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.

Griseofulvin

• Griseofulvin is an antifungal drug. It is used both in animals and in humans, to treat ringworm infections of the skin and nails. It is derived from the mold Penicillium griseofulvum.
• It is administered orally.

Pharmacokinetics

Pharmacokinetics is the way that the body deals with a drug - how that drug moves throughout the body, and how the body metabolizes and excretes it.  The factors and processes involved in pharmacokinetics must be considered when choosing the most effective dose, route and schedule for a drug's use.

The four processes involved in pharmacokinetics are:

Absorption:  The movement of a drug from its site of administration into the blood.

Several factors influence a drug's absorption:

• Rate of Dissolution:  the faster a drug dissolves the faster it can be absorbed, and the faster the effects will begin.
• Surface Area:  Larger surface area = faster absorption.
• Blood Flow:  Greater blood flow at the site of drug administration = faster absorption.
• Lipid Solubility:  High lipid solubility = faster absorption
• pH Partitioning:  A drug that will ionize in the blood and not at the site of administration will absorb more quickly.

Distribution:  The movement of drugs throughout the body.

Metabolism:  (Biotransformation) The enzymatic alteration of drug structure.

Excretion:  The removal of drugs from the body.

As a drug moves through the body, it must cross membranes.  Some important factors to consider here then are:

Body's cells are surrounded by a bilayer of phospholipids (cell membrane).

There are three ways that a substance can cross cell membranes:

• Passing through channels and pores: only very small molecules can cross cell membranes this way.

• Transport Systems:   Selective carriers that may or may not use ATP.

• Direct Penetration of the Cell Membrane: 

TRICYCLIC ANTIDEPRESSANTS

e.g. amitriptyline, imipramine, nortriptyline

Belong to first generation antidepressants

ACTION:

Inhibit 5-HT(5-hydroxytryptamine) and norepinephrine reuptake

slow clearance of norepinephrine & 5-HT from the synapse 

enhance norepinephrine & 5-HT neuro-transmission

MODE OF ACTIONMODE OF ACTION

TCAs also block
– muscarinic acetylcholine receptors
– histamine receptors 
– 5-HT receptors
– α1 adrenoceptors

Onset of antidepressant activity takes 2-3 weeks

PHARMACOKINETICS

-  Readily absorbed from the gastro-intestinal tract 
- Bind strongly to plasma albumin
- Has a large volume of distribution(as a result of binding to extravascular tissues)
- Undergo liver CYP metabolism into biologically active metabolites
- These metabolites are inactivated via glucuronidation and excreted in urine

ADVERSE DRUG REACTIONS

Antimuscarinic - dry mouth, blurred vision, constipation and urinary retention
Antihistamine – drowsiness
adrenoceptor blockage(+/- central effect) postural hypotension
Reduce seizure threshold
Testicular enlargement, gynaecomastia, galactorrhoea
AV-conduction blocks and cardiac arrhythmias

TOXICITY

- Fatal in toxicity

- Most important toxic effect is, slowing of depolarisation of the cardiac action potential by blocking fast sodium channels ("quinidine-like" effect) 

- delays propagation of depolarisation through both myocardium and conducting tissue

- prolongation of the QRS complex and the PR/QT intervals

- predisposition to cardiac arrhythmias

DRUG INTERACTIONS

Pharmacodynamic:
– ↑ sedation with antihistamines, alcohol
– ↑ antimuscarinic effects with anticholinergics– ↑ antimuscarinic effects with anticholinergics
– Hypertension and arrhythmias with MAOIs- should be given at least 14 days apart

Pharmacokinetic (via altering CYP metabolism)
– ↓ plasma concentration of TCA by- carbamazepine, rifampicin
– ↑ plasma concentration of TCA by- cimetidine, calcium channel blockers,fluoxetine

OTHER CLINICAL USES OF AMITRIPTYLINE

- Treatment of nocturnal enuresis in children
- Treatment of neuropathic pain
- Migraine prophylaxis

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.

Lithium carbonate: 1st choice (controls mania in bipolar disorders); delay before onset of therapeutic benefit; no psychotropic effects in normal humans

i. Mechanism: blocks enzymes in inositol phosphate signaling pathway; no consistent effects of lithium on NE, 5-HT, and DA
ii. Side effects: severe CNS (ataxia, delirium, coma, convulsions) and CV (cardiac dysrhythmias)