Anti-Anxiety Agents Flashcards
1
Q
Sedatives and Hypnotics
A
- an effective sedative (anxiolytic) agent should reduce anxiety and exert a calming effect
- hypnotic (sleep-promoting) effects require more pronounced CNS depression than sedation and can be achieved with many anxiolytic drugs just by increasing the dose
2
Q
Graded Dose-Dependent CNS Depression
A
- characteristic of most sedative-hypnotics
- BRs exhibit linear dose-response relationships and can thus induce anesthesia and coma at higher than hypnotic doses
- BZs and some of the newer hypnotics (like zolpidem and zaleplon) exhibit flatter non-linear dose-response relationships
- therefore, BZs safer than BRs
3
Q
- benzodiazepine
- high doses depress the CNS to the point known as stage III general anesthesia
- intermediate acting
- sufficiently selective to exert anticonvulsant effects without marked CNS depression
- clinically useful in the management of seizures
- used for panic disorder
- parenteral formulation is used to suppress delirium tremens
A
Lorazepam
4
Q
- benzodiazepine
- sufficiently selective to exert anticonvulsant effects without marked CNS depression
- clinically useful in the management of seizures
- used for GAD and social phobia
A
Clonazepam
5
Q
- benzodiazepine
- long acting
A
Chlordiazepoxide
6
Q
- benzodiazepine
- short acting
A
Oxazepam
7
Q
- benzodiazepine
- long acting
A
Clorazepate
8
Q
- benzodiazepine
- long acting
- prototypical BZ, with most other BZs being structurally related
- -high doses depress the CNS to the point known as stage III general anesthesia
- sufficiently selective to exert anticonvulsant effects without marked CNS depression
- clinically useful in the management of seizures
- muscle relaxation
- withdrawal from physiologic dependence on ethanol or other sedative-hypnotics
A
Diazepam
9
Q
- benzodiazepine
- used for GAD, panic disorder, and agoraphobia
- short acting
A
Alprazolam
10
Q
- benzodiazepine
- has short half-life and used to sedate you and then quickly go away
- short acting
- high doses depress the CNS to the point known as stage III general anesthesia
- sedative and possible amnesic effects during medical or surgical procedures and premedication prior to anesthesia
A
Midazolam
11
Q
- newer anxiolytic
- safe
- track record is not as long, but has been around for a long time and is looking very good
- selective anxiolytic effects w/o causing marked sedative, hypnotic, or euphoric effects
- thought to exert its anxiolytic effects by acting as a partial agonist at brain 5-HT1A receptors, though it also has affinity for brain dopamine D2 receptors
- does not interact directly with GABAergic systems
- patients treated with this drug show no rebound anxiety or withdrawal signs on abrupt discontinuance
- not effective in blocking the acute withdrawal syndrome resulting from abrupt cessation of the use of BZs
- used in generalized anxiety states, but is less effective in panic disorders
- unlike the BZs, the anxiolytic effects of this drug may take > 1 week to become established, making the drug unsuitable for acute anxiety states
- rapidly absorbed after PO admin.
- t1/2 = 2-4 hrs and liver dysfunction may slow its clearance
- inhibitors of CYP3A4 can markedly inc. the plasma level
- causes less psychomotor impairment than BZs and does not affect driving skills
A
Buspirone
12
Q
- beta-blocker
- do not reduce anxiety per se, but they do reduce the associated sxs
A
Propranolol
13
Q
- beta-blocker
- do not reduce anxiety per se, but they do reduce the associated sxs
A
Atenolol
14
Q
Pharmacokinetics of BZs (Absorption and Distribution)
A
- PO absorption rates of the BZs depend on lipophilicity
- increased lipophilicity leads to increased absorption in blood
- lipophilicity is major determinant of the rate at which a given BZ enters the CNS
- the BZs cross the placental barrier during pregnancy and may contribute to the depression of neonatal vital functions when administered pre-delivery
- also detectable in breast milk and may exert depressant effects in the nursing infant
15
Q
Pharmacokinetics of BZs (Metabolism)
A
- metabolic transformation to water-soluble metabolites is critical for clearance from body
- elimination half-life of the drugs depends mainly on the rate of metabolic transformation
- most BZs undergo phase I oxidative rxns catalyzed by CYP enzymes
- resulting metabolites then undergo phase II conjugation reactions to form glucoronides that are excreted in urine
- fortunately, drugs are metabolized heavily
16
Q
Metabolites of BZs and desmethyldiazepam (nordiazepam)
A
- note that many phase I metabolites of BZs are pharmacologically active, some with long half-lives
- desmethyldiazepam (nordiazepam), which has a half-life of >40 hrs is an active metabolite of chlordiazepoxide, diazepam, and clorazepate
- therefore, drugs can have accumulative effects, especially in the elderly
17
Q
Half-lives and Peak Concentration of BZs
A
- most have long half-lives due to long-lasting metabolites
- only one that has very shor thalf-live (1-7 hrs) is midazolam
- midazolam has short half-life and used to sedate you and then quickly go away
- drugs reach peak hours in only a couple hours, so effects come on quick, but then they last long
- dose sparingly and don’t take them frequently
- BZs for which parent drug or its active metabolites have long t1/2’s are more likely to cause cumulative effects (e.g. increased drowsiness) with multiple doses
18
Q
Pharmacokinetics of BZs: Factors Affecting Biodisposition
A
- disease or drug induced increases or decreases in hepatic function
- age: clearance is generally reduced in elderly
- long-term exposure to BZs does not alter hepatic drug metabolizing enzyme activity (in contrast to some older sedatives like the barbiturates)
19
Q
Pharmacodynamics of BZs
A
- bind to the molecular components of the GABAa receptor in neuronal membranes in the CNS
- this receptor functions as Cl- ion channel
- GABAa receptor is a heteropentameric glycoprotein assembled from 5 subunits
- GABA interacts between alpha and beta subunits, triggering Cl- ion channel opening with resulting membrane hyperpolarization
- BZs potentiate the Cl- ion channel effects of GABA, as well as GABAergic inhibition at all levels of the neuraxis
- this potentiation take sthe form of an increase in FREQUENCY of GABA-gated channel opening events
20
Q
BZ Organ Level Effects: Sedation
A
- at low doses, BZs exert calming effects and dec. anxiety
- anxiolytic actions are accompanied by some depressant effects on psychomotor and cognitive fxns
- at doses used to manage anxiety, BZs can cause disinhibitory effects like euphoria, impaired judgment, and loss of self-control
- BZs can also exert dose-dependent anterograde amnestic effects (inability to remember events occurring during the drug’s duration of action)
21
Q
BZ Organ Level Effects: Hypnosis
A
Promotion of Sleep
22
Q
BZ Organ Level Effects: Anesthesia
A
- high doses of certain BZs (e.g. diazepam, lorazepam, midazolam) depress the CNS to the point known as stage III general anesthesia
- these BZs are used IV in anesthesia, often in combination with other agents
- when used as adjuncts to general anesthesia, the BZs can contribute to persistent (although reversible) post-anesthetic respiratory depression
23
Q
BZ Organ Level Effects: Anticonvulsant Effects
A
- several BZs (clonazepam, lorazepam, and diazepam) are sufficiently selective to exert anticonvulsant effects without marked CNS depression
- such BZs are clinically useful in the management of seizures
24
Q
BZ Organ Level Effects: Muscle Relaxation
A
- the BZs (e.g. diazepam) exert inhibitory effects on polysynaptic reflexes and internuncial transmission
- at high doses, BZs can also depress transmission at the skeletal neuromuscular junction
- these collective actions lead to muscle relaxation and have proven useful for relaxing contracted voluntary muscle in muscle spasm
25
Q
BZ Organ Level Effects: Respiratory Depression
A
- at hypnotic doses in health pts, BZs have a comparable effect on respiration to changes that occur during natural sleep
- however, even at therapeutic doses, these agents can produce significant respiratory depression in pts with pulmonary disease
26
Q
BZ Organ Level Effects: Cardiovascular Depression
A
- at doses up to those causing hypnosis, no significant effects on the cardiovascular system are observed in healthy people
- however, normal doses can cause cardiovascular depression in hypovolemic states, heart failure, and other diseases that impair cardiovascular fxn
- at toxic doses, myocardial contractility and vascular tone may both be depressed leading to circulatory collpase
- cardiovascular (and respiratory) effects are more pronounced when the BZs are administered IV
27
Q
BZs and Treatment of Anxiety
A
- anxiety is often secondary to organic disease states (ulcers, acute MI, etc.) or unpleasant situations
- even though situational anxiety tends to be self-limiting, the short-term use of sedatives may be appropriate for the txt of such anxiety states
- excessive or unreasonable anxiety about life circumstances (GAD), panic disorders, and agoraphobia are also amenable to drug therapy
- BZs widely used for the management of acute anxiety states and for rapid control of panic attacks
- also used (though less commonly) in long-term management of GAD and panic disorders
28
Q
Advantages of BZs in Anxiety Treatment
A
- rapid onset of action
- relatively high therapeutic index and availability of flumazenil for treatment of overdose
- low risk of drug interactions based on liver enzyme induction
- minimal effects on cardiovascular and autonomic functions
29
Q
Disadvantages of BZs in Anxiety Treatment
A
- risk of dependence (both physiologically and psychologically)
- depression of CNS fxns (additive when administered with other drugs, including antihistamines, anticholinergics, and ethanol)
- amnesic effects
30
Q
Treatment of Anxiety Dosing Considerations
A
- a dose should be prescribed that does not impair mentation or motor fxns during waking hrs
- prescriptions should be written for short periods, since there is little justification for long-term therapy
- b/c the elderly are more sensitive to the effects of BZs, doses 1/2 those used in younger adults are safer and usually effective
- combinations w/ other anti-anxiety agents, antihistamines, anticholinergies, and ethanol should be avoided
31
Q
BZs: Other Therapeutic Uses
A
- sedative and possible amnesic effects during medical or surgical procedures and premedication prior to anesthesia (use PO formulations of shorter-acting drugs like midazolam)
- withdrawal from physiologic dependence on ethanol or other sedative-hypnotics (use longer-acting drugs (e.g. diazepam) administered in progressively decreasing doses)
- parenteral lorazepam is used to suppress delirium tremens
- used as central muscle relaxants, though generally with some degree of accompanying sedation
32
Q
BZs: Direct Toxic Actions
A
- at low doses, BZs can lead to drowsiness, impaired judgment, and diminished motor skills (sometimes with significant impact on driving ability, job performance, and personal relationships)
- can cause significant dose-related anterograde amnesia and can significantly impair ability to learn new information
- overuse is a common cause of confusional states in the elderly
- at high doses, toxicity can present as lethargy or a state of exhaustion or, alternatively, as gross sxs of ethanol intoxication (i.e. behavioral disinhibition)
33
Q
BZs: Tolerance, Psychologic Dependence, and Physiologic Dependence
A
- can result from extended use of BZs (see sleep note cards)
- after prolonged use, abrupt cessation can precipitate withdrawal sxs (characterized by states of increased anxiety, insomnia, and CNS excitability that my progress to convulsions)
- BZs with short half-lives cause more severe withdrawal signs than those with longer half-lives, which are eliminated slowly and achieve gradual withdrawal
- doses should be tapered slowly to avoid withdrawal sxs
34
Q
BZs: Overdoses
A
- sedative-hypnotics are the drugs most frequently involved in deliberate overdoses
- BZs are considered to be safer in this respect, since they have flatter dose-response curves
- even following ingestion of very high doses, the outcome is rarely fatal if discovery is made early and a conservative txt regimen is started
- with severe toxicity, respiratory depression can be complicated by aspiration of gastric contents (an even more likely occurrence if ethanol is present)
- txt consists of ensuring a patent airway (with a ventilator if necessary) and maintenance of plasma volume, renal output, and cardiac fxn
35
Q
- synthetic BZ derivative that binds to the BZ site on the GABAa receptor
- antagonizes the actions of the BZs and the newer hypnotics zolpidem, zaleplon, and eszopiclone, but not the barbiturates
- approved for use in reversing the CNS depressant effects of BZ overdose and hastens recovery after BZ use in medical procedures
- when given IV, it acts rapidly, but has a short t1/2 (0.7-1.3 hrs)
- because all BZs have a longer duration of action, sedation commonly recurs, requiring repeated administration of this antagonist
A
Flumazenil
36
Q
Adverse Rxns of Buspirone
A
- nonspecific chest pain, tachycardia, palpitations, dizziness, nervousness, tinnitus, GI distress, and paresthesias
- these adverse effects are extremely rare
- buspirone should not be taken in combination with MAO inhibitors, as significant elevations in blood pressure can result
37
Q
Beta-Blockers
A
- typically used to treat heart conditions and high BP
- they are also used in an off-label application to control the physical sxs of anxiety (i.e. trembling, sweating)
- taken for a short period of time, these agents can help individuals keep physical sxs under control during stressful situations (e.g. when a person with social phobia has to give a speech or attend a meeting)
38
Q
Triazolam
A
short acting BZ
