Exam 2015

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3.1

Two subdivisions of psychoses:

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a) organic (of known cause) psychoses
b) functional (of unknown cause) psychoses

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3.1

Organic psychoses :

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Associated with causes that are understood and definable. For example, toxic, metabolic, or neuropathological changes, such as drug abuse, alcoholism, or neurodegenerative diseases. Organic psychoses are characterized by confusion, disorientation, memory disturbances, and behavioural disorganization.

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Functional psychoses :

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Characterized by retention of orientation and memory in the presence of severely disordered thought or reasoning, emotion, and behaviour. The functional psychoses include schizophrenia.

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Schizophrenia

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A neurodevelopmental disorder with presumed structural and functional changes in the CNS during fetal life or that develop during childhood and adolescence. Schizophrenia has a genetic component, meaning that children who have a parent with schizophrenia are more likely to develop schizophrenia.

Schizophrenia is characterized by
chronically disordered thinking and
emotional withdrawal, and is often
associated with paranoid delusions and
auditory hallucinations. The symptoms of schizophrenia have been divided into negative and positive clusters. The positive symptoms include hallucinations, delusions, and disorganized thought. The negative cluster includes lack of emotion, poor speech and mental thought, loss of motivation, and lack of interest in day­to­day life.

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3.1

The Serotonin Hypothesis of Schizophrenia

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The discovery that the psychedelic drug, lysergic diethylamide (LSD), causes hallucinations and is a serotonin receptor agonist led to the search for endogenous hallucinogens in the urine of schizophrenic patients. (none were found)

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3.1

The Dopamine Hypothesis of Schizophrenia

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1.

Most of the “typical” antipsychotic drugs are potent blockers of postsynaptic dopamine receptors in the CNS. The binding affinity of antipsychotic drugs to the dopamine receptor is highly correlated with their clinical antipsychotic potency.

2.

Drugs that increase dopaminergic activity such as levodopa (a precursor of dopamine), amphetamines (releasers of dopamine), or apomorphine (a direct dopamine receptor agonist) either aggravate schizophrenia or induce it in some individuals.

3.

Dopamine receptor density has been found in post­mortem studies to be increased in the brains of schizophrenics who had not been treated with antipsychotic drugs. It is of interest that key studies of this type were carried out by pharmacologists at the University of Toronto.

4.

Using a technique known as positron emission tomography (PET), dopamine receptor density has been shown to be higher in brains of people suffering from schizophrenia than in non­schizophrenic persons.

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3.1

The Glutamate Hypothesis of Schizophrenia

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Glutamate is the major excitatory neurotransmitter in the brain. A number of hallucinogens (e.g. phencyclidine) are inhibitors at a subset of glutamate receptors (NMDA type) and exacerbate cognitive impairment and psychosis in patients with schizophrenia. These observations have been used in an attempt to develop novel antipsychotic drugs.

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3.1

Phenothiazine Antipsychotic Drugs Mechanism

Explain using α­adrenoceptors, Dopamine, Cholinergic or Histamine Receptors

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Blockade of Dopamine Receptors:

Therapeutic Effect: Antipsychotic action can be explained by antagonism of dopamine receptors in the mesolimbic and mesofrontal systems of the brain. Antagonism of dopamine receptors in the nigrostriatal system of the brain results in extrapyramidal movement disorders.Dopamine in the hypothalamus exerts an inhibitory effect on prolactin release from the pituitary gland. Therefore, antagonizing dopamine receptors will result in excess release of prolactin. In women, this will result in the flow of milk from the breast, and menstrual changes, and in men it will cause sexual dysfunction.

Blockade of Cholinergic (muscarinic) receptors:
Therapeutic effects: Reduction of extrapyramidal adverse effects.

Adverse effects: Blurred vision, dry mouth, constipation, difficulty urinating.

Blockade of Histamine Receptors:

Adverse effects: Sedation, drowsiness, and weight gain.

Blockade of α­adrenoceptors:

Adverse effects: Postural hypotension (hypotension when assuming an erect position), dizziness, reflex tachycardia.

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Haloperidol

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competitively blocks dopamine receptors

Its sedative and hypotensive action is less than that observed with other phenothiazines, but it has a high propensity for producing extrapyramidal movement disorders. It is considered a useful alternative for patients who do not respond to or cannot tolerate phenothiazines.

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Second ­Generation Antipsychotics

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Claimed to relieve both positive and negative symptoms, while at the same time having a lower propensity to produce extrapyramidal side effects. The improvement in negative symptoms may be partly a result of a decrease in the extrapyramidal side effects. It is thought that these second-­generation antipsychotics have a dual action by producing receptor blockade of dopamine and serotonin receptors.

Some examples are clozapine, risperidone, and olanzapine.

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Clozapine

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Second-generation antipsychotics

associated with a decrease in white blood cells and patients must be monitored for this adverse effect.

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Bipolar disorder

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Occurs in about 1­3 % of the population. The symptoms of bipolar disorder in the manic phase are excitement, hyperactivity, disinhibition, aggression, and some psychotic symptoms. In the depressive phase, the symptoms are similar to major depressive disorder, with the key features being depressed mood, sleep disturbances, and anxiety. Patients with bipolar disorder are at a high suicide risk.

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Lithium carbonate

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A mood-­stabilizing agent used to prevent mood swings in patients with bipolar disorder. It is also used to treat mania.

The mechanism of action of lithium has not been resolved. Two possibilities are under investigation:

1. Effect on electrolytes and ion transport.
2. Effect on second messengers that mediate transmitter action.

Alternatives: The anticonvulsants valproic acid, carbamazepine, and clonazepam have been found to be useful agents as mood stabilizers.

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3.1

Adverse Effects of Lithium

(doubt we will have to know)

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Nausea and fatigue may occur in the first weeks of treatment.
Tremor, thirst, excessive urination, edema, and weight gain may persist for the duration of treatment.
Confusion and loss of muscle coordination.
Acne and skin reactions.
Mild hypothyroidism is fairly common.
Toxic kidney effects are observed in some individuals treated chronically with lithium, but are uncommon.
When taken during pregnancy, it can, as a rare event, cause cardiac malformations in the fetus.

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Other Uses For the Atypical Antipsychotics

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Treating:

-delusions and aggression associated with dementia in the elderly

-autism spectrum disorder
-developmental disorder
-post-traumatic stress disorder as an alternate to antidepressants

-obsessive compulsive disorder

-borderline personality disorder

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3.2

Anxiety disorders include:

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Generalized anxiety disorder, obsessive compulsive disorder, panic disorder, post­traumatic stress disorder, and a number of phobias.

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3.2

Sedative-­hypnotic agents:

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A sedative relieves anxiety, decreases activity, moderates excitement, and generally calms the individual. A hypnotic drug produces drowsiness and aids in the onset and maintenance of sleep.

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3.2

Approach to Controlling CNS Excitation

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The major excitatory neurotransmitter system in the brain is glutamate, thus in anxiety states and in insomnia the aim of some therapies is to reduce glutamate ­induced neural excitation by enhancing the amount of GABA inhibition of the excitatory neurons. The barbiturates and benzodiazepines work in this manner

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3.2

Barbituates:

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A potent CNS depressants.

At low doses, they induce a state of relaxation and tranquillity, and will mildly impair cognitive (thinking) and motor function.

At moderate doses they can induce sleep, but prior to inducing sleep, they can impair motor and cognitive functions. This moderately impaired state can be pleasurable.

At higher doses still, barbiturates induce anesthesia

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3.2

Mechanism of Action of the Barbiturates

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They potentiate the effect of GABA at its receptor by enhancing the inhibitory effect of GABA. Barbiturates bind to the GABA receptor at a distinct site from GABA. Through this mechanism, they modulate the chloride channel.

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3.2

Pharmacological Properties of Barbiturates

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1.

They possess a low therapeutic index. The dose required to produce a beneficial effect is close to the dose that will produce toxicity.

2.

The barbiturates demonstrate a full spectrum of dose­dependent CNS depression. antianxiety → sedation → hypnosis → general anesthesia → death.

3.

When used as a hypnotic (e.g. secobarbital), they suppress REM­type sleep. REM sleep is essential so that we do not wake up with the feeling of "not having slept" or the feeling of a hangover.

4.

Some of the long­acting barbiturates are effective in suppressing epileptic seizures.

5.

Thiopental, an ultrashort­acting drug, is used to induce general anesthesia. It also suppresses

respiration, but the patient is artificially ventilated.

6.

Respiratory depression is a major problem with the barbiturates and is dose­dependent.

7.

The cardiovascular system is depressed by high doses. The response usually seen is a slowing of the

heart and lowering of blood pressure.

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3.2

Routes of Administration of Barbiturates

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For medical use in epilepsy, the usual route is oral. To induce anesthesia, the route is intravenous. The recreational use of barbiturates is usually oral. Some users (e.g. heroin addicts) will inject barbiturates in order to obtain the "rush effect", despite the inherent dangers.

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3.2

Effects of Short ­Term Use of Barbiturates

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Low doses of barbiturates usually result in tranquillity, relaxation, mild euphoria, and reduced interest in one's surroundings. There may also be dizziness and mild impairment of motor coordination. Movements or activities requiring fine motor dexterity are especially affected.

As the dose is increased, there may be a pleasurable state of intoxication and euphoria. Some users may become aggressive and hostile. Sleep will ensue if the dose is sufficient. The cardiovascular and respiratory systems are depressed.

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3.2

Effects of Long Term use of Barbiturates

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Chronic inebriation is the term which best describes long­-term use. Memory, judgement, and thinking are all impaired. The person exhibits hostility and mood swings, including depression. Death can also result during barbiturate withdrawal.

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3.2

Tolerance of Barbiturates

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Can develop very rapidly to sleep induction and the mood effects of the barbiturates, often within a few weeks of nightly administration. Tolerance develops more slowly to the impaired motor coordination and slowed reaction time. Tolerance to the anticonvulsant actions develops much more slowly and does not appear to be a major problem clinically. There is a high degree of cross-­tolerance between barbiturates and other sedatives (

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3.2

Dependence of Barbiturates

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Dependence/withdrawal usually follows abrupt discontinuance of the barbiturates.

Syndromes

- after low doses presents as sleep disturbances. - occur in 12 to 24 hours and initially appear as tremors, anxiety, weakness, and insomnia, as well as postural hypotension.

- severe weakness, a hyperactive blink, and other reflexes.

-peak between 24 and 72 hours after the last administration and may eventually include seizures, delirium, visual hallucinations, and a high body temperature.

- If the person survives, the symptoms will decline after several days.

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3.2

Addiction of Barbituates

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Addiction to barbiturates can result from regular use, irrespective of the dose. Users crave the psychological effects of the drug, even though they may not use it every day. There may be a feeling of panic if they cannot get an adequate supply. The craving often persists long after use has stopped.

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3.2

Mechanisms of Action Benzodiazepines

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Increases synaptic inhibition and thus dampen neuronal responses.

Activates the benzodiazepine receptor, enhancing the action of gamma-­aminobutyric acid (GABA). The sites of action include the cerebellum, cerebral cortex, limbic system, reticular activating system, and the spinal cord. Benzodiazepines act on the same receptor (ion channel) as GABA and barbiturates, but on a different binding site.

Binding of a benzodiazepine to the benzodiazepine binding site on the receptor causes an increase in the efficiency of GABA­mediated opening of the chloride channel, leading to enhanced GABA-­mediated neural inhibition.

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3.2

Pharmilogical Properties of Benzodiazepines

(list 3 out of 8)

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1. They possess a very high therapeutic index.

2. They produce relief from anxiety.
3. They can decrease aggression.
4. They produce sedation and amnesia.

5. Some members of this group are effective hypnotics (drowsiness, facilitates onset and maintenance of sleep).

6. They produce minimal suppression of rapid­eye­movement (REM)­type sleep with hypnotic

benzodiazepines (e.g. flurazepam) at normal doses.
7. They produce skeletal muscle relaxation (e.g. diazepam).
8. They have anticonvulsant action (e.g. diazepam for status epilepticus; i.e. an acute episode of seizures).

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3.2

Pharmacokinetics

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This is the pharmacological property for which there are appreciable differences among the various benzodiazepines.

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3.2

Administration of Benzodiazepines

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Usually taken as a capsule or tablet, but some are available for intravenous use.

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3.2

Effects of Short ­Term Use of Benzodiazepines

(On CNS, Lung, Gastrointestinal and motor)

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CNS: relief from anxiety and tension, relaxation, and calmness. Mild to moderate impairment of motor coordination, drowsiness, lethargy, fatigue, and impairment of thinking and memory.

Lung: Respiratory depression following rapid intravenous administration.

Gastrointestinal: Gastrointestinal symptoms are nausea, constipation, dry mouth, and abdominal discomfort.

Motor coordination: Moderate doses of all benzodiazepines can impair motor coordination and impair driving. it is suggested that patients taking these drugs during the day refrain from driving or operating dangerous machinery.

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3.2

Effects of Long ­Term Use of Benzodiazepines

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impaired thinking
poor memory and judgement disorientation
slurred speech incoordination
weak muscles

*Some individuals can take large amounts of benzodiazepines for long periods of time without any major evidence of intoxication

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3.2

Tolerance of Benzodiazepines

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Tolerance develops to the sedative effects and impairment of coordination caused by the benzodiazepines.

Tolerance to the anxiolytic effect is less common.

A high degree of cross­-tolerance occurs among the benzodiazepines and other sedative­ hypnotic drugs, such as barbiturates and alcohol

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3.2

Dependence and Addiction of Benzodiazepines

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The risk of dependence and addiction is low.

Withdrawal symptoms would include agitation, paranoia, seizures, and delirium.

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3.2

Flumazenil

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a benzodiazepine receptor antagonist that blocks the effect of the benzodiazepines. As such, it can be used as an antidote for benzodiazepine poisoning.

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Zolpidem

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Binds to a subset of the GABA receptors, causing sedation. They have advantages over the benzodiazepines as a hypnotic, as they disturb sleep patterns (REM sleep) less than the benzodiazepines.

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3.2

Buspirone

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Acts at the serotonin receptor.

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3.2

Therapeutic Uses of the GABA Modifying Drugs

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(a) Antianxiety relief

(b) Sedative (reduce sensory­motor function, reduce tension)

(c) Hypnotic (sleep): short­-acting benzodiazepines

(d) Anticonvulsant agent for certain types of epilepsy: Phenobarbital has been used to control generalized tonic­-clonic and partial seizures.

(e) Treatment of skeletal muscle spasm: Benzodiazepines reduce elevated skeletal muscle tone and are useful in neuromuscular disorders (e.g. cerebral palsy).

(f) Treatment of alcohol withdrawal syndrome: Most of the benzodiazepines are useful in the treatment of alcohol withdrawal. There is cross­dependence on the two agents, diazepam substituting for alcohol. Diazepam is the drug of choice.

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3.2

Gamma­Hydroxybutyric Acid (GHB)

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GHB is an agonist at a subset of GABA receptors, causing sedation and anesthesia.

GHB causes euphoria, a feeling of social closeness, enhanced sensory perceptions, and amnesia

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3.3

Overall absorptionrate for a given dose of ethanol is affected by:

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Stomach­ emptying time, or the time required for thealcohol to reach the small intestine.Ethanol concentration in the gastrointestinal tract andthe presence of food.

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3.3

Metabolism and Excretion of Ethanol

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Over 95% of ethanol in the body is eliminated by biotransformation, primarily in the liver. Theremaining 5% is excreted in the breath, urine, and sweat.

Alcohol dehydrogenase (ADH) convertsalcohol to acetaldehyde, and in turn,aldehyde dehydrogenase convertsacetaldehyde (ALDH) to acetic acid.Acetic acid is then further metabolized bya number of tissues. The rate controllingstep in alcohol metabolism is the alcoholdehydrogenase.

The metabolism of alcohol is unusual, in that it occurs at a constant rate, irrespective of the bloodalcohol concentration.

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3.3

Ethanol

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A general CNS depressant and teratogen. Acute use of ethanol most obviously affectsthe CNS, whereas chronic, high­dose use of ethanol affects many organ systems of the bodyincluding the CNS, cardiovascular system, gastrointestinal tract, and liver. Chronic, maternal useof high­dose ethanol can adversely affect the fetus, including teratogenesis, which can manifest asthe fetal alcohol syndrome or fetal alcohol effects.

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3.3

Medical uses for Ethanol

(3 reasons)

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a skin disinfectant

antidote in the treatment of methanol

a hand sanitizer

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3.3

Mechanisms of Ethanol in the body

Back 45

Alcohol binds to the GABA receptor andaugments GABA­ mediated neuronaltransmission. Alcohol binds to a differentsite on the GABA receptor complex thanother GABA agonists enhancing the neural depressant propertiesof GABA. As the effect of alcohol onGABA receptors is not selective, theinfluence of GABA receptor activity onother transmitter systems can be enhancedby alcohol. The interaction of alcohol withthe GABA receptors on dopamine cellbodies in the reward areas of the brain mayexplain the reinforcing effects of the drug.

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3.3

Ethanol Short term effects

1-Acute

2-Chronic

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Alcohol is a CNS depressant, but at low doses the response observed is one of disinhibition.Drinkers feel gregarious, jovial, relaxed, and more self-­confident.

Low doses of alcohol lead to vasodilation of the vessels to the skin, resulting in a feelingof warmth. High doses of alcohol can depress the cardiovascular system and lead to alterations inthe normal rhythm of the heart.

Low doses of alcohol will stimulate gastric secretion. Higher doses of alcoholwill irritate the lining of the stomach, causing inflammation and erosion.

Acute high doses of alcohol (alcohol binge) will inhibit glucose production, and inassociation with fasting, can lead to hypoglycaemia

Chronic:

Alcohol damages the axons of the brain, resulting in fewer connections between neurons. Dementia can be defined as a global decrease in cognitive functioning,affecting memory, judgement, and thinking. Leads to alcoholic liver disease

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3.3

Three stages to alcoholic liver disease

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1 - The liver cells accumulate fat, causing the liver to enlarge (reversible)

2- The liver cells are damaged and inflamed. (reversible with absence)

3- Damaged calls have been replaced byscar tissue. The scar tissue in the liver can modify the blood flow from the portal vein and the blood backs up into other veins causingdistention. Occasionally these veins rupture and bleed. (not reversible)

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3.3

Effect of Alcohol on Vitamin B1

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Alcohol increases the metabolism of vitamin B1 (thiamine), resulting in thiamine deficiency. Can result in

1) Wernicke’s encephalopathy: the patient becomes drowsy, confused, and cannot walkproperly.

2) Korsakoff’s psychosis: a severe form of dementia.

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3.3

Fetal Alcohol Syndrome

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Symptoms:

CNS dysfunction

Impairment in attention, learning, memory, problem­solving, and emotionalmanagementPre­natal and post­natal growth deficiencyCluster of facial abnormalities (flat midface, short upturned nose, poorly definedphiltrum, and thin upper lip).

There is also a condition known as FetalAlcohol Effects (FAE), where the neonate has some, but not all, of the features of fetal alcoholsyndrome. FAE is five times more common than FAS.

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3.3

Ethanol Tolerance

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During chronic use of ethanol, the user becomes tolerant, in that there is a decreased intensity ofethanol action or a shortened duration of action. A larger dose of ethanol is needed to produce theoriginal pharmacologic effect.

Normally minimal tolerance develops to the lethal dose ofethanol.

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3.3

Ethanol Dependence

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Withdrawal from ethanolproduces excitability of the CNS (arousal, stimulation). Hyperexcitability leads to tremors,irritability, restlessness, anxiety, sweating, sleeplessness, agitation, nausea, muscular tension, hyperthermia, and increased heart rate. A severe ethanol withdrawal syndrome may involveconvulsions, coma, and possibly death. In severe cases of ethanol withdrawal, delirium tremens (DTs) may occur. Delirium tremens ischaracterized by tremulousness, auditory, visual and tactile hallucinations, confusion, psychomotoragitation, disorientation, and sleep disorders.

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3.3

Ethanol Cross-tolerance

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Ethanol +______

Sedative ­hypnotics: A higher dose of asedative­hypnotic drug is required for thedesired therapeutic effect. Both classes ofdrugs affect the GABA receptor complex.

General anesthetics: A higher dose ofanesthetic agent is required for surgicalanesthesia in someone who has developedtolerance to alcohol.

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3.3

Ethanol Addiction

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A compulsive desire to seek, obtain, and drink ethanol.

The drug­ induced effects of relieffrom anxiety, disinhibition, and euphoria are perceived as pleasurable and reinforce the use ofethanol.

Addiction could be the most powerful factor in chronicuse of ethanol, leading to problem­drinking.

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3.3

Treatment of Alcoholism

Back 54

- Maintain fluid and electrolyte balances

- Oraladministration of diazepam, a benzodiazepine­type sedative­hypnotic drug.

- Disulfiram inhibits hepatic aldehyde dehydrogenase, and results in increasedacetaldehyde concentration if the patient drinks ethanol, thereby producingcardiovascular/respiratory changes that are perceived as aversive.

- Naltrexone, diminishes the craving for ethanol, and assists in the maintenance of abstinence. (blocks reward pathway)

- Acomprosate is an ethanol substitute, in that it affects many receptor systems. Most notably,acomprosate acts as a GABA activator and a weak glutamate receptor antagonist.

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3.4

Marijuana

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A central nervous system depressant, euphoriant, and hallucinogen.

A narcotic and controlled under the Controlled Drugs and SubstancesAct, Schedule II.

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3.4

Mechanisms of Action for Marijuana

Back 56

THC binds specifically to receptorslocated in the cerebral cortex, cerebellum, hippocampus,hypothalamus, and other areas of the brain and spinal cord.

Thesereceptors have been designated type 1 cannabinoid receptors(CB1). ( CB1 receptors in the cortex mediate the distortions of time, colour, sound, and taste. )

A second receptor, CB2, is found only in peripheral tissue. ( it is thought that the immunosuppressive properties of THC are mediated via this receptor. )

THC produces most of its effects by modulating the release of neurotransmitters.

THC is slowly metabolized, having a half­life of approximately 30 hours, but elimination fromadipose tissue may take longer. It is the metabolites of THC that are measured in drug tests.Chronic users will be positive for the metabolites for several weeks after use has stopped.

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3.4

Short term effects of Marijuana

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Early effects will be seen as relaxation and drowsiness; there is disinhibition andtalkativeness.

A feeling of well­-being, exhilaration, and euphoria.

Distortions in perception of time, body image, and distance.

Sense of hearing and vision areenhanced. The perception of the senses of touch, smell, and taste are enhanced.

Spontaneous laughter, confusion, and impairment of short-­term memory and concentration.Attention span may be reduced. Balance and stability on standing and walking can be impaired.

The user may havedecreased muscle strength.Motor coordination is impaired.

The occasional user may experience fearfulness, anxiety, and mild paranoia.

The user may experience flashbacks, especially if they abused hallucinogens in the past.

As the dose is increased, the user may experience pseudo­hallucinations, a running together of senses, judgement andcoordination is impaired.

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3.4

Cardiovascular, respiratory and gastrointestinal effects of marijuana

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short term

Increased heart rate and increased blood flow to the extremities. Usersmay experience postural hypotension.

Smoke irritates the mucous membranes lining the respiratorysystem. There is also bronchodilation.

Increased appetite and dryness of the mouth and throat.

Long term

increased heart rate (reversible)

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3.4

Long term effects of marijuana

Back 59

Loss of short-­term memory

lack of concentration

loss of ability in abstract thinking

Amotivational syndrome: mental slowing, loss of memory, difficulty with abstract thinking, loss of ambition, and emotionalflatness

Bronchitis,asthma, sore throat, and chronic irritation of and damage to membranes of the respiratory tract areall higher in heavy users of marijuana.

folliclestimulating hormone and luteinizing hormone are reduced, and cycles may be an­ovulatory

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3.4

Marijuana Tolerance

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Tolerance occurs to thepsychoactive properties of THC, but also to the effects on the cardiovascular system, theimpairment of performance, and cognitive function.

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3.4

Marijuana Dependance

Back 61

Dependence can occur with high-­dose use. Upon termination, there is a mild withdrawalsyndrome. This is characterized by sleep disturbances, irritability, loss of appetite, nervousness,mild agitation, upset stomach, and sweating.

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3.4

Marijuana Addiction

Back 62

often a persistent craving for the drug

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3.4

Medical uses for Marijuana

Back 63

Sedatives, hypnotics, nausea and vomiting, anorexia (loss of appetite), epilepsy,glaucoma, spasticity, migraine, and certain types of pain.

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3.5

Opioid

Back 64

Any natural or synthetic substance which exerts actions on the bodythat are similar to those induced by morphine and that are antagonized by the drug naloxone.

-Opiate narcotics (analgesic agents obtained from the opium poppy).

-Substances structurally related to morphine.

-Synthetic drugs with structures different from that of morphine.

-Endogenous brain peptides that exert analgesic actions (Endorphins)

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3.5

Three known families of endorphins

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enkephalins, dynorphins, and β­endorphins

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3.5

MOP (formerly Mu (μ))

Back 66

Receptors are present in all structures of the brain and spinal cord. They mediate analgesia.They are also responsible for morphine ­mediated depression of respiration in the brain stem.

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3.5

KOP (formerly Kappa (k))

Back 67

Receptors are involved in analgesia, dysphoria, and miosis (pin­point pupils). The mixedagonists/antagonists (for example pentazocine), act predominantly on these receptors. Theendogenous ligands for KOP receptors are the dynorphins, although the endorphins have someactivity at these receptors.

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3.5

DOP (formerly Delta (δ))

Back 68

Receptors are involved in analgesia at the level of the spinal cord and brain. They may alsomodulate the emotional response to opioids. The endogenous ligands for DOP receptors are theenkephalins.

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3.5

Opioid agonist

Back 69

Bind to receptor producing a full response, includes natural and synthetic compounds

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3.5

Opioid Mixed antagonist/agonist

Back 70

Can bind to receptor but not produce a full response

can illicit a response when given alone, but can block part of the response to morphinewhen given together with morphine.

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3.5

Opioid antagonist

Back 71

Helps with withdrawl

Bind to receptor but do not produce a full response

agents block the response to morphine, heroin, and other opiates at the respective receptor.

( The prototype antagonist is naloxone, which has noanalgesic activity and is used in: Reversal of opioid overdose.Treatment of opioid dependence.Diagnosis of opioid dependence. Naltrexone, another opioid antagonist, is used to treat alcohol dependence.)

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3.5

short term effects of Opioids

Back 72

Analgesia, Euphoria, Sedation, Hypnosis, narcotic, suppression of cough, respiratory depression, Decreased gastrointestinal motility, Endocrine effects, Miosis, Nausea, vomiting,

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3.5

Long term effects of Opioids

Back 73

mood instability,pupillary constriction (impairs night vision), constipation, reduced libido, menstrual irregularity,and respiratory impairment.

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3.5

Mechanisms of Action of Opioids

Back 74

Pain: Injury causes the release of a number ofmediators of pain, including prostaglandins(PG), serotonin, and bradykinin (BK). Therelease of these mediators of pain willactivate and sensitize nerve fibres, whichterminate in the spinal cord. The spinal cordalso receives input from the brain, modulatingthe input from the site of injury. When athreshold is reached in the spinal cord, signalsare sent to the higher centres, and pain isperceived.

Morphine and other opioids will block transmission of these pain pathways in the spinal cord andin the brain.

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3.5

Medicinal Uses for Opioids

Back 75

Relief of severe pain, treatment of diarrhea, suppression of cough

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3.5

Opioid tolerance

Back 76

reversible a few days after use is discontinued

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3.5

Opioid Cross tolerance

Back 77

Cross­-tolerance between all narcotic (opioid) analgesicsoccurs, providing they act on the same receptor.

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3.5

Opioid Dependence

and Treatment

Back 78

Withdrawal syndrome manifests as: Restlessness, anxiety, insomnia, Sweating, fever, chills, Increased respiratory rate, Retching and vomiting, Cramping, Explosive diarrhea

Treatment:

Cessation of drug use: Oral methadone replaces the drug of dependence, dose is reduced over time

or

Methadone maintenance: This is a method where methadone replaces the drug ofdependence, but the dose is not reduced.

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3.5

Opioid Addiction

and pregnancy

Back 79

Pronounced craving and compulsion for narcotic (opioid) analgesics can develop.

During pregnancy faces an increased risk ofpremature delivery and a low birth weight infant. At birth, the infant undergoes an abrupttermination of drug supply, resulting in a withdrawal reaction