Rofecoxib

Inhibit prostacyclin(PGI2) in vascular  endothelium , letting TXA2 act freely and  promote platelet aggregation. 

used in the treatment of osteoarthritis, acute pain conditions, and dysmenorrhea

Higher incidence of cardiovascular thrombotic  events.

Not used due to increase risk of heart attack, stroke

Morphine

Morphine is effective orally, but is much less effective than when given parenterally due to first-pass metabolism in the liver. Metabolism involves glucuronide formation, the product of which is excreted in the urine.

1. Central Nervous System Effects

• Morphine has mixed depressant and stimulatory actions on the CNS.

• Analgesia:

• Dysphoria – Euphoria

- morphine directly stimulates the chemoreceptor trigger zone, but later depresses the vomiting center in the brain stem. This center is outside the blood/brain barrier.

- opiates appear to relieve anxiety

• Morphine causes the release of histamine and abolishes hunger.

- causes the body to feel warm and the face and nose to itch.

• Pupils are constricted.- due to stimulation of the nuclei of the third cranial nerves.

- tolerance does not develop to this effect.

• Cough reflex is inhibited. - this is not a stereospecific effect.

- dextromethorphan will suppress cough but will not produce analgesia.

• Respiration is depressed

- due to a direct effect on the brain stem respiratory center.

- death from narcotic overdose is nearly always due to respiratory arrest.

- the mechanism of respiratory depression involves:

• a reduction in the responsiveness of the brain stem respiratory centers to an increase in pCO₂.

• depression of brain stem centers that regulate respiratory rhythm.

- hypoxic stimulation of respiration is less affected and O2 administration can produce apnea.

2. Cardiovascular Effects

• Postural orthostatic hypotension.- due primarily to peripheral vasodilation, which may be due in part to histamine release.

• Cerebral circulation is also indirectly influenced by increased pCO2, which leads to cerebral vasodilation and increased cerebrospinal fluid pressure.

• In congestive heart failure, morphine decreases the left ventricular workload and myocardial oxygen demand.

3. Endocrine Effects

• Increases prolactin secretion

• Increases vasopressin (ADH) secretion

• Decreases pituitary gonadotropin (LH & FSH) secretion.

• Decreases stress induced ACTH secretion.

4. Gastrointestinal Tract Effects

• Constipation (tolerance does not develop to this effect).

• Several of these agents can be used in the treatment of diarrhea.

There is an increase in smooth muscle tone and a decrease in propulsive  contractions.

Adverse Reactions

Generally direct extensions of their pharmacological actions.

1. respiratory depression, apnea

2. nausea and vomiting

3. dizziness, orthostatic hypotension, edema

4. mental clouding, drowsiness

5. constipation, ileus

6. biliary spasm (colic)

7. dry mouth

8. urine retention, urinary hesitancy

9. hypersensitivity reactions (contact dermatitis, urticaria)

Precautions

1. respiratory depression, particularly in the newborn

3. orthostatic hypotension

4. histamine release (asthma, shock)

5. drug interactions (other CNS depressants)

6. tolerance:

- analgesia, euphoria, nausea and vomiting, respiratory depression

7. physical dependence (psychological & physiological)

Classification

I) Esters

 1. Formed from an aromatic acid and an amino alcohol.

 2. Examples of ester type local anesthetics:

 Procaine

Chloroprocaine

Tetracaine

Cocaine

Benzocaine- topical applications only

2) Amides

 1. Formed from an aromatic amine and an amino acid.

 2. Examples of amide type local anesthetics:

Articaine

Mepivacaine

Bupivacaine

Prilocaine

Etidocaine

Ropivacaine

Lidocaine

Osmotic diuretics

An osmotic diuretic is a type of diuretic that inhibits reabsorption of water and sodium. They are pharmacologically inert substances that are given intravenously. They increase the osmolarity of blood and renal filtrate.

Mechanism(s) of Action

1.    Reduce tissue fluid (edema) 
2.    Reflex cardiovascular effect by osmotic retention of fluid within vascular space which increases blood volume (contraindicated with Congestive heart failure) 
3.    Diuretic effect

o    Makes H2O reabsorption far more difficult for tubular segments insufficient Na & H2O capacity in distal segments
o    Increased intramedullary blood flow (washout)
o    Incomplete sodium recapture (asc. loop). this is indirect inhibition of Na reabsorption (Na stays in tubule because water stays) 
o    Net diuretic effect: 
    Tubular concentration of sodium decreases 
    Total amount of sodium lost amount increases 
    GFR unchanged or slightly increased

Toxicity

Circulatory overload, dilutional hyponatremia,  Hyperkalemia, edema, skin necrosis

Agents
Mannitol

A. Sympathetic Nervous System Depressants

1. Antagonists

Both α-adrenoceptor antagonists and β-adrenoceptor antagonists are useful  antihypertensives.

• α-blocker                     Prazosin, phentolamine, phenoxybenzamine
• β-blocker                     Propranolol ,Metoprolol, atenolol
• α/β-blocker                  labetalol

2. Sympathetic depressants

a. Examples of peripherally acting agents include

• reserpine This agent interferes with the storage of norepinephrine
• quanethidine This agent interferes with the release of norepinephrine
• trimethaphan This agent blocks transmission through autonomic ganglia.

b. Examples of Centrally acting agents include

• alphamethyldopa
• clonidine. These agents act by decreasing the number of impresses along sympathetic nerves.

Adverse Effect

include nasal congestion, postural hypotension, diarrhea, sexual dysfunction, dry mouth. sedation and drowsiness.

B. Directly Acting Vasodilators

Act on vascular smooth muscle cells independently of adrenergic nerves and adrenergic receptors.

Relaxation of vascular smooth muscle which leads to a decrease in peripheral vascular resistance.

Sites of action of vasodilators are many. For example

 Calcium Channel Blocker’s  MOA

. Decrease automaticity & conduction thru SA & AV nodes

. Decreased myocardial contractility

. Decreased peripheral & coronary 

smooth muscle tone = decrease SVR

Potassium channels activators

minoxidil, cause vasodilation by activating potassium channels in vascular smooth muscle.

An increase in potassium conductance results in hyperpolarization of the cell membrane which is associated with relaxation of smooth muscle.

Nitrovasodilators, such as sodium nitroprusside,

Increase in intracellular cGMP. cGMP in turn activates a protein kinase. Directly-Acting Vasodilators are on occasion used alone but more frequently are used in combination with antihypertensive agents from other classes (esp. a β-blocker and a diuretic.)

PLASMA FRACTIONS:

a) Fresh frozen plasma.

b) Platelets.

c) Plasma concentrates.

d) Non-plasma recombinant factor concentrates.