Peptic Ulcer and its Mechanisms of Action

Peptic Ulcer

It’s mainly occurs in that part of the g.i.t (gastrointestinal tract) which is exposed to gastric acid and pepsin, i.e. the stomach and duodenum. The physiology of peptic ulcer is not clearly known. It results probably due to an imbalance between the aggressive (acid, pepsin, bile and H. pylori) and the defensive (gastric mucus and bicarbonate\ secretion, prostaglandins, nitric oxide, high\ mucosal blood flow, innate resistance of the mucosal cells) factors. A variety of psychosomatic, humoral and vascular derangements have been implicated and the importance of Helicobacter pylori infection as a contributor to ulcer formation and recurrence has been recognized. In gastric ulcer, generally acid secretion is normal or low, while deficient mucosal defense (mostly impaired mucus and bicarbonate secretion) plays a greater role. In duodenal ulcer, acid secretion is high in about half of the patients but normal in the rest. Whether production of acid is normal or high, peptic ulcer does contribute to ulceration as an aggressive factor, reduction of which is the main approach to ulcer treatment. An understanding of the mechanism and control of gastric acid secretion will elucidate the targets of antisecretory drug action.

Mechanisms of Action of Peptic Ulcer

The mechanisms operating at the gastric parietal cells are summarized in The terminal enzyme H+K+ATPase (proton pump) which secretes H+ ions in the apical canaliculi of parietal cells can be activated by histamine, ACh and gastrin acting via their own receptors located on the basolateral membrane of these cells. Out of the three physiological secretagogues, histamine, acting through H2 receptors, plays the dominant role, because the other two, gastrin and ACh

act partly directly and to a greater extent indirectly by releasing histamine from paracrine enterochromaffin-like (ECL) cells called “histaminocytes” located in the oxyntic glands. While H2 receptors activate H+K+ATPase by generating cAMP, muscarinic and gastrin/cholecystokinin (CCK2) receptors appear to function through the phospholipase C → IP3–DAG pathway that mobilizes intracellular Ca2+. The cAMP and proton pump activation also involve Ca2+. Secretomotor response to gastrin and cholinergic agonists is expressed fully only in the presence of cAMP generated by H2 activation. Some of histamines are participates in the acid secretion response to gastrin and ACh at more than one levels, and H2 antagonists suppress not only histamine, but also ACh, Penta gastrin also in fact any gastric acid secretory stimulus.

Local Anesthetics and its Ideal properties

Local Anesthetics and its Ideal properties

Local anesthetics are applied topical and its target injection cause reversible loss of sensory perception, especially of pain, in a restricted area of the body. They block generation and conduction of nerve impulse at any part of the neuron with which they come in contact, without causing any structural damage. Thus, not only sensory but also motor impulses are interrupted when a local anesthetic is applied to a mixed nerve, resulting in muscular paralysis and loss of autonomic control as well.

CLASSIFICATION

Injectable anesthetic

Low potency, short duration

Procaine

Chloroprocaine

Intermediate potency and duration

Lidocaine (Lignocaine)

Prilocaine

High potency, long duration

Tetracaine (Amethocaine)

Bupivacaine

Ropivacaine

Dibucaine (Cinchocaine)

Surface anesthetic

Soluble                          Insoluble

Cocaine                           Benzocaine

Lidocaine                        Butylaminobenzoate

Tetracaine                      (Butamben)

Benoxinate                      Oxethazaine

The clinically useful local anesthetics are weak bases with amphiphilic property. A hydrophilic tertiary or secondary amine on one side and a lipophilic aromatic residue on the other are joined by an alkyl chain through an ester or amide linkage.

Ester-linked Las- Cocaine, procaine, chloroprocaine, tetracaine, benzocaine.

Amide-linked Las- Lidocaine, bupivacaine, dibucaine, prilocaine, ropivacaine.

Because of their short duration, less intense analgesia and higher risk of hypersensitivity, the ester-linked local anesthetics are rarely used for infiltration or nerve block but are still used topically on mucous membranes.

Ideal properties of LocalAnesthetics

•   Duration of action should be enough to allow time for the surgical procedure.
•   It should be effective both when injected into tissue and when applied topically to mucous   membranes.
•  It should be effective oral as well as intravenous.
•   It should have low toxicity.
•   It should not deteriorate by the heat of sterilization.
•   Its effects should be completely reversible.
•   Rapid onset of action and short duration of action.
•   The local anesthetics should be non-irritating.
•   The local anesthetic should be soluble in water and stable in solution.
•   The onset of action should be quick.

Radioimmunoassay And its Application

Radioimmunoassay (RIA)

Radioimmunoassay is an in vitro assay. It calculates the presence of an antigen with very high sensitivity. Mainly, any biological product or substance for which a specific antibody exists can be measured, even in minute concentrations. Radioimmunoassay has been the first immune-assay procedure developed to analyze picomolar and nanomolar concentrations of hormones in biological fluids.

Method

The target antigen is labeled by radioactive isotope and it bound to its specific antibodies. For example, sample A & blood-serum, is then added to initiate a competitive reaction of the labeled radioactive antigens from the preparation.  The unlabeled antigens serum-sample react with the specific antibodies. The competition for the antibodies will release a certain amount of labeled antigen. This proportional to the ratio of labeled antigen & unlabeled antigen. A curve is plot which allows the amount of antigen in the patient's serum to be derived.

It means the concentration of unlabeled antigen is increased, more of it binds to the antibody, displacing the labeled radioactive variant. The bound antigens are separated from the unbound antigens. And the radioactivity of the free antigens remaining in the supernatant is measured. A binding curve can be generated using a known standard, which allows the number of antigens in the patient's serum to be derived.

Fig; Radioimmunoassay and radioactivity vs concentration graph.

Radioactive isotope uses for RIA           

Test Isotopes	Major Range of Gamma Emission (keV)
Iodine 131	80.2-637
Gallium 67	93.3-388
Thallium 201	135-167
Technetium 99	140
Cobalt 57	114-136
Iodine 125	25-36

Application of RIA

1.      Detection of narcotic Drugs.

2.      Radioimmunoassay of Hydromorphone & Hydrocodone in Human plasma.

3.      Radioimmunoassay of Flunisolide in human plasma.

4.      Measurement of Ferritin.

5.      Detection of digoxin.

6.      Thyroid testing.

ANTI-RHEUMATOID DRUGS & THER GOALS AND SIDE EFFECT

ANTI-RHEUMATOID DRUGS & THER GOALS AND SIDE EFFECT

These are drugs which (except corticosteroids), can suppress the rheumatoid process, bring about a remission and retard disease progression, but do not have nonspecific anti-inflammatory or analgesic action. They are used in rheumatoid arthritis (RA) in addition to NSAIDs and are also referred to as disease modifying antirheumatic drugs (DMARDs) or slow acting antirheumatic drugs (SAARDs).

Rheumatoid arthritis (RA) is an autoimmune disease in which there is joint inflammation, synovial proliferation and destruction of articular cartilage. Immune complexes composed of IgM activate complement and release cytokines (mainly TNFα and IL-1) which are chemotactic for neutrophils. These inflammatory cells secrete lysosomal enzymes which damage cartilage and erode bone, while PGs produced in the process cause vasodilatation and pain. RA is a chronic progressive, crippling disorder with a waxing and waning course. NSAIDs are the first line drugs and afford symptomatic relief in pain, swelling, morning stiffness, immobility

CLASSIFICATION

I. Disease modifying antirheumatic drugs (DMARDs)

A. Nonbiological drugs

1. Immunosuppressants: Methotrexate, Azathioprine, Cyclosporine

2. Sulfasalazine

3. Chloroquine or Hydroxychloroquine

4. Leflunomide

B. Biological agents

1. TNFα inhibitors: Etanercept, Infliximab, Adalimumab

2. IL-1 antagonist: Anakinra

II. Adjuvant drugs

Corticosteroids: Prednisolone and others

The goals of drug therapy in RA are:

• Ameliorate pain, swelling and joint stiffness

• Prevent articular cartilage damage and bony erosions

• Prevent deformity and preserve joint function. In some mild/early cases are mainly treated with NSAIDs drugs only, the current recommendation is to add DMARDs as soon as the diagnosis of RA is confirmed. However, use of DMARDs in early/mild RA should be weighed against their potential adverse effects, which may be serious. More than one DMARD may be used concurrently; advanced cases may require 2 or 3 drugs together, because all DMARDs tend to lose effectiveness with time.

Side effects-

Stomach Upset, Diarrhea, Nausea - The most common side effect of methotrexate is stomach upset, especially it make Diarrhea.

Infection Risk - DMARDs work by suppressing your over-active immune system. This can put you at increased risk for a variety of infections. Biologic agents, such as TNF inhibitors, are even more associated with increased risk of infection.

Hair Loss - Both methotrexate and leflunomide can cause hair loss.

Fatigue - Another common side effect of DMARDs is fatigue. You may feel winded or tired, most commonly with methotrexate.

Liver Damage - Some DMARDs can cause liver damage.

Anticholinergic Drugs and their Pharmacological actions

Anticholinergic Drugs and their Pharmacological actions

‘Anticholinergic drugs’ is restricted the drugs which block actions of Ach on CNS muscarinic receptors and autonomic effectors. This nicotinic receptor antagonists also block some actions of ACh, they are generally known as ‘neuromuscular blockers’ and ‘ganglion blockers’.

Ex- Atropine- It is highly work for muscarinic receptors, but it also synthetic substitutes do possess significant nicotinic blocking property in addition.

CLASSIFICATION

1. Natural alkaloids - Hyoscine, Atropine

2. Semisynthetic derivatives - Atropine methonitrate, Homatropine, Atropine methonitrate, Hyoscine butyl bromide, Ipratropium bromide, Tiotropium bromide.

3. Synthetic compounds-

(a) Mydriatics: Cyclopentolate, Tropicamide.

(b) Antisecretory-antispasmodics:

(i) Quaternary compounds: Propantheline, Oxyphenonium, Clidinium, Pipenzolate methyl bromide, Isopropamide, Glycopyrrolate.

(ii) Tertiary amines: Dicyclomine, Valethamate, Pirenzepine.

(c)Vasicoselective: Oxybutynin, Flavoxate,

(d)Antiparkinsonian: Trihexyphenidyl (Benzhexol), Procyclidine, Biperiden.

PHARMACOLOGICAL ACTIONS

Central nervous system

Atropine has an overall CNS stimulant action. However, these effects are not appreciable at low doses which produce only peripheral effects because of restricted entry into the brain Atropine stimulates many medullary centers—vagal, respiratory, vasomotor. On excessive use it causes cortical excitation, disorientation, hallucinations, restlessness, delirium followed by respiratory depression and coma.

Cardiovascular system

Heart the most prominent effect of atropine is tachycardia. It blocks the M2 receptors on the SA node through which vagal tone decreases HR. Higher the existing vagal tone— more marked is the tachycardia (maximum in young adults, less in children and elderly). On i.m./s.c. injection transient initial bradycardia often occurs. Earlier believed to be due to stimulation of vagal center, it is now thought to be caused by blockade of muscarinic auto receptors (M1) on vagal nerve endings, thereby 

augmenting Ach release.

Fig- Cholinergic-Blocking Drugs acts on cardiac muscle and smooth muscle.

Blood pressure

Since cholinergic impulses are not involved in the maintenance of vascular tone, atropine does not have any consistent or marked effect on BP.

Eye

The autonomic control of iris muscles and the action of mydriatics as well as miotics is illustrated. If they are use topical it makes mydriasis. Atropine shows cycloplegia and abolition in light reflex, lasting 6–10 days. This results in photophobia and blurring of vision.