Oxycodone  
About equal potency to morphine. Very effective orally.

It is combined with aspirin or acetaminophen for the treatment of moderate pain and is available orally

Oxycodone is a semisynthetic compound derived from thebaine, with agonist activity primarily at mu receptors.

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

Hydromorphone

• About 8-10 times more potent than morphine when given intravenously.
• Slightly shorter duration of action.
• More soluble than morphine, thus higher concentrations may be injected if necessary.
• Better oral/parenteral absorption ratio than morphine, but not as good as codeine or oxycodone.

• It is used for the treatment of moderate to severe pain

Propoxyphene

• A methadone analog.Used orally to relieve mild to moderate pain.
• A typical opiate, it does not possess anti-inflammatory or antipyretic actions, but has little or no antitussive activity.
• Cannot be used parenterally because of irritant properties.
• Has a low addiction potential primarily due to its lack of potency as an opiate.
• The most common adverse side effects are:• dizziness, drowsiness, and nausea and vomiting. • these effects are more prominent in ambulatory patients.
• Withdrawal symptoms have occurred in both adults and in neonates following use of the drug by the mother during pregnancy.
• CNS depression is additive with other CNS depressants.

Pharmacodynamic Effects of NSAIDs

A. Positive

analgesic - refers to the relief of pain by a mechanism other than the reduction of inflammation (for example, headache);

- produce a mild degree of analgesia which is much less than the analgesia produced by opioid analgesics such as morphine

anti-inflammatory - these drugs are used to treat inflammatory diseases and injuries, and with larger doses - rheumatoid disorders

antipyretic - reduce fever; lower elevated body temperature by their action on the hypothalamus; normal body temperature is not reduced

Anti-platelet - inhibit platelet aggregation, prolong bleeding time; have anticoagulant effects

B. Negative

Gastric irritant

Decreased renal perfusion

Bleeding

(CNS effects)

Adverse effects

The two main adverse drug reactions (ADRs) associated with NSAIDs relate to gastrointestinal (GI) effects and renal effects of the agents.

Gastrointestinal ADRs

The main ADRs associated with use of NSAIDs relate to direct and indirect irritation of the gastrointestinal tract (GIT). NSAIDs cause a dual insult on the GIT - the acidic molecules directly irritate the gastric mucosa; and inhibition of COX-1 reduces the levels of protective prostaglandins.

Common gastrointestinal ADRs include:

Nausea, dyspepsia, ulceration/bleeding, diarrhoea

Risk of ulceration increases with duration of therapy, and with higher doses. In attempting to minimise GI ADRs, it is prudent to use the lowest effective dose for the shortest period of time..

 Ketoprofen and piroxicam appear to have the highest prevalence of gastric ADRs, while ibuprofen (lower doses) and diclofenac appear to have lower rates.

Commonly, gastrointestinal adverse effects can be reduced through suppressing acid production, by concomitant use of a proton pump inhibitor, e.g. omeprazole

Renal ADRs

NSAIDs are also associated with a relatively high incidence of renal ADRs. The mechanism of these renal ADRs is probably due to changes in renal haemodynamics (bloodflow), ordinarily mediated by prostaglandins, which are affected by NSAIDs.

Common ADRs associated with altered renal function include:

salt and fluid retention,hypertension

These agents may also cause renal impairment, especially in combination with other nephrotoxic agents. Renal failure is especially a risk if the patient is also concomitantly taking an ACE inhibitor and a diuretic - the so-called "triple whammy" effect.

In rarer instances NSAIDs may also cause more severe renal conditions.

interstitial nephritis, nephrotic syndrome, acute renal failure

Photosensitivity

Photosensitivity is a commonly overlooked adverse effect of many of the NSAIDs. These antiinflammatory agents may themselves produce inflammation in combination with exposure to sunlight. The 2-arylpropionic acids have proven to be the most likely to produce photosensitivity reactions, but other NSAIDs have also been implicated including piroxicam, diclofenac and benzydamine.

ibuprofen having weak absorption, it has been reported to be a weak photosensitising agent.

Other ADRs

Common ADRs, other than listed above, include: raised liver enzymes, headache, dizziness.

Uncommon ADRs include: heart failure, hyperkalaemia, confusion, bronchospasm, rash.

The COX-2 paradigm

It was thought that selective inhibition of COX-2 would result in anti-inflammatory action without disrupting gastroprotective prostaglandins.

The relatively selective COX-2 oxicam, meloxicam, was the first step towards developing a true COX-2 selective inhibitor. Coxibs, the newest class of NSAIDs, can be considered as true COX-2 selective inhibitors and include celecoxib, rofecoxib, valdecoxib, parecoxib and etoricoxib.

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