Anx

ANXIOLYTIC

and

SEDATIVE-

HYPNOTIC DRUGS

Prof. Martínková 2006

Anxiolytic and sedative-hypnotic drugs

A sedative-hypnotic drug (terminology)

Sedation

can be definedas

a supression of responsiveness to a constant level of stimulation,

with decreased spontaneous activity and ideation.

Anxiolytic and hypnotic drugs

Ah y p n o t i c drug should produce drowsiness

and encourage the onset and maintenance of a state

of „sleep“ that as far as possible resembles

the natural state of sleep.

H y p n o t i ceffects involve more pronounced

depression of the CNS than s e d a t i o n,

and this can be achieved with most sedative drugs simply

by increasing the dose.


A n x i e t y

In anxiety states the fear response to threatening stimuli occur in an anticipatory manner independently of external events.

Among other the fear response includes defensive behaviours, autonomic reflexes, arousal and alertness, corticoid secretion and negative emotions.

An effective anxiolytic agent should reduce anxiety

and exert a calming effect - sedation - with

little or no effect on motor and menthal function.

Anxiolytic and hypnotic drugs (Fig 1)

Graded dose-dependent depression of the CNS function

is a characteristic of sedative-hypnotics. However, individual drugs differ in the relationship between the dose and the degree of CNS depression (see Fig 1). The linear slope for drug A is typical of many of the older sedative-hypnotics. With such drugs, an increarse in dose above that needed for hypnosis may lead to a state of general anesthesia. At still high doses, sedative-hypnotics may depress respiratory and vasomotor centres in the medulla, leading to coma and death.

Anxiolytic and hypnotic drugs (Fig 1)

Deviation from a linear dose-response relationship, as shown for drug B, will require proportionately greater dosage increments in order to achive CNS depression more profound than hypnosis.

This appears to be the case for most drugs of

the benzodiazepine class, and the greater margin of safety is an important reason for their clinical use to treat anxiety states and sleep disorders.


Anxiety disorders include:

- generalised anxiety disorder (an ongoing state

of excessive anxiety lacking any clear reason )

- panic disorder (attacks of overwhelming fear

occuring in association with somatic symptoms

(sweating, tachycardia, chest pain)

- phobias (strong fears of specific things or situation

(snakes, flying)

- postraumatic stress disorder (anxiety triggered

by insistent recall of past stressful experiences

Anxiolytic and hypnotic drugs In most developed countries anxiolytic drugs are among the most frequently prescribed drugs Classes: benzodiazepines newer drugs: 5 -HT1A -receptor agonists (buspiron) zolpidem, zaleplon miscellaneous other drugs older sedative-hypnotics

barbiturates (obsolete)

Anxiolytic and hypnotic drugs benzodiazepines Pharmacodynamics:(BZ) act selectively

o on gamma-aminobutyric acid A (GABAA) receptors,

oo

which mediate fast inhibitory synaptic transmission through the CNS. They bind specifically to a regulatory site of the receptor, distinct from the GABA binding site and act allosterically to increase the affinity of GABA for the receptors.

By facilitating the opening of GABA activated chloride-channels

BZenhancethe response to GABA.

The antagonist – f l u m a z e n i l


Fig 2:

A model of the GABAA receptor-chloride ion channel macromolecular complex.

The complex consists of five or more membrane-spanning subunits. GABA appears to interact with alpha or beta subunits triggering chloride channel opening with resultant membrane hyperpolarization.

Binding of BZs to gamma subunits facilitates the process of channel opening.

Anxiolytic and hypnotic drugs - benzodiazepines (BZ)

Pharmacokinetics:

absorption: well absorbed if given orally , Cmax reached in about 1 h binding:strongly bound to plasma proteins distribution: large Vd: accumulation in body fat (high lipid solubility) metabolism:(Fig 2): hydroxylation conjugation with glucuronic acid short-, medium- and long-acting BZ

the role of N-desmethyldiazepam


Fig.3

Anxiolytic and hypnotic drugs – benzodiazepines (BZ)

Fig.3 : demonstrates the short-acting drugs are those that are metabolised directly by conjugation

with glucuronide. gradual bild-up and slow disappearance of nordazepam from the plasma

gives long-acting drugs. RememberAGE: advancing age affects the rate of oxidative reactions more

than that of conjugation.

the effect of long-acting BZs tends to increase with age (drowsiness and confusion)


Pharmacological effects and uses: The main effects: reduction of anxiety and agression sedation and induction of sleep reduction of muscle tone and coordination anticonvulsant effects

anterograde amnesia

Anxiolytic and hypnotic drugs – benzodiazepine (BZ)

reduction of anxiety and agression Note: BZ may paradoxically produce an increase in irritability and aggression in some individuals (particularly if short- acting drugs are given (triazolam) sedation and induction of sleep BZs decreasethe timetaken to get to sleep

increase the total durationof sleep (only in subjects who normally sleep for less than about 6 hours each night)


REM sleep ( rapid eye movement) is less affected if compared with the same effect of other hypnotics.

Is that important? Yes, artificial interruption of REM sleep causes irritability and anxiety even if the total amount of sleep is not reduced).


reduction of muscle tone and coordination may be clinically useful: increased muscle tone is a common feature of

anxiety states and may contribute to pains (headache). Influence of manual skills (!)

anticonvulsant effects (GABAA receptors) clonazepam to treat epilepsy diazepam (i.v.) status epilepticusto control life-threatening seizures anterograde amnesia

BZs obliterate memoryof events experienced while under their influence


Unwanted effects acute overdosage effects occuring during normal therapeutic use

tolerance and dependence acute overdosage (BZs are relatively safe in overdose) BZs produce prolonged sleep, without serious depression of respiration or

cardiovascular function Severe even life-threatening respiratory depression may appear in BZ

combination with other CNS depressants, particularly alcohol.

Acute overdosage can be counteracted withflumazenil


unwanted effects occuring duringtherapeuticuse ---Influence of manual skills (such as driving performance) due to

drowsiness, confusion, amnesia and impaired coordination --- enhance of depressant action of other drugs (in a more than additive way) tolerance , dependence Tolerance (gradual escalation of dose needed to produce the required effect)

occurs with all BZs. T.appears to represent a change at the receptor level.

Dependence –In human subjects and patients, stopping BZ treatment after weeks and months causes an increase in symptoms of anxiety, together with tremor and dizziness.


The withdrawal syndrome: short acting BZs

cause more abrupt withdrawal effects

Addiction (-craving -severe psychological dependence) is not a major problem.

Anxiolytic and hypnotic drugs - 5 -HT1A -receptor agonists

newer drugs 5 -HT1A -receptor agonists Buspiron-anxiolytic effects take days or weeks to develop.That is the most

distinctive drug in terms of antianxiety actions, since these are achieved with minimal effects on psychomotor functions.

Unwanted effects appear to be less troublesome: dizziness, nauzea, headache,

not sedation or loss of coordination

Anxiolytic and hypnotic drugs –zoplidem, zaleplon Zolpidempharmacodynamics binds selectively to the BZ1 subtype of BZ receptors and facilitates GABA-mediated neuronal inhibition like the BZs, the actions of zolpidem are antagonised by f l u m a z e n i l minimal muscle relaxing and anticonvulsant effects the risk of development of tolerance and dependence with extended use is less than with the use of hypnotic BZs pharmacokinetics

rapidly metabolized to inactive metabolites by the liver, T1/2 1.5-3.5 h. Dosage reduction in hepatic dysfuction, elderly.

Anxiolytic and hypnotic drugs –zoplidem, zaleplon

Ind- short-term treatment of insomnia

Zaleplon

resembles zolpidem, t1/2 = 1h

Rapid onset and short duration of action are favorable properties for those patients who have difficulty falling asleep.

Anxiolytic and hypnoptic drugs – miscellaneous other drugs

miscellaneous other drugs-

older sedative-hypnotics:

meprobamate, glutethimide

rarely used

Anxiolytic and hypnotic drugs – barbiturates (BA) barbiturates (obsolete) BA: the sleep-inducing properties were discovered early in the 20th century . Until the 1960s, they formed the largest group of hypnotics and sedatives in clinical use. Pharmacodynamics:

BA share with BZs the ability to enhance the action of GABA, but they bind to a different site of the GABAA-receptor/chloride

channel- their action is less specific.

Anxiolytic and hypnotic drugs – barbiturates (BA) Disadvantage of use: if given in a large dose—death from respiratory and cardiovascular depression (flumazenil not effective) a high degree of tolerance: BA strongly induce the synthesis and activity of hepatic CYP450 and conjugating enzymes thus increasing the rate of metabolic degradation of many other drugs --- drug-drug interactions . dependence BA are now little used

as anxiolytic and hypnotic drugs

Anxiolytic and hypnotic drugs – barbiturates (BA) BA in practical use use as sedative and hypnotic agents is no longer recommended BAs are mainly used: in anaesthesia - thiopental (i.v.)

treatment of epilepsy - phenobarbital


Fig.1.

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