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Pharmacology

Thrombolytic Agents:

Tissue Plasminogen Activator (t-PA, Activase)

t-PA is a serine protease. It is a poor plasminogen activator in the absence of fibrin. t-PA binds to fibrin and activates bound plasminogen several hundred-fold more rapidly than it activates plasminogen in the circulation.

Streptokinase (Streptase)

Streptokinase is a protein produced by β-hemolytic streptococci. It has no intrinsic enzymatic activity, but forms a stable noncovalent 1:1 complex with plasminogen. This produces a conformational change that exposes the active site on plasminogen that cleaves a peptide bond on free plasminogen molecules to form free plasmin.

Urokinase (Abbokinase)

Urokinase is isolated from cultured human cells.Like streptokinase, it lacks fibrin specificity and therefore readily induces a systemic lytic state. Like t-PA, Urokinase is very expensive.

Contraindications to Thrombolytic Therapy:

• Surgery within 10 days, including organ biopsy, puncture of noncompressible vessels, serious trauma, cardiopulmonary resuscitation.

• Serious gastrointestinal bleeding within 3 months.

• History of hypertension (diastolic pressure >110 mm Hg).

• Active bleeding or hemorrhagic disorder.

• Previous cerebrovascular accident or active intracranial bleeding.

Aminocaproic acid:

Aminocaproic acid prevents the binding or plasminogen and plasmin to fibrin. It is a potent inhibitor for fibrinolysis and can reverse states that are associated with excessive fibrinolysis.

Flucloxacillin, important even now for its resistance to beta-lactamases produced by bacteria such as Staphylococcus species. It is still no match for MRSA (Methicillin Resistant Staphylococcus aureus).

The last in the line of true penicillins were the antipseudomonal penicillins, such as ticarcillin, useful for their activity against Gram-negative bacteria

Antianginal Drugs

Organic Nitrates :
Short acting: Glyceryl trinitrate (Nitroglycerine, GTN), Amyl Nitrate
Long Acting: Isosrbide dinitrate (Short acting by sublingual route), Erythrityl tetranitrate, penta erythrityl tetranitrate

Beta-adrenergic blocking agents : Propanolol, Metoprolol
Calcium channel blockers Verapamil, Nifedipine, Dipyridamole
 
Mechanism of action 
– Decrease myocardial demand 
– increase blood supply to the myocardium

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.)

Codeine

Codeine is methyl morphine, with a methyl substitution on the phenolic hydroxyl group of morphine. It is more lipophilic than morphine and thus crosses the blood–brain barrier faster.

  • classified as a simple, or mild analgesic, codeine is often used in low doses as an oral analgesic has a much better oral/parenteral absorption ratio than morphine.
  • Effective for mild to moderate pain.
  • Constipation occurs
  • Dizziness may occur in ambulatory patients.
  • More potent histamine-releasing action than does morphine.
  • Should not be administered by IV injection.
  • Extremely effective antitussive agent and is used therapeutically for suppressing cough.
  • In contrast to morphine, codeine overdose can occasionally lead to the production of seizures.
  • Seizures can be treated with barbiturates.
  • Respiratory depression can be counteracted with Naloxone.
  • orally, 30 mg of codeine is equi-analgesic to 600 mg of aspirin, however, the effects of the two are additive, and occasionally synergistic

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