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:

1. 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.

2. 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.

3. 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.

4. 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.

5. 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.

Mixed Narcotic Agonists/Antagonists

These drugs all produce analgesia, but have a lower potential for abuse and do not produce as much respiratory depression.

A. Pentazocine

• Has a combination of opiate analgesic and antagonist activity.
• Orally, it has about the same analgesic potency as codeine.
• In contrast to morphine, cardiac workload tends to increase due to an increase in pulmonary arterial and cerebrovascular pressure. Blood pressure and heart rate both also tend to increase.
• Adverse reactions to Pentazocine

• Nausea, vomiting, dizziness.

• Psychotomimetic effects, such as dysphoria, nightmares and visual hallucinations.

• Constipation is less marked than with morphine.

B. Nalbuphine

• Has both analgesic and antagonist properties.
• Resembles pentazocine pharmacologically.
• Analgesic potency approximately the same as morphine.
• Appears to be less hypotensive than morphine.
• Respiratory depression similar to morphine, but appears to peak-out at higher doses and to reach a ceiling.
• Like morphine, nalbuphine reduces myocardial oxygen demand. May be of value following acute myocardial infarction due to both its analgesic properties and reduced myocardial oxygen demand.
• Most frequent side effect is sedation.

C. Butorphanol

• Has both opiate agonist and antagonist properties.Resembles pentazocine , pharmacologically., 3.5 to 7 times more potent than morphine., Produces respiratory depression, but this effect peaks out with higher doses. The respiratory depression that does occur lasts longer than that seen following morphine administration.
• Butorphanol, like pentazocine, increases pulmonary arterial pressure and possibly the workload on the heart.
• Adverse reactions include sedation, nausea and sweating.

D. Buprenorphine

• A derivative of eto`rphine. Has both agonist and antagonist activity. 20 to 30 times more potent than morphine.Duration of action only slightly longer than morphine, but respiratory depression and miosis persist well after analgesia has disappeared.
• Respiratory depression reaches a ceiling at relatively low doses.
• Approximately 96% of the circulating drug is bound to plasma proteins.
• Side effects are similar to other opiates:
  • sedation, nausea, vomiting,
  • dizziness, sweating and headache.

Ketoconazole

synthetic antifungal drug

used for infections such as  athlete's foot, ringworm, candidiasis (yeast infection or thrush), jock itch.

Ketoconazole is used to treat eumycetoma, the fungal form of mycetoma.

MOA: Ketoconazole is imidazole structured, and interferes with the fungal synthesis of  ergosterol, the main constituent of cell membranes, as well as certain enzymes. It is specific for fungi, as mammalian cell membranes contain no ergosterol.

Sensitive fungi Ketoconazole inhibits growth of  dermatophytes and  yeast species (such as Candida albicans).

Biguanides

metformin

Mechanism

↓ gluconeogenesis

appears to inhibit complex 1 of respiratory chain

↑ insulin sensitivity
↑ glycolysis
↓ serum glucose levels
↓ postprandial glucose levels

Clinical use

first-line therapy in type II DM

Toxicity

no hypoglycemia
no weight gain
lactic acidosis is most serious side effect 
contraindicated in renal failure 

Fifth Generation:

These are extended spectrum antibiotics.

Ceftaroline, Ceftobiprole

Specific Agents

Hydralazine [orally effective]

MOA: Not completely understood. Seems to be partially dependent on the release of EDRF and perhaps partially due to K+-channel activation
- in clinical doses action is manifest primarily on vascular smooth muscle (non-vascular muscle is not much affected).
- Re: Metabolism & Excretion. In cases of renal failure the plasma half life may be substantially increased (4-5 fold). One mode of metabolism is
via N-Acetylation (problem of slow acetylators)

Side Effects

- those typical of vasodilation = headache, nasal congestion, tachycardia etc.
- chronic treatment with high doses > 200 mg/day may induce a rheumatoid-like state which may resemble lupus erythematosus.

Minoxidil (Loniten) [orally effective]

MOA: K+-channel agonist

-    very effective antihypertensive. Used primarily to treat life-threatening hypertension or hypertension resistant to other agents.

Side effects - growth of hair

Diazoxide (Hyperstat) [used only IV]

MOA: K+-channel agonist

- Administered by rapid IV injection; action appearing after 3-5 min; action may last from 4 to 12 hours.

Nitroprusside (Nipride) [used only IV]

MOA: increase in cGMP

- unlike the other vasodilators, venous tone is substantially reduced by nitroprusside.
- rapid onset of action (.30 sec); administered as an IV-infusion.
- particularly useful for hypertension associated with left ventricular failure.