Module D Flashcards
Signalling in the CNS is ________ (electrical / chemical / both)
Both
neurotransmitters and neuromodulators act at synapses, but there is also direct voltage signalling at electrotonic gap junctions
Most neurotransmitters are ________ (inhibitory / excitatory / either) with the exception of ______, which is only inhibitory
either, GABA
The only purely inhibitory CNS neurotransmitter is ________
GABA
Excitatory effects promote:
release of NTs from the neruronal terminal
inhibitory effects cause _________ and inhibit release of _________
hyperpolarization, neurotransmitters
Fast NTs act on what kind of receptors?
ligand-gated ion channels
Slow NTs act on which kinds of receptors
GPCRs
GABA is a _____ (fast / slow) NT
Fast
it acts on ligand-gated ion chanels
CNS agents act in the following 4 ways:
- Altering synthesis, storage, or release of an NT
- Inhibiting reuptake of an NT
- Inhibiting degredation of an NT
- Activating or blocking the receptor
receptors respond to long-term drug treatments by which two processes?
- sensitization (up-regulation)
- desentization/tolerance (down-regulation)
Delirium is a disorder of ________, as seen in _________
cognitive processing, schizophrenia
Dementia is a disorder of _________, as seen in __________ and ________
memory, alzheimers and parkinson
emotional disorders arise from the ________ system
limbic
Three classes of drugs used in the management of delirium are:
- antipsychotics
- CNS stimulants
- Sedative-hypnotics
Sedative-hypnotic drugs tend to have dose-dependent effects, first causing ________ and then ________
sedation/anxiolysis first, and then hypnosis (drowsiness, then sleep)
contrast the common anxiety disorders and their common pharmacological treatments
- Acute Anxiety: self-limiting acute arousal, may be treated with benzodiazepines
- Panic Disorder: recurrent, acute periods of anxiety with marked psychological and physiological manifestations. May be treated acutely with benzodiazepines and chronically with an SSRI
- Phobic Disorders: panic diorder with specific triggers. managment is similar to panic disorder, but performance anxiety may be managed with a beta-blocker like propranolol
- OCD: marked by compulsions, best treated with an antidepressant
- Generalized anxiety disorder: chronic worry and apprehension, best managed acutely with benzodiazepines and chronically with an SSRI
- PTSD: similar treatment to panic disorder, GAD, etc.
Generally, treatment for anxiety disorder involves:
treatment of acute episodes with a benzodiazepine and chronic managment with an SSRI antidepressent.
There are ___ stages of sleep which tend to occur in ___ minute cycles in healthy individuals. The REM stage is stage ___ and is critical for stable emotional status
5, 90, 5
The clinical term for difficulty falling asleep is
sleep latency
Benzodiazepines and antidepressants may decrease sleep latency, but have the adverse effect of:
changing sleep architecture, reducing REM sleep, and causing emotional disturbance
The advantage of modern sleep agents like sublinox (zolpidem) is:
they have a minimal effect on sleep architecture
A disadvantage of all sleep agents is that they may cause:
tolerance and dependence
Compare and contrast physical and psychological dependence
both manifest as continued seeking of exposure to a drug. Physical dependence is continued use to avoid unpleasant physical withdrawal symptoms. Psychological dependence is continued use to receive the pleasurable effects of the drug or escape reality
Sedative drugs are also called:
anxiolytics
The main advantage of benzodiazepines over other sedative-hypnotics is
very broad therapeutic index
Explain why some patients taking benzodiazepines may experience increased sedation after a high-fat meal
this is due to enterohepatic cycling (active metabolites are reabsorbed from the gut after biliary excretion)
Describe the MOA of benzodiazepine drugs
- bind to an allosteric site on the GABA-gated chloride channel receptor, increasing GABA activity
- this increases duration and frequency of opening of the chloride channel
- cause post-synaptic hyper-polarization (puts on the brakes)
- also inhibit neuronal reuptake of adenosine
Benzodiazepines _____ (can / can not) produce sedation sufficient for general anesthesia
can not!
Most BZ drugs are metabolized by the liver to produce _________ and are therefore classified as _________
active metabolites, prodrugs
Benzodiazepines have a ________ (fast / slow / etc.) onset
fast or very fast
A benefit of BZs like midazolam is that they prodruce __________, limiting unpleasant memories of procedures
anterograde amnesia
Five pharmacological effects of BZ drugs are:
- anxiolyis (sedation)
- amnesia (anterograde)
- hypnosis
- skeletal muscle relaxation
- anticonvulsant
Whereas _________ sedative-hypnotics have a strong ceiling effect, ____________ do not
benzodiazepine, barbiturates
this is due to the dependence of BZs on already-existing GABA for their MOA
List advantages and disadvantages of BZ drugs
Advantages: Little respiratory/cardiac depression, large therapeutic index, very dose-dependent response (can produce sedation without hypnosis)
Disadvantages: Cause physical and cognitive impairment, rebound effect if discontinued suddenly, physical dependence which may result in delirium
Valium (Diazepam)
- Benzodiazepine, sedative-hypnotic
- Lipid-soluble GABA agonist, causes CNS depression due to potentiation of GABA receptors and post-synaptic hyperpolarization
- Fast onset with long duration of action
- Dose dependent effects with ceiling effect: at low doses sedation only, at higher doses hypnosis and anterograde amnesia
Ativan (Lorazepam)
- Benzodiazepine, sedative-hypnotic
- Lipid-soluble GABA agonist, causes CNS depression due to potentiation of GABA receptors and post-synaptic hyperpolarization
- Fast onset with medium duration of action and no active metabolites
- Dose dependent effects with ceiling effect: at low doses sedation only, at higher doses hypnosis and anterograde amnesia
Versed (Midazolam)
- Benzodiazepine, sedative-hypnotic
- Lipid-soluble GABA agonist, causes CNS depression due to potentiation of GABA receptors and post-synaptic hyperpolarization
- Fast onset with short duration of action, generally only given IV (or IM)
- Dose dependent effects with ceiling effect: at low doses sedation only, at higher doses hypnosis and anterograde amnesia
- used in acute settings for induction of anaesthesia, termination of seizures, and delirium
Barbiturates are recognized by their names ending in ____
-tal
Anexate (Flumazenil)
- Benzodiazepine antagonist, reversal agent
- Competitive BZ receptor antagonist
- used to reverse BZ overdose and BZ sedation
- short half-life (7-15 minutes) with unpredictable effects that may potentiate seizures. Rarely indicated due to low mortality with benzo overdose
Briefly describe the MOA of barbiturates and explain why they do not demonstrate a ceiling effect
- Bind to an allosteric site on the GABA-gated chloride gate (different from BZ site) which increases GABA affinity
- unlike BZs, also increases chloride gate activity in absence of GABA, explaining the lack of a ceiling effect
Explain some disadvantages of barbiturates
- high risk of physical dependency (unpleasant withdrawal)
- low therapeutic index
- less dose-dependent, cause simultaneous sedation, anxiolysis, and hypnosis
describe benefits of modern sedative-hypnotics used for non-acute insomnia (zopiclone, zaleplon, eszoplicone) vs BZs
- less effect on sleep archtecture (protection of REM sleep)
- lower risk of dependence/tolerance
- shorter duration of action for less daytime effects
Imovane (Zopiclone)
- non-BZ sedative-hypnotic
- used in management of sleep disorders
- increases GABA activity in CNS
- less tolerance and dependence forming than the BZ drugs
- preserves sleep architecture
Sublinox (Zolpidem)
- non-BZ sedative-hypnotic
- used in management of sleep disorders
- increases GABA activity in CNS
- less tolerance and dependence forming than the BZ drugs
- preserves sleep architecture, less effect on next-day cognitive performance and coordination
Sotacor (Zaleplon)
- non-BZ sedative-hypnotic
- used in management of sleep disorders
- increases GABA activity in CNS
- less tolerance and dependence forming than the BZ drugs
- preserves sleep architecture
Noctec (Chloral hydrate)
- Non-BZ sedative hypnotic
- given as a prodrug
- generally only given as preanesthetic sedation in pediatric patients
Precidex (Dexmetetomidine)
- alpha-2 agonist
- used in treatment of hypertension and for sedation in anaesthetized/intubated patients in an ICU setting
- used due to lack of respiratory depression
contrast analgesia and anaesthesia
analgesia is the blockage or reduction of only pain sensation. Anaesthesia is the blockage of all sensation
The two major classes of local anaesthetics and the prototype drugs of each are:
Ester-type (procaine/cocaine) and Amide-type (lidocaine)
Describe the MOA of local anaesthetics
they bind to sodium channels and prolong the inactivated state, reducing excitability.
Describe the methods of administration of local anaesthetics
Topical: may reduce pruritis or pain of IV placement. May be given as a eutectic mixture of agents
Infiltration: most common, injected into SC tissue. Duration depends on local blood flow (slow flow prolongs duration) so sometimes given with epinephrine (but never at terminal arterioles in digits)
Iontophoreis: delivery using small electric current, mainly in dentistry
Nerve block and field block
Intrathecal and epidural
Describe the effects of size-dependent and use-dependent blockade in local anaesthetics
Local anaesthetics have greatest effect on small, unmyelinated fibres (size-dependent) and on fibres that are actively firing frequently (use-dependent).
Xylocaine (Lidocaine)
- Amide-type local anaesthetic
- sodium channel blocker that produces use-dpendent and size-dependent blockade
- may be given with epi to induce vasoconstriction and prolong duration of action
- relatively strong local anaesthetic effect
Cocaine
- Ester-type local anaesthetic
- Sodium channel blocker
- causes local vasoconstriction, prolonging duration of action
- relatively weak anaesthetic effect and high risk of abuse, so rarely used
Adverse effects of local aneasthetics include:
- CNS effects (stimulation, then inhibition)
- Cardiovascular effects (hypotension and arrhythmogenesis)
- NMBA potentiation
- Allergic reactions (especially ester-type)
The 4 stages of general anaesthesia are:
- Analgesia and conscious sedation
- Paradoxical excitation (not commonly seen with modern, balanced anaesthesia)
- Surgical anaesthesia (desired state)
- Vasomotor and respiratory depression with cardiovascular collapse (not desired!)
Factors that effect the rate of induction when using inhalational anaesthetics are: (list 4)
- Solubility of the gas
- Alveolar partial pressure of the anaesthetic
- Pulmonary ventilation
- Pulmonary blood flow
Inhalational anaesthetics with _______ (high / low) blood:gas partition coefficient will have a rapid onset
Low
gasses with a high BG partition require high concentrations to achieve saturation of blood proteins and exist as free gas at tissue beds
Decribe the MOA of inhalational anaesthetics
the free gas form of these drugs binds to GABA receptors and increases chloride influx, leading to cell hyperpolarization
inhalational anaesthetics with a _________ (high / low) oil:gas partition coefficient have the highest efficacy
high
give examples of halogenated and non-halogenated inhalational anaesthetics
halogenated: Halothane, desflurane, isoflurane, sevoflurane
non-halogenated: nitrous oxide
describe why sevoflurane is considered a near-ideal inhalational anaesthetic
- it has a relatively low blood:gas partition coefficient and high oil:gas partition coefficient leading to rapid induction and high efficacy
- it provides smooth induction and emergence
- it has very little CV or other toxicity
A rare but important adverse effect of inhaled halogenated anaesthetics is:
malignant hyperthermia
explain why inhalational anaesthetics should be used with caution in patients with low cardiac output
these patients may have pulmonary arterial hypertension which will increase pulmonary bloodflow and potentiate the rate and depth of induction
the value used to measure the potency of inhalational anaesthetics is the:
minimum alveolar concentration
this is the partial pressure in the lungs required to produce desired anaesthesia in 50% of patients
The inhalational anaesthetic which provides the most potent analgesia is:
nitrous oxide
All halogenated anaesthetics cause _______ (CP effects)
cardiovascular and respiratory depression (decreased cardiac ouput, decreased resp rate and tidal volume)
What are three advantages of parenteral (IV) anaesthetics over inhalational ones?
- they have a rapid onset
- they do not require specialized equipment
- they have fast recovery/emergence rates
Fast on, fast off, and easy
Outline popular parenteral anaesthetic agents
Benzodiazepines: especially midazolam, used as a sedative-hypnotic for premedication and during surgical procedures. Amnesic properties useful
Opioids: especially Fentanyl, for analgesia and combined with sedatives to provide general anaesthesia without CV depression
Propofol: Rapid on, rapid off sedation and amnesia which reduces ICP and BP. Ideal for head injury, caution in hypotension.
Etomidate: Rapid induction with minimal CV effects, but causes long term inhibition of steroid synthesis so only useful in acute setting (RSI)
Ketamine: Rapid induction, strong analgesia, minimal CV effects, but unpleasant emergence. Useful in children since emergence effects are less pronounced
Diprivan (Propofol)
- Parenteral, non-opioid anaesthetic
- Cause GABA potentiation (similar to BZs) to produce sedation and anaesthesia
- generally used to induce anaesthesia which is maintained by an inhalational anaesthetic, except in short, minor procedures. (20s onset, 5-10 min duration)
- Reduces ICP and BP, so near ideal for head injury management
- prolonged use potentiates cardiovascular depression
Amidate (Etomidate)
- Parenteral anaesthetic
- Acts on GABA receptors to produce anaesthesia/sedation
- Rapid onset and very few cardiovascular side effects, so ideal for hyperacute situations
- used in RSI and conscious sedation
- Prolonged use inhibits steroid synthesis
Ketamar (Ketamine)
- Non-opioid parenteral anaesthetic, sedative, dissociative
- Blocks excitatory NTs at NMDA receptors. Produces dissociative anaesthesia
- Anaesthesia characterized by analgesia, reduced sensory perception, incomplete loss of consciousness, immobility, and amnesia
- Causes increased BP and no respiratory depression (great for trauma)
- produces unpleasent emergence including hallucinations and delirium; less common in pediatric patients!
Typical and atypical antipsychotics are also known as _________ and are differentiated based on _________
first and second generation anipsychotics; differentiated based on D2 to 5-HT2 receptor specificity (second-generation have greater 5-HT2 specificity)
Common drug name endings for atypical (2nd gen) antipsychotics are:
- -Pine (Clozapine, Olanzapine, Quetiapine)
- -Idone (Respiridone, Paliperidone)
- Apripirazole (gets its own darn name!)
The schizoprenic pt, afraid his penis had disappeared, shouted “help, my ole peen is done!” for -ole, -pine, -idone.
The advantages of 2nd generation antipsychotics are:
effective in management of positive symptoms (hallucinations, delusions, agitation) with fewer extrapyramidal symptoms (EPSs) and less exacerbation of negative symptoms (social withdrawal, anhedonia)
Long term treatment with antiphsychotics may lead to __________, an irreversible disorder of movement that includes involuntary repetitive movements of the perioral and ocular muscles
tardive dyskinesia
the ________ hypothesis is an attempt to explain the underlying cause of schizophrenia and states:
dopamine; schizophrenia is caused by imbalances in dopamine trasnmission in the mesolimbic and mesocortical pathways.
Haldol (Haloperidol)
- first generation, typical antipsychotic
- blocks D2 receptors in the mesocortical, mesolimbic and other pathways
- high potency, very high risks of extrapyramidal side effects
- generally only useful in treatment of positive symptoms of schizophrenia.
- prolonged use may lead to tardive dyskinesia or neuroleptic malignant syndrome
Clozaril (Clozapine)
- second generation, atypical antipsychotic
- blocks 5-HT and D2 receptors in the mesocortical, mesolimbic and other pathways
- high potency, low risk of EPSs, but many other systemic side effects stemming from alpha blockade and anticholinergic effects
- useful in treating both positive and negative symptoms of schizophrenia
- prolonged use may lead to tardive dyskinesia or neuroleptic malignant syndrome
The two types of affective disorder are:
depressive and bipolar
Affective disorders are thought to be rooted in imbalance of _______, _______, and _________ as stated by the ___________ hypothesis
norepinephrine, serotonin (5-HT), and dopamine; biogenic amine hypothesis
The most commonly used, and first-line anti-depressants are _________ due to _______
SSRIs due to good effectiveness and lower risk of adverse effects than other antidepressents
TCAs ______ (are / are not) highly effective in treating depression and have many potentially severe side effects, including:
- They are very effective
- Side effects include; sedation, anticholinergic effects, orthostatic hypotension, and cardiac conduction disturbances
- prolonged use and overdose may cause serotonin syndrome and wide-QRS tachycardia with seizures, respectively
Elavil (amitryptiline)
- tricycylic antidepressent (TCA)
- inhibits reuptake of serotonin and norepinephrine, increasing synaptic concentration
- highly effective in treatment of depression, but with many adverse effects
- onset of 2-4 weeks
- adverse effects include; sedation, anticholinergic effects, orthostatic hypotension, and cardiac dysrhythmia. OD may cause wide-QRS tachy. Prolonged use may lead to serotonin syndrome
serotonin syndrome, which may be caused by TCA, MAOI, SSRI, or SNRI antidepressents as well as other drugs, manifests as:
- flushing
- tremor and hyperreflexia
- diaphoresis
- hyperthermia
- agitation
- dilated pupils
- diarrhea
Because many antidepressants are biogenic amine analogues, they end their names in _____
-ine
ex: amitryptiline (TCA), fluoxetine (SSRI), sertraline (SSRI), venlafaxine (SNRI), selegiline (MAOI)
Prozac (fluoxetine)
- SSRI antidepressent
- selectively blocks reuptake of serotonin, increasing serotonin concentration in the synaptic cleft
- highly effective with a low rate of adverse effects (e.g. sedation, anticholinergic effects, ortho hypo, dysrhythmia)
- most common and first line drug in treatment of depression
Compare and contrast TCA and SNRI antidepressants
- both inhibit the reuptake of serotonin and norepinephrine
- SNRIs are much more selective for these two NTs, whereas TCAs have far more broad systemic effects, and therefore more adverse effects
Cymbalta (duloxetine)
- SNRI antidepressant
- Inhibits reuptake of Serotonin and Norep with few other NT interactions
- Used in treatment of affective and anxiety disorders
- Fewer adverse effects than TCAs
The major potential adverse effect of MAOIs is:
Hypertensive Crisis
Identify three common classifications of pain
Somatic, visceral, and neuropathic
Identify neurotransmitters that are important to the neurotransmission and modulation of pain
Substance P and glutamate are important in the ascending transmission of pain
Serotonin and norep are important in downregulation of the pain cascade
Enkephalins inhibit pain transmission and the release of substance P
The three common classifications of opioids based on efficacy are:
full agonists, partial agonists, and mixed agonists/antagonists
Common pharmacologic effects of opioids include:
- analgesia
- sedation
- euphoria/dysphoria
- miosis
- nausea/vomiting
- cough supression
- Constipation
- respiratory depression
- vasodilation and decreased HR
- pruritis and flushing
Describe the general mechanism of action of opioid analgesics
- primarily bind to mu-opioid receptors (along with delta and kappa) in the CNS and descending inhibitory pathways of pain
- opioid receptors are Gi GPCRs and their activation decreased cAMP and decreases Ca2+ transmission, leading to decreased activation of pain pathways
Give examples of common opioid full agonists, partial agonists, and mixed agonists/antagonists
- Full: Morphine, hydromorphone, fentanyl, meperidine, methadone, oxycodone
- Partial: Codeine, hydrocodone
- Mixed: Buprenorphine (with naloxone = suboxone)
Dilaudid (Hydromorphone)
- Strong, semi-synthetic opioid, full opioid agonist
- 10x potency relative to morphine with fewer CNS, GI, and CV effects than morphine
- powerful analgesic for acute and chronic pain
- adverse effects include sedation, respiratory depression, constipation, miosis, N/V
Morphine
- Strong, natural opioid, full opioid agonist
- considered the prototype opioid
- powerful analgesic for acute and chronic pain
- adverse effects include sedation, respiratory depression, constipation, miosis, N/V
- hydromorphone preferred for chronic pain management due to fewer adverse effects
describe benefits of morphine in MI management
- decreased pain and agitation due to analgesic and sedative effects
- vasodilation and negative chronotropy reduce myocardial workload and oxygen demand
Sublimaze (Fentanyl)
- Strong, synthetic opioid, full opioid agonist
- 100x potency relative to morphine with fewer CV effects, faster onset, and less hangover than morphine
- powerful analgesic for acute and chronic pain
- adverse effects include sedation, respiratory depression, constipation, miosis, N/V
Sufenta (Sufentanil)
- Strong, synthetic opioid, full opioid agonist
- 1000x potency relative to morphine with fewer CV effects, faster onset, and less hangover than morphine
- powerful analgesic for acute and chronic pain
- adverse effects include sedation, respiratory depression, constipation, miosis, N/V
Demerol (Meperidine)
- Strong synthetic full opioid analgesic
- 0.1X potency relative to Morphine
- Less smooth muscle effects less pronounced than with other opioids. Fewer GI, biliary, and uterine side effects
- Safer for pregnant patients, or those with cholecystitis
Dolophine (Methadone)
- Long-acting synthetic full opioid agonist
- Does not tend to produce euphoria or other reinforcing effects
- Used in management of chronic pain and in opioid addiction treatment
The 6 modes of brain function that neuropharmacological agents can act on are:
- Cognitive Processing
- Memory
- Emotional Processing
- Sensory Processing
- Motor Processing
- Autonomic Processing
