Module 3- Drugs that Influence the CNS Flashcards
Excessive CNS excitation can lead to…
Deleterious effects including
- anxiety
- insomnia
- seizures
Neurochemistry of brain is dependent on
The balance between excitatory and inhibitory signals
What is the primary excitatory neurotransmitter in the brain?
Glutamate
What is the primary inhibitory neurotransmitter in the brain?
Gamma-aminobutyric acid (GABA)
Treatment for anxiety and insomnia?
Appropriate treatment can include
- behavioural changes (i.e. stress reduction and physical exercise)
- Prescription medication (i.e. sedative hypnotic agents)
Sedative Hypnotic agent examples
- anti-anxiety effect- used to treat anxiety disorders (OCD)
- sedation: relieve anxiety, decrease activity, moderate excitement and calm individual
- hypnosis: produce drowsiness and aid in the onset and maintenance of sleep
- general anesthesia: state of unconsciousness with absence of pain sensation
Examples of anxiety disorders sedative hypnotics treat
- generalized anxiety
- obsessive compulsive disorder
- panic disorder
- post traumatic stress disorder
- phobias
How doe sedative hypnotics treat anxiety?
Reduces the amount of glutamate-induced neural excitation by increasing the GABA inhibitory signalling in the brain
The Chloride ion channel
- GABA binds to chloride channel on the membrane of neuron in the brain and spinal cord
- binding causes channels to open and allows negatively charged ions to flow into the cell, resulting in an inhibitory effect
- SHAs also bind here, on a different site on the chloride channel -> resulting in an increase in synaptic inhibition and dampening neuronal responses
Drugs that bind to the chloride channel
- benzodiazepines
- Barbiturates
- The “Z” drugs
Where do benzodiazepines bind
bind to the chloride channel at the benzodiazepine receptor, and increases the frequency of GABA receptor mediated opening of the chloride channel
How are benzodiazepines classified?
Allosteric activator
Benzos bind to and activate a separate receptor on the chloride channel than the neurotransmitter GABA, which makes it an allosteric activator
Pharmacokinetics of benzodiazepines
absorption: usually taken as a capsule, or tablet
metabolism: have different durations of action, determined by the rate of liver metabolism and formation of, or lack of formation of pharmacologically active metabolites
Pharmacological properties of Benzodiazepines
- possess very high therapeutic index
- relieve anxiety
- produce sedation and amnesia
- decreased aggression
- some are effective hypnotics
- minimal suppression of REM type sleep
- skeletal muscle relaxation
- anticonvulsant action
Short term use of benzodiazepines
Produces: relaxation, calmness, and relieve from anxiety of tension
Adverse effects: drowsiness, lethargy, impairment of thinking/memory, nausea, and constipation
Moderate doses can impair motor coordination and driving, so patients should refrain
Long term use of benzodiazepines
Varies between individuals
- some take large amounts for long periods of time without major evidence of intoxication
- others demonstrate symptoms of chronic-sedative hypnotic intoxication (i.e. impaired thinking, poor memory/judgement, disorientation and incoordination)
Elderly and benzodiazepines
can produce cognitive dysfunction, because benzos metabolize more slowly than young adults, often leading to over-sedation, falls and injury
Pregnant/breastfeeding women and benzodiazepines
benzos freely cross the placenta and distribute int the fetus
- risk of fetal abnormalities
lethality and benzodiazepines
Death from overdose is rare, but does occur following ingestion of enormous doses
Flumazenil
Benzodiazepine receptor antagonist that blocks the effect of benzodiazepines
- Antidote for benzo overdosing
Benzodiazepines misuse potential
Low- as they are weaker reinforcing properties than barbiturates, opioids, and stimulants
Benzodiazepine use disorder
Low misuse, but high degree of cross tolerance among benzos and other sedative-hypnotic drugs
Barbiturates
Potent CNS depressants
Classes of barbiturate
Long acting (1-2 days)- phenobarbital
Short acting (3-8 hours)- secobarbital
ultrashort acting (20 mins)- thiopental
Where do barbiturates bind to?
bind to chloride channel at barbiturate receptor, and increase the duration that the channel is open
Pharmacological properties of barbiturates
- low therapeutic index
- suppress REM type sleep
- lethality is common (especially combined w alcohol)
- death can occur from withdrawal
Barbiturate antidote
There is none
Clinical use of barbiturates
Limited use since replaced with safer drugs
Ultrashort and short acting can be used to induce anesthesia,
Long acting agents- anti seizure drugs
Barbiturate misuse potential
equal to or greater than alcohol
- pleasurable effects
- inherent harmfulness is high
barbiturate use disorder
tolerance develops very rapidly to sleep induction and mood effects, often within a few weeks of nightly administration
- addiction can result from regular use
- withdrawal syndrome occurs after discontinuation of chronic use
The “Z” drugs
Zolpidem
zopiclone
similar drugs that start w “Z”
Where do the “Z” drugs bind
Bind to a subset of the GABA receptors, causing sedation and minimal REM disruption
What do “Z” drugs have advantages over benzodiazepines as a hypnotic?
they disturb sleep patterns (REM) even less than benzos
Therapeutic uses of GABA-modifying drugs
Anxiety- benzos effective in reducing symptoms of anxiety
Insomnia- “Z” drugs or short acting barbiturates (cause drowsiness)
Seizures- long acting barbiturates (i.e. phenobarbital) used to treat partial seizures
- benzos used for status epilepticus
Skeletal muscle spasms- benzos
Alcohol withdrawal syndrom- benzos due to cross tolerance
Seizure disorders
second most common neurological disorder after a stroke
- Generalized seizures
- partial seizures
General seizures
account for 40% of all seizures
involve the entire CNS, arising in both cerebral hemispheres, and are accompanied by loss of consciousness
Can be subdivided into several classes based on the type of movement and duration of loss of consciousness
- tonic-clonic
- status epilepticus
Partial seizures
account for the other 60% of seizures
May involve motor disturbances and alterations of perception or behaviour
How do seizures happen?
Result from a sudden repeated spontaneous discharge of groups of excitatory neurons on CNS, that may radiate to involve surrounding areas of the brain
- must involve glutamatergic neurons since they are major excitatory neurons in CNS
Treatment of seizures
Mechanism 1-increasing inhibitory input
Mechanism 2- blocking electrical activity of nerve
Mechanism 3- decrease excitatory transmission
Seizure treatment- mechanism 1
Increasing inhibitory input to the neuron to suppress firing
- accomplished by increasing GABA activity in the brain
i.e. valproate, phenobarbital, and benzodiazepines
Seizure treatment- mechanism 2
blocking electrical activity of nerve to slow the nerve impulses
- accomplished by blocking sodium channel electrical activity, which will slow the conduction of the nerve impulse
i.e. lamotrigine and valproate
Seizure treatment- mechanism 3
Decrease excitatory transmission
- accomplished by decreasing the release of glutamate at the synapse
i.e. lamotrigine
Pharmacokinetics of anticonvulsants
Regardless of specific drug, most anti-seizure medications have similar pharmacokinetics since they all must cross the blood-brain barrier and enter the CNS
absorption rate= 80-100%
Cleared= mostly by liver
Adverse effects of anticonvulsants
CNS- sedation, tremors, ataxia, and cognitive/visual impairment
Immune system: benign skin rashes occur in 5-20% of patients
Hepatic: enzymes may become elevated, but generally asymptomatic
GI: nausea, vomiting, and diarrhea
Anticonvulsants and drug interactions
most anticonvulsants induce biotransformation enzymes, the metabolism of concurrently administered drugs is increased, resulting in a decrease in the duration of action of concurrent drugs
Toxicity and overdose in anticonvulsants
Even though they act by decreasing CNS activity, they are rarely lethal
most dangerous effect = respiratory depression, which can be potentiated by other CNS depressants
Overdose treatments = supportive therapy
Withdrawal and anticonvulsants
does occur, and severity depends on the drug being withdrawn
withdrawal can cause increased frequency and severity of seizures
Depression
Mental illness affecting 10-15% of the population over a lifetime
Feeling of intense
- sadness
- hopelessness
- despair
- self-disproval
- physical and mental slowing
- sometimes suicidal thoughts
Types of depression
- Major depression (25%)
- Depression associated with bipolar disorder (10-15%)
- Reactive depression (60%)
Major Depression
Characterized by depressed mood for at least 2 weeks and/or a loss of interest or pleasure in activities
associated with significant morbidity and mortality
The amine hypothesis
depression may be due to a reaction in the activity of one or more neurotransmitter systems in the CNS
- serotonin + norepinephrine are released from presynaptic neuron
- neurotransmitters are removed from synaptic cleft via SERT and NET, this terminating their action
- MAO-A inactivates the neurotransmitters, and they cannot be repackaged into vesicles for subsequent release
- theorizes that in depression, the levels of released neurotransmitters fall below normal levels, leading to impaired excitation of neurons… depression
What does SERT and NET stand for?
SERT- serotonin reuptake transporters
NET- norepinephrine uptake transporters (NET)
What does MAO stand for?
enzyme monoamine oxidase
Neurotrophic hypothesis
Depression may be due to a loss of neurotrophic support characterizes by a decrease in neurogenesis and synaptic connectivity
A reduction in nerve growth factors are responsible for a loss of neural plasticity and neurogenesis, and antidepressants stimulate neurogenesis and synpatic connectivity in cortical areas of the brain is a protein required for neural growth and axon sprouting within the NS
Nerve growth factors and major depression
brain derived neurotrophic factors (BDNF) is a protein required for neural growth and axon sprouting within the nervous system
changes in trophic factors (BDNF) plays a major role in the development of MDD
the neuroendocrine hypothesis
depression may be due to an abnormality in hormones affecting mood
Hormones affecting mood
- cortisol
- thyroid hormones
- sex hormones
Mechanism of action of antidepressants
- block neurotransmitter reuptake systems
- block metabolism of neurotransmitters, thereby increasing amount of neurotransmitter released
- directly increasing the amount of neurotransmitter released
Types of antidepressants that block neurotransmitter reuptake systems
- tricyclic antidepressants (TCAs)
- serotonin reuptake inhibitors (SSRIs)
- serotonin norepinephrine reuptake inhibitors (SNRIs)
Tricyclic antidepressants
inhibit the reuptake transporters of both serotonin and norepinephrine (SERT/NET) into presynaptic axon, causing increased concentration of these neurotransmitters to be present in the synaptic cleft
example: Nortriptyline; tricyclic antidepressant used to treat depression
Adverse effects of tricyclic antidepressants
- anticholinergic effects (dry mouth, urinary retention, constipation, blurred vision)
- antiadrenergic (alpha) effects (hypotension when standing)
- antihistaminic actions (sedation)
- block sodium channels (arrhythmias, seizures, fatal in overdose)
- weight gain
Serotonin reuptake inhibitors (SSRIs)
most widely used class of drugs in treatment of depression
much less of an effect on ANS than TCAs
Example: Fluoxetine
Adverse effect of SSRIs
Cause nausea, headaches, nervousness, and insomnia more commonly than TCAs
High incidence of sexual dysfunction
Drug-drug interactions of SSRIs
- decreased metabolism
- SSRIs inhibit the CYP450 enzymes, so metabolism of concurrently administered drugs is altered
- may lead to drug toxicity or loss of drug efficacy
- serotonin syndrome
- occurs due to concurrent use of multiple drugs that increase serotonin
Serotonin norepinephrine reuptake inhibitors (SNRIs)
block the transporters for both serotonin and norepinephrine
Unlike TCAs, these drugs do not have effects at autonomic and histaminic receptors
taken if patients do not respond to SSRIs
Example: venlafaxine
Adverse effects of SNRIs
increase in blood pressure and heart rate
types of antidepressants that block neurotransmitter metabolism
Monoamine oxidase (MAO) inhibitors
Monoamine oxidase (MAO) inhibitors
by blocking a major pathway for the monoamine neurotransmitters, the MAO inhibitors allow more amines to accumulate in presynaptic stores, resulting in more to be released when the nerve impulse reaches the presynaptic neuron
MAO-A
enzyme primarily responsible for metabolism of norepinephrine, serotonin and tyramine
MAO-B
more selective for metabolism of dopamine
Drug-drug interactions of MAOIs
if MAO inhibitors are prescribed, patients must be warned that they interact with many other drugs and w tyramine-containing foods
- a MAO inhibitor can cause serotonin syndrome
antidepressants that increase the amount of neurotransmitter released
autoreceptor antagonists
autoreceptor antagonists
new drug that inhibits the activation of alpha-2 receptors
- alpha-2 receptors located on the presynaptic neuronal membrane are autoreceptors, meaning that activation of these receptors inhibits the release of neurotransmitter from the presynaptic neuron
- drugs that block alpha-1 autoreceptors remove this negative feedback loop, allowing the presynaptic neuron to release more neurotransmitter into the synaptic cleft
Example: mirtazapine
Electroconvulsive therapy
patients are given a muscle relaxant to prevent movement and are put under general anesthesia
- electrodes are then placed on the head to sent ~500-900 milliamo current through brain, sparking a brief seizure
Bipolar disorder
brain disorder characterized by manic and depressive phases
Symptoms of manic phase:
- elation
- excitement
- hyperactivity
- disinhibition
- aggression
- some psychotic symptoms
Symptoms of depressive phase:
- depressed mood
- sleep disturbances
- anxiety
Treatment of manic phase of BPD
- reduces the patient’s mood to a “normal” range with antipsychotic medications such as haloperidol, chlorpromazine, or new typical antipsychotics
- stabalize the patient’s mood within “normal” range with a mood stabilizer
treatment of depressive phase of BPD
The depressive phase is not the same as MDD, antidepressants are sometimes used, but may actually make matters worse. Mood stabilizers tend to be effective
Antipsychotics
class of drugs used to reduce psychotic symptoms caused by a variety of disorders, including bipolar disorder, schizophrenia, and drug-induced psychoses
Three classes of antipsychotics
- phenothiazine
- Haloperidol
- Atypical antipsychotics
Phenothiazine antipsychotics
block dopamine receptors in different regions of the CNS
Not highly specific to dopamine receptors, therefore some effects are related to the antagonism of other receptor systems, such as cholinergic, histaminic, and alpha-adrenergic receptors
Adverse effects of phenothiazine
antagonism of dopamine receptors in the
- nigrostriatal system of the brain results in extrapyramidal movement disorders (tremor, rigidity of limbs and slowing of movement, reduction in spontaneous activity, dystonia)
- hypothalamus will result in the excess release of prolactin
Blockade of cholinergic (muscarinic) receptors due to phenothiazine
Therapeutic effects: reduction of extrapyramidal adverse effects
Adverse effects: blurred vision, dry mouth, constipation, difficulty urinating
Blockade of histamine receptors due to phenothiazine
Adverse effects: sedation, drowsiness, and weight gain
Blockade of a-adrenoreceptors due to phenothiazine
adverse effects: postural hypotension, dizziness, reflex tachycardia
Haloperidol
Like phenothiazines, it competitively blocks dopamine receptors
Useful alternative for patients who do not respond to or cannot tolerant phenothiazines
Second-generation antipsychotics (i.e. atypical antipsychotics)
Produce less extrapyramidal side effects
Have dual action by blocking dopamine and serotonin receptors
Examples of second generation antipsychotics
clozapine, risperidone, and olanzapine
Side effects of atypical antipsychotics
weight gain, increased risk of developing diabetes, and sudden cardiac death due to abnormality in the rhythm of the heart
Other uses for atypical antipsychotics
- schizoprenia
- delusions and aggression associated with dementia in the elderly
- autism spectrum disorder
- developmental disorder
- posttraumatic stress disorder (as an alternate to antidepressants)
- obsessive compulsive disorder
- borderline personality disorder
Mood stabilizers
Second category, used to prevent mania (highs) and depression (lows)
Two categories
- Lithium carbonate
- Anticonvulsants
Lithium carbonate
mood stabilizing agent used to prevent mood swings in patients, also used to treat mania
Mechanism of action of lithium carbonate
not yet resolved but 2 possibilities under consideration…
1. Effect on electrolytes and ion transport
2. Effect on second messengers that mediate terminate transmitter action
Pharmacokinetics of lithium
- period of 2-4 weeks of administration may be required for lithium to have a full therapeutic effect
- body elims lithium as if it were sodium
- increased sodium intake increases lithium excretion
-narrow therapeutic index
Adverse effects of lithium
- tremour, thirst, excessive urination, edema, and weight gain
- confusion and loss of muscle coordination
- mild hypothyroidism
- toxic kidney effects are observed in some individuals treated chronically with lithium, but are uncommon
- when taking during pregnancy, it can cause cardiac malformations in the fetus
Anticonvulsants as mood stabilizers
(i.e. valproic acid) have a more rapid onset of action than lithium, and are often preferred
Note: not all anticonvulsants are mood stabilizers
