Antifungal

There are several classes of antifungal drugs.

The polyenes bind with sterols in the fungal cell wall, principally ergosterol. This causes the cell's contents to leak out and the cell dies. Human (and other animal) cells contain cholesterol rather than ergosterol so are much less suceptible.

Nystatin

Amphotericin B

Natamycin

The imidazole and triazole groups of antifungal drugs inhibit the enzyme cytochrome P450 14α-demethylase. This enzyme converts lanosterol to ergosterol, and is required in fungal cell wall synthesis. These drugs also block steroid synthesis in humans.

Imidazoles:

Miconazole

Ketoconazole

Clotrimazole

The triazoles are newer, and are less toxic and more effective:

Fluconazole

Itraconazole

Allylamines inhibit the enzyme squalene epoxidase, another enzyme required for ergosterol synthesis:

Terbinafine

Echinocandins inhibit the synthesis of glucan in the cell wall, probably via the enzyme 1,3-β glucan synthase:

Caspofungin

Micafungin

Others:

Flucytosine is an antimetabolite.

Griseofulvin binds to polymerized microtubules and inhibits fungal mitosis.

First Generation Cephalosporins

Prototype Drugs are CEFAZOLIN (for IV use) and CEPHALEXIN (oral use).

1. Staph. aureus - excellent activity against b-lactamase-producing strains
Not effective against methicillin-resistant Staph. aureus & epidermidis

2. Streptococci - excellent activity versus Streptococcus sp.
Not effective against penicillin-resistant Strep. pneumoniae

3. Other Gm + bacteria - excellent activity except for Enterococcus sp.

4. Moderate activity against gram negative bacteria.

Caution: resistance may occur in all cases.
Susceptible organisms include:

E. coli
Proteus mirabilis
Indole + Proteus sp. (many strains resistant)
Haemophilus influenzae (some strains resistant)
Neisseria sp. (some gonococci resistant)

Uses
1. Upper respiratory tract infections due to Staph. and Strep.
2. Lower respiratory tract infections due to susceptible bacteria e.g. Strep.pneumoniae in penicillin-allergic patient (previous rash)
3. Uncomplicated urinary tract infections (Cephalexin)
4. Surgical prophylaxis for orthopedic and cardiovascular operations (cefazolin preferred because of longer half-life)
5. Staphylococcal infections of skin and skin structure

Stages of anesthesia

Stage I

Analgesia

Still conscious but drowsy

Stage II

Excitement stage

Loss of consciousness, however, irregular ventilation may be present which affects absorption of inhalation agents.

Reflexes may be exaggerated.

This is a very dangerous stage

Stage III

Surgical anesthesia

Loss of spontaneous movement

Regular, shallow respiration

Relaxation of muscles

Stage IV

Medullary paralysis

Death

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. 

Neurotransmitters can be classified into:
1. Biogenic amines:
ACh, NA, DA, 5-HT, Histamine
2. Amino acids:
Excitatory (glutamate & asparate)
Inhibitory (GABA& glycine)
3. Others:
Adenosine, melatonin

Pharmacodynamics

Pharmacodynamics is the study of what drugs do to the body and how they do it.

Dose-Response Relationships

- Basic Features of the Dose-Response Relationship:  The dose-response relationship is graded instead of all-or-nothing (as dose increases, response becomes progressively larger).

- Maximal Efficacy and Relative Potency

- Maximal Efficacy: the largest effects that a drug can produce

- Relative Potency:  Potency refers to the amount of drug that must be given to elicit an effect.

- Potency is rarely an important characteristic of a drug.

- Potency of a drug implies nothing about its maximal efficacy.