Indomethacin

commonly used to reduce fever, pain, stiffness, and swelling. It works by inhibiting the production of prostaglandins, molecules known to cause these symptoms.

Indications

ankylosing spondylitis, rheumatoid arthritis, osteoarthritis, juvenile arthritis, psoriatic arthritis, Reiter's disease, Paget's disease of bone, Bartter's disease, pseudogout, dysmenorrhea (menstrual cramps), pericarditis, bursitis, tendonitis, fever, headaches, nephrogenic , diabetes insipidus (prostaglandin inhibits vasopressin's action in the kidney)

Indomethacin has also been used clinically to delay premature labor, reduce amniotic fluid in polyhydramnios, and to treat patent ductus arteriosus.

Mechanism of action

Indomethacin is a nonselective inhibitor of cyclooxygenase (COX) 1 and 2, enzymes that participate in prostaglandin synthesis from arachidonic acid. Prostaglandins are hormone-like molecules normally found in the body, where they have a wide variety of effects, some of which lead to pain, fever, and inflammation.

Prostaglandins also cause uterine contractions in pregnant women. Indomethacin is an effective tocolytic agent, able to delay premature labor by reducing uterine contractions through inhibition of PG synthesis in the uterus and possibly through  calcium channel blockade.

Indomethacin easily crosses the placenta, and can reduce fetal urine production to treat polyhydramnios. It does so by reducing renal blood flow and increasing renal vascular resistance, possibly by enhancing the effects of vasopressin on the fetal kidneys.

Adverse effects

Since indomethacin inhibits both COX-1 and COX-2, it inhibits the production of prostaglandins in the  stomach and intestines which maintain the mucous lining of the

gastrointestinal tract. Indomethacin, therefore, like other nonselective COX inhibitors, can cause ulcers.

Many NSAIDs, but particularly indomethacin, cause lithium retention by reducing its excretion by the kidneys.

Indomethacin also reduces plasma renin activity and aldosterone levels, and increases

sodium and potassium retention. It also enhances the effects of vasopressin. Together these may lead to:

edema (swelling due to fluid retention)

hyperkalemia (high potassium levels)

hypernatremia (high sodium levels)

hypertension (high blood pressure)

Sulindac:  Is a pro‐drug closely related to Indomethacin. 

Converted to the active form of the drug. 

Indications and toxicity similar to  Indomethacin

Glitazones (thiazolidinediones)

Thiazolidinediones, also known as the "-glitazones"

pioglitazone
rosiglitazone

Mechanism

bind to nuclear receptors involved in transcription of genes mediating insulin sensitivity
peroxisome proliferator-activating receptors (PPARs)

↑ insulin sensitivity in peripheral tissue
↓ gluconeogenesis
↑ insulin receptor numbers
↓ triglycerides

Clinical use

type II DM
as monotherapy or in combination with other agents
contraindicated in CHF
associated with increased risk of MI (in particular rosiglitazone)

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.

Erythromycin

used for people who have an allergy to penicillins. For respiratory tract infections, it has better coverage of atypical organisms, including  mycoplasma. It is also used to treat outbreaks of chlamydia, syphilis, and gonorrhea.

Erythromycin is produced from a strain of the actinomyces Saccaropolyspora erythraea, formerly known as Streptomyces erythraeus.

Angiotensin

It is generated in the plasma from a precursor plasma globulin. It is involved in the electrolyte balance, plasma
volume and B.P

Angiotensin I:
Renin is an enzyme produced by the kidney in response to a number of factors including adrenergic activity (β1-
receptor) and sodium depletion. Renin converts a circulating glycoprotein (angiotensinogen) into an inactive material angiotensin-I. It gets activation during passage through pulmonary circulation to angiotensin II by (ACE). ACE is located on the luminal surface of capillary endothelial cells, particularly in the lungs & also present in many organ (e.g brain).

Angiotensin II:
Is an active agent, has a vasoconstrictor action on blood vessels & sodium and water retention

Serotonin-norepinephrine reuptake inhibitors(SNRIs)

e.g. venlafaxine and duloxetine
- Inhibit the reuptake of both 5-HT and norepinephrine 
- Has a more favourable adverse effect profile than TCAs

Norepinephrine reuptake inhibitor

e.g. bupropion, reboxetine

Monoamine receptor antagonists

e.g. mirtazapine, trazodone, mianserin