Histamine: 

Involved in inflammatory and anaphylactic reactions 
Local application causes swelling redness, and edema, mimicking a mild inflammatory reaction.

Large systemic doses leads to profound vascular changes similar to those seen after shock or anaphylactic origin.

Storage: widely distributed; in tissues, primarily in mast cells; in blood- in basophils, platelets; non-mast cell sites (epidermis, CNS, regenerating cells)

Histamine Stored in complex with:
Heparin
Chondroitin Sulfate
Eosinophilic Chemotactic Factor
Neutrophilic Chemotactic Factor
Proteases

Release: during type I (IgE-mediated) immediate hypersensitivity rxns, tissue injury, in response to some drugs
a.    Process: Fcε receptor on mast cell or basophil binds IgE, when Ag binds → ↑ PLC activity → histamine

Symptoms: bronchoconstriction, ↓ Pa, ↑ capillary permeability, edema

Action

H1 receptors are located mainly on smooth muscle cells in blood vessels and the respiratory and GI tracts. When histamine binds with these receptors producing the following effects.

-Contraction of smooth muscle in the bronchi and bronchioles producing bronchoconstraction.

-stimulation of vagus nerve endings to produce reflex bronchoconstraction and cough.

-Increased permeability of veins and capillaries, which allows fluid to flow into subcutaneous tissues and form edema (little lower blood pressure).

-Increased secretion of mucous glands. Mucosal edema and increased nasal mucus produce the nasal congestion characteristic of allergic rhinitis and the common cold.

-Stimulation of sensory peripheral nerve endings to cause pain and pruritus.

Histamine promotes vasodilation by causing vascular endothelium to release nitric oxide. This chemical signal diffuses to the vascular smooth muscle, where it stimulates cyclic guanosine monophosphate production, causing vasodilation.

H2-receptors present mostly in gastric glands and smooth muscle of some blood vessels. When receptors are stimulated, the main effects are increased secretion of gastric acid and pepsin, increased rate and force of myocardial contraction.

The H3-receptor functions as a negative-feedback mechanism to inhibit histamine synthesis and release in many body tissues. Stimulation of H3 receptors opposes the effects produced by stimulation of H1 receptors.

The H4- receptor is expressed in only a few cell types, and their role in drug action is unclear.

Drugs cause release of histamine: 

Many drugs can cause release of histamine in the body.
-Intracutaneouse morphine injection in humans produced localized redness, localized edema and a diffuse redness. This is due to release of histamine.

-I.V. inj of curare may cause bronchial constriction due to release of histamine.

-codeine , papaverine, meperidine (pethedine), atropine, hydralizine and sympathomimetic amines, histamine releases by these drugs may not be significant unless they are administered I.V in large doses

Pharmacological effects

-  If injected I.V. (0.1 mg of histamine) causes a sharp decline in the blood pressure, flushing of the face and headache. 
- There is also stimulation of gastric acid secretion. 
- If this injection is given to an asthmatic individual, there will be a marked decrease in vital capacity and a sever attack of asthma. 

Circulatory effects of histamine:

The two factors involved in the circulatory action of histamine are:
Arteriolar dilatation and
Capillary permeability
So it leads to loss of plasma from circulation

Effect on gastric secretion:
Histamine is a potent stimulant of gastric Hcl secretion. 

Paracetamol

Paracetamol or acetaminophen is analgesic and antipyretic drug that is used for the relief of fever, headaches, and other minor aches and pains.

paracetamol acts by reducing production of prostaglandins, which are involved in the pain and fever processes, by inhibiting the cyclooxygenase (COX)  enzyme.

Metabolism Paracetamol is metabolized primarily in the liver. At usual doses, it is quickly detoxified by combining irreversibly with the sulfhydryl group of glutathione to produce a non-toxic conjugate that is eventually excreted by the kidneys.

Ketoprofen

It acts by inhibiting the body's production of prostaglandin.

Monoamine oxidase inhibitors (MAOIs) 

e.g. phenelzine, tranylcypromine, moclobemide

- Belong to first generation antidepressants with TCAs
- Most MAOIs irreversibly inhibit the intraneuronal catabolism of norepinephrine and serotonin by MAO-A and MAO-B
- increase brain levels of noradrenaline and 5-HT
- Moclobemide causes selective, reversible inhibition of MAO-A

DRUG INTERACTIONS

Hypertensive crises similar to cheese reaction with OTC cough/cold preparations containing indirect-sympathomimetics
e.g. ephedrine

- Other antidepressants should not be started at least 2 weeks after stopping MAOIs and vice versa due to risk of serotonin syndrome
- Similar interaction with pethidine

ADVERSE DRUG REACTIONS

- Antimuscarinic side effects (e.g. dry mouth, blurred vision, urinary retention)vision, urinary retention)
- Excessive central stimulation causes tremors, excitement and insomnia
- Postural hypotension
- Increased appetite with weight gain

Immunosuppressive antibodies can be classified mainly into monoclonal and polyclonal antibodies, targeting specific components of the immune system.

1. Monoclonal Antibodies:

   • Basiliximab: Targets the IL-2 receptor on T cells, inhibiting T-cell activation. It is FDA approved for use in renal transplantation to prevent acute rejection.

   • Alemtuzumab: Targets CD52, a protein found on the surface of mature lymphocytes. It is used for treating chronic lymphocytic leukemia and as an induction agent in kidney transplantation.

   • Rituximab: Targets CD20 on B cells, leading to B-cell depletion. It is used in various conditions, including non-Hodgkin lymphoma and rheumatoid arthritis.

   • Daclizumab: Targets the IL-2 receptor (CD25) and is used in renal transplantation to prevent acute rejection.

   • Eculizumab: Targets complement component C5, inhibiting the complement cascade. It is used in conditions like paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome.

2. Polyclonal Antibodies:

   • Rabbit Antithymocyte Globulin (rATG): A polyclonal antibody that targets multiple T-cell surface markers, leading to T-cell depletion. It is used as an induction agent in kidney transplantation and for treating acute rejection.

   • Equine Antithymocyte Globulin (eATG): Similar to rATG, it targets T cells and is used in transplantation settings.

3. Mechanisms of Action:

   • Depletion of Immune Cells: Many antibodies work by depleting specific immune cell populations (e.g., T cells or B cells) to reduce the immune response against transplanted organs or in autoimmune diseases.

   • Blocking Activation Signals: Some antibodies block key receptors involved in T-cell activation, preventing the immune response from being initiated.

   • Inhibition of Complement Activation: Antibodies like eculizumab inhibit the complement system, which can contribute to tissue damage in antibody-mediated rejection.

4. Clinical Applications:

   • Organ Transplantation: Antibodies are commonly used to prevent rejection in kidney, liver, and heart transplants.

   • Autoimmune Diseases: They are also used in treating conditions like rheumatoid arthritis, lupus, and multiple sclerosis.

5. Potential Side Effects:

   • Infections: Due to immune suppression, patients are at increased risk of infections.
   • Allergic Reactions: Some patients may experience allergic reactions to antibody therapies.
   • Infusion Reactions: These can occur during the administration of monoclonal antibodies, leading to symptoms like fever, chills, and hypotension.

Fifth Generation:

These are extended spectrum antibiotics.

Ceftaroline, Ceftobiprole