Sedative-Hypnotic Drugs

Sedative drug is the drug that reduce anxiety (anxiolytic) and produce sedation and referred to as minor tranquillisers. 

Hypnotic drug is the drug that induce sleep

Effects: make you sleepy; general CNS depressants

Uses: sedative-hypnotic (insomnia ), anxiolytic (anxiety, panic, obsessive compulsive, phobias), muscle relaxant (spasticity, dystonias), anticonvulsant (absence, status epilepticus, generalized seizures—rapid tolerance develops), others (pre-operative medication and endoscopic procedures,  withdrawal from chronic use of ethanol or other CNS depressants)

1- For panic disorder alprazolam is effective.

2- muscle disorder: (reduction of muscle tone and coordination) diazepam is useful in treatment of skeletal muscle spasm e.g. muscle strain and spasticity of degenerative muscle diseases.

3-epilepsy: by increasing seizure threshold.

Clonazepam is useful in chronic treatment of epilepsy while diazepam is drug of choice in status epilepticus.

4-sleep disorder: Three BDZs are effective hypnotic agents; long acting flurazepam, intermediate acting temazepam and short
acting triazolam. They decrease the time taken to get to sleep They increase the total duration of sleep

5-control of alcohol withdrawals symptoms include diazepam, chlordiazepoxide, clorazepate and oxazepam.

6-in anesthesia: as preanesthetic amnesic agent (also in cardioversion) and as a component of balanced anesthesia

Flurazepam significantly reduce both sleep induction time and numbers of awakenings and increase duration of sleep and little rebound insomnia. It may cause daytime sedation.

Temazepam useful in patients who experience frequent awakening, peak sedative effect occur 2-3 hr. after an oral dose.

Triazolam used to induce sleep in recurring insomnia and in individuals have difficulty in going to sleep, tolerance develop within few days and withdrawals result in rebound insomnia therefore the drug used intermittently.

Drugs and their actions

1. Benzodiazepines: enhance the effect of gamma aminobutyric acid (GABA) at GABA receptors on chloride channels. This increases chloride channel conductance in the brain (GABA A A receptors are ion channel receptors).

2. Barbiturates: enhance the effect of GABA on the chloride channel but also increase chloride channel conductance independently of GABA, especially at high doses 

3. Zolpidem and zaleplon: work in a similar manner to benzodiazepines but do so only at the benzodiazepine (BZ1) receptor type. (Both BZ1and BZ2 are located on chloride channels.)

4. Chloral hydrate: probably similar action to barbiturates.

5. Buspirone: partial agonist at a specific serotonin receptor (5-HT1A).

6. Other sedatives (e.g., mephenesin, meprobamate, methocarbamol, carisoprodol, cyclobenzaprine): 
mechanisms not well-described. Several mechanisms may be involved.

7. Baclofen: stimulates GABA linked to the G protein, Gi , resulting in an increase in K + conductance and a decrease in Ca²⁺ conductance. (Other drugs mentioned above do not bind to the GABA B receptor.) 

8. Antihistamines (e.g., diphenhydramine): block H1 histamine receptors. Doing so in the CNS leads to sedation.

9. Ethyl alcohol: its several actions include a likely effect on the chloride channel.

Eicosanoid compounds

Prostaglandines, Leukotriens and Thromboxanes.

They are produced in minute amounts by all cells except RBCs and they act locally at the same site of synthesis.
These agents have many physiological processes as mediators and modulators of inflammatory reactions.

Anti-Histamines:
 
The effect of histamine can be opposed in three ways:
1. Physiological antagonism: by using a drug to oppose the effect (e.g adrenaline). Histamine constricts bronchi,
causes vasodilatation which increases capillary permeability. Adrenaline opposes this effect by a mechanism unrelated to histamine.
2. By preventing histamine from reaching its site of action (receptors), By competition with H1-H2 receptors (Drug antagonisms).
3. By preventing the release of histamine. (adrenal steroids and sodium-cromoglycate can suppress the effect on the tissues)

Types of Anti-histamine drugs

Selected H1 antagonist drugs

First-generation H1 receptor antagonists:

Chlorpheniramine (Histadin) & Dexchlorpheniramine 
Diphenhydramine (Allermine)
Promethazine (Phenergan) -  strong CNS depressants
Cyproheptadine (Periactin)

ACTION
These drugs bind to both central and peripheral H1 receptors and can cause CNS depression or stimulation.

- They usually cause CNS depression (drowsiness,sedation) with usual therapeutic doses
- Cause CNS stimulation (anxiety, agitation) 
with excessive doses, especially in children. 
They also have Anticholinergic effects (e.g. dry mouth, urinary retention, constipation, blurred vision).

Second-generation H1 receptor antagonists (non-sedating) agents

Terfenadine
Fexofenadine
Loratadine
Acravistine and Cetirizine
Astemizol

Action

They cause less CNS epression because they are selective for peripheral H1 receptors and do not cross the blood brain barrier.

Indications for use

The drugs can relieve symptoms but don’t relieve hypersensitivity.

1) Allergic rhinitis. Some relief of sneezing, rhinorrhea, nasal airway obstruction and conjunctivitis are with the use of antihistamine.
2) Anaphylaxis. Antihistamine is helpful in treating urticaria and pruritus.
3) Allergic conjunctivitis. This condition, which is characterized by redness, itching and tearing of the eyes.
4) Drug allergies. Antihistamines may be given to prevent or treat reactions to drugs (e.g, before a dignostic test that
uses an iodine preparation).
5) Transfusions of blood and blood products.
6) Dermatologic conditions. Antihistamines are the drug of choice for treatment of allergic contact dermatitis and
acute Urticaria. Urticaria often occurs because the skin has many mast cells to release histamine.
7) Miscellaneous. Some antihistamines are commonly used for non-allergic disorder such as motion sickness, nausea, vomiting, sleep, cough or add to cough mixtures.

Contraindication

hypersensitivity to the drugs, narrow-angle glaucoma, prostatic hypertroph, stenosing peptic ulcer, bladder neck obstruction, during pregnancy and lactating women

Adverse effects:

Drowsiness and sedation
Anticholinergic
Some antihistamines may cause dizziness, fatigue, hypotention, headache, epigastric distress and photosensitivity
Serious adverse reaction including cardiac arrest & death, have been reported in patients receiving high dose astemizole

H2-receptor antagonists

 Cimetidine (Tagamate), Ranitidine (Zantac), Fomatidine, Nizatidine. 

Mechanism of action

Numerous factors influence acid secretion by the stomach, including food, physiological condition and drugs. H2 receptor blockers reduce basal acid-secretion by about 95% and food stimulated acid-secretion by about 70%. Both conc. and vol. of H ions will decrease.

Pharmacokinetics:
1) They are all well absorbed after oral dose.
2) Antacids decrease their absorption in about 10-20%

Uses
Cimetidine -  reduction of gastric secretion is beneficial, these are in main duodenal ulcer, benign gastric ulcer, stomach ulcer and reflux eosophagitis.

Rantidine -used as alternative for duodenal ulcer

Adverse effects:
headache, dizziness, constipation, diarrhoea, tiredness and muscular pain. 

On the basis of Receptors, drugs can be divided into four groups,

a. agonists

b. antagonists

c. agonist-antagonists

d. partial agonists

a. Agonist

morphine fentanyl pethidine

Action : activation of all receptor subclasses, though, with different affinities

b. Antagonist

Naloxone , Naltrexone

Action :  Devoid of activity at all receptor classes  

c. Partial Agonist: (Mixed Narcotic Agonists/Antagonists)

Pentazocine, Nalbuphine, Butorphanol , Buprenorphine

Action: activity at one or more, but not all receptor types

With regard to partial agonists, receptor theory states that drugs have two independent properties at receptor sites,

a. affinity

The ability, or avidity to bind to the receptor
Proportional to the association rate constant, Ka

b. efficacy

or, intrinsic activity, and is the ability of the D-R complex to initiate a pharmacological effect

Drugs that produce a less than maximal response and, therefore, have a low intrinsic activity are called partial agonists.

These drugs display certain pharmacological features,

a. the slope of the dose-response curve is less than that of a full agonist

b. the dose response curve exhibits a ceiling with the maximal response below that obtainable by a full agonist

c. partial agonists are able to antagonise the effects of large doses of full agonists

Classification

I) Esters

 1. Formed from an aromatic acid and an amino alcohol.

 2. Examples of ester type local anesthetics:

 Procaine

Chloroprocaine

Tetracaine

Cocaine

Benzocaine- topical applications only

2) Amides

 1. Formed from an aromatic amine and an amino acid.

 2. Examples of amide type local anesthetics:

Articaine

Mepivacaine

Bupivacaine

Prilocaine

Etidocaine

Ropivacaine

Lidocaine

Class I Sodium Channel Blockers 

• Block movement of sodium into cells of the cardiac conducting system
• Results in a stabilizing effect and decreased formation and conduction of electrical impulses 
• Have a local anesthetic effect
• Are declining in use due to proarrhythmic effects and increased mortality rates 

• Na channel blockers - Class 1 drugs are divided into 3 subgroups 
• 1A. 1B, 1C based on subtle differences in their mechanism of action. 
• Blockade of these channels will prevent depolarization. 
• Spread of action potential across myocardium will slow and areas of  pacemaker activity is suppressed.

Class IA Sodium Channel Blockers 

• Treatment of: symptomatic premature ventricular contractions, supraventricular tachycardia, and ventricular tachycardia, prevention of ventricular fibrillation
– Quinidine (Cardioquin, Quinaglute) 
– Procainamide (Pronestyl, Procanbid) 
– Disopyramide (Norpace) 

• Quinidine – prototype 
• Low therapeutic index
• High incidence of adverse effects 

Class IB Sodium Channel Blockers 

• Treatment of: symptomatic premature ventricular contractions and ventricular tachycardia, prevention of ventricular  fibrillation
– Lidocaine (Xylocaine) 
– Mexiletine (Mexitil) 
– Tocainide (Tonocard) 
– Phenytoin (Dilantin) 

Side Effects: Lidocaine 
• Drowsiness • Paresthesias  • Muscle twitching • Convulsions  • Changes in mental status (disorientation, confusion) • Hypersensitivity reactions (edema, uticaria, anaphylaxis) 

Side Effects: Phenytoin (Dilantin)
• Gingival hyperplasia 
• Nystagmus 
• Ataxia, slurring of speech 
• Tremors 
• Drowsiness 
• Confusion 

• Lidocaine – prototype 
• Must be given by injection 
• Used as a local anesthetic 
• Drug of choice for treating serious ventricular arrhythmias associated with acute myocardial infarction, cardiac surgery, cardiac catheterization and electrical conversion 

Class IC Sodium Channel Blockers
• Treatment of: life-threatening ventricular tachycardia or fibrillation and supraventricular tachycardia unresponsive to other  drugs 

– Flecainide 
– Propafenone 

Adverse Effects 
• CNS - dizziness, drowsiness, fatigue, twitching, mouth numbness, slurred speech vision changes, and tremors that can progress to convulsions.
• GI - changes in taste, nausea, and vomiting. CV - arrhythmias including heart blocks, hypotension, vasodilation, and potential for cardiac arrest. 
• Other Rash, hypersensitivity reactions loss of hair and potential bone marrow depression. 

Drug-Drug Interactions
• Increased risk for arrhythmias if combined with other drugs that are know to cause arrhythmias- digoxin and beta blockers 
• Increased risk of bleeding if combined with oral anticoagulants. 

Drug Food Interactions
• Quinidine needs an acidic urine for excretion. Increased levels lead to toxicity 
• Avoid foods that alkalinize the urine- citrus juices, vegetables, antacid, milk products