose
- will produce immediate withdrawal in an opioid dependent person
- used in some forms of addiction treatment
- has an important role in opioid research
Analgesia site of action in CNS
- act on spinal cord andperiaqueductal grey
- different agonists are effective on different types of pain
- opioids reduce both the sensory and emotional aspects of pain.
Analgesia :
mu
kappa
delta
- broad range of pain reduction, all acute types and some chronic but not phantom pain
- visceral pain but are effective only against low intensity thermal and mechanical pain
- effective against thermal and mechanical pain but are ineffective against visceral pain
Reinforcement sites of action in CNS?
diff between Kappa and mu agonists
- results from activation of mu receptors in the mesolimbic DA system, amygdala and hippocampus
- mu agonists inhibit gaba release…disinhibits DA…increasing DA release
- kappa agonists inhibit DA…and have no reinforcing properties…
Vital life functions? - Sites of action in the CNS
Mu agonists!
- depress respiratory centres- slow shallow breaths
- depress the vomiting centres
- depress the cough centers - only reason why opioids are included in cough med
Dependence - Sites of action in the CNS
Mu
- does not involve the mesolimbic reward system
2. repeated injection of morphine into the PAG (not VTA) will cause physical dependence
Effects on Human Behaviour and performance?
A. Subjective Effects
- vivid, dream-like states ( pipe dreams) (nods)
2. an intense rush when injected or smoked
Effects on Human Behaviour and performance?
B. Systematic Studies of mood?
Meyer and Mirin (1979)
unpleasant effects removed via injection for?
-physical activity?
decreases in what with continued use?
- study with heroin addicts : 10 days in which injections could be earned
- positive effects ( first days) aka relieved tensions and provided euphoria, unpleasant mood states and increased psychiatric symptoms
L> relief 30-60 mins
- also a decrease in physical activity and social interaction with increase in aggressive behaviour and social isolation.
Effects on Human Behaviour and performance?
B. Systematic Studies of mood?
part 2
first experiences?
- first experiences with opioids are usually negative, you have to work at becoming an addict
Nonusers vs Users???
re use stats??
- users report feelings of positive feelings
- nonusers report feelings of sedation, mental clouding and feelings of sickness
- 17/30 former users wanted to repeat
- 2/30 non users wanted to repeat
Performance? 2
- some cognitive and psychomotor impairments early in low doses but tolerance develops to these
- Surgeon William Halstead was a morphine addict but functioned fine!
Partial agonists or mixed antagonists and performance
- cause more impairments than full agonists ex: propoxyphene vs morphine
Tolerance ?
A. euphoric effects?
A. is great with regular intake to the pint of reaching lethal levels ( in non users )
Tolerance ?
B. Tolerance to different effects occurs at differing degrees: (3)
- Analgesic effects: complete tolerance
- pinpoint pupils : partial tolerance
- constipation: no tolerance
Tolerance ?
C. Conditioned tolerance
it can be context dependant….. it can depend on the environment in which the drug is given…
Tolerance ? Withdrawal? Heroin ? first signs second sleep? awake severity? common symptoms?
-opioid withdrawal is not dangerous…never fatal
-origin 6-12 hours after
L>first signs: restlessness, agitation
L> yawning after….can become violent yawns
L> chills, occasional hot flashes and breathes with short jerky breaths..goose bumps
L> yen sleep..deep sleep
L> once awoken : vomiting, diarrhoea and craps in stomach , back and legs , twitching of extremities, profuse sweating
*** severity depends on daily dose
- common symptoms basically mirror flu
withdrawal can be stopped at any point instantly by?
taking of an opioid
What can reduce withdrawal symptoms?
- alcohol
Withdrawal in a physically dependent individual can be generated instantaneously by?
- administration of a mu opioid antagonist
Mu opioid withdrawal causes a rebound in what? which leads to???
- Cyclic AMP levels
- enhancement of the release of many NY….increasing activity in periaqueductal grey( if inhibited this reduces withdrawal)
The central grey involves what?
L> made of periaqueductal gray and periventricular gray
- producing opioid withdrawal……pain transmission and modulation..site of action for analgesic effects of mu opioids
Withdrawal from kappa opioids?
- milder and not associated with graving or drug seeking behaviour
Self Administration in Humans ? A. chipping B. Introduction to heroin C. Initial experience D. Maturing out E. Spontaneous remission
A. used occasionally when the drug and opportunities to take it are available
B. via friends not drug pushers (heroin)
C. unpleasant- you do not become hooked initially
D. occurs in an unknown number of addicts, spontaneously discontinue use of the drug (30’s or 40’s..after 5-10 years of use)
E. recovery without medical intervention ,,,after a period of non use is also common
Patterns of Use?
2
- when freely available the amount of self administered drug is regulated carefully
L> remains steady after gradual increases…plateau
-no intake/abstinence cycle
Extent of Use
- heroin use has been stable in canada and the us
- currently the use of prescription opiates isa growing problem… Vicodin ( hydrocodone and acetaminophen) and OxyContin (oxycodone) are the most popular…..
Harmful Effects ?
- *Acute!
- How frequent is opioid poisoning?
- Heroin overdose rank?
- Purity?
- Quinine
- Combination of drugs
- Tolerance?
- Death from opioid poisoning (overdose) has become the most frequent type of drug poisoning 2.Heroin overdose is the leading cause of death among heroin users
A. no change in purity of street heroin
B. Quinine poisoning - used to dilute heroin and can be lethal when given intravenously causing frothing from nose and mouth…
C. Combination with other drugs:potentiates the effects of heroin making a safe dose of heroin lethal.
D. Loss of tolerance: due to a period of abstinence or using in a novel environment
Harmful Effects?
Chronic effects
-Health (2)
- a. surprisingly few health effects- constipation
b. greater incidence of some cancers (interfere with the bodies ability to repair damaged DNA = cancer promoters..heroin increase chance of Bladder cancer like alcohol
Harmful effects?
Chronic effects
-Reproduction (3)
a. reduced testosterone (lowers sex drive and fertility may cause changes in secondary sex characteristics)
b. pregnancy complications ( causes a decrease of blood oxygen levels going to the baby)
c. withdrawal symptoms in babies shortly after birth …
Harmful effects?
Chronic effects
-Lifestyle effects
- requires a lot of money
- housing, nutrition and health suffer since the drug takes priority
- exposure to diseases..via shooting up = hepatitis and HIV/AIDS
- accidental death via poisoning and overdose
Years of potential life lost? HUH
- deaths occurring in younger population
- number of years of potential life lost in a population per 1,000 individuals
- subtract age of death from 65
- main death = unintentional injury
- chronic liver disease, hep B and C
Detoxification?
-abrupt approach
-Switch from Illicit opioid
L> Alpha2 adrenergic receptor agonists
-withdrawal is initiated via abstinence or administration of an opioid antagonist (shorten length of withdrawal, intensify symptoms though)
- switch ti methadone or buprenorphine and then slow taper the dose so that withdrawal symptoms are alleviated (10-28 days)
L> given med to lower blood pressure via …inhibiting the release of norepinephrine…blocking SNS
Maintenance therapies ? Methadone: A. Administration B. withdrawal? C. acts as what to heroin D. euphoric effects? E. treatment purpose F. side effects? G. complete detoxification H. end of treatment and detoxification
A. orally
B. prevents symptoms for 24 hours (once a day no need to take home)
C. antagonist
D. weak
E. aid to treatment,,not a cure..psychological treatment is needed
F. sweating, sexual dysfunction and Constipation
G. not easy and must be done gradually
H. difficult at the end of treatment…when doses become low
Maintenance therapies?
Buprenorphine (4)
Naloxone with it? number four
- treatment method is similar to methadone but withdrawal from buprenoprhine is easier….
- partial mu antagonist ..slow to unbind and has little agonistic effects
- blocks effects of other drugs
- not absorbed because its under the tongue (sublingually..blocks effects of buprenorphine if crushed for a high.
Maintenance Therapies ?
Heroin
UK
short acting
needs to be injected and sent home with patient….risk of sharing …
Antagonist Therapies ? (3) most common dropout and noncompliance rates? effective for who?
- naltrexone is the most common pure antagonist for this
- dropout and noncompliance rates are high
- Primarily effective for highly motivated individuals.
Antagonist therapies?? Give me the lay down .
- Detoxified first from the opioid…for 7-10 days
- Relapse prevention phase: daily doses of antagonist naltrexone, reducing craving, completely blocks ALL effects from opioids including euphoric and reinforcing effects.
Issue with naltrexone ?
becomes a discriminative stimulus ….they know they cannot take the opioid and get effects…they simply stop using the naltrexone to get high off the opioid of their choice…
