PHARMACOLOGY Lecture four
The pharmacokinetic profile of a drug also depends on its mode of administration.Example: Intravenous Infusions EMBED PowerPoint.Slide.8
With continuous intravenous infusion, the rate of drug entry into the body is constant. In the majority of cases, Plasma concentration rises until elimination = inputFaster infusions get more drugs on board, but does not change the time to achieve a steady state. The rate of approach to steady state is not affected by the rate of drug infusion. Although increasing the rate of infusion of a drug increases the rate at which any given concentration of drug in the plasma is achieved, it does not influence the time required to reach the ultimate steady-state concentration. This is because the steady-state concentration of drug rises directly with the infusion rate
Example: Intravenous Injection
EMBED PowerPoint.Slide.8Peak plasma concentration of the drug is achieved at time = 0
There is no steady state concentration. Why?
Example: Oral Dose
EMBED PowerPoint.Slide.8
A single oral dose will give you a single peak plasma concentration
The drug concentration then continuously declines
Repeated doses result in oscillations in plasma concentration.
Notes: Most drugs that are administered on an outpatient basis are taken orally on a fixed-dose fixed-time interval regimen, for example, a specific dose, taken one, two or three times daily. In contrast to intra-venous injection, orally administered drugs may be absorbed slowly, and the plasma concentration of the drug is influenced by both the rate of absorption and the rate of drug elimination.
When a drug is given repeatedly at regular intervals, the plasma concentration increases until a steady state is reached (Figure 2.5). Because most drugs are given at intervals shorter than 5 half-lives and are eliminated exponentially with time, some drug from the first dose remains in the body at the time that the second dose is administered, and some from the second dose at the time that the third is given and so forth. Therefore, the drug accumulates until, within the dosing interval, the rate of drug loss (driven by elevated plasma concentration) exactly balances the rate of drug administration, that is, a steady state is achieved.
Plasma half life of a drug (t ):
It is the time needed for drug concentration in the plasma to decline by one half. It depends on drug clearance and is a measure for drug elimination.
Half-life (t1/2) is important to indicate the time required to attain steady state, which is reached after 4-5 t1/2. It is constant in first order kinetic and is increased in zero order kinetic.
Types of drug elimination kinetics
* First order kinetics: where the rate of absorption, metabolism or elimination is exponential, i.e., a constant proportion of drug is absorbed, metabolized or eliminated depending on the drug concentration. It is a linear type of kinetic and t1/2 is constant.
* Zero order kinetics: where a constant number of moles are absorbed or eliminated irrespective of the total amount present. It can occur whenever absorption or elimination is saturated. It is a non-linear kinetic and t1/2 will increase with dose. It is common with phenytoin, salicylates and ethyl alcohol.
Selectivity-refers to the effects that the medication precipitates-medications rarely produce a single effect, most produce multiple effects
Drug selectivity is best described by discussing the pattern and incidence of adverse ant toxic effects that are produced by a therapeutic dose of the medication. The proportion of clients who had to lower the dosage or discontinue the medication because of these effects is also summarized.
Therapeutic dose-produces the desired effect
non-therapeutic dose-too high or too low-will not
Therapeutic index-describes the relative safety of a drug. A drugs therapeutic index is equal to the lethal dose divided by the effective dose.
LD50: lethal dose 50, or dose that kill50 percent of the animals tested.
Therapeutic index
Therapeutic Index = LD50
ED50
As long as the slopes of the curves are similar, however, if not similar, we use the Standard Margin of safety:
Standard Margin of safety = LD11 x 100
ED99EMBED PowerPoint.Slide.12
Which determines the percent to which the dose effective in 99% of the population must be raised to cause toxicity in 1% of the population.Variation in drug responsiveness
Individuals may vary considerably in their responsiveness to a drug
Idiosyncratic drug response unusual, one that is infrequently observed in most patientsCaused by:
Genetic differences in metabolism
Immunologic mechanism (allergy)
tolerance
Hyporeactive intensity of effect is decreased
Hyperreactive intensity of effect is increased
Hypersensitivity allergic or other immunologic response to drugs resulting from previous sensitizing exposure
Tolerance responsiveness usually decreases as a consequence of continued drug administration.
Need greater doses of a drug to produce original degree of effect as time progresses or need to substitute different drug
Tachyphylaxis responsiveness diminishes rapidly after administration of a drug (the first few doses), very rapid
Variation in drug responsiveness Patients may differ in the rate of absorption of a drug, in distributing it through body compartments, or in clearing the drug from the blood which may alter the concentration of drug that reaches receptor
This can be due to age, weight, sex, disease state, liver and kidney function, and genetic differences
Variation in drug responsiveness Four general mechanisms:
1. Patients may differ in the rate of absorption of a drug, in distributing it through body compartments, or in clearing the drug from the blood which may alter the conc of drug that reaches receptor.This can be due to age, weight, sex, disease state, liver and kidney function, and genetic differences.
2. Patients may vary in their concentrations of endogenous receptor ligand
Can vary in the response to pharmacologic antagonist
Ex: Propranolol (β blocker)
Pt with pheochromocytoma opposed to healthy runner
3. Patients may have differences in the number of receptor sites or differ in the function of their receptors due to the efficiency of coupling receptor to effector
Drug Induced down-regulation
The overshoot phenomena
Antagonists when discontinued, the elevated number of receptors can produce an exagerated response to physiologic conc of agonist
Agonist when discontinued, # of receptors that have been dec by down regulation is too low for endogenous agonist to produce effective stimulation
Ex: Clonidine (α agonist) decreases blood pressure. When withdrawn, can produce hypertensive crisis. Pt will have to be weaned slowly
4-Patients vary in functional integrity of biochemical processes in the responding cell and physiologic regulation by interacting organ systems
Can be caused by age of pt or general health of pt. Most importantly, severity and pathophysiologic mechanism of the disease
Drug therapy will be most successful when there is correct diagnosis and if it is accurately directed at the pathophysiologic mechanism responsible for the disease
Why Do We Study Pharmacology?
A. Its good for youB. You will be able to use fancy terms like bioavailabilty
C. My instructor likes torture
D. A competent dentist must understand why his/her patient is getting a medication, and HOW IT WORK