Analgesics

.

Analgesic
The major classes
1. Paracetamol and NSAIDs 2. COX-2 inhibitors 3. Opiates and morphinomimetics 4. Specific agents

Analgesics
analgesics (also known as a painkillers) are a group of drugs used to relieve pain (achieve analgesia). Analgesic drugs act in various ways on the peripheral and central nervous systems; they include paracetamol (acetaminophen), the non-steroidal anti-inflammatory drugs (NSAIDs) ,narcotic drugs such as morphine, synthetic drugs with narcotic properties such as tramadol, and various others.

Mode of action Most NSAIDs act as non-selective inhibitors of the enzyme cyclooxygenase, inhibiting both the cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) isoenzymes. Cyclooxygenase catalyzes the formation of prostaglandins and thromboxane from arachidonic acid (itself derived from the cellular phospholipid bilayer by phospholipase A2). Prostaglandins act as messenger molecules in the process of inflammation.

PGs
of lipid compounds that are derived enzymatically from fatty acids and have important functions in the body. Prostaglandins are found in most tissues and organs. They are produced by all nucleated cells except lymphocytes. They are lipid mediators that act upon platelets, endothelium, uterine and mast cells.

Biosynthesis of PGs
phospholipid (in cell wall lipid) ↓ ←-------(phospholipase A )
2

arachidonic acid
PGsynthase↓cox1

&2 Prostaglandins ↓
prostacyclin

↓ ↓ leukotrines ↓

thromboxane

Classes of NSAIDs
Ø Salicylates Ø
 Acetylsalicylic acid (Aspirin)  Methyl salicylate  Magnesium salicylate

Arylanthranilic acids ( fenamic acids)

 Mefenamic acid  Meclofenamic acid

 

Ø Arylalkanoic acids  Diclofenac
   

Ø

Pyrazolidine derivatives

Bromfenac Indomethacin Sulindac Tolmetin

 Phenylbutazone  Phenazone  Sulfinpyrazone

Ø

Oxicams

Ø

Arylpropionic acids (profens)

 Piroxicam  Meloxicam

 Ibuprofen  Fenoprofen  Ketoprofen

Ø

COX-2 inhibitors

 Celecoxib

Pharmacokinetics
Most NSAIDs are weak acids, They are

absorbed well from the stomach and intestinal mucosa. They are highly protein-bound in plasma (typically >95%), usually to albumin. Most NSAIDs are metabolized in the liver to inactive metabolites which are typically excreted in the urine . Ibuprofen and diclofenac have short half-lives (2-3 hours). Some NSAIDs (typically oxicams) have very long half-lives (e.g. 20-60 hours).

The two main adverse drug reactions associated with NSAIDs relate to gastrointestinal (GI) effects and renal effects of the agents. These effects are dose-dependent, and in many cases severe enough to pose the risk of ulcer perforation, upper gastrointestinal bleeding, and death, limiting the use of NSAID therapy.

Adverse effects of NSAIDs

Adverse effects …CONT
1. Dyspepsia, nausea and vomiting. Gastric damage may occur in chronic users, with risk of haemorrhage. The cause is suppression of gastroprotective prostaglandins in the gastric mucosa. 2. Skin reactions. 3. Reversible renal insufficiency. Seen mainly in individuals with compromised renal function when the compensatory prostaglandin E2-mediated vasodilatation is inhibited. 4. Analgesic-associated nephropathy . This can occur following long-continued high doses of NSAIDs and is often irreversible. 5. Liver disorders, bone marrow depression. Relatively uncommon. 6. Bronchospasm. Seen in 'aspirin-sensitive'

opioid analgesic
An opioidis a morphine - acting analgesic, used for pain relief. These agents work by binding to opioid receptors, which are found principally in the CNS and the GIT. The receptors in these two organ systems mediate both the beneficial effects, and the undesirable side effects. There are three principal classes of opioid receptors , μ , κ , δ (mu, kappa, and delta).

classes of opioids
There are a number of broad classes of opioids: 2. natural opiates, including morphine, & codeine 3. semi-synthetic opiates, created from the natural opioids, such as hydromorphone, desomorphine, diacetylmorphine (Heroin ). 4. fully synthetic opioids, such as fentanyl, pethidine, methadone, tramadol . NOTE: endogenous opioid peptides, produced naturally in the body, such as endorphins, enkephalins, dynorphins, and endomorphins.

indications for opioids
The sole clinical indications for opioids in the United States, are: 2. Analgesia i.e. to combat pain of various types and induction and the continuance of anesthesia as well as allaying patient apprehension right before the procedure. Fentanyl, oxymorphone, hydromorphone, and morphine are most commonly used for this purpose, in conjunction with other drugs such as scopolamine, short and intermediate-acting barbiturates, and benzodiazepines, especially midazolam which has a rapid onset of action and lasts shorter than diazepam or similar drugs. 3. Cough (codeine, dihydrocodeine )

Indications for opioids….cont.

3.Diarrhea (generally loperamide, diphenoxylate) but , morphine may be used in some cases of severe diarrheal diseases) Diarrhea of Irritable Bowel Syndrome (Codeine, diphenoxylate, loperamide) 4.Anxiety due to shortness of breath (oxymorphone and dihydrocodeine only)

Adverse effects
 nausea and vomiting, drowsiness, itching, dry

mouth, miosis, and constipation. Fortunately, most of these are not a problem .  Infrequent adverse reactions in patient taking opioids for pain relief: These include:  dose-related respiratory depression (see below), confusion, hallucinations, hypothermia, bradycardia/tachycardia, orthostatic hypotension, dizziness, headache, urinary retention, ureteric or biliary spasm, muscle rigidity, myoclonus (with high doses), and flushing.

Adverse effects…CONT.
 Opioid-induced hyperalgesia has been

observed in some patients, whereby individuals using opioids to relieve pain may paradoxically experience more pain as a result of their medication. This phenomenon, although uncommon, is seen in some patients,when dose is escalated rapidly.  Both therapeutic and chronic use of opioids can compromise the function of the immune system. Opioids decrease the proliferation of macrophages and lymphocytes, and affect cell differentiation .

Tolerance is the process whereby

Tolerance

neuroadaptation occurs (through receptor desensitization) resulting in reduced drug effects. Tolerance is more pronounced for some effects than for others - tolerance occurs quickly to the effects on mood, itching, urinary retention, and respiratory depression, but occurs more slowly to the analgesia and other physical side effects.

Tolerance..CONT.
Tolerance to opioids is attenuated by a number of substances, including : calcium channel blockers. intrathecal magnesium and zinc . NMDA* antagonists such as ketamine. All can be used to reduce tolerance to opioid drugs.
*NMDA receptor antagonists are a class of anesthetics that work to antagonize, or inhibit the action of, the N-methyl d-aspartate receptor (NMDAR).

Dependence Dependence is characterised by extremely unpleasant withdrawal symptoms that occur if opioid use is abruptly discontinued after tolerance has developed. Addiction is the process whereby physical and/or psychological dependence develops to a drug - including opioids. The withdrawal symptoms can reinforce the addiction, driving the user to continue taking the drug.

Nausea& Vomiting: haloperidol,ondansetron

Treating opioid adverse effects

are very effective Drowsiness: oxycodone Itching: fexofenadine Constipation :stool-softeners Respiratory depression: respiratory stimulant currently approved for this purpose is doxapram. tolerance to respiratory depression occurs rapidly, so that it is not a clinical problem

Some opioids are relatively contraindicated in renal failure because of the accumulation of the parent drug or their active metabolites (e.g. morphine and oxycodone). Age (young or old) is not a contraindication to strong opioids. Some synthetic opioids such as pethidine have metabolites which are actually neurotoxic and should therefore be used only in acute situations.

Contraindications for opioids

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