Valdecoxib

used in the treatment of osteoarthritis, acute pain conditions, and dysmenorrhoea

Etoricoxib new  COX-2 selective inhibitor

Estimation of the risk of anesthesia (American Society of Anesthesiologists scale)

• ASA 1: healthy patient.

• ASA 2: patient with stable, treated illness like arterial hypertension, diabetes melitus, asthma bronchiale, obesity

• ASA 3: patient with systemic illness decreasing sufficiency like heart illness, late infarct

• ASA 4: patient with serious illness influencing his state like renal insuficiency, unstable hypertension, circulatory insuficiency

• ASA 5: patient in life treatening illness

• ASA 6: brain death- potential organ donor

Non-barbiturate sedatives

1- Chloral hydrate is trichlorinated derivative of acetaldehyde that is converted to trichlorethanol in the body. It induces sleep in about 30 minutes and last up to 6 hr. it is irritant to GIT and produce unpleasant taste sensation.

2- Ramelteon melatonin receptors are thought to be involved in maintaining circadian rhythms underlying the sleep-wake cycle. Ramelteon is an agonist at MT1 and MT2 melatonin receptors , useful in patients with chronic insomnia with no rebound insomnia and
withdrawal symptoms

3- Ethanol (alcohol) it has antianxiety sedative effects but its toxic potential out ways its benefits.
Ethanol is a CNS depressant producing sedation and hypnosis with increasing dose.

Absorption of alcohol taken orally is rapid, it is highly lipid soluble, presence of food delayed its absorption, maximal blood concentration depend on total dose, sex, strength of the solution, the time over which it is taken, the presence of food and speed of metabolism.

Alcohol in the systemic circulation is oxidized in the liver principally 90% by alcohol dehydrogenase to acetaldehyde and then by acetaldehyde dehydrogenase to products that enter the citric cycle. 

Alcohol metabolism by alcohol dehydrogenase follows first order kinetics in the smallest doses. Once the blood concentration exceeds about 10 mg/100 ml, the enzymatic processes are saturated and elimination rate no longer increases with increasing
concentration but become steady at 10-15 ml/ 1 hr. in occasional drinkers. 

Thus alcohol is subject to dose dependant kinetics i.e. saturation or zero order kinetics.

Actions

- Ethanol acts on CNS in a manner similar to volatile anesthetic.
- It also enhances GABA so stimulating flux of chloride ions through ion channels.
- Other possible mode of action involve inhibition of Ca-channels and inhibition of excitatory NMDA receptors.
- Ethanol has non selective CNS depressant activity.
- It causes cutaneous vasodilatation, tachycardia and myocardial depression

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.

Cells of the Nervous System 

1-Neurons (Nerve Cells):function units of the nervous system by conducting nerve impulses, highly specialized and amitotic. Each has a cell body (soma), one or more dendrites, and a single axon. 
• Cell Body: it has a nucleus with at least one nucleolus and many of the typical cytoplasmic organelles, but lacks centriolesfor cell division. 

• Dendrites:Dendrites and axons are cytoplasmic extensions (or processes), that project from the cell body. They are sometimes referred to as fibers. Dendrites (afferent processes) increase their surface area to receive signals from other neurons, and transmit impulses to the neuron cell body. 

• Axon: There is only one axon (efferent process) that projects from each cell body.        
It carries impulses away from the cell body.

2-Glial cells: do not conduct nerve impulses, but support, nourish, and protect the neurons. They are mitotic, and far more numerous than neurons. 

Astrocyte: A glialcell that provides support for neurons of the CNS, provides nutrients regulates the chemical composition of the extracellularfluid.

• Oligodendrocyte: A type of glialcell in the CNS that forms myelin sheaths.

• Microglia:The smallest glialcells; act as phagocytes (cleaning up debris) and protect the brain from invading microorganisms.

• Schwann cell:A cell in the PNS that is wrapped around a myelinatedaxon, providing one segment of its myelin sheath.

TRICYCLIC ANTIDEPRESSANTS

e.g. amitriptyline, imipramine, nortriptyline

Belong to first generation antidepressants

ACTION:

Inhibit 5-HT(5-hydroxytryptamine) and norepinephrine reuptake

slow clearance of norepinephrine & 5-HT from the synapse 

enhance norepinephrine & 5-HT neuro-transmission

MODE OF ACTIONMODE OF ACTION

TCAs also block
– muscarinic acetylcholine receptors
– histamine receptors 
– 5-HT receptors
– α1 adrenoceptors

Onset of antidepressant activity takes 2-3 weeks

PHARMACOKINETICS

-  Readily absorbed from the gastro-intestinal tract 
- Bind strongly to plasma albumin
- Has a large volume of distribution(as a result of binding to extravascular tissues)
- Undergo liver CYP metabolism into biologically active metabolites
- These metabolites are inactivated via glucuronidation and excreted in urine

ADVERSE DRUG REACTIONS

Antimuscarinic - dry mouth, blurred vision, constipation and urinary retention
Antihistamine – drowsiness
adrenoceptor blockage(+/- central effect) postural hypotension
Reduce seizure threshold
Testicular enlargement, gynaecomastia, galactorrhoea
AV-conduction blocks and cardiac arrhythmias

TOXICITY

- Fatal in toxicity

- Most important toxic effect is, slowing of depolarisation of the cardiac action potential by blocking fast sodium channels ("quinidine-like" effect) 

- delays propagation of depolarisation through both myocardium and conducting tissue

- prolongation of the QRS complex and the PR/QT intervals

- predisposition to cardiac arrhythmias

DRUG INTERACTIONS

Pharmacodynamic:
– ↑ sedation with antihistamines, alcohol
– ↑ antimuscarinic effects with anticholinergics– ↑ antimuscarinic effects with anticholinergics
– Hypertension and arrhythmias with MAOIs- should be given at least 14 days apart

Pharmacokinetic (via altering CYP metabolism)
– ↓ plasma concentration of TCA by- carbamazepine, rifampicin
– ↑ plasma concentration of TCA by- cimetidine, calcium channel blockers,fluoxetine

OTHER CLINICAL USES OF AMITRIPTYLINE

- Treatment of nocturnal enuresis in children
- Treatment of neuropathic pain
- Migraine prophylaxis