Midazolam -Intravenous Anesthetics
�Midazolam is a benzodiazepine used for preoperative sedation, induction of anesthesia, or maintenance of anesthesia in short procedures.

Selective serotonin reuptake inhibitors (SSRIs)

e.g. fluoxetine, paroxetine, citalopram, and sertraline
- Most commonly used antidepressant category
- Less likely to cause anticholinergic side effects
- Relatively safest antidepressant group in overdose
- Selectively inhibits reuptake of serotonin(5-HT)

Mode of Action;
- Well absorbed when given orally
- Plasma half-lives of 18-24 h allowing once daily dosagedaily dosage
- Metabolised through CYP450 system and most SSRIs inhibit some CYP isoforms
- Therapeutic effect is delayed for 2-4 weeks

ADVERSE DRUG REACTIONS

- Insomnia, increased anxiety, irritability
- Decreased libido
- Erectile dysfunction, anorgasmia, and ejaculatory delay
- Bleeding disorders
- Withdrawal syndrome

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. 

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.
 

Antiplatelet Drugs:

Whereas the anticoagulant drugs such as Warfarin and Heparin suppress the synthesis or activity of the clotting factors and are used to control venous thromboembolic disorders, the antithrombotic drugs suppress platelet function and are used primarily for arterial thrombotic disease. Platelet plugs form the bulk of arterial thrombi.

Acetylsalicylic acid (Aspirin)

• Inhibits release of ADP by platelets and their aggregation by acetylating the enzymes (cyclooxygenases or COX) of the platelet that synthesize the precursors of Thromboxane A2 that is a labile inducer of platelet aggregation and a potent vasoconstrictor.

• Low dose (160-320 mg) may be more effective in inhibiting Thromboxane A2 than PGI2 which has the opposite effect and is synthesized by the endothelium.

• The effect of aspirin is irreversible.

RENIN-ANGIOTENSIN SYSTEM INHIBITORS

The actions of Angiotensin II include an increase in blood pressure and a stimulation of the secretion of aldosterone (a hormone from the adrenal cortex) that promotes sodium retention. By preventing the formation of angiotensin II, blood pressure will be reduced. This is�the strategy for development of inhibitors. Useful inhibitors of the renin-angiotensin system are the Angiotensin Converting Enzyme Inhibitors�

First line treatment for: Hypertension , Congestive heart failure [CHF]�

ACE-Inhibitor�s MOA (Angiotensin Converting Enzyme Inhibitors)

Renin-Angiotensin Aldosterone System:�
. Renin & Angiotensin = vasoconstrictor�
. constricts blood vessels & increases BP�
. increases SVR or afterload�
. ACE Inhibitors blocks these effects decreasing SVR & afterload�
�
. Aldosterone = secreted from adrenal glands�
. cause sodium & water reabsorption�
. increase blood volume�
. increase preload�
. ACE I �blocks this and decreases preload�

Types�

Class I: captopril�
Class II (prodrug) : e.g., ramipril, enalapril, perindopril�
Class III ( water soluble) : lisinopril.�

Mechanism of Action�

Inhibition of circulating and tissue angiotensin- converting enzyme.�
Increased formation of bradykinin and vasodilatory prostaglandins.�
Decreased secretion of aldosterone; help sodium excretion.�

Advantages�

- Reduction of cardiovascular morbidity and mortality in patients with atherosclerotic vascular disease, diabetes, and heart failure.�
- Favorable metabolic profile.�
- Improvement in glucose tolerance and insulin resistance.�
- Renal glomerular protection effect especially in diabetes mellitus.�
- Do not adversely affect quality of life.�

Indications�
- Diabetes mellitus, particularly with nephropathy.�
- Congestive heart failure.�
- Following myocardial infraction.�

Side Effects �

- Cough (10 - 30%): a dry irritant cough with tickling sensation in the throat.�
- Skin rash (6%).�
- Postural hypotension in salt depleted or blood volume depleted patients.�
- Angioedema (0.2%) : life threatening.�
- Renal failure: rare, high risk with bilateral renal artery stenosis.�
- Hyperkalaemia�
- Teratogenicity.�

Considerations�
- Contraindications include bilateral renal artery stenosis, pregnancy, known allergy, and hyperkalaemia.�
- High serum creatinine (> 3 mg/dl) is an indication for careful monitoring of renal function, and potassium. Benefits can still be obtained in spite of renal insufficiency.�
- A slight stable increase in serum creatinine after the introduction of ACE inhibitors does not limit use.�
- ACE-I are more effective when combined with diuretics and moderate salt restriction.�
�

ACE inhibitors drugs

Captopril 50-150 mg � � ��
Enalapril 2.5-40 mg
Lisinopril 10-40 mg
Ramipril 2.5-20 �mg � � � �
Perindopril 2-8 �mg

Angiotensin Receptor Blocker �

Losartan � �25-100 mg�
Candesartan 4-32 �mg
Telmisartan 20-80 mg

Mechanism of action�

They act by blocking type I angiotensin II receptors generally, producing more blockade of the renin -angiotensin - aldosterone axis.�

Advantages�

� Similar metabolic profile to that of ACE-I.�
� Renal protection.�
� They do not produce cough.�

Indications�

Patients with a compelling indication for ACE-I and who can not tolerate them because of cough or allergic reactions.�