1 Principles of therapy

Part 1

Principles of therapy

Focke Ziemssen MD, Manfred Zierhut MD


“Pharmacodynamics” can be defined as the quantitative relationship between the observed tissue concentration of the active drug and its pharmacologic effects. In contrast to pharmacokinetics, which describe how the body interacts with a drug, pharmacodynamic models predict what the drug does to the body. Ocular pharmacodynamics is therefore not just an abstract issue. Knowing how a substance causes the response, which pathways are involved and which cell will be affected is of the utmost importance not only in drug development, but also when applying a drug. Exact understanding of the concentration-dependent response for an individual patient provides more precise information for deciding how to dose. The main challenge in designing a drug dosage regimen is the variability that exists from patient to patient.

Extensive studies and clear specifications have to be made during the approval process of a drug. The effect of a formulation might vary with its dosage, the affected tissue and confounding comorbidity. Because some of the different reactions to a molecule are not known at the time of approval, caution is important when treating understudied populations such as women, minorities and patients who have multiple health problems or preexisting medication.

Initially, the term “receptor” was introduced as an abstract model, before any molecular structure had been exactly identified (Langley 1904). The leading aspect of the receptor is the quantitative relationship between drug dose and the pharmacological effect.

Where does the drug act?

The target of the active agent is not necessarily the body itself but e.g. a foreign organism, as is the case in antibiotics. The action of the drug can be initiated either by extracellular localization or by intracellular binding. Very often, membrane proteins, forming receptors (beta-blockers) and ion channels (glutamate receptor antagonists), are the target structures of a drug. There are also examples of drugs targeting structures of the intracellular compartment, e.g. the cytoskeleton (taxanes).

Many drugs make an impact on enzymatic activity (inhibitors of carboanhydrase). However, more and more substances are developed that influence promoter regions of the DNA or directly interfere with transcriptional activity. By binding the messenger RNA, small aptamers can prevent syntheses of new proteins.

Biotechnological engineering enables the design of drugs that are specifically directed against a cytokine, a surface receptor or a key step in signal transduction. The invention of the so-called “biologicals” has revolutionized the opportunity to intervene more specifically with particular reactions by focusing on single pathophysiological sequences. In terms of toxicity, these treatment modalities bear the risk of antigenicity. When using fully humanized proteins, specific autoantibodies can provoke loss of function. If biotechnological synthesis leaves residuals of different species, anaphylactic reactions can occur during treatment with foreign proteins.

Besides the receptor-mediated effects, mechanisms that are caused by chemical or physical interaction also have to be considered. Ophthalmologic examples are the rinsing solutions neutralizing the ocular surface after alkali burn injuries.

In reality, some drugs may have several mechanisms of actions; e.g. it is possible to distinguish a fast from a slower effect. For example, the delayed decline in the intraocular pressure by prostaglandins seems to be related to collagen degradation after the activation of metal-matrix proteases. In contrast, the early decrease in intraocular pressure within the first hours was assigned to relaxation of the trabecular meshwork after inhibition of a Ca2+-dependent contraction (Thieme et al 2006).

Nonspecific effects are typically mediated through a generalized effect in many organs, and the response observed depends on the distribution of the drug. It must be appreciated that many drugs exist whose sites of action have not been elucidated in detail. Furthermore, many drugs are known to bind to plasma proteins as well as to various cellular compartments, without producing any obvious physiological effect.

How does a drug interact with its target?

A variety of different types of drug actions exists. Accordingly, drugs can be classified into specific categories such as agonists, antagonists, partial agonists, inverse agonists, allosteric modulators and enzyme inhibitors or activators.

Agonists bind to a receptor or site of action and produce a conformational change, which mimics the action of the normal physiological binding ligand. At low concentrations, the activity of the drug can be additive to the natural ligand. The affinity of the drug to the receptor ultimately determines the con­centration necessary to produce a response. The presence of spare receptors becomes an important point when considering changes in the numbers of available receptors resulting from adaptive responses in chronic exposure or irreversible binding. The effect of a drug is thought to be proportional to the number of occupied receptors. Drug antagonists bind either to the receptor itself or to a component of the effector mechanism, which then prevents the agonist’s action. If the antagonist-mediated inhibition can be overcome by increasing agonist concentration, ultimately reaching the same maximal effect, the antagonist is termed competitive (Fig. 1.1). In contrast, a noncompetitive agonist will prevent the agonist from producing a maximal effect. If the antagonist is reversible and binds at the active site, the inhibition will be competitive.

However, often the rate of binding/dissociation is not so important in determining the onset or termination of the elicited effect because such behavior mostly depends on the delivery and distribution.

Antagonists bind to the receptor without eliciting the necessary conformational changes required to produce the response effect. These drugs block access to the receptor. Most antagonists shift the dose-response curve to the right but do not alter the magnitude of the maximum response. Functional antagonism is defined as antagonism of tissue response that is unrelated to blockade at receptors but instead represents blockade at a site distal to receptors. Functional antagonists may affect second messenger production. Nonspecific antagonism might depress all cellular excitability, e.g. by energy charge.

Receptors and signal cascades

A receptor is a macromolecule whose biological function changes when a drug binds to it. Most drugs produce their pharmacological effects by binding to specific receptors in target tissues. Affinity is the measure of the propensity of a drug to bind to a receptor and depends on the force of attraction between drug and receptor. There are different structural and functional classifications of receptors, but generally speaking there are just a few functional families whose members share both common mechanisms of action and similarities in molecular structure. There are at least four main types.

Type 1 receptors are typically located in a membrane and are directly coupled to an ion channel. Receptors for several neurotransmitters send their signals by altering a cell’s membrane potential or its ionic composition. This group includes nicotinic cholinergic receptors and γ-aminobutric acid receptors. These receptors are all multiple subunit proteins arranged symmetrically to form a channel.

Type 2 receptors are also located in a membrane and are coupled by a G protein to an enzyme or channel. There is a large family that utilizes heterotrimeric guanosine 5′-triphosphate (GTP)-binding regulatory proteins. Ligands for G-protein receptors include eicosanoids and biogenic amines. Second messengers include adenyl cyclase, phospholipase C, Ca2+ currents and phosphatidyl inositol-3-kinase. G-protein-coupled receptors span the cell membrane and exist as a bundle of seven helices.

Type 3 receptors, usually located in membranes, are directly coupled to an enzyme. Receptors with inherent enzymatic activity are most commonly cell-surface protein kinases. These receptors demonstrate their regulatory activity by phosphorylating various effector proteins at the inner face of the cell membrane. Phosphorylation changes the structures, biological properties and, hence, the biological activity.

Finally, type 4 receptors are located in the nucleus or cytoplasm and are coupled via DNA to gene transcription. Receptors for steroid hormones, thyroid hormones, retinoids, vitamin D and other molecules are soluble proteins and can bind DNA. These transcription factors are regulated by phosphorylation, association with other proteins, binding metabolites or regulatory ligands.

Drug-receptor binding triggers a cascade of events known as signal transduction, through which the target tissue responds. Within a physiologic entity there are myriad possible chemical signals that can affect multiple different processes. Subsequently, a very important, but not totally understood, property of a receptor is its specificity or the extent to which a receptor can recognize, discriminate and respond to only one signal. Some receptors demonstrate a very high degree of specificity and will bind only a signal endogenous ligand, while other receptors are less specific. In most cases the binding is transient and each binding triggers a signal. Furthermore, there may be different subtypes of a given receptor, each of which recognizes or binds to the same specific ligand but generates different intracellular responses. Spatial organization is one possible explanation why cross talk between the pathways does not lead to tremendous confusion.

The magnitude of receptor-mediated responses can decrease with repeated drug administration, thus after exposure to catecholamines there is a progressive loss of the ability of the target site to respond. This phenomenon is termed tachyphylaxis. The receptor desensitization is usually reversible.

Spare receptors allow maximal response without total receptor occupancy by increasing the sensitivity of the system. Spare receptors can bind extra ligands, preventing an exaggerated response if too much ligand is present.

A question of quantity dose response

Characterizing the dose-response relationship in populations often is not informative enough when the inter-subject variation is relatively high. The response can vary across subjects who achieve the same concentration. In the majority of cases, the effect of a drug is dependent on the number of bound receptors, although mostly there is no linear relationship.

It is necessary to differentiate between efficacy and potency. From the clinician’s point of view, the efficacy is more important as it stands for the maximum effect achievable (EDmax). ED50 indicates the dose of a drug that produces 50% of the maximal response. In contrast, the potency is a measure of the affinity and indicates which concentration has to be provided at the site of action (Fig. 1.2).

Graphically, potency is illustrated by the relative position of the dose-effect curve along the dose axis. Because a more potent drug is not necessarily clinically superior, potency has little clinical significance for a given therapeutic effect. However, low potency is a disadvantage only if it is so large that it is awkward to administer. Potency is determined by the affinity and intrinsic activity of a drug.

Pharmacodynamics is very tightly connected with toxicodynamics, both showing a very similar dose-response curve. The curve progression is characterized by the concentration where 50% (95% for LD95) of the effect appears. For many years, the LD50 (median lethal dosage) was tested in rodents before approval of new drugs. Since 1991, LD50 estimations in animals have become obsolete and are no longer required for regulatory submissions as a part of preclinical development. In addition to the effect level, the relationship between time and response is crucial.

In practice, the therapeutic window is much more relevant than the maximum efficacy (treatment dosage in g or mg). Drugs with a narrow margin are more difficult to dose and administer, and may require therapeutic drug monitoring. The more innocuous a drug is, the higher is its therapeutic width (Fig. 1.3). Side effects can be classified by the dosage or the cause. Adverse drug reactions (ADRs) can be seen following overdose or therapeutic dose. The intended pharmacological action, effects which are independent from the primary effect or interactions with other drugs can cause the undesired effects. Correspondingly, ADRs can be classified as type A (augmented) or type B (bizarre) reactions. Withdrawal reactions, which may occur with abrupt withdrawal of some drugs, and delayed onset were assigned to type A reactions.

In overdose, increased development of the therapeutic effect often occurs. Although the patient may be prescribed a dose within the normal recommended range, impaired organ function affects clearance and may result in adverse effects. However, when the level is accordingly further increased, nearly every drug shows toxicity.

Examples of undesired effects unrelated to the primary effect are hemolytic anemia following sulfonamides, atropine-like effects in the use of tricyclic antidepressives and thrombophilia induced by contraceptives. Some serious side effects do not occur before longer-lasting therapy, e.g. osteoporosis in chronic steroid treatment.

Various type B reactions are unexpected because they are unrelated to the known pharmacological action of the drug. Many of these reactions have an immunological basis, e.g. anaphylaxis with antibiotics. Others are due to genetic abnormalities such as drug-induced hemolysis in patients with glucose-6-phosphate dehydrogenase deficiency when given oxidative drugs. Allergic reactions are idiosyncratic and normally unrelated to dosage. Management of such ADRs usually requires stopping the offending drug.

Some ocular reactions (miosis, mydriasis or intraocular pressure) show a very reproducible pattern of the pharmacodynamic response. Ophthalmic pharmacological responses are therefore often used to investigate the administration and pharmacokinetics of a drug with special interest in the quantitative response.


Because a later part of this book concentrates on ocular pharmacokinetics and drug delivery in detail, only some general considerations are given here.

The bioavailability describes the proportion of the unchanged drug delivered to the site of potential action regardless of the route of administration. To facilitate the calculation of absorption and elimination rates, a compartment is usually postulated as a space where the drug is supposed to be homogeneously distributed. First-order kinetics are found when the rates (absorption, elimination) are proportional to the concentration. However, usually zero-order kinetics are detectable for most eye drops because the rates are independent of the concentration but proportional to the functional capacity of the body.

It has been estimated that only 1–5% of the active drug enclosed in an eye drop penetrates the eye (Schoenwald 1997). The maximum bioavailability is afforded by a drop size of 20 µL. An increase in volume or number of drops only leads to systemic toxicity due to increased lacrimal outflow and mucosal absorption of the drug. Up to 80% may reach the general circulation. Otherwise, after intraocular penetration there is no first-pass metabolism. Tissue binding has to be taken into consideration, reducing the elimination process by retention.

Barriers of the eye

Despite its apparent easy accessibility, the eye is well protected against the absorption of foreign materials, including therapeutic agents. The corneal epithelium acts as a trilaminar barrier to the penetration of topical drugs. Absorption of drugs depends on their solubility; lipophilic substances seem to penetrate readily in the corneal epithelium.

Drugs administered topically will drain into the nasolacrimal duct and be absorbed through the epithelial mucosa lining into the systemic circulation. One of the reasons for this behavior is that the fornix of the lower eyelid can hold only the volume of one drop of topical medication, which is approximately 40 µl at most. Most ophthalmic drugs are adapted from other therapeutic applications and were not specifically developed for the treatment of eye disease; hence, they are not well suited to provide eye-specific effects.

For maximal corneal drug penetration, a molecule must have an optimized ratio of hydro- and lipophilicity, as nonionized molecules penetrate the epithelium/endothelium well and ionize the stroma. The clinical state of the eye also strongly determines ocular pharmacokinetics. Transcorneal drug penetration is greater when the epithelium is altered or the corneal stroma is edematous (Ueno et al 1994). Similarly, preservatives improve the penetration of the drug (Ramselaar et al 1982). The blood ocular barrier is based on tight junctions of the nonpigmented ciliary epithelium, the retinal pigment epithelium and the retinal capillary endothelial cells. Intraocular structures are also shielded by these barriers from systemic toxins. However, these natural ocular barriers may also act as drug depots and can play an important role in the pathogenesis of drug-induced ocular toxicity.

The retinal pigment epithelium (RPE) is metabolically very active and can participate in the detoxification of various drugs. As chlorpromazine and chloroquine have an affinity to the melanin of the pigment epithelium, both drugs are metabolized by the RPE and are, therefore, retinotoxic (Koneru et al 1986).

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Nov 21, 2017 | Posted by in OPHTHALMOLOGY | Comments Off on 1 Principles of therapy

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