Atp

t cAMP

Protein kinase A

Phosphorylation of functional proteins e. g., Glycogenolysis lipolysis Ca-channel activation

Activation Phosphorylation of enzymes e. g., Contraction of smooth muscle, glandular secretion

Facilitation of ion channel opening

Transmembrane ion movements

Effect on:

e. g., Membrane action potential, homeostasis of cellular ions

B. G-Proteins, cellular messenger substances, and effects

Time Course of Plasma Concentration and Effect

After the administration of a drug, its concentration in plasma rises, reaches a peak, and then declines gradually to the starting level, due to the processes of distribution and elimination (p. 46). Plasma concentration at a given point in time depends on the dose administered. Many drugs exhibit a linear relationship between plasma concentration and dose within the therapeutic range (dose-linear kinetics; (A); note different scales on ordinate). However, the same does not apply to drugs whose elimination processes are already sufficiently activated at therapeutic plasma levels so as to preclude further proportional increases in the rate of elimination when the concentration is increased further. Under these conditions, a smaller proportion of the dose administered is eliminated per unit of time.

The time course of the effect and of the concentration in plasma are not identical, because the concentration-effect relationships obeys a hyperbolic function (B; cf. also p. 54). This means that the time course of the effect exhibits dose dependence also in the presence of dose-linear kinetics (C).

In the lower dose range (example 1), the plasma level passes through a concentration range (0 ^ 0.9) in which the concentration effect relationship is quasi-linear. The respective time courses of plasma concentration and effect (A and C, left graphs) are very similar. However, if a high dose (100) is applied, there is an extended period of time during which the plasma level will remain in a concentration range (between 90 and 20) in which a change in concentration does not cause a change in the size of the effect. Thus, at high doses (100), the time-effect curve exhibits a kind of plateau. The effect declines only when the plasma level has returned (below 20) into the range where a change in plasma level causes a change in the intensity of the effect.

The dose dependence of the time course of the drug effect is exploited when the duration of the effect is to be prolonged by administration of a dose in excess of that required for the effect. This is done in the case of penicillin G (p. 268), when a dosing interval of 8 h is being recommended, although the drug is eliminated with a half-life of 30 min. This procedure is, of course, feasible only if supramaximal dosing is not associated with toxic effects.

Futhermore it follows that a nearly constant effect can be achieved, although the plasma level may fluctuate greatly during the interval between doses.

The hyperbolic relationship be tween plasma concentration and effect explains why the time course of the effect, unlike that of the plasma concentration, cannot be described in terms of a simple exponential function. A halflife can be given for the processes of drug absorption and elimination, hence for the change in plasma levels, but generally not for the onset or decline of the effect.

A. Dose-linear kinetics
Adverse Effect
B. Concentration-effect relationship

C. Dose dependence of the time course of effect

Adverse Drug Effects

The desired (or intended) principal effect of any drug is to modify body function in such a manner as to alleviate symptoms caused by the patient's illness. In addition, a drug may also cause unwanted effects that can be grouped into minor or "side" effects and major or adverse effects. These, in turn, may give rise to complaints or illness, or may even cause death.

Causes of adverse effects: over-dosage (A). The drug is administered in a higher dose than is required for the principal effect; this directly or indirectly affects other body functions. For instances, morphine (p. 210), given in the appropriate dose, affords excellent pain relief by influencing nociceptive pathways in the CNS. In excessive doses, it inhibits the respiratory center and makes apnea imminent. The dose dependence of both effects can be graphed in the form of dose-response curves (DRC). The distance between both DRCs indicates the difference between the therapeutic and toxic doses. This margin of safety indicates the risk of toxicity when standard doses are exceeded.

"The dose alone makes the poison" (Paracelsus). This holds true for both medicines and environmental poisons. No substance as such is toxic! In order to assess the risk of toxicity, knowledge is required of: 1) the effective dose during exposure; 2) the dose level at which damage is likely to occur; 3) the duration of exposure.

Increased Sensitivity (B). If certain body functions develop hyperreactivity, unwanted effects can occur even at normal dose levels. Increased sensitivity of the respiratory center to morphine is found in patients with chronic lung disease, in neonates, or during concurrent exposure to other respiratory depressant agents. The DRC is shifted to the left and a smaller dose of morphine is sufficient to paralyze respiration. Genetic anomalies of metabolism may also lead to hypersensitivity. Thus, several drugs (aspirin, antimalarials, etc.) can provoke Lullmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.

premature breakdown of red blood cells (hemolysis) in subjects with a glucose-6-phosphate dehydrogenase deficiency. The discipline of pharmacogenetics deals with the importance of the genotype for reactions to drugs.

The above forms of hypersensitivity must be distinguished from allergies involving the immune system (p. 72).

Lack of selectivity (C). Despite appropriate dosing and normal sensitivity, undesired effects can occur because the drug does not specifically act on the targeted (diseased) tissue or organ. For instance, the anticholinergic, atropine, is bound only to acetylcholine receptors of the muscarinic type; however, these are present in many different organs.

Moreover, the neuroleptic, chlor-promazine, formerly used as a neuro-leptic, is able to interact with several different receptor types. Thus, its action is neither organ-specific nor receptor-specific.

The consequences of lack of selectivity can often be avoided if the drug does not require the blood route to reach the target organ, but is, instead, applied locally, as in the administration of parasympatholytics in the form of eye drops or in an aerosol for inhalation.

With every drug use, unwanted effects must be taken into account. Before prescribing a drug, the physician should therefore assess the risk: benefit ratio. In this, knowledge of principal and adverse effects is a prerequisite.

Adverse Effect

Effect

Decrease in Nociception Respiratory

Safety activity margin

Effect

Decrease in Nociception Respiratory

Safety activity margin

Dose

A. Adverse drug effect: overdosing

A. Adverse drug effect: overdosing

Adverse Drug Effects
B. Adverse drug effect: increased sensitivity
Blood Pressure Health

Blood Pressure Health

Your heart pumps blood throughout your body using a network of tubing called arteries and capillaries which return the blood back to your heart via your veins. Blood pressure is the force of the blood pushing against the walls of your arteries as your heart beats.Learn more...

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