Anti-anxiety,Sedative - Hypnotics drugs and their effects

What is ANXIETY ?

• Anxiety is a state characterized by psychological symptoms, and often accompanied by physical symptoms.   
• The accompanying tension of anxiety is manifested by objective signs: fatigue, dizziness, vague pains, palpitations, headache, irritability, indigestion, etc.
• Anxiety may accompany physical illness, such as hypertension, asthma, irritable colon, peptic ulcer, etc. 
• Anxiety may be present in schizophrenics and depressed patients are frequently anxious.

Yerksen-Dodson Law

The Yerksen-Dodson law demonstrates an empirical relationship between arousal and performance. It dictates that performance increases with cognitive arousal, but only to a certain point: when levels of arousal become too high, performance will decrease. A corollary is that there is an optimal level of arousal for a given task. 
Classification of Anxiety

1.   Generalized anxiety
2.   Panic attack
3.   Phobia
4.   Obsessive compulsive disorder

 INSOMNIA
Insomnia is  characterized by a relative deficiency in the amount or quality of sleep: inability to induce sleep, inability to stay asleep, premature awakening, interrupted sleep, sleep that is not refreshing.

Sedative-Hypnotic-Anxiolytic Drugs
A. An anxiolytic drug reduces anxiety and makes the user feel more peaceful or tranquil. 
B. A sedative drug decreases activity, moderates excitement, and calms the     recipient. 
C. A hypnotic drug produces drowsiness and facilitates the onset and maintenance of a state of sleep that resembles natural sleep, and from which the patient can be easily aroused.

CNS depression: dose-response curve

BZs are not general CNS depressants! a general CNS depressant can cause any degree of depression, ranging from the slightest sedation to anesthesia, coma, and death. BZs will not cause anesthesia, and in fact have extensively replaced the barbiturates and other sedative hypnotics because they are much less likely to cause fatal CNS depression.

An ideal hypnotic drug should:
1. promote sleep quickly
2. alter the architecture and patterns of sleep only toward the norm
3. ensure a complete night's sleep
4. produce no residual daytime sedation
5. influence no other body system or drug action
6. have a wide margin of safety
7. be without danger of producing habituation, tolerance and dependence

Based on time Drugs Classification
First generation 
- Prior to 1864
Alcohol, Bromides, Chloral Hydrate, Opium
- Barbiturates (1864)
Purpose: Sedate and calm 
“Downers” – street-use name in  the 60s 
Phenobarbital still used to prevent seizures
- Others (no longer used)
Methaqualone (Quaaludes; 1960s) 
Meprobamate (1960s)

Second Generation 

1. Benzodiazepines (1950s)
2. Chlordiazepoxide (Librium; 1957) 
3. Diazepam (Valium; 1963) 
4. Flunitrazepam (Rohypnol; 1990s)

Third Generation 
Most prevalent by the 1990s
1-Zolpidem 
2-Zaleplon

Benzodiazepines

1,4-Benzodiazepine nucleus:
a benzene ring 
a seven-member heterocyclic 
two nitrogens
NOTE: Benzodiazepines are the most widely used anxiolytic-hypnotic drugs.  (benzene ring ,lateral chain)

CLASSIFICATION OF BDZs
Benzodiazepines can be divided into three groups
according  to the duration of drug action.

1. Long-acting: diazepam,flurazepam, nitroazepam
2. Intermediate-acting: chlordiazepoxide, oxazepam
3. Short-acting: triazolam

 Pharmacokinetics
In this dynamic process, lipophilicity plays a major role.

• Administration: orally or iv. injection. im. injection unreliable.  
• Absorption: small intestine. PPBR is high.
• Distribution: rapidly cross BBB and placenta; 
• Metabolism: in liver; 
• Elimination: excreted primarily in the urine ; renal tubular reabsorption, enterohepatic cycle
• Some however are metabolized to products which are active and may have a much longer half life than the parent drug. 
• The major route of metabolism is N-demethylation.  N-demethylation is inhibited by concurrent administration of the anti-ulcer drug Cimetidine. This will result in a prolonged duration of action.  
• The rate of N-demethylation is also diminished in the elderly, therefore the dose of BZs is lower in the elderly. 

Pharmacological effects and Clinical Uses 
CNS
- Anti-anxiety
- Sedation and Hypnosis
- Amnesic effect
- Anti-convulsion and anti-epilepsy
- Muscle relaxation
 Anti-anxiety
>Benzodiazepines show anti-anxiety at low doses with high potency (efficacy) and rapid onset. (without  producing sedation)
>Action site: the limbic system of the brain  (inhibiting the neuronal circuits)
> Therapeutic uses:  to treat anxiety 
   Diazepam: for continued state of anxiety
   Chlordiazepoxide: for intermittent severe anxiety.
 >BDZs are less subject to tolerance than the sedative and  hypnotic effects when used as anti-anxiety drugs.
 Sedation and Hypnosis

• ↓ Sleep latency
• ↓ Swakening frequency
• ↑ Sleep duration
• ↓ Stage 3 & 4 NREM sleep
• ↑ Stage 2 NREM sleep
• ↑ Total sleep time 
• ↓ REM sleep, but < older drugs

Clinical Uses
Rx: Insomnia 
Usually a short to medium acting benzodiazepine, administered orally. 
- BZs (lorazepam, triazolam, midazolam ) 
Day time sedation side effect 
REM sleep reduced; rebound / bizarre dreams

- Zolpidem & Zaleplon 
Less daytime sedation 
No effect on REM sleep. No dependence

Note: All hypnotics will lose efficacy if taken daily. Nightly use of sedative-hypnotics be limited to < 3 weeks.
  Hypnosis
Advantages (compare with BARBs) 

1. Greater dose margin 
2. Higher therapeutic index  (1000?)-less effects on respiratory and cardiovascular function. 
3. Large dosage not induce anesthesia 
4. No hepatic enzyme induction effect – less tolerance 
5. Withdrawal symptoms and rebound is small 

Disadvantages: (VS 3rd  generation drugs) 

1. Shorten the REM sleep – rebound 
2. Little tolerance and dependence

 Amnesic effect
- anterograde amnesia
- cognitive impairment
Rx: Preanesthetic and preoperative  administration               
- Preparation of patients for anesthesia, surgery, and other frightening or unpleasant medical and dental procedures and diagnostic tests (before using endoscope and cardioversion). 
- Midazolam is a frequently used, i.v.
why ? Because it;
* Reduce anesthetic doses,  diminish 
  side- effects
* Enhance the safety of anesthetics
* Forget unpleasant event during surgical
   procedures 
 Anti-convulsion and anti-epilepsy

• Depressant activity on the brain and spinal cord 
• Only inhibit  development and  spread of epileptiform activity 
• Selectivity anticonvulsant -- without CNS general depression

Mechanism: Enhancing GABA-mediated synaptic inhibition,controlling the development and spread of the abnormal neuronal firing to the adjacent normal brain areas. Clonazepam, nitrazepam, and diazepam are more selective in anti-convulsion.

RX: Convulsion: high doses 

1. Tetanus 
2. Eclampsia(delivery; in labor ) 
3. drug  intoxication 
4. fever (children) 

RX: Seizures: high doses 

• Grand mal and status epileptics 
• Diazepam: status epileptics (primary choice, iv)  
• Nitrazepam and clonazepam:  other types of epilepsy

NOTE: The long-acting drugs are commonly used for epileptics : clonazepam, diazepam  minor seizure;petit mal;PM

Muscle relaxation (centrally based) 
BDZs induce muscle hypotonia  and relax the spasticity of skeletal muscle without interfering with normal locomotion
Mechanism of muscle relaxation
Depress spinal cord polysynaptic reflexes ; decrease  internuncial transmission -at lower dosage 
Depress transmission at the skeletal neuromuscular junction -- high dosage  
muscle spasm (muscle strain) 
Clinical Uses

1. muscle rigidity
2. tetanus
3. Parkinson’s (stiff-man syndrome)
4. endoscopy, orthopedic manipulations

Diazepam:   i.v.
Note : the sedative and anxiolytic properties of the drug also promote relaxation and relieve tension

Summary 

• Therapeutic indications for BDZs include:
• Anxiety states associated with neurotic, phobic,and depressive disorders,or myocardial infarction;
• Insomnia; 
• Preanesthetic (preoperative) medication; 
• Epileptic seizures;
• Hypertonia of skeletal musculature (treatment for spasticity,rigidity).

 Mechanism of Action 
Benzodiazepines enhance GABAergic neurotransmission in all areas of the CNS. 

 BDZs receptors in brain: 
- spinal cord
- cuneate nucleus
- cerebellum
- brain stem
- hippocampus
- neocortex
BDZ-R exist parallel to GABAA 
The four types of receptors:
I) Receptor-operated channels
N-AchR, GABAA R, glycine R, EAA ionotropic R, 5-HT3 R
II) G protein-linked receptors
M-AchR, adrenoceptors, GABAB R
III) Receptors that are enzymes
insulin R, growth factors R
IV) DNA-linked receptors
steroid hormone R, thyroid hormone R

GABAA receptor is a GABA/Cl- ion channel complex. It consists of a pentamer of homologous subunits. The binding of GABA (?-GABA:Gamma-aminobutyric acid------GABA) to the receptor causes Cl- channel open, induces Cl-inflow and neuronal hyperpolarization. 

Mechanism of Action of BZs

• The mechanism of action of BZs is thought to be due to an allosteric effect on GABA-A receptors which facilitates or amplifies the inhibitory effect of endogenous CNS GABA. BZs do not directly activate GABA-A receptors and require endogenous GABA to express their effects. 
• BDZs potentiate the affinity of GABAA receptor for GABA, increase the frequency of the Cl--channel openning and cause neuronal hyperpolarization. 
• BDZs do not directly gate Cl--channel but require GABA to express their effects, i.e. BDZs produce no effects on Cl--channel  conductance in the absence of GABA.

Summary of MOA 

 Adverse effects and toxicities
 Inhibition of CNS    —  most  commonly 
> Hangover
    drowsiness, dizziness, headache, fatigue, weakness, poor concentration, motor incoordination, confusion
> Development of rebound insomnia
   Early morning awakening, next-day anxiety
   More pronounced with short-acting agents (triazolam)
> Anterograde amnesia
    cognitive impairment: decreased long-term recall and acquisition of new knowledge
 Dependence  and tolerance — less commonly 
Psychological and physical dependence and tolerance on BDZs can develop when drugs are given over a prolonged period. 
 Withdrawal syndrome: 

• anxiety
• tension
• agitation
• depression
• panic
• insomnia
• tremor
• myalgia
• paranoia
• convulsions and delirium
• Short-acting agents (triazolam) induce more abrupt and severe withdrawal reactions than long-acting agents do. 

Teretogenicity (fetal deformation)  
Prevention of benzodiazepine dependence
1.Recognize persons likely to become dependent, e.g. alcoholics and those with passive dependent personality traits
2.Avoid continuous, high dosage
3.Discourage regular consumption for long periods of time
4.Encourage flexible dosage up to an agreed maximum

Acute intoxication

• More likely in children or some patients; 
• BP and respiration are depressed; 
• nystagmus on lateral gaze; 
• tendon reflexes depressed; 
• Ataxia; confusion; coma; shock => Risk of Death (rare).

Treatment 
Drug overdose is treated with flumazenil 
Respiratory  function should be adequately supported and carefully monitored.

Benzodiazepine binding site ligands
1-Agonists (positive modulators)
benzodiazepines
2-Antagonists (null modulators)
flumazenil
3-Inverse agonists (negative modulators)
ß-carbolines
BDZs  ANTAGONIST——Flumazenil
Flumazenil rapidly reverses the effects of benzodiazepines.
Characteristics:

•  Rapid onset
•  The duration of action is short. The half-life is about 1hr.
•  Repeated intravenous administration is needed.
•  Induce withdrawal in dependent patients
•  Cause seizures when used to epileptic patients.
•  Clinic uses: BDZs detoxication, hepatic encephalopathy 
•  Side effects: dizziness, nausea, vomiting, anxiety.
•  No antagonistic action on barbiturates. 

  Drug interactions –  carefully 
 - BDZs enhanced depression when combined
       with other CNS depressants incl. alcohol. 
 -  oxidation impaired by cimetidine, estrogen,
        disulfiram, isoniazid, etc.      
Caution: 
potentially dangerous tasks  operating machinery or driver

BARBITURATES

• Long-acting: Barbital Phenobarbital
• Intermediate-acting: AmobarbitalPentobarbital
• Short-acting: Secobarbital
• Ultra-short-acting: Thiopental 

Pharmacokinetics
Potent inducers of hepatic enzymes – multiple drug interactions (major reason for tolerance)

Pharmacological effects 
CNS 
- Depression from mild sedation to  general anesthesia 
- Sedative and Hypnotic
- Anticonvulsive and antiepileptic (phenobarbital)
- Anesthetic (thiopental)

Note:Bariturates show CNS depression effect ranging from mild sedation  to general anesthesia in a dose-dependent fashion.   
obvious individual difference ;

• Decrease sleep latency, increase total sleep time, decrease the number of awakenings;
• Shorten the duration of REMS, cause non-natural sleep

 Clinical Uses 
Anticonvulsion and antiepilepsy
Phenobarbital is mainly used in grand mal epileptic seizures and status epileptics, recurrent febrile seizures for children. 
Anesthesia and pre-anesthesia
  Thiopental: intravenous anaesthesia, inducing  anaesthesia.
  Phenobarbital: pre-anesthesia.
  Long-, intermediate-acting drugs are used in pre-operation to preclude apprehensive emotion. 

Mechanism of action 
Enlarging GABA-induced Cl- currents by prolonging periods of individual Cl- channel opening (not frequency)
Reducing glutamate-induced depolarizations, inhibiting voltage-dependent Na+ , K+ channels at higher concentration
Depressing the reticular ascending activating system
Simulating the effect of GABA in the absence of GABA  (agonists at GABAA) .

MOA of BARBs

Difference between BDZs and Barbiturates
Barbiturates

1. No change in numbers of Cl－ channel opening, but prolonging  the duration of the channel opening
2. GABA independent

Benzodiazepines

1.  No change of duration, just increasing the frequency of Cl－ channel opening
2.  GABA dependent

Safety? Barbiturates and benzodiazepine

Barbiturates are general CNS depressants; ie as one increases the dose, one can cause any degree of CNS depression, from the mildest sedation through hypnosis, anesthesia, coma, and death.  
Thus, benzodiazepines possess a therapeutic margin considerably wider than that of barbiturates.
So ?
Benzodiazepines are the Drugs of Choice. Why ? Because;
1. Benzodiazepines  have a higher 
     therapeutic index
2. Slower development of tolerance
3. Lower incidence of physical dependence
4. Fewer drug interactions
5. Not respiratory depressants
6. They have few peripheral effects
NOTE: Since benzodiazepine intoxication may become life-threatening only when other central nervous depressants(ethanol) are taken simultaneously.

 Adverse effects
 Hangover Effect
   Drowsiness, fatigue, dizziness, diarrhea, impairment of judgment and fine motor skills, paradoxical excitement
 Tolerance / dependence:   > 4 weeks
   withdrawl syndromes: tremors, anxiety, weakness, restlessness, insomnia, nausea, vomiting, seizures, delirium
 Acquired hypersensitivity  
    urticaria, skin rash, dermatitis exfoliative
Toxicities

• Barbiturates have a relatively low therapeutic index .  As a rough rule of thumb, 10 therapeutic doses taken simultaneously will lead to a fatal outcome.
• Major cause of death is respiratory depression. 

First Aid
artificial respiration 
gastric lavage ， purgation ，transfusion, diuresis

Drug interactions

• Barbiturates induce the hepatic enzymes thus increase the metabolism of many endogenous compounds including steroids and hormones, and many other drugs as well as barbiturates.
• Ethanol potentiates the CNS depressant effects of barbiturates, as do some antihistamines, and MAO inhibitors.

MISCELLANEOUS SEDATIVE-HYPNOTIC DRUGS
Over the years, many drugs with diverse structures have been used for their sedative-hypnotic properties. 
Several of these are still marketed now     
        
Chloral hydrate
 > Effective sedative and hypnotic
 >  Shorten sleep latency 
 >  No hangover
 >  Do not shorten REM
 Disadvantage:
 > Irritation to the gastrointestinal tract 
 > Unusual, unpleasant taste
 > Because of rapidly developing tolerance, choral hydrate is suitable only for short-term use. 
 >  It has very limited uses now.

Zaleplon and Zolpidem 

• They are agonists act at the same receptor site as the BDZs (i.e; GABAA).  
• Their effects are blocked by flumazenil.
• Produce pure sedation (less anxiolytic, anticonvulsive or muscle relaxing effects) .
• They are used in the relief of sleep onset insomnia.  
• Although they act at the same site as the Bzs, their chemical structure does not resemble a benzodiazepine. 

Characteristics:
1. Both drugs have sustained hypnotic efficacy (i.e; little or no tolerance develops) without occurrence of rebound insomnia or withdrawal symptoms on abrupt discontinuation.  
2.  Zolpidem  has a longer duration of action and is more likely to cause residual morning side effects including sedation, delayed reaction time, and anterograde amnesia.  
3.  The toxicity of these agents is similar to that of the Bzs; ie they have a high therapeutic index unless combined with other CNS depressants & hypnotic doses can exaggerate the deleterious hypoxic and hypercarbic effects of obstructive sleep apnea. 
4.  Abuse potential appears to be the same as Bzs.

ADVANTAGES OF BENZODIAZEPINES VS OTHER SEDATIVE-HYPNOTICS

1. Clearly anti-anxiety at low doses.
2. Skeletal muscle relaxation effect
3. High therapeutic index （TI; more safe or not? ）
4. No induction of hepatic metabolizing enzymes
5. The rebound is slight after withdrawal.
6. Mild side effects, less tolerance and dependence

  Principles of treatment of insomnia
1-Insomnia is a symptom. It may well be a symptom without recognizable disease, but one should be alert to underlying causes that may require more specific treatment. These include pain (e.g., arthritis, dyspepsia),  dyspnea (left ventricular failure,  bronchospasm), high frequency of micturition, mood disorders, anxiety.
2-Common prescription drugs and over-the-counter medication known to cause insomnia include anti-hypertensives (clonidine, β-blockers), anticholinergics (ipratropium), CNS stimulants (methylphenidate), hormones (thyroid preparations, cortisone) sympathomimetic amines (bronchodilators), xanthine derivatives (caffeine, theophylline), decongestants in cough and cold preparations.
3-Treatment with hypnotics should be on short-term or intermittent basis.
4-Benzodiazepines and the newer benzodiazepine receptor agonists (e.g. zaleplon) should be considered to be hypnotic drugs of choice for most insomniacs; one or two standard drugs can manage majority of cases.
5-The smallest dose suitable for obtaining the desired effects should be used.
6-Hypnotic effect of drug should be exploited by association with habitual activities; habit alone may substitute for the drug or enhance its effect.
7-Sleep apnea syndrome, heavy use of alcohol, pregnancy and necessity of alert night time performance precludes the use of hypnotics.
8-Advanced age, heavy snoring, lung disease (preexisting respiratory failure in patients with severe pulmonary insufficiency can be aggravated by a usual dose of any hypnotic), liver disease, tendency of drug abuse, suicidal risk and special job requirements (pilot, driver) constitute relative contraindications of the use of hypnotics.

Study questions
Question 1:
Benzodiazepine’s mechanism of action is ?
 A. Directly open chloride channels.
 B. Directly inhibit CNS.
 C. Enhance the affinity of GABA receptor for GABA by  binding to benzodiazepines receptor. 
 D. Act at GABA receptor and increase inhibitory transmitter effects. 
Question 2:  How do benzodiazepines affect the action of GABA? 
Answer: Benzodiazepines enhance the ability of GABA to activate the GABA-A receptor. 
Question 3:  What ion channel is associated with the GABA-A receptor? 
Answer:  A chloride channel. 
Question 4:  What are some of the current clinical uses of benzodiazepines? 
Answer: Reducing anxiety, amnesia, muscle relaxants, epilepsy, and producing sedation before surgery.
Question 4: Which drugs, benzodiazepines or barbiturates, are considered safer? Why? 
Answer: Benzodiazepines are considered safer than barbiturates because they work at lower doses, thus producing less sedation, motor impairment and danger of overdose. In addition, tolerance to barbiturates develops quickly and many people become dependent on them.