CLASSICATION OF ANTICOAGULANT DRUGS

1. Direct Acting Anticoagulants

a) Calcium Chelators (sodium citrate, EDTA)

b) Heparin

2. Indirect Acting Anticoagulant Drugs

a) Warfarin

Barbiturates (BARBS): 

were used for antianxiety, sedation but now replaced by BZs; for IV sedation & oral surgery

Advantages: effective and relatively inexpensive (common in third world countries), extensively studied so have lots of information about side effects/toxicity

Peripheral effects: respiratory depression (with ↑ dose), CV effects (↓ BP and HR at sedative-hypnotic doses), liver effects (bind CYP450 → induction of drug metabolism and other enzymes → ↑ metabolism of steroids, vitamins K/D, cholesterol, and bile salts)

General mechanisms: potently depress neuron activity in the reticular formation (pons, medulla) and cortex 
o    Bind barbiturate site on GABAA receptor → enhanced inhibitory effect and ↑ Cl influx; → ↓ frequency of Cl channel opening but ↑ open time of Cl channels (in presense of GABA) so more Cl enters channel (at high [ ] they directly ↑ Cl conductance in absence of GABA- act as GABA mimetics)

Metabolism: liver microsomal drug metabolizing enzymes; most are dealkylated, conjugated by glucoronidation; renal excretion

Uses: anticonvulsant, preoperative sedation, anesthesia

Side effects: sedation, confusion, weight gain, N/V, skin rash

Contraindications: pain (can ↑ sensitivity to painful situations → restlessness, excitement, and delirium) and pulmonary insufficiency (since BARBS → respiratory depression)

Drug interactions: have additive depressant affects when taken with other CNS depressants, enhance depressive effects (of antipsychotics, antihistamines, antiHTNs, ethanol, and TCAs), and accelerates metabolism (of β blockers, Ca-channel blockers, corticosteroids, estrogens, phenothiazines, valproic acid, and theophylline; occurs with chronic BARB ingestion)

Acute toxicity: lower therapeutic index; can be fatal if OD; BARB poisoning a major problem (serious toxicity at only 10x hypnotic dose; → respiratory depression, circulatory collapse, renal failure, pulmonary complications which can be life-threatening)

Symptoms: severe respiratory depression, coma, severe hypotension, hypothermia

Treatment: support respiration and BP, gastric lavage (if recent ingestion)

Tolerance: metabolic (induce hepatic metabolic enzymes, occurs within a few days), pharmacodynamic (↓ CNS response with chronic exposure occurs over several weeks; unknown mechanism), and cross tolerance (tolerance to other general CNS depressants)

Physical dependence: develops with continued use; manifest by withdrawal symptoms (mild = anxiety, insomnia, dizziness, nausea; severe = vomiting, hyperthermia, tremors, delirium, convulsions, death)

Other similar agents: meprobamate (Equanil; pharmacological properties like BZs and barbiturates but mechanism unknown) and chloral hydrate (common sedative in pediatric dentistry for diagnostic imaging; few adverse effects but low therapeutic index)

Other drugs for antianxiety: β-adrenoceptor blockers (e.g., propranolol; block autonomic effects- palpitations, sweating, shaking; used for disabling situational anxiety like stage fright), buspirone (partial agonist at serotonin 1A receptor, produces only anxiolytic effects so no CNS depression, dependence, or additive depression with ethanol but onset of action is 1-3 weeks), lodipem (not a BZ but does act at BZ receptors)

PLASMA FRACTIONS:

a) Fresh frozen plasma.

b) Platelets.

c) Plasma concentrates.

d) Non-plasma recombinant factor concentrates.

Thiopental 

- A barbiturate that is generally used to induce anesthesia.
- The temporal course of effects from induction to recovery depends almost entirely upon progressive redistribution.
- Metabolic degradation or excretion during anesthesia is negligible, except in the case of methohexital.
- The barbiturates produce minimal analgesia.
- Respiratory depression may be pronounced.
- Cardiac output is reduced while total peripheral resistance is increased.
- It does not sensitize the heart to catecholamines.
- It may cause bronchiospasm, especially in asthmatics.
- It is contraindicated in acute intermittent porphyria.

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. 

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.