PHARMA NOTES

Pharmacokinetics:

Definition:

quantitative study of absorption, distribution, metabolism, and elimination of chemicals in the body, as well as the time course of these effects.

Pharmacokinetics is the study of what the body does to a drug.

Pharmacodynamics is the study of what a drug does to the body.

Summary:
- absorption
- distribution
- metabolism
- elimination
Administration=When the drug is given

Absorption=When the drug is taken up by the body

Distribution=When the drug spreads through the body

Elimination=When the drug is removed from the body

Pharmacokinetics Principle:

Pharmacon=Medicine

Kinesis=Movement.

• Concentration of a drug at its site of action is a fundamental determinant of its pharmacologic effects.

• Drugs are transported to and from their sites of action in the blood – because of that: the concentration at the active site is a function of the concentration in the blood.

• The change in drug concentration over time in the blood, at the site of action, and in other tissues is a result of complex interactions of multiple biologic factors with the physicochemical characteristics of the drug.

Pharmacokinetic Concepts: Rate Constants and Half-Lives

• Disposition of most drugs follows first-order kinetics – a constant fraction of the drug is removed during a finite period of time.
• The absolute amount of drug removed is proportional to the concentration of the drug
• In first-order kinetics, the rate of change of the concentration at any given time is proportional to the concentration present at that time.
• When the concentration is high, it will fall faster than when it is low.

• First-order kinetics apply not only to elimination, but also to absorption and distribution.

Half-Lives

• The rapidity of pharmacokinetic processes is often described with half-lives

• Half-Life = the time required for the concentration to change by a factor of 2.
• 
  Half-Life = the period of time required for the concentration or amount of drug in the body to be reduced to exactly one-half of a given concentration or amount.

• Half-Life = the time required for half the quantity of a drug or other substance deposited in a living organism to be metabolized or eliminated by normal biological processes. Also called biological half-life.

Drug Elimination:

• Elimination = all the various processes that terminate the presence of a drug in the body.

• Processes:
  - metabolism
  - renal excretion
  - hepato-biliary excretion
  - pulmonary excretion (inhaled anesthetics mainly)
  - other: saliva, sweat, breast milk, tears

Renal Excretion:

• Both metabolically changed and unchanged drugs
• LMW substances: filtered from blood through the Bowman membrane of the capsule
• Some: actively secreted
• Reabsorption in the tubule: depending on the lipid solubility, degree of ionization, molecular shape, carrier mechanism (for some).
• Weak acid: best reabsorbed from an acidic urine.
  Important to know if the drug is dependent on renal function or excretion.

Hepatobiliary Excretion:

• Drugs metabolites – excreted in the intestinal tract with the bile.
• Majority: reabsorbed into the blood and excreted through urine. (enterohepatic cycle).
• Poorly lipid-soluble organic compounds – at least three active transport mechanisms

Pulmonary Excretion:

• Volatile anesthetics and anesthetic gases: in large part eliminated unchanged through the lung
• The factors that determine uptake operate in reverse manner

DRUG ABSORPTION AFTER ORAL ADMINISTRATION:

First Order Kinetics:

A constant fraction of the drug in the body is eliminated per unit time. The rate of elimination is proportional to the amount of drug in the body. The majority of drugs are eliminated in this way.

The Volume of Distribution (Vd) is the amount of drug in the body divided by the concentration in the blood. Drugs that are highly lipid soluble, such as digoxin, have a very high volume of distribution (500 litres). Drugs which are lipid insoluble, such as neuromuscular blockers, remain in the blood, and have a low Vd.

The Clearance (Cl) of a drug is the volume of plasma from which the drug is completely removed per unit time. The amount eliminated is proportional to the concentration of the drug in the blood.

The fraction of the drug in the body eliminated per unit time is determined by the elimination constant (kel). This is represented by the slope of the line of the log plasma concentration versus time.

Cl = kel x Vd

Rate of elimination = clearance x concentration in the blood.

Elimination half life (t1/2): the time taken for plasma concentration to reduce by 50%. After 4 half lives, elimination is 94% complete.

It can be shown that the kel = the log of 2 divided by the t1/2 = 0.693/t1/2.

Likewise, Cl = kel x Vd, so, Cl = 0.693Vd/t1/2.

And t1/2 = 0.693 x Vd / cl

The rate of elimination is the clearance times the concentration in the plasma

Roe = Cl x Cp

Fraction of the total drug removed per unit time = Cl/Vd.

If the volume of distribution is increased, then the kel will decrease, the t1/2 will increase, but the clearance won't change.

Confused?

Example: You have a 10ml container of orange squash. You put this into a litre (ok 990ml!) of water. The Vd of the orange squash is 1000ml. If, each minute, you empty 10ml of the orange liquid into the 10ml container, discard this, and replace it with 10ml of water. The clearance is 10 ml per minute. The elimination half life is: 70 minutes . The kel is Cl/Vd = 10/1000 = 0.01. Shown the other way, 0.693/50 = 0.01.

If the volume of the container is increased to 2000ml, then the clearance remains the same, but the Vd, and consequently the t1/2, increases (to 140 minutes).

Simple, isn't it?

What is described above is a single compartment model, what would occur if the bloodstream was the only compartment in the body (or if the Vd = the blood volume). But the human body is more complex than this: there are many compartments: muscle, fat, brain tissue etc. In order to describe this, we use multicompartment models.

Multicompartment Models:

Why does a patient wake up after 5 minutes after an injection of thiopentone when we know that it takes several hours to eliminate this drug from the body? What happens is that, initially the drug is all in the blood and this blood goes to "vessel rich" organs; principally the brain. After a few minutes the drug starts to venture off into other tissues (fat, muscle etc) it redistributes, the concentration in the brain decreases and the patient wakes up! The drug thus redistributes into other compartments.

If you were to represent this phenomenon graphically, you would follow a picture of rapid fall in blood concentration, a plateau, and then a slower gradual fall. The first part is the rapid redistribution phase, the alpha phase, the plateau is the equilibrium phase (where blood concentration = tissue concentration), and the slower phase, the beta phase, is the elimination phase where blood and tissue concentrations fall in tandem. This is a simple two compartment model and is as much as you need to know.

An couple of interesting pieces of information can be derived from the log concentration versus time graph. If you extrapolate back the elimination line to the y axis, then you get to a point called the CP0 - a theoretical point representing the concentration that would have existed at the start if the dose had been instantly distributed (dose/Vd). From this new straight line you can figure out how long it takes for the concentration to drop by 50%: the elimination half life. Likewise, a similar procedure can be performed on the α phase: the redistribution half life.

While it is very important that you understand these concepts, the reality is that most drugs are infinitely more complicated that this, and computer calculations are required to derive this data.

Bioavailability:

This is the fraction of the administered dose that reaches the systemic circulation. Bioavailability is 100% for intravenous injection. It varies for other routes depending on incomplete absorption, first pass hepatic metabolism etc. Thus one plots plasma concentration against time, and the bioavailability is the area under the curve.

Zero Order Elimination:

Why if I have 10 pints (PINT= Unit of volume in the U.K) of beer before midnight will I fail a breathalyser (Braeth Analyser) test at 8 am the following morning? Either this is due to alcohol having a very long half life (which it does not) or that alcohol is cleared in a different way.

What happens is that the metabolic pathways responsible for alcohol metabolism are rapidly saturated and that clearance is determined by how fast these pathways can work. The metabolic pathways work to their limit. This is known as zero order kinetics: a constant amount of drug is eliminated per unit time. This form of kinetics occours with several important drugs at high dosage concentrations: phenytoin, salicylates, theophylline, and thiopentone (at very large doses). Because high dose thio is very slow to clear, we no longer use it in infusion for status epilepticus (as it takes ages for the patient to wake up!).

=================================================================

Cardiac Uses of β-blockers (CARDIOSELECTIVE ):
1. Mild to Moderate Hypertension
2. Angina Pectoris.
3. Arrhythmias
4. prophylaxis of MI (Post MI)
5. hypertrophic obstructive cardiomyopathy (Heart disease characterised by thickening of the internal heart muscle and a blockage inside the heart)

Non-Cardiac Uses:

1. Thyrotoxicosis
2. Migraine
3. Glucoma
4. Essential tremon
5. Anxiety.
6. Pre-surgical management of adrenal gland tumours (phaeochromocytoma), but only in combination with an alpha blocking medicine

Role of Propranolol in thyrotoxicosis:

The clinical manifestations of hyperthyroidism have suggested to physicians for many years that the sympathetic nervous system may be involved in their production. Despite this, the precise interrelationship between the thyroid gland and the sympathetic nervous system has never been defined but controlled investigations have shown that hypersensitivity to catcholamines does not occur in animals or man with artificially produced thyrotoxicosis.

In recent years beta-adrenoceptor blocking drugs, and in particular propranolol, have been used in patients with hyperthyroidism. Evidence exists that they control some of the peripheral manifestations of the disease, including nervousness, palpitations, tachycardia, increased cardiac output and tremor, but they do not appear to affect the underlying thyrotoxic process itself.

Propranolol has been used with sucess in the treatment of
1. acute hyperthyroid crisis Or Thyroid Storm:

40 mg orally 6 hourly or,

1mg slowly I.V (not exceeding 1mg/min.)
It rapidly decreases heart rate, usually within 2 to 3 h when given orally and within minutes when given IV.

2. In tachycardia or atrial fibrillation with thyrotoxicosis, particularly in elderly, because antithyroid drugs usually take several weeks to become fully effective.

3. in pre-operative preparations for thyroidectomy,

4. for the control of symptoms and signs following the administration of radioactive iodine therapy and antithyroid drugs,

5. during the period of diagnostic thyroid investigations and

6. occasionally as the sole therapy.

•