Nitrous Oxide (N2O)

MAC 100%, blood/gas solubility ratio 0.47
- An inorganic gas., low solubility in blood, but greater solubility than N2
- Inflammable, but does support combustion.
- Excreted primarily unchanged through the lungs.
- It provides amnesia and analgesia when administered alone.
- Does not produce muscular relaxation.
- Less depressant to both the cardiovascular system and respiratory system than most of the other inhalational anesthetics.
- Lack of potency and tendency to produce anoxia are its primary limitations.
- The major benefit of nitrous oxide is its ability to reduce the amount of the secondary anesthetic agent that is necessary to reach a specified level of anesthesia.

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.

Buspirone

1. Short half-life (2–4 hours).
2. Relieves anxiety.
3. Does not act as an anticonvulsant.
4. Is not a good muscle relaxant.
5. Minimum abuse potential.

Sympatholytics (Antiadrenergic Agents)

PHENOXYBENZAMINE
It is a potent alpha-adrenergic blocking agent 

It effectively prevents the responses mediated by alpha receptors and diastolic blood pressure tends to decrease.
It interferes with the reflex adjustment of blood pressure and produces postural hypotension. 
It increases the cardiac output and decreases the total peripheral resistance.

It is used in the management of pheochromocytoma and also to treat peripheral vasospastic conditions e.g. Raynaud’s disease and shock syndrome.

Phentolamine, another alpha blocker is exclusively used for the diagnosis of pheochromocytoma and for the prevention of abrupt rise in blood pressure during surgical removal of adrenal medulla tumors.

ERGOT ALKALOIDS

 Ergotamine is an  important alkaloid that possesses both vasoconstrictor and alpha-receptor blocking activity. Both ergotamine and dihydroergotamine are used in the treatment of migraine.

METHYSERGIDE

It is a 5-hydroxytryptamine antagonist ). It is effective in preventing an attack of migraine. 

SUMATRIPTAN

It is a potent selective 5-HT 1D  receptor agonist used in the treatment of migraine.

PRAZOSIN
It is an piperazinyl quinazoline effective in the management of hypertension. It is highly selective for α1  receptors. It also reduces the venous return and cardiac output. It is used in essential hypertension, benign prostatic hypertrophy and in Raynaud’s syndrome.
Prazosin lowers blood pressure in human beings by relaxing both veins and resistance vessels but it dilates arterioles more than veins.

TERAZOSIN
It is similar to prazosin but has higher bioavailability and longer plasma t½

DOXAZOSIN
It is another potent and selective α1 adrenoceptor antagonist and quinazoline derivative.
It’s antihypertensive effect is produced by a reduction in smooth muscle tone of peripheral vascular beds.

TAMSULOSIN
It is uroselective α1A  blocker and has been found effective in improving BPH symptoms.

Other drugs used for erectile dysfunction

Sildenafil: It is orally active selective inhibitor of phosphodiesterase type 5 useful in treatment of erectile dysfunction.

CARDIAC GLYCOSIDES

Cardiac glycosides (Digitalis)

Digoxin

Digitoxin

Sympathomimetics

Dobutamine

Dopamine

Vasodilators

α-blockers (prazosin)

Nitroprusside

ACE-inhibitors (captopril)

Pharmacology of Cardiac Glycosides

1. Positive inotropic effect (as a result of increase  C.O., the symptoms of CHF subside).

2. Effects on other cardiac parameters

1) Excitability

2) Conduction Velocity; slightly increased in atria & ventricle/significantly

reduced in conducting tissue esp. A-V node and His-Purkinje System

3) Refractory Period; slightly ^ in atria & nodal tissue/slightly v in ventricles

4) Automaticity; can be greatly augmented - of particular concern in ventricle

3. Heart Rate

-Decrease due to 1) vagal stimulation and 2) in the situation of CHF, due to improved hemodynamics

4 Blood Pressure

-In CHF, not of much consequence. Changes are generally secondary to improved cardiac performance.

-In the absence of CHF, some evidence for a direct increase  in PVR due to vasoconstriction.

5. Diuresis

-Due primarily to increase in  renal blood flow as a consequence of positive inotropic effect (increase CO etc.) Possibly some slight direct diuretic effect.

 Mechanism of Action of Cardiac Glycosides

Associated with an interaction with membrane-bound Na+-K+ ATPase (Na-K pump).

Clinical ramifications of an interaction of cardiac glycosides with the Na⁺ K pump.

I. Increase levels of Ca⁺⁺, Increase therapeutic and toxic effects of cardiac glycosides

II. Decrease levels of K⁺ , Increase toxic effects of cardiac glycosides

Therapeutic Uses of Cardiac Glycosides

• CHF
• CHF accompanied by atrial fibrillation
• Supraventricular arrhythmias

Selective serotonin reuptake inhibitors (SSRIs)

e.g. fluoxetine, paroxetine, citalopram, and sertraline
- Most commonly used antidepressant category
- Less likely to cause anticholinergic side effects
- Relatively safest antidepressant group in overdose
- Selectively inhibits reuptake of serotonin(5-HT)

Mode of Action;
- Well absorbed when given orally
- Plasma half-lives of 18-24 h allowing once daily dosagedaily dosage
- Metabolised through CYP450 system and most SSRIs inhibit some CYP isoforms
- Therapeutic effect is delayed for 2-4 weeks

ADVERSE DRUG REACTIONS

- Insomnia, increased anxiety, irritability
- Decreased libido
- Erectile dysfunction, anorgasmia, and ejaculatory delay
- Bleeding disorders
- Withdrawal syndrome