People all over the world, rely on modern medicine to cure diseases. Whether it is a simple painkiller for a headache, or medication needed for a chronic disease like hypertension, we are using medications produced by the current pharmaceutical industry on a regular basis. While consuming these medications, followers of certain faith traditions want to make sure that these medications do not have any ingredient that is unlawful in their tradition. Muslims, who constitute nearly a quarter of the entire human population, seek “halal” status of drugs for lawfulness according to Islam.

The word halal is mentioned 30 times in the Qur’an. For example, “O people, eat what is halal (lawful) and good from what is on the earth, and do not follow the footsteps of the devil; for the devil is a real enemy to you” (Al-Baqarah 168). In another verse, “They ask you: ‘What is allowed (halal) for them [to eat]’? It is allowed for you to eat good things…” (Al-Ma’idah 4). Another legal source related to halal consumption is the hadith, Prophet Muhammad’s traditions, peace be upon him. In one hadith, he mentioned the importance of eating halal food by emphasizing that “A believer will be in adherence to his religion as long as he does not eat unlawful food” (Bukhari).

Muslims are also encouraged to consume everything that is pure and clean. Indeed, the word halal is often followed by the word “pure” in many Qur’anic verses. The word pure means “good,” “delicious,” and “lawful.” It usually refers to the hygiene and safety of food consumed by Muslims. The recommendation to consume such hygienic and safe food is clearly stated in the Qur’an: “Eat of the good and halal things provided by Allah. And be mindful of Allah in Whom you believe” (Al-Ma’idah 88). The Prophet is also reported as having said, “God is pure, and He accepts only what is purely good” (Muslim). Islam also encourages medical research to find right medications to treat diseases. In a hadith reported by Abu Darda’, the Prophet said: “Indeed, God has sent down both the illness and its cure, and He has appointed a cure for every illness, so treat yourselves medically, but use nothing unlawful” (Abu Dawud).

Halal pharmaceuticals not only should contain ingredients that are halal, but they should also be produced according to Islamic regulations. Many medications contain ingredients or excipients that are not halal or are manufactured in a manner that is not aligned with Islamic values. There is a general lack of knowledge concerning the halal status of most of the medications. There are also many discussions about what makes a drug (or food, for that matter) halal or not.

The Global Islamic Economic Report 2020/2021 estimated the value of the global halal product market at around $2.02 trillion in 2019, reflecting a 3.2% year-on-year growth from 2018. It has been reported that Muslim spending on halal pharmaceutical products increased from $92 billion in 2018 to $94 billion in 2019. Muslim consumer spending in the pharmaceutical sector is expected to increase by 2.3% from 2019 onwards, reaching $105 billion by 2024.

In a study by Sarriff et al, out of 221 pharmaceutical products in the categories of cardiovascular, respiratory and endocrine medications, only 63 were suitable for assessment of their halal status. These products contained a total of 240 active ingredients and 570 excipients. They have concluded that the lack of information about the product’s constituents was the main factor hindering the identification of halal status. Many manufacturers were not cooperative in providing detailed information about their products in this study. They could not assess 73 out of 240 active ingredients. This was due to the difficulty in obtaining accurate information related to their origins. The percentage of active ingredients categorized as halal, mushbooh (doubtful) and haram was 83.8% (140), 13.2% (22), and 3% (5), respectively. On the other hand, they could not evaluate 54 excipients out of 570 due to lack of information. They found that the distribution of halal, mushbooh, and haram excipients was at 70% (361), 27.3% (141), and 2.7% (14), respectively.

Most of the haram substances had ethanol, which was used particularly in the formulation of respiratory medications. The most common substance categorized as mushbooh was magnesium stearate, followed by gelatin and glycerol. While investigating the halal status of cardiovascular, respiratory, and endocrine medications, interestingly, 23.8% of products surveyed were categorized as haram, while more than half (57.1%) were evaluated as mushbooh. As a rare study made on the halal status of pharmaceuticals, this research shows that there is big gap in this area and there is a need for further investigation and exploration for alternative products.

In Muslim countries, there also lacks sufficient regulations and guidelines published by public authorities for the classification of halal drugs. One such rarity is the Halal Pharmaceuticals General Guidelines, published by the Department of Malaysian Standards in 2012. According to this guideline, products that contain ingredients permitted under Islamic law and fulfill the following conditions are considered as halal pharmaceuticals:

1. They do not contain any parts or products of animals that are non-halal by Islamic law or any parts or products of animals which are not slaughtered according to Islamic law,
2. They do not contain any ingredients that are najs (impure) according to Islamic law,
3. They are safe for human use, non-poisonous, non-toxic, or non-hazardous to health according to their prescribed dosage, not prepared, processed or manufactured using equipment contaminated with najs according to Islamic law,
4. They do not contain any human parts or its derivatives that are not permitted by Islamic law,
5. During preparation, processing, handling, packaging, storage and distribution, the halal pharmaceutical products are physically separated from any other pharmaceutical products that do not meet the requirements stated in items a), b), c), d) or e) or any other items that
   have been decreed as non-halal and najs by Islamic law.

Only pure items may come into contact with halal products. Impure items cause contamination which is prohibited in the halal system. Impure items (contaminants) which are called as filth (najasa) are listed as following:

1. Pig (all parts, including skin and bones) both while alive or dead,
2. Dog (all parts, including saliva) both while alive or dead,

1. Animals not slaughtered according to Islamic ritual rites (dead animals/maytah – all parts),
2. Urine,
3. Excrement,
4. Vomit,
5. Blood,
6. Pus,
7. Untanned animal skin (unprocessed leather),
8. Land animals that have consumed more than 50% of their diet of anything of the above (this includes its milk, sweat, and other excretions),
9. Any part of a land animal that falls off or is removed while the animal is alive (besides hair).

All materials used in manufacturing of halal pharmaceuticals including starting and packaging materials should be halal. Materials may be from synthetically or naturally derived sources. All najs are prohibited. Also, the consumable and non-consumable packaging and printed materials shall be from any origin that is decreed as halal by Islamic law.

There are many aspects that may affect the halal status in pharmaceuticals:

Gelatin in capsule shells in soft and hard gelatin capsules: Gelatin is the primary ingredient to confer filming property to the thin capsule shells. In the industry of pharmaceuticals, gelatin is used to make soft gel capsules, tablets and serums and also used in injection. There are three sources of gelatin, namely bovine, porcine and goat. For gelatin derived from bovine and goat, the animals must be slaughtered in the Islamic way to conform to halal regulation. Muslims should find alternatives for halal sources of gelatin that come from plant sources for capsules.

Gelatin in parenteral formulation: Gelatin is a standard pharmaceutical stabilizer in the parenteral dosage form. The source of gelatin can be derived from bovine and porcine. Such parenteral formulations include vaccines, antibiotics, anti-inflammatory and anticoagulant drugs.

Alcohol in orally administered medicine: Some medicines to be consumed orally (e.g. liquid or suspension) may contain alcohol (mainly ethanol). There could be two functions of this ethanol in this medicine, either as co-solvent, antiseptic, or both.

Usually, ethanol is present in less than 11 percent of cough syrups and in high concentration (approximately20-30 %) in any tincture preparation. Some Islamic Authorities state that ethanol could be used for medical purposes without saying the limit, as long as the ethanol origin is from a non-beverage, alcohol-making factory. Nevertheless, there are always other medicines for the same indication that do not contain ethanol. Alcohol is mainly used as a solvent, and other good solvents should be investigated as replacements for alcohol.

Alcohol (ethanol) in topical dosage form: Ethanol in topical dosage form pharmaceuticals (lotion, cream, hand sanitizer) is used as antiseptic or penetration enhancers.

Magnesium stearate: Magnesium stearate is mainly used as an excipient in tablet form. It is a lubricant in manufacturing solid dosage forms (tablets, capsules) and some inhaler preparations such as dry powder inhalers of many brands and technologies. It can be derived from either plant or animal origin. Whenever it originates from an animal, the animal must be halal and slaughtered in the Islamic way.

There are some regulations for halal pharmaceuticals in developed countries. For example, according to the United States Department of Agriculture (USDA), in the Food Safety and Inspection Service, if a manufacturer intends to add the word “Halal” to product packaging, the product and facility must be certified by a third-party halal certification agency. If the term “Halal” is utilized without the term “Certified,” The Labeling and Program Delivery Staff (LPDS) does not need to approve the label, however, the requirement to be certified by a halal establishment is not waived. Anytime the term halal is applied to any product, it is considered as a legal statement which must be verifiable.

In the current pharmaceutical industry, there is still plenty of work to be done to create consistent awareness around the “halal status” of the medications we consume. We cannot claim that the current pharmaceutical industry is giving sufficient importance to the development of the halal pharmaceutical market. The Muslim population is not giving enough pressure on the industry for awareness, nor are Muslim scientists giving enough effort to make contributions in this area. Another issue is that there are varying opinions of Muslim scholars on pharmaceutical products due to different theological approaches. On the other hand, halal consumers do not know if the ingredients’ names have been masked or considered “proprietary” and therefore undisclosed. Halal consumers rely upon the insight, knowledge base, and expertise of a certifying agency to do the intensive work required. When the halal certification seal is found on a product, the consumer finds confidence via the trust of the organization that backs it. Halal certification agencies focus on 4 core principles when fulfilling their service: sanitation, traceability, integrity, and composition. But it is certain that there is a lack of standardization and quality control for these agencies.

Chemical analysis is crucial for verifying and authenticating halal products. However, it’s important to note that this method doesn’t address all non-halal aspects, particularly those unrelated to chemistry, such as the slaughtering system.

To sum up, many drug products contain high levels of alcohol or questionable products derived from animals. Every ingredient in the drug must be traceable to be certified halal. Products must not contain any ingredient derived from pig, alcohol, blood, predatory animals, human parts, or insects. Animal-derived ingredients must come from permissible animals slaughtered as per the method prescribed by Islamic law.

Moreover, the ingredients used must be safe for humans and should not be intoxicating nor should they be prepared with equipment contaminated by najis (impurity). During its preparation, processing, handling, packaging, storage, and distribution, halal pharmaceutical products need to be physically separated from any other pharmaceutical products that do not meet the aforementioned requirements.

In conclusion, there exists a significant gap in the pharmaceutical field when it comes to understanding the halal status of a drug. In the Quran, it is stated that “He has explained to you in detail what is forbidden to you ― except under compulsion of necessity” (Al-An’am 111) but Muslim scientists should give more importance to this area and new analytical techniques should be investigated to understand the halal status of pharmaceuticals continuously as there is an increase in the complexity of these consumer products. The development, effects, and results of developed halal pharmaceuticals should be followed in a scientific way. Muslim scholars should also discuss and come to an agreement about a well-regulated and harmonized halal accreditation procedure for pharmaceuticals.

References

1. https://halalwatch.us/faqs
2. Sarriff A, Abdul Razzaq HA. Exploring the halal status of cardiovascular, endocrine, and respiratory group of medications. Malays J Med Sci. 2013 Jan;20(1):69-75.
3. Achmad Mursyidi, The role of chemical analysis in the halal authentication of food and pharmaceutical products, J.Food Pharm.Sci. 1 (2013), 1-4.
4. Malaysian Standard, Halal pharmaceuticals-General guidelines https://law.resource.org/pub/my/ibr/ms.2424.2012.pdf

Halal is an Arabic word that means “lawful or permitted.” It is a term used in the Islamic religion in contrast with the word haram which means “unlawful or not allowed.” While these terms refer to much more than just dietary practices and indicate which life practices are allowed or not allowed for those who practice Islam, they are most often used for food and drinks. Depending on their formulations, medications, too, need to be evaluated for their halal compliance.

Medicines consist of numerous ingredients, encompassing both active and inactive components that necessitate careful consideration when discussing the halal status of a drug. Thus, it becomes imperative to understand the composition of medicinal ingredients and the intricacies involved in drug formulation before assessing their halal compliance. This article delves into an exploration of drug ingredients and formulations, while the subsequent article in the next issue will address the potential implications of these factors on the halal status of medicines.

Pharmaceutical formulation

A pharmaceutical formulation refers to the combination of an active pharmaceutical ingredient and various inactive components, culminating in the production of the final medicinal product. After undergoing various processes, the active drug is combined with other components, with careful consideration given to factors such as particle size, polymorphism, pH, and chemical solubility. Through evaluation of these chemical properties, the final beneficial medicinal product is meticulously crafted. Equally important is the design, development, and validation of the chosen drug product to guarantee its safety, effectiveness, and consistent delivery of the intended therapeutic benefits. Prudent selections of appropriate ingredients, dosage forms, manufacturing techniques, and packaging are crucial for optimizing the drug’s properties and ensuring its long-term stability.

The active ingredient represents the primary chemical component responsible for the desired therapeutic effect. Each inactive ingredient within the formulation serves a specific purpose, ensuring optimal product performance and compliance. Any additional ingredient not integral to the drug formulation is strictly excluded. Consequently, each ingredient present serves a necessary function. Various types of drugs exist, and common inactive ingredients in tablet formulations, for instance, encompass diluents, binders, disintegrants, lubricants, glidants, colorants, and specialized additives that can modulate drug release or facilitate absorption. Among these, diluents, binders, disintegrants, and lubricants are prevalent in tablet formulations and fulfill the roles implied by their names. An effective drug formulation must be both manufacturable and chemically and physically stable throughout the manufacturing process and the product’s shelf life. It should contain a precise dosage of the active pharmaceutical ingredient that can be easily absorbed by the human body. Moreover, it must adhere to numerous quality standards and specific requirements to guarantee both efficacy and safety. Additionally, the cost-effectiveness of each added ingredient should also be taken into consideration. Establishing a clear target product profile is crucial for ensuring the efficacy and focus of the formulation process. This profile typically encompasses the chosen route of administration, specific dosage form and size, any unique delivery requirements, as well as parameters related to the pharmaceutical appearance. Factors that influence the target product profile often include existing competing drugs in the market and the characteristics of the target patient population. For instance, pediatric formulations might necessitate the development of chewable tablets or suspensions. Moreover, individual circumstances, such as certain patients being unable to take the drug orally, may require alternative modes of administration. The formulation development process involves several stages, each playing   a crucial role in the successful development of a drug product:

1. Pre-formulation studies: This step entails the thorough analysis of a drug’s physical, chemical, and mechanical attributes to determine the optimal ingredients for its preparation. These studies evaluate the chemical properties of the drug substance, such as solubility, stability, and compatibility with other excipients. The results from pre-formulation studies help in formulation design and evaluation, which are in the second stage.
2. Formulation design and evaluation: This is the process of selecting the appropriate dosage form and excipients for the drug substance. The dosage form can be solid, liquid, semisolid, or dispersion depending on the physical and chemical properties of the drug and the target patient population. The ingredients are selected based on their compatibility with the drug substance, their function in the formulation, and their safety profile. The particle size, polymorphism, pH, and solubility of the ingredients can influence the activity of a drug. The drug must be combined with inactive ingredients by a method that ensures that the quantity of drug is consistent in each dosageunit, for example in each tablet. The dosage should have a uniform appearance, with an acceptable taste, tablet hardness, and capsule disintegration and even color.
3. Manufacturing and process development: Process development is the optimization of the manufacturing process to ensure consistent quality, yield, and purity of the drug product. The manufacturing process is designed to ensure that the drug product meets the required specifications and is produced in compliance with regulatory requirements. The appropriate scale of the manufacturing process needs to be consistent with the needs of pre-clinical, clinical, and commercial requirements for the drug product.
4. Analytical development and characterization: Analytical methods must be developed to ensure that the drug product meets the identity, purity, and potency specifications and requirements. The purity and potency of a drug product are measured and residual water, critical excipient levels and other impurities, drug dissolution or release, pH, osmolarity, appearance, particle size, and other critical quality attributes are also tested.
5. Stability and shelf-life: Stability testing is a critical aspect of the formulation development process. It ensures that the drug product maintains its quality and efficacy over time because the drugs are stored at pharmacies and stores for long periods of time. Pharmaceutical stability testing encompasses the storage of the drug product under various environmental conditions, including temperature, humidity, and light, while monitoring its physical and chemical properties over a period. The data obtained from these tests aids in establishing the optimal storage conditions and determining the shelf-life of the drug product. The drug formulation is also influenced by the chosen route of administration, which can vary significantly. With various routes of administration available, the formulations may undergo modifications accordingly.

Enteral formulations: Oral drugs are normally taken as tablets or capsules. The active drug must exhibit controlled solubility in aqueous solutions, with the dissolution process being significantly influenced by factors such as particle size and crystal form. It’s important to note that fast dissolution rates are not always optimal. For instance, slower dissolution rates can extend the duration of action or prevent initial high plasma levels, serving specific therapeutic objectives. A tablet is usually a compressed preparation that contains:

• 5-10% of the drug (active substance)
• 80% of fillers, disintegrants, lubricants, glidants, and binders
• 10% of compounds which ensure easy disintegration, disaggregation, and dissolution of the tablet in the stomachor the intestine.

Formulation studies revolve around drug preparation that is both stable and well-tolerated by patients. For orally administered drugs, this usually involves incorporating the drug into a tablet or a capsule. It is important to make the distinction that a tablet contains a variety of other potentially inert substances apart from the drug itself, and studies have to be carried out to ensure that the encapsulated drug is compatible with these other substances in a way that does not cause direct or indirect harm to the patient.

The dissolution time of a tablet or capsule can be adjusted to achieve either rapid absorption or sustained release. Special coatings can render the tablet resistant to stomach acids, allowing the drug to disintegrate only in the duodenum, jejunum, or colon due to enzymatic action or an alkaline pH. Pills can be coated with sugar, varnish, or wax to disguise the taste. There are other forms of oral drugs. A capsule is a gelatinous envelope enclosing the active substance. Capsules can be designed to remain intact for some hours after ingestion in order to delay absorption. They may also contain a mixture of slow and fast release particles to produce rapid and sustained absorption in the same dose.

There are a number of methods by which tablets and capsules can be modified in order to allow for sustained release of the active compound as it moves through the digestive tract. One of the most common methods is to embed the active ingredient in an insoluble porous matrix, such that the dissolving drug must make its way out of the matrix before it can be absorbed. In other sustained release formulations, the matrix swells to form a gel through which the drug exits.

Another method by which sustained release is achieved is through an osmotic controlled-release oral delivery system, where the active compound is encased in a water-permeable membrane with a laser drilled hole at one end. As water passes through the membrane the drug is pushed out through the hole and into the digestive tract where it can be absorbed.

Another category of drugs, known as parenteral formulations or injectable formulations, is administered via various routes such as intravenous (into the vein), subcutaneous (under the skin), intramuscular (into the muscles), and intra-articular (into the joints). These drugs are typically stored in liquid form, while unstable drugs are stored in lyophilized form. Liquid drugs are stored in vials, intravenous bags, ampoules, cartridges, and prefilled syringes. As with solid formulations, liquid formulations combine the drug product with a variety of compounds to ensure a stable active medication following storage. These include solubilizers, stabilizers, buffers, tonicity modifiers, bulking agents, viscosity enhancers/reducers, surfactants, chelating agents, and adjuvants.

Another form of the parenteral formulation is lyophilized drugs. Lyophilized drugs are stored in vials, cartridges, dual chamber syringes, and prefilled mixing systems. Lyophilization or freeze drying, is a process that removes water from a liquid drug creating a solid powder or cake. The lyophilized product is stable for extended periods of time and could allow storage at higher temperatures. In protein formulations, stabilizers are added to replace the water and preserve the structure of the molecule. Before administration, a lyophilized drug is reconstituted as a liquid before being administered. This is done by combining a liquid diluent with the freeze-dried powder, mixing, then injecting. Reconstitution often necessitates a dedicated system for mixing and administering the drug accurately. Drugs administered via the skin are commonly used in topical formulations. Some options for topical formulations include the following:

Cream: Emulsion of oil and water in approximately equal proportions. Penetrates stratum corneum outer layers of skin well.

Ointment: Combines oil (80%) and water (20%). It makes an effective barrier against moisture loss.

Gel: Liquefies upon contact with the skin.

Paste: Combines three agents – oil, water, and powder; an ointment in which a powder is suspended.

Powder: A finely subdivided solid substance.

Formulated drugs, conversely, are stored within container closure systems for prolonged durations. These systems encompass blisters, bottles, vials, ampules, syringes, and cartridges. Containers can be crafted from diverse materials such as glass, plastic, and metal, accommodating drugs in solid, liquid, or gas form. It is crucial to assess the possibility of any undesirable interactions between the formulation and its container. For example, when a plastic container is utilized, evaluations are conducted to determine whether any of the ingredients become adsorbed onto the plastic surface and whether plasticizers, lubricants, pigments, or stabilizers leach out from the container into the preparation. Even the adhesives used for container labels require testing to verify that they do not permeate the plastic container and affect the preparation. While the chemical properties of the ingredients remain pivotal in drug development, it’s crucial to recognize that containers can also influence these properties. Therefore, the selection of appropriate containers for each drug is paramount. Thus, assessing the halal status of a drug requires consideration not only of the active and inactive ingredients but also of the containers.

In conclusion, a multitude of drug formulations are employed, encompassing various inactive ingredients and containers, which vary based on the chemical properties of the active ingredient and the chosen route of administration. Considering the diverse array of active and inactive ingredients, as well as the containers used, is essential when addressing the halal status of a drug.

References

1. https://en.wikipedia.org/wiki/Pharmaceutical_formulation
2. https://www.ncbi.nlm.nih.gov/books/NBK562239/ Pharmaceutical Formulation Shanta Afrin; Vikas Gupta.
3. https://ascendiapharma.com/newsroom/2021/11/10/formulation-development
4. https://law.resource.org/pub/my/ibr/ms.2424.2012.pdf
5. https://www.emerald.com/insight/content/doi/10.1108/JIMA-06-2021-0192/full/html#ref058

When someone has a headache, they take a pain reliever; usually, the pain soon goes away. If a child has a fever, its parents will give them an antipyretic to reduce the fever. How do these drugs work? What effects do they have on the body? In the previous issue of The Fountain, we covered Pharmacokinetics and explored what our body does to a drug when we take one. In this issue we will explore pharmacodynamics, in other words, what a drug does to our body.

Pharmacodynamics is the study of the biochemical, physiological, and molecular effects of drugs on the body. It comes from the Greek words “pharmakon,” meaning “drug,” and “dynamikos,” meaning “power.” Dynamo typically refers to energy or power. But in terms of pharmacodynamics, it refers to how the drug works and how it exerts its power on the body. Pharmacodynamics describes how biological processes in the body respond to or are impacted by a drug. Understanding the basics of pharmacodynamics provides answers to questions such as, “how does this drug work?” and, “how much of a drug is needed to safely treat the patient?”

All drugs produce their effects by interacting with biological structures or targets at the molecular level, inducing a change in how the target molecule functions in regard to subsequent intermolecular interactions. These interactions include receptor binding, post-receptor effects, and chemical interactions. The pharmacological response depends on the drug binding to its target. The concentration of the drug at the receptor site also influences the drug’s effect. By testing large concentrations of a drug in a lab, a drug’s maximum effect can be determined.

Receptor principle

The most common way a drug works is by interacting with tissue receptors located either in cell membranes or in the intracellular fluid. Receptors respond to specific neurotransmitters, hormones, antigens, chemicals, or substances. A chemical (ligand) binds to a specific site (receptor) and triggers a response (signal) in the cells. The intracellular changes initiated by the ligand–receptor complex can be through direct or indirect action; however, the ligand generally functions as either an agonist or an antagonist. An agonist will mimic the endogenous ligand to produce a similar response (e.g., morphine is an agonist for opioid receptors), whereas an antagonist blocks the usual ligand and thus inhibits the physiologic response (e.g., naloxone is an antagonist for opioid receptors).

When drug molecules bind with receptor molecules, the drug–receptor complex initiates physiochemical reactions that stimulate or inhibit normal cellular functions. One type of reaction involves activation, inactivation, or other alterations of intracellular enzymes. Because almost all cellular functions are catalyzed by enzymes, drug-induced changes can markedly increase or decrease the rate of cellular metabolism.

A second type of reaction involves changes in the permeability of cell membranes to one or more ions. The receptor protein is a structural component of the cell membrane, and by binding to a drug molecule, it may open or close ion channels.

A third reaction may modify the synthesis, release, or inactivation of the neurohormones (e.g., acetylcholine, norepinephrine, or serotonin) that regulate many physiological processes.

There are some additional characteristics to keep in mind about drug-receptor bindings:

1. The site and extent of a drug’s effect on the body’s cells is determined primarily by the specific characteristics of receptors and drugs. Receptors vary in type, location, number, and functional capacity.
2. The number of receptor sites available to interact with drug molecules also affects the extent of a drug’s effect. A minimal number of receptors must be occupied by drug molecules to produce pharmacological effects. If many receptors are available but only a few are occupied by drug molecules, few drug effects occur. In this instance, increasing the drug dosage increases the pharmacological effects. Conversely, if only a few receptors are available for many drug molecules, receptors may be saturated. In this instance, if most receptor sites are occupied, increasing the drug dosage produces no additional pharmacological effect.
3. Once a drug action occurs, drug molecules may detach from receptor molecules (i.e., the chemical binding is reversible), return to the bloodstream, and circulate to the liver to be metabolized and the kidneys for excretion.
4. Receptors are dynamic cellular components that can be synthesized by body cells and altered by endogenous substances and exogenous drugs. For example, prolonged cellular stimulation by an agonist usually reduces the sensitivity of the receptors. As a result, the cell becomes less responsive to the agonist (a process called receptor desensitization or down-regulation). Prolonged inhibition of normal cellular functions with an antagonist may increase receptor sensitivity. If the antagonist is suddenly reduced or stopped, the cell becomes excessively responsive to an agonist (a process called receptor upregulation). These changes in receptors may explain why some drugs must be tapered in dosage and discontinued gradually if withdrawal symptoms are to be avoided.

Some drugs acting at the same receptor (or tissue) differ in the magnitude of the biological responses that they can achieve (efficacy) and the amount of the drug required to achieve a response (potency). Drug receptors can be classified on the basis of their selective response to different drugs. Constant exposure to drugs sometimes leads to a reduced response (desensitization).

How can a drug’s pharmacodynamics be affected?

A drug’s pharmacodynamics can be affected by physiological changes due to

• A disorder or disease
• Aging
• Other drugs

Disorders that affect pharmacodynamic responses include genetic mutations and different diseases. These disorders can change receptor binding, alter the level of binding proteins, or decrease receptor sensitivity. Aging tends to affect pharmacodynamic responses through alterations in receptor binding or in post-receptor response sensitivity. Pharmacodynamic drug–drug interactions result in competition for receptor binding sites or alter post-receptor responses.

A drug’s action may be increased or decreased by its interaction with another drug. Most interactions occur whenever the interacting drugs are present in the body; some, especially those affecting the absorption of oral drugs, occur when they are given at or near the same time. The basic cause of many drug–drug interactions is altered drug metabolism. For example, drugs metabolized by the same enzymes may compete for enzyme binding sites, and there may not be enough binding sites for two or more drugs. Also, some drugs induce or inhibit the metabolism of other drugs.

Protein binding is also the basis for some important drug–drug interactions. A drug with a strong attraction to protein-binding sites may displace a less tightly bound drug. The displaced drug then becomes pharmacologically active, and the overall effect is the same as taking a larger dose of the displaced drug.

At pharmacodynamic level, there are four kinds of drug interactions:

1. Additive: occurs when two or more drugs combine to produce an effect greater than the effect of either drug taken alone. (Additive: 1 + 1 = 2).
2. Synergistic (hyper additive: 1 + 1 = 6).
3. Potentiation: a drug with no effect is combined with another drug to cause a greater effect (1 + 0 = 2)
4. Antagonistic: one drug weakens or cancels out the effect of another drug.

Drugs and humans: an analogy

Interactions between drugs are similar to interactions between humans. Sometimes the person who comes into our life adds value to our lives only as much as their own value but does not change our potential. Some people, on the other hand, help us go beyond our own potential by adding synergy to our lives. Some people are not our equal, although they allow us to exceed our potential, and it may be necessary to carry such people as a burden. Some other completely block our lives and prevent us from having a positive effect, just as they do not produce any effect themselves. Since we will encounter all types of people throughout our lives, we must be prepared for all of them. And we should keep this in mind the next time we put a drug into our body.

Figure 1. The receptor theory

References

• https://www.merckmanuals.com/professional/clinical-pharmacology/pharmacodynamics/overview-of-pharmacodynamics
• https://en.wikipedia.org/wiki/Pharmacodynamics
• Pharmacodynamics Mark Marino; Zohaib Jamal; Patrick M. Zito.
• http://www.pharmacologyeducation.org/clinical-pharmacology/clinical-pharmacodynamics
• Clinical Drug Therapy: Rationales for Nursing Practice – Seventh 7th Edition, Lippincott Williams &Wilkins.

When we get a prescription from a doctor, the drug usually comes with instructions for how to use it. These include when we take the drug (before or after a meal), how many times a day and for how long we take it, and what we have to avoid while using the drug. Doctors also ask if we use any other medication or if we have any chronic disease before prescribing any new medication. Most medicines look similar, but drugs themselves can be very different. Have you thought about what happens to a drug when it gets into our body?

All body functions and disease processes—as well as most drug reactions—occur at the cellular level. Drugs are chemicals that alter basic processes in body cells. They cannot add functions and activities but can only affect normal cellular functions and activities. Drugs given for systemic effects must reach adequate concentrations in the blood and other tissue fluids surrounding our cells to have an effect. Drugs must circulate through their body, reach their intended cells, and, after affecting the cells, be eliminated from the body. But how do all these processes occur? How do systemic drugs reach, interact with, and leave the body’s cells?

The answers to these questions are answered by one of the main domains of pharmacology—pharmacokinetics. Pharmacokinetics is derived from the Greek words pharmakon (drug) and kinetikos (movement) and means “what the body does to a drug.” It refers to the movement of a drug into, through, and out of the body.

Knowledge of pharmacokinetic principles helps healthcare providers to adjust dosages more accurately and rapidly. Application of pharmacokinetic principles to individualize pharmacotherapy is termed therapeutic drug monitoring and aims to give the exact amount of drug to each person.

The four main parts of the pharmacokinetic processes are

• Absorption
• Distribution
• Metabolism
• Elimination

These processes are abbreviated as ADME.

Figure. Entry and movement of drug molecules through the body to sites of action, as well as metabolism and excretion 

Absorption

Absorption is the process that occurs when a drug enters the body until it enters the bloodstream to be circulated. The duration of a drug’s action is largely determined by the rate of absorption, and intensity is determined by the extent of absorption.

Numerous factors affect the rate and extent of drug absorption, including dosage, form, route of administration, blood flow to the site of administration, gastrointestinal function, and the presence of food or other drugs.

Most oral drugs must be swallowed, dissolved in gastric fluid, and delivered to the small intestine (which has a large surface area for absorption of nutrients and drugs) before they are absorbed. Liquid medications are absorbed faster than tablets or capsules because they need not be dissolved. Rapid movement through the stomach and small intestine may increase drug absorption by promoting contact with absorptive mucous membrane; it also may decrease absorption because some drugs may move through the small intestine too rapidly to be absorbed. For many drugs, the presence of food in the stomach slows the rate of absorption and may decrease the amount of drug absorbed. That is why some drugs are taken before meals and some after.

Drugs cannot be absorbed well when a patient has diarrhea and the intestines are working excessively; the effect of the drug will be reduced. Absorption may be increased if the patient has constipation and the intestines are working very slowly; this could have unforeseen adverse effects.

Drugs injected into subcutaneous (under the skin) or intramuscular (in the muscles) tissues are usually absorbed more rapidly than oral drugs because they move directly from the injection site to the bloodstream. Absorption is rapid from muscle sites because muscle tissue has abundant blood supply. Drugs injected intravenously (into the veins) do not need to be absorbed because they are placed directly into the bloodstream.

Other absorptive sites include the skin, mucous membranes, and lungs. Most drugs applied to the skin are given for local effects (e.g., muscle relaxant creams, itch relief ointments, and burn ointments). Systemic absorption is minimal from intact skin but may be considerable when the skin is inflamed or damaged. Also, a number of drugs have been formulated in adhesive skin patches for absorption through the skin. Some drugs applied to mucous membranes also are given for local effects. However, systemic absorption occurs from the mucosa of the oral cavity, nose, eyes, etc. Drugs absorbed through mucous membranes pass directly into the bloodstream. For example, nitroglycerin sublingual tablets are used to treat episodes of angina (chest pain) in people who have coronary artery disease. It is also used just before activities that may cause episodes of angina to prevent symptoms. It works by relaxing the blood vessels so the heart does not need to work as hard and therefore does not need as much oxygen. The lungs can be a good absorption site, as they have a large surface area for absorption of anesthetic gases and a few other drugs.

Distribution

Distribution involves the transport of drug molecules within the body. Once a drug is injected or absorbed into the bloodstream, it is carried by the blood and tissue fluids to its sites of pharmacologic action, metabolism, and excretion. Most drug molecules enter and leave the bloodstream at the capillary level, through gaps between the cells that form capillary walls.

Distribution depends largely on the adequacy of blood circulation. Drugs are distributed rapidly to organs receiving a large blood supply, such as the heart, liver, and kidneys. Distribution to other internal organs, muscle, fat, and skin is usually slower.

An important factor in drug distribution is protein binding. Most drugs form a complex with plasma proteins such as albumin. These proteins act as carriers for the drugs. Drug molecules bound to plasma proteins are pharmacologically inactive because the large size of the complex prevents their leaving the bloodstream through the small openings in capillary walls and reaching their sites of action. Only the free or unbound portion of a drug acts on the body’s cells. As the free drug acts on cells, the decrease in plasma protein levels causes some of the bound drug to be released.

Protein binding allows part of a drug dose to be stored and released as needed. Some drugs also are stored in muscle, fat, or other body tissues and released gradually when plasma drug levels fall. These storage mechanisms reduce the risk of toxicity. Drugs that are highly bound to plasma proteins or stored extensively in other tissues have a long duration of action. This affects the frequency of intake of a drug and is why some drugs are taken more frequently.

Drug distribution into the central nervous system (CNS) is limited because of the blood–brain barrier, which is composed of capillaries with tight walls and limits the movement of drug molecules into brain tissue. This barrier has been created to act as a selectively permeable membrane to protect the CNS. However, it also can make drug therapy for CNS disorders more difficult because drugs must pass through the cells of the capillary wall rather than between cells. As a result, only drugs that are lipid soluble or have a transport system can cross the blood–brain barrier and reach therapeutic concentrations in brain tissue.

Drug distribution during pregnancy and lactation is also unique. During pregnancy, most drugs cross the placenta and may affect the fetus. During lactation, many drugs enter breast milk and may affect the nursing infant. This barrier is also important and protects the fetus from the adverse effects of drugs.

If we have valuable things at home or at work, we put them in extra safe places and use extra security systems to protect them. So it is with our body: our brain and a fetus are extra protected by these barriers.

Metabolism

Metabolism is the chemical reaction by which drugs are inactivated or bio-transformed by the body. Most often, an active drug is changed into one or more inactive metabolites, which are then excreted. Some active drugs yield metabolites that are also active and that continue to exert their effects on the body’s cells until they are metabolized further or excreted. Other drugs (called prodrugs) are initially inactive and exert no pharmacologic effects until they are metabolized.

Most drugs are lipid soluble, a characteristic that aids their movement across cell membranes. However, the kidneys, which are the primary excretory organs, can excrete only water-soluble substances. Therefore, one function of metabolism is to convert fat-soluble drugs into water-soluble metabolites.

Hepatic drug metabolism—or clearance—is a major mechanism for terminating drug action and eliminating drug molecules from the body. Most drugs are metabolized by enzymes in the liver, red blood cells, plasma, kidneys, lungs, and gastrointestinal mucosa.

With long term administration, some drugs stimulate liver cells to produce larger amounts of drug metabolizing enzymes (a process called enzyme induction). Enzyme induction accelerates drug metabolism because larger amounts of the enzymes allow larger amounts of a drug to be metabolized during a given time. As a result, larger doses of the rapidly metabolized drug may be required to produce or maintain therapeutic effects. Metabolism also can be decreased or delayed in a process called enzyme inhibition, which most often occurs with concurrent administration of two or more drugs that compete for the same metabolizing enzymes. In this case, smaller doses of the slowly metabolized drug may be needed to avoid adverse reactions and toxicity from drug accumulation. Thus, doctors always ask about any medications already being used before prescribing a new medication. Also, some foods (eg. grapefruit), drinks (alcohol), and smoking affect the activity of the enzymes which are metabolizing the drugs in the liver. Thus, we must be careful and follow a doctor’s instructions while using any medication.

The rate of drug metabolism is also reduced in infants (their hepatic enzyme system is immature), in people with impaired blood flow to the liver or severe hepatic or cardiovascular disease, and in people who are malnourished or on low-protein diets. Metabolism in  elderly people and pregnant women also changes a lot; thus, the dose given to each individual should be carefully calculated—especially in children, the elderly, and pregnant women.

Excretion

Excretion refers to the elimination of a drug from the body. Effective excretion requires adequate functioning of the circulatory system and of the organs of excretion (kidneys, bowel, lungs, and skin). Most drugs are excreted by the kidneys and eliminated unchanged or as metabolites in urine. Some drugs or metabolites are excreted in bile, then eliminated in feces; others are excreted in bile, reabsorbed from the small intestine, returned to the liver (called enterohepatic recirculation), metabolized, and eventually excreted in urine. Some oral drugs are not absorbed and are excreted in the feces. The lungs mainly remove volatile substances, such as anesthetic gases. The skin has minimal excretory function. Factors impairing excretion, especially severe renal disease, lead to accumulation of numerous drugs and may cause severe adverse effects if dosage is not reduced. Doctors always ask about any chronic diseases before prescribing any medication.

The process of developing a drug is long and difficult. The instructions for usage are decided after many experimental and clinical trials. None of the instructions given with medications are decided randomly; thus, we must completely follow the instructions to maximize the positive effects of a drug and to avoid any possible adverse effects.

References

• Abrams, Anne Collins., Carol Barnett Lammon, and Sandra Smith Pennington. Clinical Drug Therapy: Rationales for Nursing Practice. 7th ed. Philadelphia: Lippincott Williams & Wilkins, 2007.
• Basic&Clinical Pharmacology, 12^th Edition, McGrawHill Lange.
• Modern Pharmacology with Clinical Applications, Sixth Edition, Charles R. Craig and Robert E. Stitzel, Lippincott Williams &Wilkins.

Most of us have taken, or at least interacted with, medicine at some point or another in our lives. This can range from more “simple” over-the-counter drugs to more complex medicines specifically designed for exact illnesses. Considering the Covid-19 era we are going through and as search for a vaccine is at the highest possible speed, it is important to have at least a general idea on how medicines are developed for our use. This article aims to explore how a complicated mix of chemical compounds in a laboratory end up as pills on a shelf in your local pharmacy. We will also explore a brief history of pharmacology, where drugs get their names, how drugs come into fruition, the various affects that drugs can have on our bodies, along with the discrepancies that exist between them in regard to when, how, and why they should be taken.

Pharmacology is the study of the interactions that occur between a living organism and the chemicals that affect normal or abnormal biochemical functions. It includes the study of how a drugs can affect our biological systems, such as individual organs or an entire part of the body, and how the body overall responds to the drug. The discipline encompasses the sources, chemical properties, biological effects and, therapeutic uses of drugs. Substances with medicinal properties are considered pharmaceuticals, whereas drugs given for therapeutic purposes are usually called medications. Drug therapy, which is also called pharmacotherapy, is the use of drugs to prevent, diagnose, and treat signs, symptoms, and disease processes. When prevention or cure is not a reasonable goal, relief of symptoms can greatly improve quality of life and the ability to function properly on a day-to-day basis. Developing an understanding of this craft can allow us to better appreciate how molecules interact to form the drugs and medicines that can change our lives, and perhaps even allow us to contemplate their complex creation and existence.

In its most simplistic definition, a medication is a substance that is ingested or placed onto the body in order to cure a disease or condition (antibiotics are given to cure an infection), treat a medical condition (anti-depressants are given to treat depression), relieve symptoms of an illness (pain relievers are given to reduce pain), given to prevent diseases (flu vaccine helps to prevent the person from complications of having the flu).

Source of drugs

Historically, drugs were mainly derived from plants, animals, and minerals. Morphine, insulin, and iron are all commonly used examples of their respective sources. Belief in the curative powers of plants and certain substances rested exclusively upon traditional knowledge. But empirical information was not subjected to critical examination. Until the end of the 19th century, medicines were made by natural organic or inorganic products including mostly dried or fresh plants and their parts. These compounds might contain substances that possess healing properties or reactions that exert a toxic effect. It is important to remember that many fruits, vegetables, and plants still possess great power despite not having a “modern” origin.

Most drugs used nowadays are synthetic chemical compounds manufactured in laboratories which are synthesized by altering the chemical structure of an existing drug. The first drug of a particular group of drugs are called prototypes. For example, morphine is the prototype of opioid analgesics, and penicillin is the prototype of antibacterial drugs. Drug classifications and prototypes are defined and most new drugs can be assigned to a group. We must be hopeful and continue to search far and wide for cures for all  diseases, whether they be organic or synthetic, since our world is full of an infinite amount of possibilities and discoveries.

Drug names

The systematic naming of pharmaceutical drugs is called “drug nomenclature.” Drugs primarily have three types of names: chemical names, generic names, and trade names. The chemical names are the scientific names that often sound complex and are based upon the molecular structure of a drug. During development, the company will apply for regulatory approval of the drug by the relevant national regulatory agency, such as the U.S. Food and Drug Administration (FDA), and will be granted a generic name for it. Generic names usually indicate, via their stems, what drug class the drug belongs to. For example, oseltamivir is an antiviral drug because its name ends in the -vir suffix.

After development, testing, and regulatory acceptance of a drug, the pharmaceutical company gives the drug a trade name, which is a standard term in the pharmaceutical industry for a brand name or trademark name. Many drugs have multiple trade names which can reflect separate marketing strategies in different countries, manufactured by different companies, or both.

Drug investigation

A new drug investigation is the beginning of the journey of a chemical compound to a drug that will be used in clinics. The testing process of a chemical compound begins with animal studies to determine potential beneficial uses and also potential toxic side effects of the candidate compound.  The results from these animal studies are reviewed, and if the results are satisfactory, the compound then undergoes clinical trials in humans that people can voluntarily sign up for. Most clinical trials use a randomized, controlled experimental design that involves selection of subjects according to established criteria, random assignment of subjects to experimental groups, and administration of the test drug to one group and a control substance to another group.

Patent protection

New drugs that are developed by pharmaceutical companies will be covered under patent protection. This means that only the pharmaceutical company that holds the patent is allowed to manufacture, market, and eventually profit from the drug. This is seen as a return on the company’s investment that it took to develop the drug, which may require years of work and millions of dollars, along with an incentive for developing other drugs. Other pharmaceutical companies cannot manufacture and market the drug during the patent period.

Usually, the drug patent is awarded for around twenty years in the United States, however the number of years varies across countries and drugs. Pharmaceutical companies apply for a patent long before the clinical trial period even begins. The effective patent period after the drug has finally received approval is often around seven to twelve years. After the patented period expires the drug can be manufactured and sold by other companies. The drug is referred to as a generic drug at this point, and they are required to be therapeutically equivalent and much less expensive than trade name drugs.

Pharmacoeconomics

Pharmacoeconomics involves all of the costs that are accrued due to drug therapy and experimentation including those related to purchasing supplies, dispensing the drug, storing it, administrative fees, laboratory and other tests that are used to monitor patient responses, and losses from expiration. The length of a patient’s illness or hospitalization is also considered. While the most important factor is the health of the patient the costs for treatment are increasingly being considered as a major factor when choosing medications, and research projects that compare costs have greatly increased in recent years. The goal is to make it easier for patients to choose the most cost-effective drugs that combine high quality treatment at an affordable price. For drugs or regimens of similar efficacy and toxicity, there is considerable pressure upon doctors and pharmacies to prescribe less costly drugs for shorter duration.

Prescription and non-prescription drugs

In many countries, consumers have two legal routes of access to therapeutic drugs. One route involves a prescription or order from a licensed health care provider, such as a physician, dentist, or nurse practitioner. The other route is by over-the-counter (OTC) purchase of drugs that do not require a prescription. Both of these routes are regulated by various drug laws that change from country to country. Acquiring and using prescription drugs for non-therapeutic purposes, by persons who are not authorized to have the drugs or for whom they are not prescribed, is illegal.

The rejection of drugs in modern society

Nowadays, there are some people who deny various kinds of treatments because of their religious beliefs. This category of people is only a minority, as the majority of religions advocate for people to be healthy and to take care of their health as much as they can. In almost all belief traditions, the human body is believed to be a trust, and in case of any disease, the most appropriate and fastest treatment methods should be used. Even substances that are not normally permitted are allowed by scholars to be used if the person’s safety is concerned. For believers, the most important goal in life is to worship God, and for this to be possible the body must be healthy.

One day, people asked Prophet Muhammad, peace be upon him:

“Should we make use of medical treatment?”

He replied: “Make use of medical treatment, for God has not made a disease without appointing a remedy for it, with the exception of one disease, namely old age.”

People are encouraged to seek out those remedies and to use them with skill and kindness. Let us also remember that Jesus, peace be upon him, too, was very active in his ministry of healing. He showed by God’s permission miracles like curing the blind and the deaf, and bringing the dead back to life. Thus, religions do not refuse treatment with any available methods, and they even strongly encourage treatment and prevention of diseases.

Religions are also well known to treat stress, which wreaks havoc on the mind and body. It is still not known exactly how stress harms our health, but researchers have found that chronic psychological stress is associated with body’s losing its ability to regulate the inflammatory response. It has been shown that the effects of psychological stress on the body’s ability to regulate inflammation can promote the development and progression of disease. We know that religions and beliefs give people hope and significantly decrease the stress.

Human beings are the most precious creation, and health is necessary for us to achieve the purpose of our existence. Using scientific medicine together with faith and religion can help people to protect their health. Being the science of drugs and by investigating new drug therapies, pharmacology helps us exactly with that.

History of Pharmacology

Claudius Galen (129–200 A.D.) was the first person who attempted to consider the theoretical background of pharmacology.

Ali al-Tabari (838 A.D.) Medieval Islamic physicians used natural substances such as Papaver somniferum Linnaeus, poppy, and Cannabis sativa Linnaeus, hemp as a source of medicinal drugs. Although poppy had medicinal benefits, Ali al-Tabari explained that the extract of poppy leaves was lethal, and the extracts and opium should be considered poisons (4).

Theophrastus von Hohenheim (1493–1541), also known as “Paracelsus”, began to question doctrines from antiquity. He prescribed chemically defined substances with such success that professional enemies had him prosecuted as a poisoner. Against such accusations, he defended himself with the thesis that has become an axiom of pharmacology:

“If you want to explain any poison properly, what then isn‘t a poison? All things are poison, nothing is without poison; the dose alone causes a thing not to be poison.”

Johann Jakob Wepfer (1620–1695) was the first to use animal experimentation for pharmacological or toxicological actions.

Rudolf Buchheim (1820–1879) founded the first institute of pharmacology at the University of Dorpat (Tartu, Estonia) in 1847, which firstly made pharmacology as an independent scientific discipline. In addition to a description of effects, he strove to explain the chemical properties of drugs.

Oswald Schmiedeberg (1838–1921), together with his many disciples, helped to establish the high  reputation of pharmacology. He partnered with pathologist Bernhard Naunyn (1839–1925) to found the first journal of pharmacology, which has since been published without interruption.

After 1920, the pharmacological industry had their own pharmacology laboratories outside established university institutes. After 1960, departments of clinical pharmacology were set up at many universities and in industry.

References

1. Clinical Drug Therapy: Rationales for Nursing Practice – Seventh 7th Edition, Lippincott Williams &Wilkins.
2. Basic&Clinical Pharmacology, 12^th Edition, McGrawHill Lange.
3. Modern Pharmacology with Clinical Applications, Sixth Edition, Charles R. Craig and Robert E. Stitzel, Lippincott Williams &Wilkins.