TASK 2 Flashcards
Sedative hypnotics
a group of medicines primarily prescribed for the treatment of anxiety, panic disorders, sleep disturbance and seizure disorders. They are medically prescribed but are commonly misused, which can lead to dependence.
Barbiturates
classic prototype of sedative-hypnotic drug, but rarely used by now
Barbiturates pharmacokinetics
All have a similar structure
half-lives: can be quite short (terminated by redistribution) or as long as several days (terminated by their rate of metabolism by enzymes in the liver)
Lipid soluble: cross blood-brain barrier rapidly
- rapid effects
Pharmacological effect of Barbiturates
GABA a agonists and antagonists of glutamatergic AMPA receptors – inhibitory net effect
- not analgesic - don’t reduce pain
- They have a low degree of selectivity
- REM sleep is suppressed – after withdrawal, dreaming becomes extremely vivid
- Cognitive inhibitors- suppress memory function. Drowsiness, alterations of judgment, cognitive functioning, motor skills and coordination may persist for hours or days
- Overdose or combination with alcohol can lead to death
Barbiturates can induce tolerance by these mechanisms:
- Induction of drug-metabolizing enzymes in the liver
- Adaptation of neurons in the brain to the presence of drug: tolerance develops primarily to the sedative effects but not to brain-stem depressant effects on respiration
Effects of low dose and high dose of barbiturates (psychological effects)
Low doses: relief from anxiety or withdrawal, emotional depression, aggressive and violent behavior
High doses: behavioral depression and sleep
Use of barbiturates has declined due to several reasons:
Use has declined due to several reasons:
- They are lethal in overdose
- They have a narrow therapeutic index
- They have a high potential for inducing tolerance
- They interact dangerously with many other drugs, sometimes fatally
Benzodiazepines use
most commonly prescribed psychotherapeutic drug
USE: anxiety, anticonvulsant (epilepsy and alcohol detoxification), sedative hypnotics (insomnia), central muscle relaxant (spasticity), potentiation of CNS depressant (anesthesia)
- not effective for OCD and PTSD, affective disorder
- effective for GAD, SAD, panic disorder
Benzo pharmacokinetics
Absorption and distribution: well absorbed when taken orally, peak plasma concentrations in about an hour. Some are absorbed more slowly, others more rapidly.
Metabolism: some have active metabolites, thus half lives are increased
Half life: vary sign between drug types
Elderly: reduced ability to metabolize and sign decreases in cognitive performance due to drug use - can lead to dementia, depression, falls
Pharmacological effect of Benzodiazepines
GABA receptor agonist: facilitate the binding of GABA to its receptor. They bind to a site adjacent to the GABAa receptors producing a three-dimensional conformational change in the receptor structure that increase the affinity of GABA for this receptor
- Exert anxiolytic properties by acting on GABA neurons at limbic centers. Actions at other regions produce side effects such as sedation, increased seizure threshold, cognitive impairment, amnesia, and muscle relaxation
- low dose of benzo moderate anxiety agitation and fear by acting on amygdala, orbitorfrontal cortex, and insult
- muscle relaxant effects: : effects on GABA receptors located in the spinal cord, cerebellum and brain stem
- antileptic action: actions on GABA receptors located in the cerebellum and hippocampus (anticonvulsant effects)
- reward effects: GABA neurons in VTA and nucleus accumbent
- anterograde amnesia: GABA neurons in hippocampus and cortex: Amnesia is thought to be due to benzos binding to GABA a receptors containing A5 subunits
Side effects and limitations of benzodiazepines
Dose related extensions of the intended action:
Short-term: sedation, drowsiness, ataxia, lethargy, mental confusion,
Long term: motor and cognitive impairments, disorientation, amnesia, dementia
- high doses: mental and psychomotor dysfunction progress to hypnosis
When treating insomnia, controversial effects can occur: paradoxical agitation (anxiety, aggression, hostility and disinhibition); REM rebounds, anxiety
Impairment of motor abilities is common
Cognitive deficits: interfere with learning behaviors, academic performance and psychomotor functioning (can persist even after drug use is stopped)
- can interfere with CBT
OVERDOSE when used together with alcohol or other drugs
benefits of benzodiazepines
Antidote flumazenil: reverse effects of Benzodiazepines when having an overdose
large therapeutic index
fast onset of effects
short half-life: side effects may be gone in the morning
long half-life: withdrawal is easier
Benzos in pregnancy
Diazepam: is one of the most frequently prescribed drugs in pregnancy (33%)
All benzos cross the placenta and accumulate in the fetal circulation
- benzos administered during the first trimester of pregnancy do not seem to be associated with an increased risk of congenital malformations
- near delivery, a fetus can develop benzodiazepine dependency or a ‘floppy-infant syndrome’
- benzos are excreted in breast milk, one should not take them while breastfeeding
Z- drugs
Three drugs are structurally not classified as benzos but nevertheless are agonist at the benzodiazepine receptors. Prescribed as hypnotic drugs for treating insomnia. They are not prescribed as anxiolytics because they more specifically bind to the alpha-1 subunit of the GABAa receptor
TYPES:
a) Zolpidem:
- Half-life: 1.5-2.5 hours
- Side effects: : adverse memory effects, black-outs and sleep-related activities (BIG PROBLEM), drowsiness, dizziness, nausea
b) Zaleplon: Half life: less than 1 hour - no next day effects
c) Eszopiclone: Half life = 5-7 hours
- improves sleep latency and maintenance
- Side effects: next day effects and sedation
what happens in the brain in response to fear=
AFFECT OF FEAR: may be regulated via reciprocal connections that the amygdala shares with the orbitofrontal cortex and the anterior cingulate cortex, which regulate emotions
MOTOR RESPONSE: fight, flight or freezing - Regulated in part by connections between the amygdala and the periaqueductal gray area of the brainstem
ENDOCRINE REACTIONS: : changes in the HPA axis (due to connection between the amygdala and the hypothalamus) cause changes in cortisol levels.
- A quick boost of cortisol may enhance survival when encountering short-term threat
- chronic activation = mental and physical illness
BREATHING CHANGES: connections between the amygdala and parabrachial nucleus of the brainstem (to enhance survival)
AUTONOMIC NS: increased pulse and blood pressure mediated by connections between amygdala and locus coeruleus (adrenergic cell bodies are located there)
INTERNALLY TRIGGERED ANXIETY: traumatic memories stored in the hippocampus and activated by connections with the amygdala
CORTICO-STRIATO-THALAMO-CORTICAL (CSTC) LOOPS
Worry (anxious misery, apprehensive expectations, catastrophic thinking…) is linked to CSTC feedback loops from the prefrontal cortex. Many NTM modulate these circuits, including GABA, serotonin, dopamine
Various genotypes for the enzyme COMT regulate the availability of dopamine in the PFC: differences in dopamine may impact the risk for worry and anxiety disorders
- MET variant of COMT: more efficient information processing in the DLPFC during a cognitive task.
- lower COMT activity, higher dopamine levels
- Problem: stressors can increase the dopamine levels too much, leading to a decrease in efficiency of information processing under stress - VAL variant of COMT: higher COMT activity, lower dopamine
- able to handle increased stress better by showing more efficient information processing
GABA NEUROTRANSMITTER SYSTEM
- GABA is produced from the amino acid glutamate via the actions of GAD
- GABA is transported by vesicular inhibitory amino acid transporters (VIAATs) into synaptic vesicles and stored until they are released
- GABA’s synamptic actions are terminated by the presynaptic GABA transporter (GAT / GABA reuptake pump) or it can be terminated by GABA transaminase which converts GABA into an inactive substance
GABA RECEPTORS
- GABAa: various subtypes are targets of benzos, sedative hypnotics,
barbiturates and/or alcohol. Involved with
tonic or phasic inhibitory neurotransmission
- Ligand gated ion channel - inhibitory - GABAb: g-protein linked receptors. They are coupled to calcium and/or potassium and may be involved in pain,
memory, mood and other functions - GABAc: role is not well clarified, they are not targets of benzos.
- Ligand gated ion channel - inhibitory
GABA a receptor subunits
GABAa receptor subunits: : Each subunit of the receptor has four transmembrane regions. When 5 units cluster together, they form an intact GABAa receptor with a chloride channel in the center.
Benzodiazepine-sensitive GABA receptors:
They increase the affinity of GABA for its own bindings site – they don’t prolong the response of GABA. Benzos have no effect on their own, only when GABA binds to receptor as well
There must be two ß units plus a y unit (y2 or y3), plus two a units (a1,a2,a3)
- Binding: benzos bind to the region of the receptor between the y and the a unit (one molecule per receptor complex) called allosteric modulatory side
- Location: postsynaptic, mediate a type of inhibition that is PHASIC triggered by peak concentrations of released GABA
- Subtypes: benzodiazepines acting at these receptors (a2/3 subtypes) should exert and anxiolytic effect due to enhancement of postsynaptic inhibition
- Receptors with a a1 unit may be most important for regulating sleep and are presumed targets of sedative-hypnotic agents
Receptors with a a2 (and/or a3) subunit regulate anxiety
Currently developed benzodiazepines are nonselective for GABAa receptors: this is why it is searched for partial agonists selective for a2/3 agents that would treat anxiety without having the sedative effects
Benzodiazepine-insensitive GABAa receptors:
Those with a4, a6, y1 or beta subunits
They don’t bind to benzos but to other modulators called neurosteroids and alcohol, and general anesthetics
- Binding site: located between a and beta subunits
(2 molecules of GABA bind per receptor complex to the GABA agonist site)
- location: extrasynaptically
- mediate TONIC inhibition: sets the overall tone and excitability of the postsynaptic neuron
Benzodiazepines as positive allosteric modulators or PAMs:
Since GABAa receptor complexes are not only regulated by GABA but also by benzodiazepines, there might be an endogenous or naturally occurring benzodiazepine synthesized in the brain
- Not found until now
- Any synthetic drug without benzodiazepine structure also binds to these ‘benzodiazepine receptors
measuring fear with animal models
ANIMAL MODELS: Elevated cross maze: rat usually spends more time in the closed arms, but this effect is reduced when administering anxiolytic drugs
CONFLICT TEST: when animals receive an electric shock every time a certain signal is present and they press a lever to receive food, they usually stop to press the lever during that time.
This effect is reduced with anxiolytic drugs, so they press the lever anyways
Measuring fear in humans
Galvanic skin reactions
Experience akin to panic attack can be induced by breathing increased levels of Co2- drugs reduce that attack
Drugs besides Benzos and antidepressants that are used to treat anxiety
Gabapentin & Pregabalin: Treat general anxiety disorder and social anxiety disorder by increasing GABA activity.
It causes sedation and dizziness as a side effect
Atypical psychotic agents: May be effective in treating generalized anxiety disorder and PTSD
ß-adrenoceptor antagonist: treat some forms of anxiety
Buspirone- used for general anxiety disorders and mixed symptoms of depression
Tricyclic antidepressants: reuptake inhibition of serotonin and noradrenaline - used in anxiety disorders
- many side effects
MAOi: increase availability of serotonin, noradrenaline and dopamine - used for panic disorder, PTSD and social anxiety disorder
Carbamazepine: history of treating PTSD
- many side effects
Buspirone
A selective partial 5-HT1A agonist with anxiolytic and antidepressant properties.
- 5HT1A receptors are expressed on the soma and dendrites of 5-HT containing neurons where they function as inhibitory autoreceptors.
- effects take several weeks to develop
- mechanism of action: over time they induce desensitization of somatodendritic h-HT1A autoreceptors, leading to heightened excitation of serotonergic neurons and enhanced 5-HT release
- inhibits the activity of noradrenergic locus coeruleus neurons interferes with arousal reactions
- increased safety & lack of dependency aspects
- side effects: dizziness, anxiety, nausea and headachy
- Overdose: no serious toxic effects and no drug-interactions
First line of treatment for anxiety disorders
SSRI - drugs acting via monoaminergic NTM
- they have antidepressant effects, which goes hand in hand with anxiety
- more tolerable
Abuse of benzodiazepines
- Deliberate abuse by people who use the drug for their euphoriant effect:
- Often abuse other substances for the same purpose
- Used to self-medicate the withdrawal effects or increase effects of other substances
- Usually found within polydrug use pattern
FACTORS INFLUENCING USERS CHOICE OF BENZOS:
Drug effect: depends on half life, speed of onset, offset and age of the person
Benzos with slower onset tend to be abused less often
Relative high: diazepam = Greatest high
Street value: It is affected by drug reputation and supply and demand,
Use again value
- Unintentional abuse by patients who begin using benzodiazepines to treat anxiety disorder and end up using them inappropriately
ABUSERS ARE NOT NECESSARILY DEPENDENT AND DEPENDENT INDIVIDUALS MAY NOT NECESSARILY ABUSE THEM
Type of dependence
ADDICTION:
Compulsive drug-seeking behavior and loss of control
- Tolerance, need for increasing amounts to achieve intoxication or the desired effect, withdrawal symptoms, drug-using behavior that require a lot of time or effort, negligence of important familial or occupational obligations
- Although physiologic dependence is typical of addiction, it is not a required criterion for addiction
PHARMACOLOGICAL DEPENDENCE: Natural physiological adaptation in response of the continual use of many types of drugs that affect the NS
- Basis for pharmacological tolerance and withdrawal symptoms
LONG-TERM USE OF BENZODIAZEPINES
No clinical evidence exist that say that dependence outweigh anxiolytic benefits when using the drug over a longer time.
- Tolerance develops selectively to different drug effects – it might be possible that antianxiety effects do not show tolerance, but this is difficult to address experimentally
WITHDRAWAL FROM BENZODIAZEPINES
3 factors seem to influence the intensity and duration of withdrawal
- Amount of time spent in treatment – the longer the treatment, the more withdrawal symptoms
- Dose of medication – does so in combination
- Half-lives- shorter half-lives lead to more withdrawal symptoms
Pseudowithdrawal: occurs as a result of a patient’s apprehension about discontinuing the medication
WITHDRAWAL VS. RELAPSE OF ANXIETY
- Length of time between discontinuation of treatment and appearance of symptoms, as well as the tendency of symptoms to improve or worsen
a) Withdrawal symptoms usually develop within a few days of stopping the medication & are most severe directly after discontinuation of benzo use but continue to lessen until they disappear
o longer half-lives take longer to generate withdrawal symptoms
b) Relapse of anxiety return more than a week after discontinuation and get progressively worse - Symptoms of withdrawal and relapse differ:
a) Withdrawal: anxiety, agitation, irritability, increased sensitivity to light and sound, parenthesis, muscle cramps, myoclonic jerks, fatigue, insomnia, headache, dizziness, concentration problem, seizure, nausea, loss of appetite and weight, depression
ONSET OF SYMPTOMS NOT PREVIOUSLY EXPERIENCED
b) Anxiety relapse: several symptoms of withdrawal are not characteristic
CLINICAL OPTION FOR DISCONTINUING BENZODIAZEPINE TREATMENT:
- gradual taper: dose is slowly reduced (patients may still experience withdrawal symptoms)
- substitution with a long-acting Benzodiazepine: prevents or lessens withdrawal symptoms
- treating symptoms of withdrawal with extra medication
continue treatment in severe cases
Names of benzodiazepine drugs
alprazolam, clobazam, donazepam, chlordiazepam, diazepam, brazepam, oxazepam, temazepam, triazolam
treatment of insomnia:
benzo, z-drug, melatonin receptor agonist, orexin receptor antagonist (orexin = low at night)
