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Farmacologia Das Drogas Ansiolà Ticas
Farmacologia Das Drogas Ansiolà Ticas
Optimal Performance
Performance
Sedated
Nervous Breakdown
Anxiety
GA OL
Normal
_________ _________________
SEDATION (Drowsiness/decrease reaction time)
HYPNOSIS
Surgical Anesthesia
center COMA
DEATH
SEDATIVE/HYPNOTICS ANXIOLYTICS
Major therapeutic use is to relief anxiety (anxiolytics) or induce sleep (hypnotics). Hypnotic effects can be achieved with most anxiolytic drugs just by increasing the dose. The distinction between a "pathological" and "normal" state of anxiety is hard to draw, but in spite of, or despite of, this diagnostic vagueness, anxiolytics are among the most prescribed substances worldwide.
Manifestations of anxiety:
Verbal complaints. The patient says he/she is anxious, nervous, edgy. Somatic and autonomic effects. The patient is restless and agitated, has tachycardia, increased sweating, weeping and often gastrointestinal disorders. Social effects. Interference with normal productive activities.
Pathological Anxiety
Generalized anxiety disorder (GAD): People suffering from GAD have general symptoms of motor tension, autonomic hyperactivity, etc. for at least one month. Phobic anxiety: Simple phobias. Agoraphobia, fear of animals, etc. Social phobias. Panic disorders: Characterized by acute attacks of fear as compared to the chronic presentation of GAD. Obsessive-compulsive behaviors: These patients show repetitive ideas (obsessions) and behaviors (compulsions).
Causes of Anxiety
1). Medical: a) Respiratory b) Endocrine c) Cardiovascular d) Metabolic e) Neurologic.
Causes of Anxiety
2). Drug-Induced:
Stimulants Amphetamines, cocaine, TCAs, caffeine. Sympathomimetics Ephedrine, epinephrine, pseudoephedrine phenylpropanolamine. Anticholinergics\Antihistaminergics Trihexyphenidyl, benztropine, meperidine diphenhydramine, oxybutinin. Dopaminergics Amantadine, bromocriptine, L-Dopa, carbid/levodopa.
Causes of Anxiety
Miscellaneous: Baclofen, cycloserine, hallucinogens, indomethacin.
Anxiolytics
Anxiolytics
1) Benzodiazepines (BZDs). 2) Barbiturates (BARBs). 3) 5-HT1A receptor agonists. 4) 5-HT2A , 5-HT2C & 5-HT3 receptor antagonists.
If ANS symptoms are prominent: -Adrenoreceptor antagonists. 2-AR agonists (clonidine).
Anxiolytics
Other Drugs with anxiolytic activity. TCAs (Fluvoxamine). Used for Obsessive compulsive Disorder. MAOIs. Used in panic attacks. Antihistaminic agents. Present in over the counter medications. Antipsychotics (Ziprasidone). Novel drugs. (Most of these are still on clinical trials). CCKB (e.g. CCK4). EAA's/NMDA (e.g. HA966).
Sedative/Hypnotics
A hypnotic should produce, as much as possible, a state of sleep that resembles normal sleep.
Sedative/Hypnosis
By definition all sedative/hypnotics will induce sleep at high doses. Normal sleep consists of distinct stages, based on three physiologic measures: electroencephalogram, electromyogram, electronystagmogram. Two distinct phases are distinguished which occur cyclically over 90 min:
1) Non-rapid eye movement (NREM). 70-75% of total sleep. 4 stages. Most sleep stage 2. 2) Rapid eye movement (REM). Recalled dreams.
Other Properties of Sedative/Hypnotics Some sedative/hypnotics will depress the CNS to stage III of anesthesia. Due to their fast onset of action and short duration, barbiturates such as thiopental and methohexital are used as adjuncts in general anesthesia.
Sedative/Hypnotics
1) Benzodiazepines (BZDs):
2) 3)
4) 5)
Alprazolam, diazepam, oxacepam, triazolam Barbiturates: Pentobarbital, phenobarbital Alcohols: Ethanol, chloral hydrate, paraldehyde, trichloroethanol, Imidazopyridine Derivatives: Zolpidem Pyrazolopyrimidine Zaleplon
Sedative/Hypnotics
6) Propanediol carbamates: Meprobamate 7) Piperidinediones Glutethimide 8) Azaspirodecanedione Buspirone 9) -Blockers** Propranolol 10) 2-AR partial agonist** Clonidine
Sedative/Hypnotics
Others:
11) Antyipsychotics ** Ziprasidone 12) Antidepressants **
TCAs, SSRIs
Sedative/Hypnotics
All of the anxiolytics/sedative/hypnotics should be used only for symptomatic relief. ************* All the drugs used alter the normal sleep cycle and should be administered only for days or weeks, never for months. ************
Sedative/Hypnotics
Relationship between Older vs Newer Drugs
SEDATIVE/HYPNOTICS ANXYOLITICS
B E N Z O D I A ZB EA PR I BN I ET U S R
GABAergic SYSTEM
Sedative/Hypnotics
The benzodiazepines are the most important sedative hypnotics. Developed to avoid undesirable effects of barbiturates (abuse liability).
Benzodiazepines
Diazepam Chlordiazepoxide Triazolam Lorazepam Alprazolam Clorazepate => nordiazepam Halazepam Clonazepam Oxazepam Prazepam
Barbiturates
Phenobarbital Pentobarbital Amobarbital Mephobarbital Secobarbital Aprobarbital
NORMAL
HYPNOSIS
RS OS E P NE
Ax ta ia EO TH S d tio ea n
A tic n u a t n o v ls n A x ly n io tic
DS OE
RS OS E P NE
Ax ta ia S d tio ea n
A tic n u a t n o v ls n A x ly n io tic
DS OE
GABAergic SYNAPSE
g cs lu o e
g ta a lu mte GB AA GD A
C l
GABA-A Receptor
BZ Ds
BRs AB
GABA AGONISTS
Oligomeric ( ) glyc oprotein. Major player in Inhibitory Synapses. It is a Cl- Channel. Binding of GABA causes the channel to open and Cl- to flow into the cell with the resultant membrane hyperpolarization.
Mechanisms of Action
1) Enhance GABAergic Transmission
frequency of openings of GABAergic channels. Benzodiazepines opening time of GABAergic channels. Barbiturates receptor affinity for GABA. BDZs and BARBS
F mK tz n e a 1 9 ro a u g t l., 9 6
Benzodiazepines
PHARMACOLOGY BDZs potentiate GABAergic inhibition at all levels of the neuraxis. BDZs cause more frequent openings of the GABA-Clchannel via membrane hyperpolarization, and increased receptor affinity for GABA. BDZs act on BZ1 ( 1 and 2 subunit-containing) and BZ2 ( 5 subunit-containing) receptors. May cause euphoria, impaired judgement, loss of cell control and anterograde amnesic effects.
Pharmacokinetics of Benzodiazepines
Although BDZs are highly protein bound (60-95%), few clinically significant interactions.* High lipid solubility high rate of entry into CNS rapid onset.
*The only exception is chloral hydrate and warfarin
Lipid solubility
Pharmacokinetics of Benzodiazepines
Hepatic metabolism. Almost all BDZs undergo microsomal oxidation (Ndealkylation and aliphatic hydroxylation) and conjugation (to glucoronides). Rapid tissue redistribution long acting long half lives and elimination half lives (from 10 to > 100 hrs). All BDZs cross the placenta detectable in breast milk may exert depressant effects on the CNS of the lactating infant.
Pharmacokinetics of Benzodiazepines
Many have active metabolites with halflives greater than the parent drug. Prototype drug is diazepam (Valium), which has active metabolites (desmethyldiazepam and oxazepam) and is long acting (t = 20-80 hr). Differing times of onset and elimination half-lives (long half-life => daytime sedation).
Biotransformation of Benzodiazepines
F mK tz n , 1 9 ro a u g 9 8
Biotransformation of Benzodiazepines
Keep in mind that with formation of active metabolites, the kinetics of the parent drug may not reflect the time course of the pharmacological effect. Estazolam, oxazepam, and lorazepam, which are directly metabolized to glucoronides have the least residual (drowsiness) effects. All of these drugs and their metabolites are excreted in urine.
Properties of Benzodiazepines
BDZs have a wide margin of safety if used for short periods. Prolonged use may cause dependence. BDZs have little effect on respiratory or cardiovascular function compared to BARBS and other sedative-hypnotics. BDZs depress the turnover rates of norepinephrine (NE), dopamine (DA) and serotonin (5-HT) in various brain nuclei.
Sedative/Hypnotics
They produce a pronounce, graded, dose-dependent depression of the central nervous system.
Pharmacokinetics of Barbiturates Rapid absorption following oral administration. Rapid onset of central effects. Extensively metabolized in liver (except phenobarbital), however, there are no active metabolites. Phenobarbital is excreted unchanged. Its excretion can be increased by alkalinization of the urine.
Pharmacokinetics of Barbiturates
In the elderly and in those with limited hepatic function, dosages should be reduced. Phenobarbital and meprobamate cause autometabolism by induction of liver enzymes.
Properties of Barbiturates
Mechanism of Action. They increase the duration of GABA-gated channel openings. At high concentrations may be GABAmimetic. Less selective than BDZs, they also: Depress actions of excitatory neurotransmitters. Exert nonsynaptic membrane effects.
Toxicity/Overdose
Strong physiological dependence may develop upon long-term use. Depression of the medullary respiratory centers is the usual cause of death of sedative/hypnotic overdose. Also loss of brainstem vasomotor control and myocardial depression.
Toxicity/Overdose
Withdrawal is characterized by increase anxiety, insomnia, CNS excitability and convulsions. Drugs with long-half lives have mildest withdrawal (. Drugs with quick onset of action are most abused. No medication against overdose with BARBs. Contraindicated in patients with porphyria.
Sedative/Hypnotics
Tolerance and excessive rebound occur in response to barbiturate hypnotics.
C NR L OT O
W H R WL IT D A A
S E PP RN H L E E IG T
(% )
RM E N E III a dIV RM n
1 2 3
N T SO D U D S G IGH F R G O IN
Miscellaneous Drugs
Buspirone Chloral hydrate Hydroxyzine Meprobamate (Similar to BARBS) Zolpidem (BZ1 selective) Zaleplon (BZ1 selective)
BUSPIRONE
Most selective anxiolytic currently available. The anxiolytic effect of this drug takes several weeks to develop => used for GAD. Buspirone does not have sedative effects and does not potentiate CNS depressants. Has a relatively high margin of safety, few side effects and does not appear to be associated with drug dependence. No rebound anxiety or signs of withdrawal when discontinued.
BUSPIRONE
Side effects: Tachycardia, palpitations, nervousness, GI distress and paresthesias may occur. Causes a dose-dependent pupillary constriction.
BUSPIRONE
Mechanism of Action: Acts as a partial agonist at the 5-HT1A receptor presynaptically inhibiting serotonin release. The metabolite 1-PP has 2 -AR blocking action.
Pharmacokinetics of BUSPIRONE
Not effective in panic disorders. Rapidly absorbed orally. Undergoes extensive hepatic metabolism (hydroxylation and dealkylation) to form several active metabolites (e.g. 1-(2pyrimidyl-piperazine, 1-PP) Well tolerated by elderly, but may have slow clearance.
Analogs: Ipsapirone, gepirone, tandospirone.
Zolpidem
Structurally unrelated but as effective as BDZs. Minimal muscle relaxing and anticonvulsant effect. Rapidly metabolized by liver enzymes into inactive metabolites. Dosage should be reduced in patients with hepatic dysfunction, the elderly and patients taking cimetidine.
Properties of Zolpidem
Mechanism of Action:
Binds selectively to BZ1 receptors. Facilitates inhibition. GABA-mediated neuronal
GB AA
(-) (-) (-) (-) (-)
N E D A 5T -H Ah C
AT OV L AT N IC N U S N /
S D T N? E A IO
AX LT ? N IOY IC
OTHER USES
1. Generalized Anxiety Disorder Diazepam, lorazepam, alprazolam, buspirone 2. Phobic Anxiety a. Simple phobia. BDZs b. Social phobia. BDZs 3. Panic Disorders
TCAs and MAOIs, alprazolam
ANXYOLITICS
Alprazolam Chlordiazepoxide Buspirone Diazepam Lorazepam Oxazepam Triazolam Phenobarbital Halazepam Prazepam
HYPNOTICS
Chloral hydrate Estazolam Flurazepam Pentobarbital Lorazepam Quazepam Triazolam Secobarbital Temazepam Zolpidem
References:
Katzung, B.G. (2001) Basic and Clinical Pharmacology. 7th ed. Appleton and Lange. Stamford, CT. Brody, T.M., Larner,J., and Minneman, K.P. (1998) Human Pharmacology: Molecular to Clinical. 2nd ed. Mosby-Year Book Inc. St. Louis, Missouri. Rang, H.P. et al. (1995) Pharmacology . Churchill Livingston. NY., N.Y. Harman, J.G. et al. (1996) Goodman and Gilman's The Pharmacological Basis of Therapeutics. 9th ed. McGraw Hill.