Unit III: How drugs work

 

One of the most fundamental concepts in pharmacology is that of molecule-receptor interactions. Receptors are specialized molecular binding sites where substances, like neurotransmitters, dock thereby producing physiologic effects. Most receptors are large proteins that span the cellular membrane, thus having three portions: one on the exterior of the cell where molecules bind; in the cell’s interior that subsequently initiate intracellular biochemical reactions, and a trans-membrane portion, which among other things helps to keep the receptor in place. This concept applies not only to the action of naturally occurring or endogenous substances such as neurotransmitters and hormones, but also to exogenous substances like drugs. Many drugs mimic the effects of hormones and neurotransmitters because they bind with the same receptors as these endogenous substances do. Hence, most drugs don’t do anything completely new to the body. Rather they mimic or influence naturally occurring processes.

 

Drugs can mimic a neurotransmitter or hormone. If the drug produces an effect to the same extent as the natural occurring molecule it is called a full agonist. If it produces the same general response but to a lesser effect than the endogenous substance it is a partial agonist. If a drug augments or facilitates an endogenous compound’s effects without actually binding to the natural substance’s receptor it is referred to as an indirect agonist.

 

Drugs can prevent endogenous compounds from binding to their receptors by occupying the receptor without producing a physiologic response. Such drugs are referred to as antagonists. As is the case with agonists, if a drug diminishes or prevents an endogenous compounds effects without actually binding to the natural substance’s receptor it is referred to as an indirect antagonist.

 

Drugs can bind to a receptor and provoke an action opposite to that of the endogenous substance. Such drugs are called inverse agonists. Just like there are full and partial agonists, there are full and partial inverse agonists, too.

 

Drugs can inhibit enzymes form performing their physiologic activities or they can activate enzymes so that they become more active than usual. For example, a drug can inhibit an enzyme that is necessary to deactivate a neurotransmitter thereby increasing or prolonging its activity (e.g. such as a MAO-I). Drugs can also block transporters or reuptake pumps that usually operate to recycle neurotransmitters. Drugs can cause more or less neurotransmitter to be released from axon terminals through various actions such as causing more vesicles to release their contents upon depolarization or by causing the vesicles themselves to become leaky thus depleting their contents. Drugs can influence the degree that ion channels open or close in the cell membranes.

 

Many drugs have multiple actions that produce not just the desirable therapeutic effect, but side effects as well. For example, the tricyclic antidepressant amitriptyline (Elavil) acts as an indirect agonist for the neurotransmitter norepinephrine, and serotonin to a lesser extent, by blocking their neuronal reuptake pumps (its postulated mechanism of therapeutic action). At the same time, it acts as an acetylcholine antagonist by occupying the acetylcholine receptor thus blocking the action of acetylcholine at its binding site (causing the so-called anticholinergic side-effects such as dry mouth and constipation). In addition, amitriptyline inhibits sodium ion channels which results in slowed depolarization especially in the cardiac muscle (causing this medicine to be prescribed with great caution to patients with any compromised cardiac function).

 

Pharmacokinetics

 

Pharmacokinetics is the study and description of the rate and extent of absorption, distribution, metabolization, and elimination of drugs in the body. In simple terms, pharmacokinetics is what the body does to a drug once it is administered. Hence, the four phases of pharmacokinetics (e.g., absorption, distribution, metabolization, and elimination) are often depicted by the acronym ADME. (Sometimes, the term biotransformation is used synonymously with metabolization, rendering the alternative acronym ADBE. Similarly, some people refer to the final phase as excretion rather than elimination, but, of course, this doesn’t change the acronyms.)

 

Absorption

 

Absorption involves the passage of the drug from its site of administration into the blood. Obviously, for a drug to have any effect it must be absorbed into the system. Usually, drugs are taken orally (i.e., po from the Latin per os which means literally by or through the mouth) and most absorption, therefore, takes place in the gastrointestinal tract, chiefly in the duodenum and proximal jejunum, the first few feet of the small intestine. While there are several other routes of administration, the vast majority of psychotropics is taken by mouth and most of the examples in this section assume the oral route of administration. Other ways through which drugs can enter the body are through the skin by topical preparations or transdermal patches, subcutaneously (under the skin), intramuscularly or intravenously via injection, rectally or vaginally with suppositories, in the eye or ear with drops, and even through inhalation as with gases. Generally, the terms take, apply, insert, and place refer to the oral, topical, rectal/vaginal, and eye/ear routes, respectively. One additional route is sublingual which refers to placing the drug under the tongue. This circumvents the gastrointestinal tract by allowing the drug to be absorbed directly into venous circulation through the capillary bed at the base of the tongue, which can have some important benefits.

 

Drugs which are taken by mouth are absorbed in the stomach and small intestine. In much the same way that nutrients are absorbed into the blood stream, drugs enter circulation by absorption into the venous blood supply of the digestive tract. This means that the drug must pass through several biological membranes before it can enter circulation such as the membranes of the cells lining the stomach and intestines, and the membranes of the blood vessels into which the drug need enter. Broadly speaking, there are two mechanisms by which molecules can cross cell membranes: passive processes where the driving force is a concentration gradient, and active transport which requires the expenditure of cellular energy and can drive molecules against concentration gradients.

 

The most common passive ways that a drug can cross a cellular membrane include diffusion (i.e., the random movement of molecules from an area of high concentration to low concentration), filtration (i.e., movement of molecules through pores in the membrane), and facilitated diffusion (i.e., when a substance temporarily binds to a specific carrier molecule that ferries it across the membrane). Active transport is the energy-dependent movement of molecules across membranes, usually against their concentration gradient. In active transport, as with facilitated diffusion, the substance to be transported reversibly binds to a carrier molecule (usually a protein) that conveys it across the membrane. In general, drugs will not be actively transported unless they very closely resemble the endogenous substances (such as glucose and amino acids) that are the normal passengers for the carrier system involved. For this reason, most drugs are absorbed from the intestinal tract through passive processes, and involve mostly diffusion.

 

There are many factors that can influence the degree to which a drug is absorbed, but most of these can be grouped into two categories: the physiochemical (i.e., relating to the physical and chemical) properties of the drug, and patient variables. Physiochemical properties include factors such as the drug’s dissolvability, its solubility in fat (lipophilicity) versus water (hydrophilicity), whether it is an acid or a base, and its molecular size, to name only a few. Patient variables include whether the drug is taken with food or on an empty stomach, as well as a variety of other factors including the patient’s age, weight, gender, and general health.

 

Distribution

 

Distribution involves the processes through which the drug, once absorbed, is delivered to the tissues and eventually to its sites of action. The system responsible for this phase of pharmacokinetics is the circulatory system which delivers drugs and other materials to the furthest outposts of the body. Once absorbed into the blood supply of the digestive tract, a drug is considered to be in general or systemic circulation. Before it can be delivered to its site of action, usually the CNS in the case of psychotropics, it will journey through a consistent passage of blood vessels. Substances that are absorbed into the blood supply from the digestive system enter into small veins called venules which along with tiny arteries called arterioles make up the capillary beds. In addition to absorbing nutrients and drugs, capillary beds deliver fresh, oxygenated blood to organs and remove waste products from them. Venous blood from the digestive tract eventually makes it way to the heart where it is pumped to the lungs for oxygenation (and to remove gaseous waste, mostly carbon dioxide), then returned to the heart from where it enters systemic circulation. As a general rule, veins convey deoxygenated blood to the heart, arteries transport oxygenated blood from the heart. (An exception to this is in adult cardiopulmonary circulation where arteries carry deoxygenated blood from the heart to the lungs, and veins return it, once oxygenated, to the heart for pumping to the rest of the body.)

 

As a drug proceeds to its ultimate destination, it encounters many barriers it must cross before it reaches its site of action. In much the same way that the drug had to pass through various biological membranes to enter the blood stream, it must similarly cross various membranes to reach its site of action. One important obstacle most centrally acting drugs must surmount is the blood-brain barrier (BBB) which insulates and protects the CNS from toxins by allowing only certain molecules to enter the brain. Most psychotropics are fat-soluble compounds and since the BBB preferentially allows fat-soluble substances to pass, as a general rule psychotropics have little difficulty entering the CNS.

 

Generally, distribution of a medication throughout the body is a two-phase process. Initially, most of the drug is delivered to the organs which have the richest supply of blood, such as the liver, heart, lungs, kidneys, and brain. Subsequently, the drug moves into the tissues which have less extensive perfusion such as muscles, fat, and bone. These latter areas of the body are referred to as reservoirs or compartments in which drugs can accumulate.

 

For example, some psychotropics do not distribute uniformly throughout the body because of their affinity for muscle and fat cells. After chronic administration, significant concentrations of drug can accumulate in these reservoirs which has obvious implications when the drug is discontinued, since it can leach out of these compartments thus prolonging the biological life of the drug in the system. While this can be problematic in some cases, this phenomenon also has important therapeutic utility in that some drugs can be delivered to these reservoirs deliberately to allow for sustained therapeutic action. For example, some antipsychotic agents (e.g., Prolixin and Haldol) can be administered by injection once every several weeks which greatly improves patient compliance due to ease of dosing and consistent drug effects.

 

Another important mechanism through which drugs can be compartmentalized in the body involves the binding of drugs to plasma proteins. Blood plasma is the fluid (noncellular) portion of circulating blood and has a great many substances dissolved in it such as electrolytes, sugars, hormones, and proteins. One of the most common proteins in blood plasma is albumin. Although some drugs are simply dissolved in the blood fluid, most are associated with plasma proteins like albumin to which they bind, partly irreversibly. Remember that the receptors to which neurotransmitters bind are large proteins into which the neurotransmitter fits like a key into a lock. Also, recall that many drugs act by binding to these same receptors. Plasma proteins are very similar in structure to receptors. Hence it is not surprising that many drugs bind to the plasma proteins in much the same way that they couple with receptors. The extent of this binding will significantly influence the drug’s distribution, concentration at effectors (i.e., sites of action), and rate of metabolization and elimination because only the unbound drug can diffuse through membranes. Thus, only the unbound fraction of the drug is biologically active. Furthermore, extensive protein binding results in the blood’s serving as a circulating drug reservoir. As free or unbound drug is eliminated from the body, more drug dissociates from the plasma proteins to replace the unbound drug that was lost. Therefore, extensive protein binding can prolong drug availability and duration of action.

 

One additional important phenomenon that warrants mention is displacement of drug from plasma proteins. The binding of drugs to plasma proteins is usually nonspecific which means that many different drugs can interact with the same binding site. A drug with a higher affinity for the protein’s binding site may displace a drug with a weaker affinity from it. Obviously, since only the unbound portion of a drug is biologically active, this can have profound pharmacologic and clinical implications. For example, if drug B displaces a significant amount of drug A from its protein binding sites, there will be more free drug A available to cross cell membranes which will result in a greater concentration at its site of action and an intensified pharmacologic effect.

 

Metabolization

Before blood form the gastrointestinal system reaches the heart, and enters systemic circulation, it first passes through the liver which is the major organ of metabolization or biotransformation. Although it is a gross simplification, the liver can be likened to a biochemical processing plant that modifies substances passing through it. Indeed, the liver contains an enormous amount and variety of enzymes that act as molecular processors, ultimately changing or transforming the biological substances that encounter them. This is why the term biotransformation is synonymous with metabolization because through the metabolic action of it’s enzymes, the liver biologically transforms molecules from their original form, the parent compound, to new products called metabolites.

 

The major drug metabolizing enzymes of the liver are often called the cytochrome (CYP) 450 system and include more than 30 related enzymes. These enzymes, which evolved over 1 billion years ago during the era of plant-animal differentiation, have the ability to metabolize foreign biological substances. These enzymes allowed the animals that possessed them to metabolize plant toxins before they could enter the animal’s systemic circulation thus protecting them from harm. Obviously, such a system would confer tremendous survival advantages and be passed on to future generations and new species. Since many drugs originally come from plant products, and resemble plant toxins, they are readily metabolized by this same system of enzymes. In addition to providing protection form toxicity, these enzymes serve to transform substances into forms that can be readily eliminated form the body. Indeed, these enzymes determine in part what compounds can become drugs because if a mechanism did not exist to eliminate a substance from the body it could not be [safely] used as a drug.

 

The activities of the CYP 450 enzymes are variable. Basically, their numbers and activity can be increased (enzyme induction) or decreased (enzyme inhibition) through the actions of drugs and their metabolites. Although the analogy is not precise, these phenomena can be thought of as similar to the agonist and antagonist effects that drugs produce at receptors which in may cases resemble the enzymes structurally. For example, the anti-epileptic and mood stabilizing agent carbamazepine (Tegratol) induces certain enzymes which can cause a reduction in a drug’s bioavailability if that drug is metabolized by the enzymes that Tegratol induces. Alternatively, the SSRI fluvoxemine (Luvox) is a potent inhibitor of the enzyme that metabolizes the antianxiety agent alprzaolam (Xanax). Therefore, if Luvox and Xanax are co-administered, the effects of the Xanax can be significantly amplified because of Luvox’s inhibitory effect on the enzyme that Xanax depends on for its biotransformation and eventual elimination from the body. Other factors, such as smoking and liver disease, respectively, can induce or inhibit many of the CYP 450 enzymes thus influencing the metabolization of many drugs.

 

Another important aspect of metabolization is the so-called first-pass effect which simply refers to the fact that drugs absorbed into the blood stream from the digestive tract first pass through the liver before entering systemic circulation. On this pass through the liver, drugs can undergo extensive metabolization by the CYP 450 system and other enzymes present in the liver. On the one hand, this phenomenon can significantly reduce the concentration of many drugs resulting in a diminished therapeutic effect. On the other hand, some drugs (called prodrugs) must first be metabolized before they become biologically active. For example, the benzodiazepine clorazepate (Tranxene) is an inactive prodrug which becomes the active compound desmethyldiazepam once it has been metabolized by liver enzymes. Parenteral drug administration (i.e., in a manner other than through the digestive tract such as by injection, topical, rectal, vaginal, or sublingual routes) circumvents the first-pass effect.

 

It is important to note that some metabolites are more pharmacologically active than the parent drug. For example, Prozac (fluoxetine) is metabolized into a form, norfluoxetine, that is believed to be more potent than Prozac at inhibiting the serotonin reuptake pump. In addition, some metabolites are more potent enzyme inhibitors than their parent drugs and/or have much longer half-lives (the amount of time it takes to eliminate one-half of the substance from the body) or biological activity.

 

Elimination

As we have discussed, the biological activity of a drug depends on many processes. To completely terminate the pharmacological effects of a drug, it must be eliminated from the body. Indeed, in addition to detoxifying substances, the process of metabolization also prepares them for removal from the body by transforming them into metabolites that are more readily excreted than the original compound. Excretion is the process whereby substances are moved to the outside of the body. Several systems participate in drug elimination, such as the lungs through exhalation, the gastrointestinal tract through defecation, and the skin through perspiration. As important as these routes of elimination are, by far the most import organ of drug elimination is the kidney which excretes drug metabolites through urine. Indeed, the kidney filters almost two thousand liters of blood a day (about 475 gallons) to produce a mere liter of urine.

 

Nevertheless, this amount is sufficient to eliminate the vast majority of drugs and other metabolic waste products from the body. It is important to consider that the physiochemical properties of a drug that govern its absorption by crossing several biological barriers also apply to drug excretion. For example, the urinary elimination of drugs can be influenced by modifying the acidity or alkalinity of the urine. Basically, increasing the acidity of urine hastens the elimination of basic substances while increasing its alkalinity speeds up excretion of acidic compounds.

Any drug that influences one or more phases of pharmacokinetics can result in a drug-drug interaction that may intensify or diminish the therapeutic effects. For example, antacids are know to interfere with benzodiazepine absorption thus diminishing their therapeutic onset. Displacement from plasma proteins of one drug by another can significantly increase the bioavailability of the displaced drug resulting in a greater therapeutic effect (or even toxicity) than would be predicted based on the original dose of the displaced drug. This would be an example of a pharmacokinetic drug-drug interaction involving the distribution phase. We have already provided an example of a pharmacokinetic interaction involving metabolization, i.e., Luvox inhibiting one of the enzymes Xanax depends on for its biotransformation, thus intensifying or prolonging its effects. Moreover, the fact that certain drugs can change the acidity of urine can influence the rate of another drug’s elimination from the body.

 

Having provided a general overview of some of the most fundamental pharmacokinetic processes (what the body does to the drug), we will now turn our attention to what the drug does to the body, or what is often called pharmacodynamics.

 

Pharmacodynamics

Following its absorption and distribution to its sites of action, a drug will produce physiological effects that ultimately result in a therapeutic response. With psychotropic medications, the major organ effected is the brain. In most cases, psychotropics produce their therapeutic effects by binding to specific receptors or enzymes. Ultimately, psychotropics produce therapeutic effects by changing neural activity which is a consequence of effecting the traffic patterns of neurotransmitters or in some cases intracellular, second-messenger systems.

 

In general terms, drugs produce both acute effects, and long-term compensatory changes in the flow of neurotransmitters and cellular activity. Acute effects are the rapid changes in neurotransmitter concentrations that follow within minutes or hours of a drug’s administration. Long-term compensatory effects refer to certain adaptations that neurons undergo after chronic administration of a drug. Usually these adaptations involve modifying the population of receptors; a genetically mediated process that requires the cell to synthesize and insert into its membrane new numbers of receptor molecules. These adaptations, which compensate for the change in neurotransmitter traffic, are often referred to as receptor down-regulation or up-regulation depending on whether the end result is that the cell has less receptors (down regulation) or more (up regulation). These phenomena, also called neural plasticity, take up to several weeks to occur. This time frame is highly correlated with the therapeutic onset of many psychotropics, leading to the generally accepted hypothesis that their therapeutic effects result from these compensatory adaptations. Similarly, the reversal of these adaptations, upon discontinuation of the drug, can take several weeks to occur thus explaining why relapse is often delayed in much the same way as response lags behind initiation of the drug. Some psychotropics, however, such as the benzodiazepines, act therapeutically by producing short-term effects. Hence, these drugs work relatively quickly and only while present at the receptors where they exert their influence.

 

Basically, pharmacodynamic processes involve drug effects at receptors. Just as there are many pharmacokinetically mediated drug-drug interactions, there are also many important pharmacodynamically mediated drug-drug interactions. In essence, any drug that influences another drug at its receptors or sites of action will produce pharmacodynamic interaction that will either potentiate or attenuate their pharmacologic effects. For example, tricyclic antidepressants have effects at several types of receptors. Hence they often potentiate antihistamines (due to their effects at histamine receptors), several antihypertensives (due to their effects at the alpha-1 adrenergic receptor), anticholinergic agents (due to their blockade of muscarinic cholinergic receptors), and certain antiarrhythmics (due to their direct membrane stabilizing properties).

 

Some additional terms and concepts that are important include efficacy, potency, toxicity, and therapeutic index. Efficacy refers to the capacity of a drug to produce a desired result or effect and can be thought of synonymous with effectiveness. If drug A (morphine) is capable of relieving more pain that drug B (ibuprofen), drug A is said to have greater analgesic efficacy that Drug B. Hence even at high doses, ibuprofen cannot match morphine’s analgesic effectiveness. Potency concerns the dosage of a drug needed to produce a therapeutic effect. If less of drug A is needed to produce a given response than drug B, drug A is more potent than drug B. For example, since 200 mg of ibuprofen is able to produce the same amount of pain relief as 500 mg of acetaminophen, ibuprofen is more potent that acetaminophen. Interestingly, just because one drug is more potent than another doesn’t mean it’s necessarily more efficacious. For example, both alprazolam (Xanax) and diazepam (Valium) are equally efficacious in reducing anxiety, but alprazolam is about ten times as potent as diazepam. Thus 1 mg of alprazolam has about the same efficacy as 10 mg of diazepam.

 

Toxicity refers to a substance’s potential for producing harm to one or more biological systems that if seriously damaged can result in injury or death. Toxicity and lethality are directly and positively correlated so that the more toxic a substance is the greater its lethality. A critical parameter that directs safe and effective drug use is the therapeutic index which is a quantitative comparison of a drug’s effective concentration (efficacy) and its toxic concentration (toxicity). The closer together these two measurements are, the narrower the index, and therefore the less safe the drug. In psychopharmacology, lithium and tricyclic compounds have small therapeutic indices (and are therefore more dangerous) than benzodiazepines and SSRIs which have large therapeutic indices.

 

DRUG ADMINISTRATION

Oral drug forms include liquids, tablets, and capsules. Liquid dosage forms have the fastest absorption rate. Tablets are absorbed more slowly. Capsules are often formulated as time-release or sustained-release products and have the advantage of requiring fewer daily doses.

 

A variety of problems may occur with oral drug administration, including stomach and intestinal problems.

Oral administration is the slowest method of absorption, and the onset of a drug's effect is less predictable because drug absorption from the gastro-intestinal tract is often erratic.

 

Variables that affect the rate of absorption of a drug are related to the concurrent intake of food and the drug's pH (acidity or basicity) relative to the pH values of the stomach and the intestines. Drugs can exist in two interconvertible forms, a water-soluble or ionized form and a lipid-soluble or less ionized form.

A drug's lipid-to-water solubility is primarily determined by the pH of the drug relative to the pH of the body fluid that harbors the drug.

 

Drugs administered orally undergo a process called first-pass metabolism, which occurs immediately after the drug is absorbed from the gastrointestinal tract. The blood carries the drug to the liver, where some of the drug is metab-olized and thus rendered inactive or unable to exert its desired effect.

 

INJECTABLE DRUGS

Three basic methods are used for injecting medication: intravenous, intramus-cular, and subcutaneous injections. Intravenous (into the vein) injection has the fastest absorption rate. Because of this, it is potentially the most dangerous form for injection of medication. Intramuscular (into the muscle) injection provides a means for rapid absorption but is not as fast as intravenous injection (e.g., antibiotics). Subcutaneous (under a layer of skin) is used when a slower and more constant rate of absorption is recommended (e.g., insulin).

Some injectable antipsychotics, such as Haldol Decanoate and Prolixin Decanoate are formulated to prolong the effects of the drug. Effects of both of these injectable drugs can last three to four weeks.

 

OTHER METHODS OF MEDICATION ADMTNISTRATTON

A variety of other methods are used for administering drugs, including sublingual (a tablet placed under the tongue) and buccal (drug positioned between cheek and gum). In each of these alternate administration methods, a drug is readily absorbed into the bloodstream because of the highly vascular membranes (high number of blood vessels) in each of these areas.

 

DISTRIBUTION

Once administered and absorbed in the bloodstream, medications are carried to various body tissues via the circulatory system. Blood capillaries deliver drugs to different areas in the body. For most drugs, capillary pores are large enough to allow free passage for the drugs to exit the blood system and exert their effects.

 

PROTEIN BINDING

Some drugs bind irreversibly to circulating proteins in the plasma or blood. A drug that becomes protein-bound is usually so large that it is unable to exit the capillary, rendering it inactive in the bloodstream until separation from the protein. Drug protein binding also hinders a drug's metabolism and excretion, thus causing a drug to remain in the body longer, which increases the drug's half-life.

 

The term half-life refers to the amount of time (usually given in hours) that is required for half of the active part of the drug to be eliminated from the body after discontinuation. Usually, it takes about 5 or 6 half lives for most of the drug to be eliminated. Drugs with a short half-life (e.g., Ritalin), must be dosed multiple times per day (TID or QID). Drugs with a long half-life may be dosed only once per day, but may be dangerous with overdose because it will take a lot longer for the drug to be eliminated (for example, the sleep medication Dalmane, which has a half-life of about 200 hours).

 

LIPID SOLUBILITY

A drug's passage across various membranes or barriers in the body, such as the stomach, intestines, blood-brain barrier (BBB), and placenta, depends on a drug's lipid (fat) solubility. Drugs with a high lipid solubility cross the BBB easily and remain in the brain tissues longer than water-soluble drugs do. This difference is explained by the fact that lipid-soluble chemicals or drugs are stored in the body's fat tissue. Unlike many categories of medication, psychotropic medications and drugs of abuse can cross the BBB and reach the central nervous system rather easily.

 

METABOLISM

Most drugs are metabolized or broken down in the body by liver enzymes, which act to transform chemicals or drugs into more water-soluble (or hydrophilic) entities so the drugs can be excreted in the urine. Because of the decline in liver activity among the elderly, it takes them longer to metabolize drugs. Therefore, drug dosages for the geriatric population are usually reduced. Risks of overmedicating are also of particular concern among persons with heart, liver, and kidney disease.

 

EXCRETION

The kidney is the body's main excretory organ. Therefore, a client with kidney problems may accumulate more drugs in the body, thus requiring smaller doses. Less frequently, drugs are eliminated from the body via the lungs, sweat glands, saliva, feces, bile, and breast milk.

 

SIDE EFFECTS, INTERACTIONS, CONTRAINDICATIONS, AND TOXICITY MEDICATION SIDE EFFECTS

Other terms used to describe drug side effects are adverse reactions and untoward or unwanted effects. Rather than being selectively carried to a specific or targeted area, drugs are widely distributed throughout the body. Therefore, a drug will bind with any receptor that its chemical structure will allow. This nonselective drug-binding capacity explains the origin of drug side effects. Adverse drug side effects must be monitored, and a drug's benefits should outweigh any detrimental side effects (often as the dosage is increased).

 

Agonists and Antagonists

 

A drug that increases the availability or mimics the action of an endogenous NT is called an agonist. Conversely, a drug that decreases the availability or action of an NT is called an antagonist.

 

Agonist drug actions include

 

1) being a precursor for an NT, resulting in an increase in NT synthesis:

Examples: L-dopa (a precursor for dopamine); trypophan

 

2) increasing release of NTs from terminal buttons (e.g., many drugs of abuse initiate and/or increase the release of dopamine)

 

3) acting like endogenous NTs and stimulating postsynaptic receptors (e.g., pain killers)

 

4) blocking reuptake by presynaptic neurons, allowing NTs to remain in synapse longer

(e.g., SSRI drugs)

 

5) immobilizing enzymes that break down NTs in synapse, thus increasing the number of NTs in the synapse available for action

(e.g., MAO-inhibitor drugs)

 

Antagonist drug actions include

 

1) decreasing the production of an NT by blocking the enzyme required for its synthesis (e.g., acting on precursors)

 

2) blocking storage of NTs in vesicles (e.g., reserpine)

 

3) preventing release of NTs (from terminal but-tons (e.g., hyperpolarization)

 

4) binding postsynaptic receptors without stimulating them, hindering NT activity

(to some extent, alcohol on GABA receptors)

 

5) stimulating receptors on presynaptic neurons, called autoreceptors, which tell neurons not to release NTs (possibly the way SSRI work on reducing panic attacks)

 

 

Cytochrome P450 Enzyme System   

 

Knowledge of cytochrome P450 liver enzymes is necessary because:

 

1) They metabolize most of the drugs we use (by oxidative, reductive or hydrolytic modification to a more water-soluble form-- for renal excretion).

 

2) The varying level of their activity in individuals (as a result of different genetic differences) determines the speed of metabolism of a drug. That in turn influences the plasma level, efficacy and the side effects.

 

3) There is great genetic variation for almost all cytochrome P450 enzymes; both between individuals within a group (e.g., caucasians) and between groups of different genetic and ethnic lineages.

For example, 2C19 poor metabolizer status is very common in people of Asian descent. (15% up to nearly 100%) as compared to Caucasians (3-6%). Also, some people (about 1% of the general population) have 'ultra-fast' 2D6 metabolizers.

 

4) There are various endogenous factors (e.g., hormones) and exogenous factors (e.g. other drugs and foods) that alter the level of CYP450 enzyme activity.

 

5) Drugs and foreign biological molecules with similar structures are likely to have similar properties; so if one member of a group is known to cause problems others may too.

 

Some substances induce P450 enzymes. These are called inducers. This speeds up metabolism.

In this case, more of the drug is eliminated from the body and the pharmaceutical action of these specific drugs DECREASE.

 

Some substances inhibit P450 enzymes. These are called inhibitors. This slows down metabolism. In this case, less of the drug is eliminate from the body and the pharmaceutical action of these specific drugs INCREASE.

 

There are more than one thousand P450 enzymes. All P450 enzymes are similar in structure and mechanism of action. 3A4 is the most abundant in the human liver and is known to metabolize the majority of drugs whose biotransformation is presently known.

 

This large family of enzymes are classified with numbers and letters as follows: the first number is the CYP P450 family (e.g., 3); the next letter indicates the sub-type (e.g., A); and the third number indicates the gene product (e.g. 4). A gene product is defined as the biochemical material, either RNA or protein, resulting from the expression of a gene)

 

The Cytochrome P450 enzymes that are particularly  important for psychotropic drugs are CYP450-1A2, 2D6, 2C9, 2C-19, 3A4 and to a lesser extent 2A6.

 

CYP-1A2:

is important because this enzyme is inhibited by fluvoxamine (Luvox). When Luvox is given with other drugs that depend on 1A2 for metabolization (such as theophyllin (Theodur) or clozapine), the level of the other drugs may get dangerously high (in both cases, this could be life threatening). Some antibiotics such as Cipro and grapefruit juice also inhibit 1A2.

 

The alergy drug Seldane (terfenadine) was removed from the market in 1998 because drugs such as ERYTHROMYCIN

Inhibit 3A4, which metabolizes Seldance. In this case, high levels of terfenadine in your system can lead to death.

 

Almost all patients treated with even low doses of fluvoxamine (only 50 mg/day) will reach population minimums for CYP1A2 activity (ie become 'PMs', poor metabolisers).

 

Fluvoxamine is also an extremely potent inhibitor of 2C19 and also significant inhibitor of 2C9 and 3A4 (but not of 2D6).

 

The use of fluvoxamine is thus fraught with risks because this potent cytochrome P450 blockade involves many other commonly used drugs. There are few clinical situations in which it represents a logical first or second choice treatment in primary care. When treating the SMI, interactions with neuroleptics, especially olanzapine and clozapine may cause serious problems.

 

Substrates

 

Cytochrome P450 1A2 metabolises several groups of compounds:

1) a number of important drugs,

2) some compounds called pro carcinogens (e.g., arylamines in cigarette smoke),

3) endogenous hormones such as 17beta-estradiol.

4) melatonin

5) fluvoxamine itself (to inactive metabolites, and also via CYP2D6)

 

Important drugs

theophylline, caffeine, tacrine, imipramine, haloperidol, pentazocine, phenacetin O-deethylation, propranolol, flecainide and estradiol and other drugs structurally related to these drugs.

For instance:-- probably all the tertiary amine tricyclic antidepressants*** (clomipramine, amitriptyline, doxepin, dothiepin, but not secondary amines nortriptyline or desipramine) and also many neuroleptics like clozapine, olanzapine, chlorpromazine.

 

*** tertiary amine tricyclics are those with two methyl groups on the terminal nitrogen of the side chain. The primary step in metabolism is demethylation to secondary amines; e.g., amitriptyline is demethylated to nortriptyline

 

Inducers

Omeprazole

Carbamazepine

nicotine [nicotine may induce the activity of:- CYP1A2, CYP2B1/2B2 and CYP2E1]

Polycyclic aromatic hydrocarbons in tobacco smoke

highly inducible by the environmental contaminants dioxin and benzo[a]pyrene

 

Clinical consequences

 

Caffeine levels are markedly elevated by even small doses of fluvoxamine; the most serious caffeine-related CNS effects include seizures and delirium. A dose of only 20 mg of fluvoxamine significantly inhibits caffeine (CYP1A2) metabolism.

 

Estrogen inhibits 1A2 and that reduces metabolism of caffeine. So exogenous estrogen given to post menopausal women may inhibit caffeine metabolism (but only by about 30%).

 

Induced metabolism of 1A2 because of cigarette smoking may have clinical consequence for some of these drugs.

 

 

Cytochrome P-450 1A2

 

INDUCERS

Nicotine

Omeprazole

Phenobarbital

Primidone

Rifampin

 

1A2 Inhibitors

 

sulconazole and tioconazole:- mexiletine, lidocaine, and (weaker) tocainide

Estrogen

some anti-psychotics especially clozapine

idrocilamide

phenylpropanolamine

bronchodilators (furafylline and theophylline)

quinolones (enoxacin)

moclobemide ? weak

flavones, a class of phytochemicals consumed in the human diet (found at high concentrations in 'Tofu") and psoralens

A wide range of flavonoids tested all proved potent inhibitors of CYP1A2

 

INHIBITORS (summary)

Anastrozole

Cimetidine

Ciprofloxacin

Diltiazem

Enoxacin

Erythromycin

Fluvoxamine

Mexiletine

Norfloxacin

Ritonavir

Tacrine

 

2D6:

 metabolizes, in part or in whole, the tricyclic drugs which include antihistamines, neuroleptics and tricyclic antidepressants, and various other drugs. CYP2D6 is potently inhibited by fluoxetine (Prozac); and paroxetine (Paxil), which may cause significant and even dangerous, interactions. For example, if Prozac is given together with a TCA, the levels of TCA can increase into toxic levels.

 

Other Substrates

 

CYP450 2D6 plays a significant part in inactivating the following drugs (along with, in varying proportions, 1A2, 2C9, 3A4)

 

paroxetine

venlafaxine (and partly 2C19)

most of the tricyclic antidepressants

dextromethorphan, dextropropoxyphene, codeine, (R)-methadone

beta-blockers

colchicine

some neuroleptics, including risperidone and sertindole

anti-histamines.

 

Genetic polymorphism

 

About 8% of the Caucasian population are genetically ‘deficient’ in 2D6 which renders them poor metabolisers and liable to develop considerably elevated blood levels with all drugs that are dependent on 2D6 for their elimination.

 

For the tricyclic antidepressants nortriptyline and desipramine 2D6 is the main metabolic pathway. The 8% of Caucasians who are ‘deficient’ in 2D6 and will have high blood levels (they are referred to as ‘poor metabolisers’ -PMs). Some people are very rapid ‘extensive’ metabolisers (EMs).

 

Fluoxetine is particularly problematic being a potent 2D6 inhibitor and also a inhibitor of 3A4 and 2C19. These effects can persist for many weeks after cessation because of its long elimination half life.

 

Sertraline has a small effect that is not usually significant; high doses may raise levels of co-administered TCAs by around 30%.

 

2D6 inhibitors

 

Potent inhibitors are likely to cause serious or dangerous interactions in some circumstances, especially because some of these drugs have a narrow therapeutic margin.

 

Of the selective serotonin reuptake inhibitor antidepressants, and the other new antidepressants to date, only fluoxetine and paroxetine are potent inhibitors of CYP450 2D6.

 

2D6  INHIBITORS (summary)

Amiodarone

Fluoxetine

Fluphenazine

Fluvoxamine

Haloperidol

Lomustine

Norfluoxetine

Paroxetine

Perphenazine

Propafenone

Quinidine

Ranitidine

Ritonavir

Sertindole

Sertraine

Thioridazine

Venlafaxine

Vinblastine

Vinorelbine

 

CYP-2C9

 

Inhibitors

Fluvoxamine is a potent inhibitor of CYP2C9 and extremely for 2C19 and 1A2).

Fluoxetine may also cause significant interactions.

sulfa-phenazole (-diazine, methizole, methoxazole)

sulconazole K(i), 0.01 microM = high affinity

Ketoconazole

trimethoprim, chloramphenicol

cimetidine

amiodorone

phenylbutazone

valproate

gemfibrozil

 

 

Substrates

Phenytoin

warfarin

tolbutamide

torasemide

Many NSAIDs:--diclofenac and ibuprofen other 'profens, mefenamic acid, naproxen, piroxicam, tenoxicam etc.

losartan

amitriptyline

fluoxetine

propofol (anesthetic)

 

 

Inducers

barbiturates

carbamazepine

ethanol

rifampicin

colchicine

 

Clinical consequences

 

Phenytoin intoxication has occurred with fluvoxamine (concentration of phenytoin increased from 16.6 to 49.1 mcg/m). This suggests significant inhibition of both CYP2C9 and 2C19 by fluvoxamine.

 

Fluoxetine at the higher dose of 40 mg per day has a significant effect on Phenytoin levels. The risk of a SSRI-phenytoin interaction is highest with fluoxetine and norfluoxetine, and less likely with sertraline and paroxetine (which do have weak 2C9 inhibitor activity).

 

Fluvoxamine is likely to convert most patients to poor metaboliser status at usual doses of 100 mg per day for 2C9 (and 1A2). Theory indicates other selective serotonin reuptake inhibitors are unlikely to have much effect on 2C9.

 

As is the case for most cytochrome P450 enzyme inhibition scenarios involving selective serotonin reuptake inhibitors citalopram (Celexa) and sertraline (Zoloft) are the safest bet. The other three selective serotonin reuptake inhibitors, fluoxetine, paroxetine and fluvoxamine all have potentially problematic and serious cytochrome P450 interactions. They are therefore best avoided as much as possible by those not fully conversant with the latest data concerning interactions.

 

2C9 INHIBITORS (summary)

Amiodarone (drug that is used to treat Arrhythmia)

Anastrozole

Cimetidine

Diclofenac

Disulfiram

Fluconazole

Fluvoxamine

Flurbiprofen

Fluvastatin

Ketoprofen

Metronidazole

Phenylbutazone

Ritonavir

Sulfinpyrazone

Sulfonamides

Sulfamethoxazole-trimethoprim

Troglitazone

Zafirlukast

 

2C19 Inhibitors

fluvoxamine (extremely potent even at sub-therapuetic doses)

miconazole K(i), 0.05 microM; sulconazole K(i), 0.008 microM; tioconazole K(i), 0.04 microM) = high affinity

sulfaphenazole

fluoxetine

Omeprazole

ticlopidine

moclobemide

isoniazid

valproate

felbamate

topirimate

 

Substrates

Flunitrazepam (and 3A4)

Citalopram (N-demethylation to N-desmethylcitalopram- partly by CYP2C19 and partly by CYP3A4)

sertraline

fluoxetine (plays a major role in N-demethylation)

moclobemide

venlafaxine (mostly 2D6)

terodiline

Omeprazole and lansoprazole (most proton pump inhibitors are predominantly inactivated by 2C19)

 

 

Inducers

colchicine

 

Clinical consequences

 

The polymorphic CYP2C19 appears to be a major enzyme involved in the N-demethylation of sertraline, extensive vs poor metabolisers had marked differences in sertraline levels.

 

CYP2C19 is an important enzyme in the elimination of moclobemide and it is inhibited by Omeprazole in extensive metabolisers, but not in poor metabolisers.

 

 

2C19 INHIBITORS (summary)

Felbamate

Fluoxetine

Fluvoxamine

Omeprazole

Ritonavir

Tolbutamide

Troglitazone

 

3A4

The newer antidepressants that are clinically significant inhibitors of CYP450 3A4 are:

 

fluoxetine (mostly its metabolite, nor-fluoxetine)

fluvoxamine (much more potent for 1A2 and 2C19 and 2C9)

nefazodone.

 

Drugs (other than antidepressants) know to inhibit 3A4 to a clinically significant extent:

isoniazid

nifedipine

macrolide antibiotics (especially clarithromycin and erythromycin and, most potent, troleandomycin)

clotrimazole K(i), 0.02 microM; miconazole K(i), 0.03 microM; tioconazole K(i), 0.02 microM) = high affinity

ketoconazole, itraconazole

gestodone

diltiazem

valproate

cyclosporin

mibefradil

cimetidine

ritnavir, indinavir, nelifinavir

 

furocoumarins in:-grapefruit juice and seville orange juice (a newly identified furocoumarin, bergapten, was detected only in Seville orange juice)

furanocoumarins in umbelliferous plants such as carrot, parsley, celery, dill (similar potency as ketoconazole)

polyphenolic compounds in red wine, including trans-resveratrol [sold as a 'nutraceutical' product]. Red wine concentrate has been shown to inhibit 3A4.

flavonolignans in 'Milk thistle' [the extract is a commonly used herbal remedy]

Dillapiol, hypericin.

 

 

INHIBITORS (summary)

Anastrozole

Cimetidine

Clarithromycin

Clotrimazole

Danazol

Delavirdine

Diltiazem

Erythromycin

Fluconazole

Fluoxetine

Fluvoxamine

Grapefruit juice

Indinavir

Itraconazole

Ketoconazole

Metronidazole

Miconazole

Nefazodone

Nelfinavir

Nevirapine

Norfluoxetine

Omeprazole

Paroxetine

Propoxyphene

Quinidine

Ranitidine

Ritonavir

Saquinavir

Sertindole

Troglitazone

Troleandomycin

Zafirlukast

Zileuton

 

Substrates

CYP3A4 is the main enzyme inactivating the following common drugs:

most of the benzodiazepines (-azepams) including diazepam, flunitrazepam, alprazolam midazolam, triazolam) and zopiclone and buspirone (but not oxazepam, temazepam or lorazepam)

carbamazepine, primidone

cisapride

fentanyl, alfentanil, methadone

nimodipine, felodipine, amiodipine

terfenidine, astemizole

some of the old antihistamines, tricyclic antidepressants and both old and new neuroleptics*. eg Quetiapine, azelastine

mirtazapine (CYP3A, CYP1A2 and CYP2D6 contribute about equally)

cisapride

Various statins

repaglinide

propafenone

sildenafil

tacrolimus

ergotamine

 

3A4 INDUCERS

Carbamazepine

colchicine

Dexamethasone

felbamate

Glucocorticoids

Phenobarbital

Phenylbutazone

Phenytoin

Primidone

Rifabutin

Rifampin and Sulfinpyrazone

 

Clinical consequences

 

(* most of these drugs, including amitriptyline, chlorpromazine, clozapine and olanzapine are metabolised by multiple CYP enzymes including P450 1A2 and 2C9 and 3A4.

Nefazodone -inhibitor of CYP3A4, had minimal effects on clozapine metabolism. When nefazodone treatment follows fluoxetine all sorts of interesting things may happen which might result in significant clinical problems, and should be done carefully).

 

2A6

 

Inhibitors

 

potent and selective

Methoxsalen (8-methoxypsoralen)

Tranylcypromine

Dialkyl disulfides [di-n-propyl disulfide, contained in onion oil- the most potent]

Diallyl disulfide, present in garlic oil

 

Substrates

 

Dexmedetomidine (Alpha 2 agonist- sedative)

nicotine (urinary cotinine, one of the main metabolites of nicotine, has been widely used as a biomarker for assessment of direct or passive exposure to cigarette smoke)

1,7-dimethylxanthine (marker, caffeine metabolite)