Pharmacokinetics

Pharmacokinetics is the way that the body deals with a drug - how that drug moves throughout the body, and how the body metabolizes and excretes it.  The factors and processes involved in pharmacokinetics must be considered when choosing the most effective dose, route and schedule for a drug's use.

The four processes involved in pharmacokinetics are:

Absorption:  The movement of a drug from its site of administration into the blood.

Several factors influence a drug's absorption:

• Rate of Dissolution:  the faster a drug dissolves the faster it can be absorbed, and the faster the effects will begin.
• Surface Area:  Larger surface area = faster absorption.
• Blood Flow:  Greater blood flow at the site of drug administration = faster absorption.
• Lipid Solubility:  High lipid solubility = faster absorption
• pH Partitioning:  A drug that will ionize in the blood and not at the site of administration will absorb more quickly.

Distribution:  The movement of drugs throughout the body.

Metabolism:  (Biotransformation) The enzymatic alteration of drug structure.

Excretion:  The removal of drugs from the body.

As a drug moves through the body, it must cross membranes.  Some important factors to consider here then are:

Body's cells are surrounded by a bilayer of phospholipids (cell membrane).

There are three ways that a substance can cross cell membranes:

• Passing through channels and pores: only very small molecules can cross cell membranes this way.

• Transport Systems:   Selective carriers that may or may not use ATP.

• Direct Penetration of the Cell Membrane: 

Local Anesthetics

1. Procaine (Novocaine)

a) Classic Ester type agent, first synthetic injectable local anesthetic.

 b) Slow onset and short duration of action

 2. Tetracaine (Pontocaine)

a) Ester type agent--ten times as potent and toxic as procaine.

 b) Slow onset but long duration of action.

 c) Available in injectable and topical applications.

 3. Propoxycaine (Ravocaine)

a) Ester type agent–five times as potent and toxic as procaine.

 b) Often combined with procaine to increase duration of action.

 4. Lidocaine (Xylocaine)

a) Versatile widely used amide type agent.

 b) Two - three times as potent and toxic as procaine.

 c) Rapid onset and relatively long duration of action.

 d) Good agent for topical application.

 5. Mepivacaine (Carbocaine)

a) Amide type agent similar to lidocaine.

 b) Without vasoconstrictor has only short duration of action.

6. Prilocaine (Citanest)

a) Amide type agent — less potent than lidocaine.

 b) Without vasoconstrictor has only short duration of action.

 c) Metabolized to o-toluidine which can cause methemoglobinemia — significant only with large doses of prilocaine.

 d) Higher incidences of paresthesia reported with 4 % preparation

7. Bupivacaine (Marcaine)

a) Amide type agent of high potency and toxicity.

 b) Rapid onset and very long duration of action even without vasoconstrictor.

 8. Articaine (Septocaine)

a) Amide type agent

 b) Only amide-type local anesthetic that contains an ester group, therefore metabolized both in the liver and plasma.

 c) Approved by the FDA in 2000

 d) Evidence points to improved diffusion through hard and soft tissues as compared to other local anesthetics.

 e) Reports of a higher incidence of paresthesia, presumably due to the 4% concentration

 f) Not recommended for use in children under 4 years of age

Organic Nitrates 
Relax smooth muscle in blood vessel
Produces vasodilatation
– Decreases venous pressure and venous return to the heart  Which decreases the cardiac work load and oxygen demand. 
– May have little effect on the coronary arteries CAD causes stiffening and lack of 
–    responsiveness in the coronary arteries 
– Dilate arterioles, lowering peripheral vascular resistance  Reducing the cardiac workload

Main effect related to drop in blood pressure by
– Vasodilation- pools blood in veins and capillaries, decreasing the volume of blood that the heart has to pump around (the preload)
– relaxation of the vessels which decreases the resistance the heart has to pump against (the afterload) 

Indications
- Myocardial ischemia 
– Prevention
– Treatment 

Nitroglycerin (Nitro-Bid)
• Used
– To relive acute angina pectoris 
– Prevent exercise induced angina 
– Decrease frequency and severity of acute anginal episodes

Type 
• Oral - rapidly metabolized in the liver only small amount reaches circulation 
• Sublingual – Transmucosal tablets and sprays 
• Transdermal  – Ointment s 
– Adhesive discs applied to the skin
• IV preparations 

Sublingual Nitroglycerine 
•  Absorbed directly into the systemic circulation,  Acts within 1-3 minutes , Lasts 30-60 min 

Topical Nitroglycerine 
• Absorbed directly into systemic circulation,   Absorption at a slower rate. ,  Longer duration of action 
Ointment - effective for 4-8 hours 
Transdermal disc - effective for 18-24 hours 

Isosorbide dinitrate 
• Reduces frequency and severity of acute anginal episodes
• Sublingual or chewable acts in 2 min. effects last 2-3 hours
• Orally, systemic effects in about 30 minutes and last about 4 hours after oral administration
    
Tolerance to Long-Acting Nitrates 
• Long-acting dosage forms of nitrates may develop tolerance
– Result in episodes of chest pain
– Short acting nitrates less effective 

Prevention of Tolerance 
• Use long-acting forms for approximately 12-16 hours daily during active periods and omit them during inactive periods or sleep 
• Oral or topical should be given every 6 hours X 3 doses allowing a rest period of 6 hours

Isosorbide dinitrate (Isordil, Sorbitrate) is used to reduce the frequency and severity of acute anginal episodes.
When given sublingually or in chewable tablets, it acts in about 2 minutes, and its effects last 2 to 3 hours. When higher doses are given orally, more drug escapes metabolism in the liver and produces systemic effects in approximately 30 minutes. Therapeutic effects last about 4 hours after oral administration

Isosorbide mononitrate (Ismo, Imdur) is the metabolite and active component of isosorbide dinitrate. It is well absorbed after oral administration and almost 100% bioavailable. Unlike other oral nitrates, this drug is not subject to first-pass hepatic metabolism. Onset of action occurs within 1 hour, peak effects occur between 1 and 4 hours, and the elimination half-life is approximately 5 hours. It is used only for prophylaxis of angina; it does not act rapidly enough to relieve acute attacks.

Roxithromycin

It is used to treat respiratory tract, urinary and soft tissue infections. Roxithromycin is derived from erythromycin, containing the same 14-membered lactone ring. However, an N-oxime side chain is attached to the lactone ring.

Roxithromycin has similar antimicrobial spectrum as erythromycin, but is more effective against certain gram-negative bacteria, particularly Legionella pneumophilae.

When taken before a meal, roxithromycin is very rapidly absorbed, and diffused into most tissues and Phagocytes Only a small portion of roxithromycin is metabolised. Most of roxithromycin is secreted unchanged into the bile and some in expired air

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.

Glucocorticoids 
Cortisol (hydrocortisone) and its synthetic derivatives 

Mechanism 

↓ the production of leukotrienes and prostaglandins   - inhibits phospholipase A2 , inhibits expression of COX-2 , will also stimulate the bone marrow to produce neutrophils resulting in leukocytosis 

halts inflammatory cascade 

↓ leukocyte migration
↓ capillary permeability
↓ phagocytosis
↓ platelet-activating factor
↓ interleukins (e.g. IL-2)

may trigger apoptosis in dividing and non-dividing cells

used in cancer chemotherapy

Clinical use

anti-inflammatory
immunosuppression
cancer chemotherapy (prednisone most common)
CLL
Hodgkin's lymphomas
part of MOPP regimen
Addison disease
asthma

Toxicity

1) must taper dose to avoid toxicity
2) suppression of ACTH → shock state if abrupt withdrawal - > cortical atrophy, malaise, myalgia, arthralgia, fever
3) iatrogenic Cushing  syndrome ->buffalo hump, moon facies, truncal obesity, muscle weakness and atrophy, thin skin, easy bruising, acne
4) osteoporosis - vertebral fractures, aseptic hip necrosis, ↓ skeletal growth in children 
5) hyperglycemia (diabetes) -due to ↑ gluconeogenesis , glaucoma, cataracts, and other complications can subsequently result
6) ↑ GI acid release -ulcers
7) Na+ retention -> edema, HTN, hypokalemia alkalosis, hypocalcemia
8)↓ wound healing
9) ↑ infections
10) mental status changes
11) cataracts