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

Clarithromycin Used to treat  pharyngitis, tonsillitis, acute maxillary

sinusitis, acute bacterial exacerbation of chronic  bronchitis,  pneumonia (especially atypical pneumonias associated with Chlamydia pneumoniae or TWAR), skin and skin structure infections, and, in HIV and AIDS patients to prevent, and to treat, disseminated Mycobacterium avium complex or MAC.

Unlike erythromycin, clarithromycin is acid-stable and can therefore be taken orally without being protected from gastric acids. It is readily absorbed, and diffused into most tissues and phagocytes.

Clarithromycin has a fairly rapid first-pass hepatic metabolism, i.e it is metabolised by the liver. However, this metabolite, 14-hydroxy clarithromycin is almost twice as active as clarithromycin.

Contraindications Clarithromycin should be used with caution if the patient has liver or kidney disease, certain heart problems (e.g., QTc prolongation or bradycardia), or a mineral imbalance (e.g., low potassium or magnesium levels).

Metabolism

Hepatic Drug-Metabolizing Enzymes:  most drug metabolism in the liverperformed by the hepatic microsomal enzyme system.

Therapeutic Consequences of Drug Metabolism
- Accelerated Renal Drug Excretion:  The most important consequence of drug metabolism is the promotion of renal drug excretion.  Metabolism makes it possible for the kidney to excrete many drugs that it otherwise could not.

- Drug Inactivation
- Increased Therapeutic Action: Metabolism may increase the effectiveness of some drugs.
- Activation of Prodrugs:  A prodrug is a compound that is inactive when administered and made active by conversion in the body.

- Increased or Decreased Toxicity

Factors that influence rate of metabolism:  

- Age:  Hepatic maturation doesn't occur until about a year old.

- Induction of Drug-Metabolizing Enzymes:  Some drugs can cause the rate of metabolism to increase, leading to the need for an increased dosage.  May also influence the rate of metabolism for other drugs taken at the same time, leading to a need for increased dosages of those drugs as well.

- First-Pass Effect:  Hepatic inactivation of certain oral drugs.  Avoided by parentaral administration of drugs that undergo rapid hepatic metabolism.

- Nutritional Status

- Competition between Drugs

Gastric acid secretion inhibitors (antisecretory drugs):

 HCl is secreted by parietal cells of the gastric mucosa which contain receptors for acetylcholine (muscarinic receptors: MR), histamine (H2R), prostaglandins (PGR) and gastrin (GR) that stimulate the production, except PGs which inhibit gastric acid production.
 
Therefore, antagonists of acetylcholine, histamine and gastrin inhibit gastric acid secretion (antisecretory). On the other hand, inhibitors of PGs biosynthesis such as NSAIDs with reduce cytoprotective mechanisms and thus promote gastric mucosal erosion. Also, the last step in gastric acid secretion from parietal cells involve a pump called H+ -K+-ATPase (proton pump). Drugs that block this pump will inhibit gastric acid secretion. Antisecretory drugs include:

1. Anticholinergic agents such as pirenzepine, dicyclomine, atropine.
2. H2-receptors blocking agents such as Cimetidine, Ranitidine, Famotidine, Nizatidine (the pharmacology of these agents has been discussed previously).
3. Gastrin-receptor blockers such as proglumide.
4. Proton pump inhibitors such as omeprazole, lansoprazole.

Major clinical indications of antisecretory drugs:

• Prevention & treatment of peptic ulcer disease.
• Zollinger Ellison syndrome.
• Reflux esophagitis. 

FUNDAMENTALS OF INJECTION TECHNIQUE

There are 6 basic techniques for achieving local anesthesia of the structures of the oral cavity:

 1. Nerve block

 2. Field block

 3. Infiltration/Supraperiosteal

 4. Topical

 5. Periodontal ligament (PDL)

 6. Intraosseous

 Nerve block- Nerve block anesthesia requires local anesthetic to be deposited in close proximity to a nerve trunk. This results in the blockade of nerve impulses distal to this point. It is also important to note that arteries and veins accompany these nerves and can be damaged. To be effective, the local anesthetic needs to pass only through the nerve membrane to block nerve conduction Field block/Infiltration/Supraperiosteal - Field block, infiltration and supraperiosteal injection techniques, rely on the ability of local anesthetics to diffuse through numerous structures to reach the nerve or nerves to be anesthetized:

  - Periosteum

 - Cortical bone

 - Cancellous bone

 - Nerve membrane

Topical - Topical anesthetic to be effective requires diffusion through mucous membranes and nerve membrane of the nerve endings near the tissue surface

PDL/Intraosseous - The PDL and intraosseous injection techniques require diffusion of local anesthetic solution through the cancellous bone (spongy) to reach the dental plexus of nerves innervating the tooth or teeth in the immediate area of the injection. The local anesthetic then diffuses through the nerve membrane

DOPAMINE

It is an immediate metabolic precursor of noradrenaline. It activates D1 receptors in several vascular beds, which causes vasodilatation. It acts on dopaminergic and other adrenergic receptors (α & β1).

Adverse effects of dopamine include nausea, vomiting, ectopic beats, anginal pain, tachycardia, palpitation and widened QRS.
Contraindications are atrial or ventricular tachyarrhythmias, hyperthyroidism and pheochromocytoma.