Pharmacology

Immunosuppressive drugs are essential in managing various medical conditions, particularly in preventing organ transplant rejection and treating autoimmune diseases. They can be classified into five main groups:

Glucocorticoids: These are steroid hormones that reduce inflammation and suppress the immune response. They work by inhibiting the production of inflammatory cytokines and reducing the proliferation of immune cells. Common glucocorticoids include prednisone and dexamethasone. Their effects include:
- Mechanism of Action: Glucocorticoids inhibit the expression of genes coding for pro-inflammatory cytokines (e.g., IL-1, IL-2, TNF-α).
- Clinical Uses: They are used in conditions like rheumatoid arthritis, lupus, and to prevent transplant rejection.
- Side Effects: Long-term use can lead to osteoporosis, weight gain, diabetes, and increased risk of infections.
Cytostatic Drugs: These agents inhibit cell division and are often used in cancer treatment as well as in autoimmune diseases. They include:
- Examples: Cyclophosphamide, azathioprine, and methotrexate.
- Mechanism of Action: They interfere with DNA synthesis and cell proliferation, particularly affecting rapidly dividing cells.
- Clinical Uses: Effective in treating cancers, systemic lupus erythematosus, and other autoimmune disorders.
- Side Effects: Can cause bone marrow suppression, leading to increased risk of infections and anemia.
Antibodies: This group includes monoclonal and polyclonal antibodies that target specific components of the immune system.
- Types:
  - Monoclonal Antibodies: Such as basiliximab and daclizumab, which target the IL-2 receptor to prevent T-cell activation.
  - Polyclonal Antibodies: These are derived from multiple B-cell clones and can broadly suppress immune responses.
- Clinical Uses: Used in organ transplantation and to treat autoimmune diseases.
- Side Effects: Risk of infections and allergic reactions due to immune suppression.
Drugs Acting on Immunophilins: These drugs modulate immune responses by binding to immunophilins, which are proteins that assist in the folding of other proteins.
- Examples: Cyclosporine and tacrolimus.
- Mechanism of Action: They inhibit calcineurin, a phosphatase involved in T-cell activation, thereby reducing the production of IL-2.
- Clinical Uses: Primarily used in organ transplantation to prevent rejection.
- Side Effects: Nephrotoxicity, hypertension, and increased risk of infections.
Other Drugs: This category includes various agents that do not fit neatly into the other classifications but still have immunosuppressive effects.
- Examples: Mycophenolate mofetil and sirolimus.
- Mechanism of Action: Mycophenolate inhibits lymphocyte proliferation by blocking purine synthesis, while sirolimus inhibits mTOR, affecting T-cell activation and proliferation.
- Clinical Uses: Used in transplant patients and in some autoimmune diseases.
- Side Effects: Gastrointestinal disturbances, increased risk of infections, and potential for malignancies.

Balanced Anesthesia
A barbiturate, narcotic analgesic agent, neuromuscular blocking agent, nitrous oxide and one of the more potent inhalation anesthetic.

Third Generation Cephalosporins

Prototype drugs are CEFOTAXIME (IV) and CEFIXIME (oral). CEFTAZIDIME (for Pseudomonas aeruginosa.).

Further expansion of Gm negative spectrum to include hard to treat organisms such as Enterobacter, Serratia, and Pseudomonas.
In addition to better Gm negative spectrum, this group has improved pharmacokinetic properties (longer half-lives) that allow once daily dosing with some agents. In general, activity toward Gm + bacteria is reduced. These are specialty antibiotics that should be reserved for specific uses.

Enterobacteriaciae that are almost always sensitive (>95% sensitive)
E. coli
Proteus mirabilis (indole –)
Proteus vulgaris (indole +)
Klebsiella pneumoniae

Gram negative bacilli that are generally sensitive (>75% sensitive)
Morganella morganii
Providencia retgerri
Citrobacter freundii
Serratia marcescens
Pseudomonas aeruginosa (Ceftazidime only)

Gram negative bacilli that are sometimes sensitive (<75% sensitive)
Enterobacter
Stenotrophomonas (Xanthomonas) maltophilia (Cefoperazone & Ceftazidime only)
Acinetobacter

--> cefepime & cefpirome are promising for these bacteria

Bacteria that are resistant
Listeria monocytogenes
Pseudomonas cepacia
Enterococcus sp.

Uses
1. Gram negative septicemia & other serious Gm – infections
2. Pseudomonas aeruginosa infections (Ceftazidime - 90% effective)
3. Gram negative meningitis - Cefotaxime, Ceftriaxone, Cefepime. For empiric therapy add vancomycin ± rifampin to cover resistant Strep. pneumoniae
4. Gonorrhea - Single shot of Ceftriaxone is drug of choice. Oral cefixime and ceftibuten are also OK.
5. Complicated urinary tract infections, pyelonephritis
6. Osteomyelitis - Ceftriaxone in home health care situations
7. Lyme disease - ceftriaxone in home health care situations

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

Antifungal

There are several classes of antifungal drugs.

The polyenes bind with sterols in the fungal cell wall, principally ergosterol. This causes the cell's contents to leak out and the cell dies. Human (and other animal) cells contain cholesterol rather than ergosterol so are much less suceptible.

Nystatin

Amphotericin B

Natamycin

The imidazole and triazole groups of antifungal drugs inhibit the enzyme cytochrome P450 14α-demethylase. This enzyme converts lanosterol to ergosterol, and is required in fungal cell wall synthesis. These drugs also block steroid synthesis in humans.

Imidazoles:

Miconazole

Ketoconazole

Clotrimazole

The triazoles are newer, and are less toxic and more effective:

Fluconazole

Itraconazole

Allylamines inhibit the enzyme squalene epoxidase, another enzyme required for ergosterol synthesis:

Terbinafine

Echinocandins inhibit the synthesis of glucan in the cell wall, probably via the enzyme 1,3-β glucan synthase:

Caspofungin

Micafungin

Others:

Flucytosine is an antimetabolite.

Griseofulvin binds to polymerized microtubules and inhibits fungal mitosis.

Antidiarrheal

Antidiarrheal drugs may be given to relieve the symptom (non-specific therapy) or may be given to treat the underlying cause of the symptom (specific therapy).

Ι. Drugs used for the symptomatic (non-specific) treatment of diarrhoea include:

• Opiates and opiate derivatives are the most effective (such as morphine), but it is not used because of potentially serious adverse effects. Other agents, such as diphenoxylate and loperamide, are commonly used.

• Adsorbent – demulcent products such as kaolin – pectin preparation may be included in antidiarrheal preparations. Unfortunately, they may adsorb nutrients and other drugs, including the antidiarrheal agents if given concurrently.

• Anticholinergic agents e.g. atropine is occasionally used to decrease abdominal cramping and pain associated with diarrhoea.

ΙΙ. Specific therapy may include the use of antibacterial agents that are recommended for use in carefully selected cases of bacterial enteritis. For example, severe diarrhoea by salmonella, shigella, campylobacter and clostridia species can be treated by antibiotics (ampicillin, chloramphenicol, co-trimoxazole).

GENERAL ANESTHETICS

General anesthesia often involves more than one drug to get different, favourable effects.
Premedication is often used to:
1. Treat anxiety - Benzodiazapenes
2. Reduce pain - Opiod anaglesics such as morphine
3. Produce muscle paralysis -E.g. Tubocurare
4. Reduce secretions
Induction of anesthesia is often done via intravenous anesthetics, which are quick and easy to administer.
Maintenance of anesthesia involves inhalation agents.

Prototype Agents:
Volatile Anesthetics:
•   Nitrous Oxide
•   Ether
•   Halothane
•   Enflurane
•   Isoflurane

Injectable Anesthetics:
•   Thiopental
•   Ketamine
•   Etomidate
•   Propofol
•   Midazolam

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