Anti-Histamines:
 
The effect of histamine can be opposed in three ways:
1. Physiological antagonism: by using a drug to oppose the effect (e.g adrenaline). Histamine constricts bronchi,
causes vasodilatation which increases capillary permeability. Adrenaline opposes this effect by a mechanism unrelated to histamine.
2. By preventing histamine from reaching its site of action (receptors), By competition with H1-H2 receptors (Drug antagonisms).
3. By preventing the release of histamine. (adrenal steroids and sodium-cromoglycate can suppress the effect on the tissues)

Types of Anti-histamine drugs

Selected H1 antagonist drugs

First-generation H1 receptor antagonists:

Chlorpheniramine (Histadin) & Dexchlorpheniramine 
Diphenhydramine (Allermine)
Promethazine (Phenergan) -  strong CNS depressants
Cyproheptadine (Periactin)

ACTION
These drugs bind to both central and peripheral H1 receptors and can cause CNS depression or stimulation.

- They usually cause CNS depression (drowsiness,sedation) with usual therapeutic doses
- Cause CNS stimulation (anxiety, agitation) 
with excessive doses, especially in children. 
They also have Anticholinergic effects (e.g. dry mouth, urinary retention, constipation, blurred vision).

Second-generation H1 receptor antagonists (non-sedating) agents

Terfenadine
Fexofenadine
Loratadine
Acravistine and Cetirizine
Astemizol

Action

They cause less CNS epression because they are selective for peripheral H1 receptors and do not cross the blood brain barrier.

Indications for use

The drugs can relieve symptoms but don’t relieve hypersensitivity.

1) Allergic rhinitis. Some relief of sneezing, rhinorrhea, nasal airway obstruction and conjunctivitis are with the use of antihistamine.
2) Anaphylaxis. Antihistamine is helpful in treating urticaria and pruritus.
3) Allergic conjunctivitis. This condition, which is characterized by redness, itching and tearing of the eyes.
4) Drug allergies. Antihistamines may be given to prevent or treat reactions to drugs (e.g, before a dignostic test that
uses an iodine preparation).
5) Transfusions of blood and blood products.
6) Dermatologic conditions. Antihistamines are the drug of choice for treatment of allergic contact dermatitis and
acute Urticaria. Urticaria often occurs because the skin has many mast cells to release histamine.
7) Miscellaneous. Some antihistamines are commonly used for non-allergic disorder such as motion sickness, nausea, vomiting, sleep, cough or add to cough mixtures.

Contraindication

hypersensitivity to the drugs, narrow-angle glaucoma, prostatic hypertroph, stenosing peptic ulcer, bladder neck obstruction, during pregnancy and lactating women

Adverse effects:

Drowsiness and sedation
Anticholinergic
Some antihistamines may cause dizziness, fatigue, hypotention, headache, epigastric distress and photosensitivity
Serious adverse reaction including cardiac arrest & death, have been reported in patients receiving high dose astemizole

H2-receptor antagonists

 Cimetidine (Tagamate), Ranitidine (Zantac), Fomatidine, Nizatidine. 

Mechanism of action

Numerous factors influence acid secretion by the stomach, including food, physiological condition and drugs. H2 receptor blockers reduce basal acid-secretion by about 95% and food stimulated acid-secretion by about 70%. Both conc. and vol. of H ions will decrease.

Pharmacokinetics:
1) They are all well absorbed after oral dose.
2) Antacids decrease their absorption in about 10-20%

Uses
Cimetidine -  reduction of gastric secretion is beneficial, these are in main duodenal ulcer, benign gastric ulcer, stomach ulcer and reflux eosophagitis.

Rantidine -used as alternative for duodenal ulcer

Adverse effects:
headache, dizziness, constipation, diarrhoea, tiredness and muscular pain. 

Gabapentin (Neurontin): newer; for generalized tonic-clonic seizures and partial seizures (partial and complex)

Mechanism: unknown but know doesn’t mimic GABA inhibition or block Ca currents

Side effects: dizziness, ataxia, fatigue; drug well-tolerated and no significant drug interactions

Heparin:

• Inhibits blood coagulation by forming complexes with an α2-globulin (Antithrombin III) and each of the activated proteases of the coagulation cascade (Kallikrein, XIIa, XIa, IXa, Xa, and Thrombin). After formation of the heparin-ATIII-coagulation factor, heparin is released and becomes available again to bind to free ATIII.
• Blocks conversion of Prothrombin to Thrombin and thus inhibits the synthesis of Fibrin from Fibrinogen.
• Inhibits platelet function and increases vascular permeability. May induce moderate to severe thrombocytopenia.
• Is prescribed on a “unit” basis.
• Heparin is not effective after oral administration and is generally administered by intravenous or subcutaneous injection. Intramuscular injections should be avoided.
• Heparin does not cross the placenta and does not pass into the maternal milk.
• is contraindicated in any situation where active bleeding must be avoided.

Ulcerative lesions, intracranial hemorrhage, etc.

Overdosage:

• Simple withdrawal.

• Protamine sulfate: Highly basic peptide that binds heparin and thus neutralizes its effects.

Levofloxacin

Levofloxacin is effective against a number of gram-positive and gram-negative bacteria. Because of its broad spectrum of action, levofloxacin is frequently prescribed in hospitals for pulmonary infections

Fluconazole: an antifungal used orally,  intravenously or vaginally to treat yeast and fungal infections. Side-effects of systemic administration include hepatotoxicity (liver damage).

• For vaginal candidiasis (vaginal thrush), a once-only oral dose is often sufficient.

Morphine

Morphine is effective orally, but is much less effective than when given parenterally due to first-pass metabolism in the liver. Metabolism involves glucuronide formation, the product of which is excreted in the urine.

1. Central Nervous System Effects

• Morphine has mixed depressant and stimulatory actions on the CNS.

• Analgesia:

• Dysphoria – Euphoria

- morphine directly stimulates the chemoreceptor trigger zone, but later depresses the vomiting center in the brain stem. This center is outside the blood/brain barrier.

- opiates appear to relieve anxiety

• Morphine causes the release of histamine and abolishes hunger.

- causes the body to feel warm and the face and nose to itch.

• Pupils are constricted.- due to stimulation of the nuclei of the third cranial nerves.

- tolerance does not develop to this effect.

• Cough reflex is inhibited. - this is not a stereospecific effect.

- dextromethorphan will suppress cough but will not produce analgesia.

• Respiration is depressed

- due to a direct effect on the brain stem respiratory center.

- death from narcotic overdose is nearly always due to respiratory arrest.

- the mechanism of respiratory depression involves:

• a reduction in the responsiveness of the brain stem respiratory centers to an increase in pCO₂.

• depression of brain stem centers that regulate respiratory rhythm.

- hypoxic stimulation of respiration is less affected and O2 administration can produce apnea.

2. Cardiovascular Effects

• Postural orthostatic hypotension.- due primarily to peripheral vasodilation, which may be due in part to histamine release.

• Cerebral circulation is also indirectly influenced by increased pCO2, which leads to cerebral vasodilation and increased cerebrospinal fluid pressure.

• In congestive heart failure, morphine decreases the left ventricular workload and myocardial oxygen demand.

3. Endocrine Effects

• Increases prolactin secretion

• Increases vasopressin (ADH) secretion

• Decreases pituitary gonadotropin (LH & FSH) secretion.

• Decreases stress induced ACTH secretion.

4. Gastrointestinal Tract Effects

• Constipation (tolerance does not develop to this effect).

• Several of these agents can be used in the treatment of diarrhea.

There is an increase in smooth muscle tone and a decrease in propulsive  contractions.

Adverse Reactions

Generally direct extensions of their pharmacological actions.

1. respiratory depression, apnea

2. nausea and vomiting

3. dizziness, orthostatic hypotension, edema

4. mental clouding, drowsiness

5. constipation, ileus

6. biliary spasm (colic)

7. dry mouth

8. urine retention, urinary hesitancy

9. hypersensitivity reactions (contact dermatitis, urticaria)

Precautions

1. respiratory depression, particularly in the newborn

3. orthostatic hypotension

4. histamine release (asthma, shock)

5. drug interactions (other CNS depressants)

6. tolerance:

- analgesia, euphoria, nausea and vomiting, respiratory depression

7. physical dependence (psychological & physiological)