Diclofenac

Short half life (1‐2 hrs), high 1stpass metab.,  accumulates in synovial fluid after oral admn., reduce inflammation, such as in arthritis or acute injury

Mechanism of action

inhibition of prostaglandin synthesis by inhibition of cyclooxygenase (COX). There is some evidence that diclofenac inhibits the lipooxygenase pathways, thus reducing formation of the

leukotrienes (also pro-inflammatory autacoids). There is also speculation that diclofenac may inhibit phospholipase A2 as part of its mechanism of action. These additional actions may explain the high potency of diclofenac - it is the most potent NSAID on a molar basis.

Inhibition of COX also decreases prostaglandins in the epithelium of the stomach, making it more sensitive to corrosion by gastric acid. This is also the main side effect of diclofenac and other drugs that are not selective for the COX2-isoenzyme.

Ofloxacin : It is a quinolone antibiotic and similar in structure to  levofloxacin. It is an alternative treatment to ciprofloxacin for anthrax.

Drug-Receptor Interactions

Drug Receptor:  any functional macromolecule in a cell to which a drug binds to produce its effects.  at receptors, drugs mimic or block the action of the body's own regulatory molecules.  

Receptors and Selectivity of Drug Action : If a drug interacts with only one kind of receptor, and if that receptor regulates just a few processes, then the effects of the drug will be limited.

Even though a drug is selective for one type of receptor, it can still produce a variety of effects.

Selectivity does not guarantee safety.

Theories of Drug-Receptor Interaction

- Simple Occupancy Theory:  Two factors - The intensity of the response to a drug is proportional to the number of receptors occupied by that drug, and the maximal response will occur when all available receptors have been occupied.

- Modified Occupancy Theory:  Assumes that all drugs acting at a particular receptor are identical with respect to the ability to bind to the receptor and the ability to influence receptor function once binding has taken place.

•    Affinity:  The strength of the attraction between a drug and its receptor.  Affinity is reflected in potency.  (Drugs with high affinity are very potent).

•    Intrinsic Activity:  The ability of a drug to activate a receptor following binding.  Reflected in the maximal efficacy (drugs with high intrinsic activity have high maximal efficacy).

Antiarrhythmic Drugs

Cardiac Arrhythmias 
Can originate in any part of the conduction system or from atrial or ventricular muscle.
Result from
– Disturbances in electrical impulse formation (automaticity) 
– Conduction (conductivity) 
– Both

MECHANISMS OF ARRHYTHMIA
ARRHYTHMIA – absence of rhythm
DYSRRHYTHMIA – abnormal rhythm

ARRHYTHMIAS result from:
1. Disturbance in Impulse Formation
2. Disturbance in Impulse Conduction
- Block results from severely depressed conduction
- Re-entry or circus movement / daughter impulse

Types of Arrhythmias

• Sinus arrhythmias 
– Usually significant only 
– if they are severe or  prolonged 

• Atrial arrhythmias 
– Most significant in the presence of underlying heart disease
– Serious: atrial fibrillation can lead to the formation of clots in the heart 

• Nodal arrhythmias 
– May involve tachycardia and increased workload of the heart or bradycardia from heart block 

• Ventricular arrhythmias 
– Include premature ventricular contractions (PVCs), ventricular tachycardia, and ventricular fibrillation 

Indications
• To convert atrial fibrillation (AF) or flutter to normal sinus rhythm (NSR) 
• To maintain NSR after conversion from AF or flutter 
• When the ventricular rate is so fast or irregular that cardiac output is impaired
– Decreased cardiac output leads to symptoms of decreased systemic, cerebral, and coronary circulation 
• When dangerous arrhythmias occur and may be fatal if not quickly terminated 
– For example: ventricular tachycardia may cause cardiac arrest 

Mechanism of Action 
• Reduce automaticity (spontaneous depolarization of myocardial cells, including ectopic pacemakers) 
• Slow conduction of electrical impulses through the heart
• Prolong the refractory period of myocardial cells (so they are less likely to be prematurely activated by adjacent cells 
 

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

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.