Sympathomimetics

Beta-Adrenergic Agonists

Beta1-adrenergic agonists (dopamine, dobutamine, prenalterol, xamoterol) have been used to treat acute and chronic heart failure, but have limited usefulness in chronic CHF because of their arrhythmogenic effects, short duration of action, the development of tolerance, and necessity of parenteral administration

Dopamine (i.v.) is used in acute heart failure (cardiogenic shock) to increase blood pressure and increase cardiac output

• It has a short half-life (1 min)
• At high doses dopamine has potent peripheral vasoconstrictor effects (alpha-receptor stimulation), in addition to its inotropic effects
• Low dose dopamine has a renal artery dilating effect and may improve sodium and water excretion in patients refractory to loop diuretics
• When systolic pressure is greater than 90 mm Hg, nitroprusside can be added to reduce ventricular filling pressure and reduce afterload
• i.v. furosemide should also be administered to reduce edema

Levodopa and ibopamine, analogs of dopamine that can be administered orally, have been shown to improve symptoms in some patients, but can exhibit arrhythmogenic side-effects and tachyphylaxis

Dobutamine is a somewhat selective beta1-adrenergic agonist that lacks vasoconstrictor activity and causes minimal changes in heart rate

• It is frequently added to nitroprusside when blood pressure is adequate to increase cardiac output
• It is administered as an i.v. infusion to treat acute severe heart failure
• It has a short half-life (2.4 min) and is only used on a short-term basis, although long-term beneficial effects on cardiac function have been noted
• After 72 hours of therapy, tolerance can develop to dobutamine necessitating switch to other inotropic support (e.g. milrinone)
• Dobutamine can enhance AV conduction and worsen atrial tachycardia

Prenalterol and xamoterol are partial beta1-adrenergic agonists that may simultaneously stimulate beta1-receptors and block the receptors from stimulation by endogenous catecholamines, thereby protecting against beta1-receptor down-regulation

Uses of NSAIDs

NSAIDs are usually indicated for the treatment of acute or chronic conditions where pain and inflammation are present. Research continues into their potential for prevention of colorectal cancer, and treatment of other conditions, such as cancer and cardiovascular disease.

NSAIDs are generally indicated for the symptomatic relief of the following conditions.

rheumatoid arthritis, osteoarthritis, inflammatory arthropathies (e.g. ankylosing spondylitis, psoriatic arthritis, Reiter's syndrome), acute gout, dysmenorrhoea, metastatic bone pain ,headache and migraine, postoperative pain, mild-to-moderate pain due to inflammation and tissue injury, pyrexia, renal colic

Aspirin, the only NSAID able to irreversibly inhibit COX-1, is also indicated for inhibition of platelet aggregation; an indication useful in the management of arterial thrombosis and prevention of adverse cardiovascular events.

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

Antidepressant Drugs

Drug treatment of depression is based on increasing serotonin (5-HT) or NE (or both) at synapses in selective tracts in the brain. This can be accomplished by different mechanisms.

Treatment takes several weeks to reach full clinical efficacy.

1. Tricyclic antidepressants (TCAs)
a. Amitriptyline
b. Desipramine
c. Doxepin
d. Imipramine
e. Protriptyline

2. Selective serotonin reuptake inhibitors (SSRIs)
a. Fluoxetine
b. Paroxetine
c. Sertraline
d. Fluvoxamine
e. Citalopram

3. Monoamine oxidase inhibitors (MAOIs)
a. Tranylcypromine
b. Phenelzine

4. Miscellaneous antidepressants

a. Bupropion
b. Maprotiline
c. Mirtazapine
d. Trazodone
e. St. John’s Wort

Antimania Drugs

These drugs are used to treat manic-depressive illness.

1. Lithium
2. Carbamazepine
3. Valproic acid

Different Systems of the CNS & their functions

These systems are pathways formed of specific parts of the brain and the neurons connecting them. 

They include:
1.The pyramidal system 
2.The extrapyramidal system 
3.The limbic system 
4.The reticular formation 
5.The tuberohypophyseal system

The pyramidal system: 

It originates from the motor area of the cerebral cortex and passes through the spinal cord, therefore it is also known as the “corticospinaltract”. 
It is responsible for the regulation of the fine voluntary movements.

The extrapyramidal system: 

It also controls the motor functionbut involves areas other than the corticospinal tract. 
It is involved in the regulation of gross voluntary movements, thus it complements the function of the pyramidal system. 

The “basal ganglia” constitute an essential part of this system. 

Degenerative changes in the pathway running from the “substantianigra”to the “corpus striatum”(or nigrostriatal pathway) may cause tremors and muscle rigidity characteristic of “Parkinson’s disease”.

The limbic system: 

The major parts of this system are: the hypothalamus, the basal ganglia, the hippocampus(responsible for short term memory), and some cortical areas. 

The limbic system is involved in the control of “behavior”& “emotions”.

The reticular formation:

It is composed of interlacing fibers and nerve cells that run in all directions beginning from the upper part of the spinal cord and extending upwards. 
It is important in the control of “consciousness” and “wakefulness”.

The tuberohypophyseal system: 

It is a group of short neurons running from the hypothalamusto the hypophysis(pituitary gland) regulating its secretions.
 

Oxytetracycline

Treats Oxytetracycline is a medicine used for treating a wide range of infections including infections of the lungs, urinary system, skin and eyes. It may also be used to treat sexually transmitted infections, infections caused by lice, rickettsial infections, cholera and plague. It is very occasionally used to treat leptospirosis, gas gangrene, and tetanus.