Intro to Neuropsychopharmacology Part 2 Flashcards
Bipolar I Disorder
-one or more manic episodes
Bipolar II Disorder
-at least one hypomanic episode and one major depressive disorder
Cyclothymic Disorder
-2 years, periods with hypomanic and depressive symptoms not meeting criteria for hypomania or major depressive episodes
Criteria for manic episode
- inflated self-esteem/grandiosity
- decreased need for sleep
- talkativeness
- flight of ideas/racing thoughts
- distractibility
- increased goal directed activity/psyhomotor agitation
- excessive involvement in pleasurable activities with potential for adverse consequences
lithium
- monovalent cation of the lightest alkali metal
- one of few psychotherapeutic drugs that has no behavioral effects in “normals”
- blocks manic behavior
Lithium act by blocking enzymes in neurotransmission explain how
-lithium inhibits the phosphatase that converts IP2 to IP1
- PLC converts PIP2 to IP3 and DAG
- the IP3is then converted to IP2 i
- IP2 is then converted to IP1 and then inositol. this is where lithium blocks. therefore it is stopping the recycling
Describe lithium pharmacokinetics
-readily absorbed after oral administration
-eliminated in urine approximately 95%
-extensive tubular reabsorption
-Na levels affect Li levels. increased Na excretion causes clinically significant increases in Li levels
ie thiazide diuretics, losses of fluids or electrolytes
-narrow therapeutic window so important to monitor levels
-ACE inhibitors and Angiotensin II receptor blockers can also raise Li levels
Why is it important to monitor li levels
-it has a low therapeutic window and the Li levels in the body can change if someone takes and ACE inhibitor or if someone uses a diuretic or change their electrolyte levels in anyway
side effects and toxic reactions
- fatigue and muscular weakness
- tremor: may be treated with beta blockers
- GI symptoms
- slurred speech and ataxia
- serious toxicity at plasma levels about 2 to 3 times therapeutic levels
- impaired conciousness
- rigidity and hyperactive deep reflexes
- coma
- lithium levels are affected by plasma sodium levels thus interactions with diuretics and some antihypertensives
- narrow therapeutic window. important to monitor lithium blood levels
- should be used in caution in pregnant women
Clinical uses of lithium
- treat mania and prevent recurrences of bipolar disease
- may be useful in preventing recurrences of unipolar depression in some patients
alternatives to lithium
- anitseizure agents
- valproic acid, divalproex
- lamotrigene
- haloperidol
Valproic acid, divalproex
- used as first line drug in bipolar disease
- blocks sodium channel and may increase synaptic GABA; sedating
Lamotrigene
-acts at sodium channel- similar mechanism for carbamazepine
Haloperidol
initial control of manic symptoms
Key syndrome for anxiety disorders
- excessive fear and anxiesty manifest by:
- symptoms of flight or fight (ANS and arousal and escape)
- muscle tension and vigilance (musculoskeletal and avoidance)
disorder in the classification of anxiety disorders
- separation anxiety disorder
- selective mutism
- specific phobia
- social anxiety disorder
- agoraphobia
- generalized anxiety disorder
Generalized anxiety disorder
- generalized persistent anxiety for at least 1 months duration
- absence of the specific symptoms and patterns that characterize other anxiety disorders such as phobias, panic attacks, or OCD
- psychological correlates include apprehensive expectation with worry fear and anticipation of misfortune to self and others, hyperattensiveness, distractibility, difficulty in concentrating, insomnia, feeling on edge and impatience
ANS arousal with anxiety
- sweating
- tachycardia and palpitations
- cold and clammy hands
- dry mouth and lump in throat feeling
- GI upset
- frequent urination and diarrhea
Voluntary muscle activation
-jitteriness and an inability to relax
complications to anxiety
-abuse of alcohol, sedatives and antianxiety medications are common
Sleep disorders
- insomnia-disorders of initiating and maintaining sleep
- hypersomnia- disorders of excessive sleep or sleepiness
treatment of anxiety and insomnia
- benzodiazepines and related drugs
- SSRIs
- Buspirone
- classical antihistamines
- alcohol, cannabis, opiates
- barbiturates
GABA localization
- substantia nigra
- globus pallidus
- hippocampus
- limbic structures: amygdala
- hypothalamus
- spinal cord
describe the GABA channel
- it is like the nicotinic channel
- it is a pore
- when GABA binds to it it opens and allows CL to rush into the cell hyperpolarizing it
how do benzodiazepenes influence GABA binding
they increase GABA binding
ligands of the benzodiazepine receptor
- agonist
- antagonist
- agonists: clinically useful benzodiazepines ie Diazepam, Zolpidem
- antagonists: block the action of benzodiazepines at the receptor, Flumazenil
Benzodiazepines used to treat anxiety
- Alprazolam
- Diazepam
- Lorazepam
Flurazepam
- onset of action
- duration of action
- active metabolites
- rapid onset
- long duration of action
- active metabolite is Desalkylflurazepam
Lorazepam
both anxiety and insomnia!!
Describe the role of lipophilicity in Diazepam
- fast onset of action: oral
- high lipid solubility: rapid absorption and entry into the brain
- rapid redistribution after single dose
- active metabolites change this in multiple dose situation
Lorazepam
- less lipophilic than diazepam
- absorption and onset of action are slower
- longer duration of action after single dose
- no active metabolites
what is the only benzodiazepine that is not metabolized to an active metabolite
Lorazepam
CNS effects of the benzodiazepines
- decreased anxiety
- sedation
- hypnosis
- muscle relaxation
- anterograde amnesia-IV administration
- anticonvulsant action
- minimal CV and respiratory actions at therapeutic doses
drug interactions for benzodiazepines
- produce additive CNS depression with most other depressant drugs such as ethanol, other sedative hypnotics and sedating antihistamines
- drugs that affect hepatic metabolism such as cimetidine
clinical uses of benzodiazepines
- anxiety states (short term)
- sleep disorders
- muscle relaxant (Diazepam)
- seizure treatment
- intravenous sedation and anesthesia
- alcohol withdrawal-chlordiazepoxide
Benzodiazepine withdrawal
- anxiety
- insomnia
- irritability
- headache
- hyperacusis
- hallucinations
- seizures
How do you treat abuse of benzodiazepines
-gradual reduction in dose, switch to longer acting drugs
Buspirone
- not related chemically or pharmacologically to the benzodiazepines
- high affinity for 5-HT1A receptos
- less sedating than benzodiaepines
- no cross-tolerance with benzodiazepines
- does not potentiate other sedative hypnotics and depressants nor suppress symptoms of their withdrawal
- used in the treatment of generalized anxiety syndrome
- therapeutic effects may take 1 t 2 weeks to occur
other treatments for anxiety besides benzodiazepines and buspirone
- SSRIs and SNRIs-panic attacks and GAD
- Beta blockers: performance anxiety
Describe the dimesions of insomnia
- symptoms may be mild or severe, or transient, chronic or intermittent
- can’t fall asleep and/or stay asleep
- daytime sequelae: tired, fatigued, sleepy, anxious, depressed
Effects of benzodiazepines on sleep
- decreased latency to sleep
- increase in stage 1 and stage 2 sleep
- decreased time in stage 3 and stage 4 and REM sleep
- rebound insomnia upon withdrawal
adverse effects of using a benzodiazepine for sleep
- daytime sedation
- ataxia
- rebound insomnia
- tolerance and dependence
- occasional idiosyncratic excitement and stimulation
Zolpidem
- not benzodiazepine chemically
- but bind to the Benzodiazepine receptor on GABA complex
- weak anxiolytic, muscle relaxant and anticonvulsant at hypnotic dose
- stage 3 and 4 sleep preserved, minor effect on REM sleep
- typical duration is 5 to 6 hours. sustained release preparation, duration of action 7 to 8 hours, also available.
- also available as an oral spray targeted at problems of sleep initiation and sublingual tablets for middle of the night waking . some forms are approved for longer term use
Barbiturate metabolism, pharmacokinetics and interactions
- rapidly absorbed and distributed
- highly lipid soluble compounds such as thiopental distribute rapidly to the brain. action terminated by redistribution
- can induce own metabolism and that of other drugs
- eliminated primarily by renal excretion
Where do barbiturates act
- GABAa receptor
- Cl ion channel complex binding to a barbiturate site, enhance action of GABA and increase inhibition
pharmacological actions and adverse effects for barbiturates
-general CNS depression
*sedation, hypnotic action, anesthesia
-anticonvulsant
-respiratory depression
-tolerance
physical dependence
-actue poisoning
additive with other CNS depressants such as alcohol other sedative hypnotics and antihistamines
-interact with drugs that affect microsomal drug metabolism
Describe tolerance of barbiturates
-both metabolic and pharmacodynamic. it is not uniform to all drug effects
describe physical dependence of barbiturates
-repeated use of barbiturates may result in withdrawal symptoms upon cessation of use. similar to BDC life threatening seizures may occur. abrupt withdrawal in chronic users is contraindicated
describe acute poisoning in barbiturate use
-stupor, coma and respiratory depression . treatment involves removing any unabsorbed drug, supporting respiration and preventing complications
Skeletal muscle relaxants
- drugs used to reduce muscle tone associated with spasticity related to multiple sclerosis injuries and other muscular skeletal disorders
- spasticity is characterized by increases in tonic stretch reflexes and flexor muscle spasms together with a possible muscle weakness
- mechanisms underlying spasticity involve both the stretch reflex arc itself and higher centers in the brain
- pharmacological treatment of spasticity targets both sites
GABAergic agent
- Diazepam
- Baclofen
Diazepam
- its action in reducing spasticity is at least partly mediated in the spinal cord
- it can be used in patients with muscle spasm of almost any origin including local trauma
- it produces sedation in most patients at the doses required to reduce muscle tone
Baclofen
- GABA-mimetic agent that works at GABA B receptors. this results in hyperppolarization, causing presynaptic inhibition
- this can result in decreased release of excitatory transmitters such as glutamate
- Baclofen is at least as effective as diazepam in reducing spasticity and produces much less sedation
Tizanidine
- an alpha2 adrenergic agonist that is related to clonidine. it may enhance both presynaptic and postsynaptic inhibition
- may have similar efficacy to diazepam and baclofen in relieving muscle spasms
- side effects include drowsiness, hypotension, dry mouth and asthenia
