Tuesday, September 29, 2009

Adverse drug reactions

Adverse drug reactions
A drug’s desired effect is called the expected therapeutic response. An adverse drug reaction (also called a side effect or adverse effect), on the other hand, is a harmful, undesirable response. Adverse drug reactions can range from mild ones that disappear when the drug is discontinued to debilitating diseases that become chronic. Adverse reactions can appear shortly after starting a new medication but may become less severe with time.
Dosage dilemma
Adverse drug reactions can be classified as dose-related or patient sensitivity’related. Most adverse drug reactions result from the known pharmacologic effects of a drug and are typically dose-related. These types of reactions can be predicted in most cases.
Dose-related reactions include:
  • secondary effects
  • hypersusceptibility
  • overdose
  • iatrogenic effects.

Extra effects
A drug typically produces not only a major therapeutic effect but also additional, secondary effects that can be harmful or beneficial. For example, morphine used for pain control can lead to two undesirable secondary effects: constipation and respiratory depression. Diphenhydramine used as an antihistamine produces sedation as a secondary effect and is sometimes used as a sleep aid

Enhanced action
A patient can be hypersusceptible to the pharmacologic actions of a drug. Such a patient experiences an excessive therapeutic response or secondary effects even when given the usual therapeutic dose.
Hypersusceptibility typically results from altered pharmacokinetics (absorption, metabolism, and excretion), which leads to higher-than-expected blood concentration levels. Increased receptor sensitivity also can increase the patient’s response to therapeutic or adverse effects.
Oh no’overdose!
A toxic drug reaction can occur when an excessive dose is taken, either intentionally or by accident. The result is an exaggerated response to the drug that can lead to transient changes or more serious reactions, such as respiratory depression, cardiovascular collapse, and even death. To avoid toxic reactions, chronically ill or elderly patients often receive lower drug doses.
Iatrogenic issues
Some adverse drug reactions, known as iatrogenic effects, can mimic pathologic disorders. For example, such drugs as antineoplastics, aspirin, corticosteroids, and indomethacin commonly cause GI irritation and bleeding. Other examples of iatrogenic effects include induced asthma with propranolol, induced nephritis with methicillin, and induced deafness with gentamicin.
You’re so sensitive
Patient sensitivity’related adverse reactions aren’t as common as dose-related reactions. Sensitivity-related reactions result from a patient’s unusual and extreme sensitivity to a drug. These adverse reactions arise from a unique tissue response rather than from an exaggerated pharmacologic action. Extreme patient sensitivity can occur as a drug allergy or an idiosyncratic response.
Friend or foe?
A drug allergy occurs when a patient’s immune system identifies a drug, a drug metabolite, or a drug contaminant as a dangerous foreign substance that must be neutralized or destroyed. Previous exposure to the drug or to one with similar chemical characteristics sensitizes the patient’s immune system, and subsequent exposure causes an allergic reaction (hypersensitivity).
An allergic reaction not only directly injures cells and tissues but also produces broader systemic damage by initiating cellular release of vasoactive and inflammatory substances.
The allergic reaction can vary in intensity from an immediate, life-threatening anaphylactic reaction with circulatory collapse and swelling of the larynx and bronchioles to a mild reaction with a rash and itching.

Idiosyncratic response
Some sensitivity-related adverse reactions don’t result from pharmacologic properties of a drug or from an allergy but are specific to the individual patient. These are called idiosyncratic responses. Some idiosyncratic responses have a genetic cause.


Drug interactions

Drug interactions
Drug interactions can occur between drugs or between drugs and foods. They can interfere with the results of a laboratory test or produce physical or chemical incompatibilities. The more drugs a patient receives, the greater the chances that a drug interaction will occur.
Potential drug interactions include:
  • additive effects
  • potentiation
  • antagonistic effects
  • decreased or increased absorption
  • decreased or increased metabolism and excretion.

Adding it all up
Additive effects can occur when two drugs with similar actions are administered to a patient. The effects are equivalent to the sum of either drug’s effects if it were administered alone in higher doses.
Giving two drugs together, such as two analgesics (pain relievers), has several potential advantages: lower doses of each drug, decreased probability of adverse reactions, and greater pain control than from one drug given alone (most likely because of different mechanisms of action). There’s a decreased risk of adverse effects when giving two drugs for the same condition because the patient is given lower doses of each drug’the higher the dose, the greater the risk of adverse effects.
A synergistic situation
A synergistic effect, also called potentiation, occurs when two drugs that produce the same effect are given together and one drug potentiates (enhances the effect of) the other drug. This produces greater effects than when each drug is taken alone.
Fighting it out
An antagonistic effect occurs when the combined response of two drugs is less than the response produced by either drug alone.
An absorbing problem
Two drugs given together can change the absorption of one or both of the drugs:
  • Drugs that change the acidity of the stomach can affect the ability of another drug to dissolve in the stomach.
  • Some drugs can interact and form an insoluble compound that can’t be absorbed.
Sometimes, an absorption-related drug interaction can be avoided by administering the drugs at least 2 hours apart.
Bound and determined
After a drug is absorbed, the blood distributes it throughout the body as a free drug or one that’s bound to plasma protein.
When two drugs are given together, they can compete for protein-binding sites, leading to an increase in the effects of one drug as that drug is displaced from the protein and becomes a free, unbound drug.
Toxic waste
Toxic drug levels can occur when a drug’s metabolism and excretion are inhibited by another drug. Some drug interactions affect excretion only.

Back to the lab
Drug interactions can also alter laboratory tests and can produce changes seen on a patient’s electrocardiogram.

Pharmacotherapeutics

Pharmacotherapeutics is the use of drugs to treat disease. When choosing a drug to treat a particular condition, health care providers consider not only the drug’s effectiveness but also other factors such as the type of therapy the patient will receive.
Not all therapy is the same
The type of therapy a patient receives depends on the severity, urgency, and prognosis of the patient’s condition and can include:
  • acute therapy, if the patient is critically ill and requires acute intensive therapy
  • empiric therapy, based on practical experience rather than on pure scientific data
  • maintenance therapy, for patients with chronic conditions that don’t resolve
    • supplemental or replacement therapy, to replenish or substitute for missing substances in the body
    • supportive therapy, which doesn’t treat the cause of the disease but maintains other threatened body systems until the patient’s condition resolves
    • palliative therapy, used for end-stage or terminal diseases to make the patient as comfortable as possible.

    I can only be myself
    A patient’s overall health as well as other individual factors can alter that patient’s response to a drug. Coinciding medical conditions and personal lifestyle characteristics must be considered when selecting drug therapy.
    Decreased response…
    In addition, it’s important to remember that certain drugs have a tendency to create drug tolerance and drug dependence in patients. Drug tolerance occurs when a patient develops a decreased response to a drug over time. The patient then requires larger doses to produce the same response.
    …and increased desire
    Tolerance differs from drug dependence, in which a patient displays a physical or psychological need for the drug. Physical dependence produces withdrawal symptoms when the drug is stopped, whereas psychological dependence is based on a desire to continue taking the drug to relieve tension and avoid discomfort.

Sunday, September 27, 2009

Pharmacodynamics

Pharmacodynamics
Pharmacodynamics is the study of the drug mechanisms that produce biochemical or physiologic changes in the body. The interaction at the cellular level between a drug and cellular components, such as the complex proteins that make up the cell membrane, enzymes, or target receptors, represents drug action. The response resulting from this drug action is the drug effect

It’s the cell that matters
A drug can modify cell function or rate of function, but it can’t impart a new function to a cell or to target tissue. Therefore, the drug effect depends on what the cell is capable of accomplishing.
A drug can alter the target cell’s function by:
  • modifying the cell’s physical or chemical environment
  • interacting with a receptor (a specialized location on a cell membrane or inside a cell).
Agonist drugs
Many drugs work by stimulating or blocking drug receptors. A drug attracted to a receptor displays an affinity for that receptor. When a drug displays an affinity for a receptor and stimulates it, the drug acts as an agonist. An agonist binds to the receptor and produces a response. This ability to initiate a response after binding with the receptor is referred to as intrinsic activity.
Antagonist drugs
If a drug has an affinity for a receptor but displays little or no intrinsic activity, it’s called an antagonist. An antagonist prevents a response from occurring.
Reversible or irreversible
Antagonists can be competitive or noncompetitive.
  • A competitive antagonist competes with the agonist for receptor sites. Because this type of antagonist binds reversibly to the receptor site, administering larger doses of an agonist can overcome the antagonist’s effects.
  • A noncompetitive antagonist binds to receptor sites and blocks the effects of the agonist. Administering larger doses of the agonist can’t reverse the antagonist’s action.
Regarding receptors
If a drug acts on a variety of receptors, it’s said to be nonselective and can cause multiple and widespread effects. In addition, some receptors are classified further by their specific effects. For example, beta receptors typically produce increased heart rate and bronchial relaxation as well as other systemic effects.
Beta receptors, however, can be further divided into beta1 receptors (which act primarily on the heart) and beta2 receptors (which act primarily on smooth muscles and gland cells).

Potent power
Drug potency refers to the relative amount of a drug required to produce a desired response. Drug potency is also used to compare two drugs. If drug X produces the same response as drug Y but at a lower dose, then drug X is more potent than drug Y.
As its name implies, a dose-response curve is used to graphically represent the relationship between the dose of a drug and the response it produces.
Maximum effect
On the dose-response curve, a low dose usually corresponds to a low response. At a low dose, a dosage increase produces only a slight increase in response. With further dosage increases, the drug response rises markedly. After a certain point, however, an increase in dose yields little or no increase in response. At this point, the drug is said to have reached maximum effectiveness.
Margin of safety
Most drugs produce multiple effects. The relationship between a drug’s desired therapeutic effects and its adverse effects is called the drug’s therapeutic index. It’s also referred to as its margin of safety.
The therapeutic index usually measures the difference between:
  • an effective dose for 50% of the patients treated
  • the minimal dose at which adverse reactions occur
Narrow index = potential danger
Drugs with a narrow, or low, therapeutic index have a narrow margin of safety. This means that there’s a narrow range of safety between an effective dose and a lethal one. On the other hand, a drug with a high therapeutic index has a wide margin of safety and poses less risk of toxic effects.

Half-life

Half-life = half the drug
The half-life of a drug is the time it takes for one-half of the drug to be eliminated by the body. Factors that affect a drug’s half-life include its rate of absorption, metabolism, and excretion. Knowing how long a drug remains in the body helps determine how frequently it should be administered.
A drug that’s given only once is eliminated from the body almost completely after four or five half-lives. A drug that’s administered at regular intervals, however, reaches a steady concentration (or steady state) after about four or five half-lives. Steady state occurs when the rate of drug administration equals the rate of drug excretion.

Onseet of Action

Onset, peak, and duration
In addition to absorption, distribution, metabolism, and excretion, three other factors play important roles in a drug’s pharmacokinetics:
  • onset of action
  • peak concentration
  • duration of action.
Lights, camera… action!
The onset of action refers to the time interval from when the drug is administered to when its therapeutic effect actually begins. Rate of onset varies depending on the route of administration and other pharmacokinetic properties.
Peak performance
As the body absorbs more drug, blood concentration levels rise. The peak concentration level is reached when the absorption rate equals the elimination rate. However, the time of peak concentration isn’t always the time of peak response.
Sticking around
The duration of action is the length of time the drug produces its therapeutic effect.

Excretion

Excretion
Drug excretion refers to the elimination of drugs from the body. Most drugs are excreted by the kidneys and leave the body through urine. Drugs can also be excreted through the lungs, exocrine (sweat, salivary, or mammary) glands, skin, and intestinal tract.

Metabolism

Drug metabolism, or biotransformation, is the process by which the body changes a drug from its dosage form to a more water-soluble form that can then be excreted. Drugs can be metabolized in several ways:
  • Most drugs are metabolized into inactive metabolites (products of metabolism), which are then excreted.
  • Other drugs are converted to active metabolites, which are capable of exerting their own pharmacologic action. Active metabolites may undergo further metabolism or may be excreted from the body unchanged.
  • Some drugs can be administered as inactive drugs, called prodrugs, which don’t become active until they’re metabolized

Where metabolism happens
The majority of drugs are metabolized by enzymes in the liver; however, metabolism can also occur in the plasma, kidneys, and membranes of the intestines. In contrast, some drugs inhibit or compete for enzyme metabolism, which can cause the accumulation of drugs when they’re given together. This accumulation increases the potential for an adverse reaction or drug toxicity.

Conditional considerations
Certain diseases can reduce metabolism. These include liver diseases such as cirrhosis as well as heart failure, which reduces circulation to the liver.
Gene machine
Genetics allows some people to metabolize drugs rapidly and others to metabolize them more slowly.
Stress test
Environment, too, can alter drug metabolism. For example, cigarette smoke may affect the rate of metabolism of some drugs; a stressful situation or event, such as prolonged illness, surgery, or injury, can also change how a person metabolizes drugs.

The age game
Developmental changes can also affect drug metabolism. For instance, infants have immature livers that reduce the rate of metabolism, and elderly patients experience a decline in liver size, blood flow, and enzyme production that also slows metabolism.

Distribution

Distribution
Drug distribution is the process by which the drug is delivered from the systemic circulation to body tissues and fluids. Distribution of an absorbed drug within the body depends on several factors:
  • blood flow
  • solubility
  • protein binding.
Quick to the heart
After a drug has reached the bloodstream, its distribution in the body depends on blood flow. The drug is quickly distributed to organs with a large supply of blood. These organs include the:
  • heart
  • liver
  • kidneys.
Distribution to other internal organs, skin, fat, and muscle is slower.
Lucky lipids
The ability of a drug to cross a cell membrane depends on whether the drug is water or lipid (fat) soluble. Lipid-soluble drugs easily cross through cell membranes; water-soluble drugs can’t.
Lipid-soluble drugs can also cross the blood-brain barrier and enter the brain.

Free to work
As a drug travels through the body, it comes in contact with proteins such as the plasma protein albumin. The drug can remain free or bind to the protein. The portion of a drug that’s bound to a protein is inactive and can’t exert a therapeutic effect. Only the free, or unbound, portion remains active.
A drug is said to be highly protein-bound if more than 80% of the drug is bound to protein.

Phharmacokinetic,(Absorption)

Pharmacokinetics
Kinetics refers to movement. Pharmacokinetics deals with a drug’s actions as it moves through the body. Therefore, pharmacokinetics discusses how a drug is:
  • absorbed (taken into the body)
  • distributed (moved into various tissues)
  • metabolized (changed into a form that can be excreted)
  • excreted (removed from the body).
This branch of pharmacology is also concerned with a drug’s onset of action, peak concentration level, and duration of action.

Absorption
Drug absorption covers a drug’s progress from the time it’s administered, through its passage to the tissues, until it reaches systemic circulation.
On a cellular level, drugs are absorbed by several means’primarily through active or passive transport.

Passive Transport
Passive transport requires no cellular energy because diffusion allows the drug to move from an area of higher concentration to one of lower concentration. Passive transport occurs when small molecules diffuse across membranes and stops when drug concentration on both sides of the membrane is equal.
Active Transport
Active transport requires cellular energy to move the drug from an area of lower concentration to one of higher concentration. Active transport is used to absorb electrolytes, such as sodium and potassium, as well as some drugs such as levodopa.


Taking a bite
Pinocytosis is a unique form of active transport that occurs when a cell engulfs a drug particle. Pinocytosis is commonly employed to transport fat-soluble vitamins (vitamins A, D, E, and K).
Watch the speed limit!
If only a few cells separate the active drug from the systemic circulation, absorption will occur rapidly and the drug will quickly reach therapeutic levels in the body. Typically, absorption occurs within seconds or minutes when a drug is administered sublingually, I.V., or by inhalation.

Not so fast
Absorption occurs at a slower rate when drugs are administered by the oral, I.M., or subQ routes because the complex membrane systems of GI mucosal layers, muscle, and skin delay drug passage.
At a snail’s pace
At the slowest absorption rates, drugs can take several hours or days to reach peak concentration levels. A slow rate usually occurs with rectally administered or sustained-release drugs.
Not enough time
Other factors can affect how quickly a drug is absorbed. For example, most absorption of oral drugs occurs in the small intestine. If a patient has had large sections of the small intestine surgically removed, drug absorption decreases because of the reduced surface area and the reduced time that the drug is in the intestine.
Look to the liver
Drugs absorbed by the small intestine are transported to the liver before being circulated to the rest of the body. The liver may metabolize much of the drug before it enters the circulation. This mechanism is referred to as the first-pass effect. Liver metabolism may inactivate the drug; if so, the first-pass effect lowers the amount of active drug released into the systemic circulation. Therefore, higher drug dosages must be administered to achieve the desired effect.
More blood, more absorption
Increased blood flow to an absorption site improves drug absorption, whereas reduced blood flow decreases absorption. More rapid absorption leads to a quicker onset of drug action.
For example, the muscle area selected for I.M. administration can make a difference in the drug absorption rate. Blood flows faster through the deltoid muscle (in the upper arm) than through the gluteal muscle (in the buttocks). The gluteal muscle, however, can accommodate a larger volume of drug than the deltoid muscle.
Slowed by pain and stress
Pain and stress can decrease the amount of drug absorbed. This may be due to a change in blood flow, reduced movement through the GI tract, or gastric retention triggered by the autonomic nervous system response to pain.

High fat doesn’t help
High-fat meals and solid foods slow the rate at which contents leave the stomach and enter the intestines, delaying intestinal absorption of a drug.
Dosage form factors
Drug formulation (such as tablets, capsules, liquids, sustained-release formulas, inactive ingredients, and coatings) affects the drug absorption rate and the time needed to reach peak blood concentration levels.
Absorption increase or decrease?
Combining one drug with another drug, or with food, can cause interactions that increase or decrease drug absorption, depending on the substances involved.



Drug Development

In the past, drugs were found by trial and error. Now they’re developed primarily by systematic scientific research. The Food and Drug Administration (FDA) carefully monitors new drug development, which can take many years to complete.
Only after reviewing extensive animal studies and data on the safety and effectiveness of the proposed drug will the FDA approve an application for an investigational new drug (IND).

Exceptions to the rule

Although most INDs undergo all four phases of clinical evaluation mandated by the FDA, some can receive expedited approval. For example, because of the public health threat posed by acquired immunodeficiency syndrome (AIDS), the FDA and drug companies have agreed to shorten the IND approval process for drugs to treat the disease. This allows doctors to give qualified AIDS patients “treatment INDs,” which aren’t yet approved by the FDA.
Sponsors of drugs that reach phase II or III clinical trials can apply for FDA approval of treatment IND status. When the IND is approved, the sponsor supplies the drug to doctors whose patients meet appropriate criteria.
Despite the extensive testing and development that all drugs go through, serious adverse reactions may occasionally occur, even though they weren’t discovered during clinical trials. It’s also possible that drug interactions aren’t discovered until after clinical trials have concluded and the drug has been approved. The FDA has procedures in place for reporting adverse events and other problems to help track the safety of drugs.

Administration

A drug’s administration route influences the quantity given and the rate at which the drug is absorbed and distributed. These variables affect the drug’s action and the patient’s response.
Routes of administration include:
  • buccal, sublingual, translingual: certain drugs are given buccally (in the pouch between the cheek and gum), sublingually (under the tongue), or translingually (on the tongue) to speed their absorption or to prevent their destruction or transformation in the stomach or small intestine
  • gastric: this route allows direct instillation of medication into the GI system of patients who can’t ingest the drug orally
  • intradermal: substances are injected into the skin (dermis); this route is used mainly for diagnostic purposes when testing for allergies or tuberculosis
  • intramuscular: this route allows drugs to be injected directly into various muscle groups at varying tissue depths; it’s used to give aqueous suspensions and solutions in oil, immunizations, and medications that aren’t available in oral form

  • intravenous: the I.V. route allows injection of substances (drugs, fluids, blood or blood products, and diagnostic contrast agents) directly into the bloodstream through a vein; administration can range from a single dose to an ongoing infusion delivered with great precision
  • oral: this is usually the safest, most convenient, and least expensive route; drugs are administered to patients who are conscious and can swallow
  • rectal and vaginal: suppositories, ointments, creams, gels, and tablets may be instilled into the rectum or vagina to treat local irritation or infection; some drugs applied to the mucosa of the rectum or vagina can be absorbed systemically
  • respiratory: drugs that are available as gases can be administered into the respiratory system; drugs given by inhalation are rapidly absorbed, and medications given by such devices as the metered-dose inhaler can be self-administered, or drugs can be administered directly into the lungs through an endotracheal tube in emergency situations
  • subcutaneous (subQ): with the subQ route, small amounts of a drug are injected beneath the dermis and into the subcutaneous tissue, usually in the patient’s upper arm, thigh, or abdomen
  • topical: this route is used to deliver a drug through the skin or a mucous membrane; it’s used for most dermatologic, ophthalmic, otic, and nasal preparations.
Drugs may also be given as specialized infusions injected directly into a specific site in the patient’s body, such as an epidural infusion (into the epidural space), intrathecal infusion (into the cerebrospinal fluid), intrapleural infusion (into the pleural cavity), intraperitoneal infusion (into the peritoneal cavity), intraosseous infusion (into the rich vascular network of a long bone), and intra-articular infusion (into a joint).

Introduction about pharmacology

This chapter focuses on the fundamental principles of pharmacology. It discusses basic information, such as how drugs are named and how they’re created. It also discusses the different routes by which drugs can be administered.

Kinetics, dynamics, therapeutics
This chapter also discusses what happens when a drug enters the body. This involves three main areas:
pharmacokinetics (the absorption, distribution, metabolism, and excretion of a drug)
pharmacodynamics (the biochemical and physical effects of drugs and the mechanisms of drug actions)
pharmacotherapeutics (the use of drugs to prevent and treat diseases).

What’s in a name?
Drugs have a specific kind of nomenclature’that is, a drug can go by three different names:
  • The chemical name is a scientific name that precisely describes its atomic and molecular structure.
  • The generic, or nonproprietary, name is an abbreviation of the chemical name.
  • The trade name (also known as the brand name or proprietary name) is selected by the drug company selling the product. Trade names are protected by copyright. The symbol ® after the trade name indicates that the name is registered by and restricted to the drug manufacturer.
To avoid confusion, it’s best to use a drug’s generic name because any one drug can have a number of trade names.
In 1962, the federal government mandated the use of official names so that only one official name would represent each drug. The official names are listed in the United States Pharmacopeia and National Formulary.

Family ties
Drugs that share similar characteristics are grouped together as a pharmacologic class (or family). beta-adrenergic blockers are an example of a pharmacologic class.
The therapeutic class groups drugs by therapeutic use. Antihypertensives are an example of a therapeutic class.

Where drugs come from
Traditionally, drugs were derived from natural sources, such as:
  • plants
  • animals
  • minerals.
Today, however, laboratory researchers use traditional knowledge, along with chemical science, to develop synthetic drug sources. One advantage of chemically developed drugs is that they’re free from the impurities found in natural substances.
In addition, researchers and drug developers can manipulate the molecular structure of substances such as antibiotics so that a slight change in the chemical structure makes the drug effective against different organisms. The first-, second-, third-, and fourth-generation cephalosporins are an example

Old-fashioned medicine
The earliest drug concoctions from plants used everything: the leaves, roots, bulb, stem, seeds, buds, and blossoms. Subsequently, harmful substances often found their way into the mixture.
As the understanding of plants as drug sources became more sophisticated, researchers sought to isolate and intensify active components while avoiding harmful ones.

Power plant
The active components consist of several types and vary in character and effect:
  • Alkaloids, the most active component in plants, react with acids to form a salt that can dissolve more readily in body fluids. The names of alkaloids and their salts usually end in “-ine.” Examples include atropine, caffeine, and nicotine.
  • Glycosides are also active components found in plants. Names of glycosides usually end in “-in” such as digoxin.
  • Gums constitute another group of active components. Gums give products the ability to attract and hold water. Examples include seaweed extractions and seeds with starch.
  • Resins, of which the chief source is pine tree sap, commonly act as local irritants or as laxatives.
  • Oils, thick and sometimes greasy liquids, are classified as volatile or fixed. Examples of volatile oils, which readily evaporate, include peppermint, spearmint, and juniper. Fixed oils, which aren’t easily evaporated, include castor oil and olive oil.
Animal magnetism
The body fluids or glands of animals can also be drug sources. The drugs obtained from animal sources include:
  • hormones such as insulin
  • oils and fats (usually fixed) such as cod-liver oil
  • enzymes, which are produced by living cells and act as catalysts, such as pancreatin and pepsin
  • vaccines, which are suspensions of killed, modified, or attenuated microorganisms.
Mineral springs
Metallic and nonmetallic minerals provide various inorganic materials not available from plants or animals. The mineral sources are used as they occur in nature or are combined with other ingredients. Examples of drugs that contain minerals are iron, iodine, and Epsom salts.
Down to DNA
Today, most drugs are produced in laboratories and can be:

  • natural (from animal, plant, or mineral sources)
  • synthetic.