- Email: [email protected]
Pharmaceutical drugs
3 Pharmaceutical drugs Chapter Objectives: 1. Introduce the integrative cardiovascular Chinese medicine perspective on pharmacology. 2. Introduce some recorded ancient influences on general pharmacology. 3. Introduce ancient scientists and physicians of many cultures internationally who contributed to medicine in general and pharmacology specifically. 4. Introduce the scientists and physicians in modern history who have contributed to medicine in general and pharmacology specifically. 5. Introduce some terminology in pharmacology.
Pharmacology is the study of the interactions that occur between a living organism and any natural, synthetic, or endogenous substance on the organism that exerts a biochemical or physiological effect on the cell, tissue, organ, or organ system, and with a normal or abnormal effect. This involves: 1. Drug composition and properties 2. Synthesis and drug design 3. Molecular and cellular mechanisms 4. Organ/system mechanisms 5. Signal transduction/cellular communication 6. Molecular diagnostics 7. Interactions 8. Toxicology 9. Chemical biology therapy, medical applications, and antipathogenic capabilities Modern pharmacology as a biomedical science was developed during the 19th century. It has evolved by continuous study of biological mechanisms, biochemistry, and genetics to adapt medicines into more effective tools against pathogenic factors and disease. The purpose is to provide tools for prevention, treatment, and personalized medicine. Pharmacology involves two distinct areas of study: Pharmacodynamics: the effects of chemicals on a biological system of receptors. Herbal, Bio-nutrient and Drug Titration According to Disease Stages in Integrative Cardiovascular Chinese Medicine. https://doi.org/10.1016/B978-0-12-817580-4.00003-2 Copyright © 2020 Elsevier Inc. All rights reserved.
25
26
Chapter 3 Pharmaceutical drugs
Pharmacokinetics: the effect of the biological system dynamics of absorption, distribution, metabolism, and excretion of biological systems on a drug. The creation of stable drugs for use involves the cooperation between scientists of various disciplines and purposes. First, the medicinal chemist creates a medicinal compound. Next, pharmacologists test existing substances for medicinal stability and develop new medicines. The criteria for determining substances for medicinal use involve: • Screening for desired activity of the constituents • Determining mode of action for indications • Quantifying drug activity for the indicated use The pharmacologist approves the compound for successful physiological activity and therapeutic effect. Next, toxicologists and microbiologists test for indication and dosage. Healthcare clinicians provide the cohorts for collecting evidence and experience of therapeutic effects.
Ancient influence on western medicine pharmacology During the times of antiquity, healers from various indigenous cultures around the world were collectively called, “witch doctors”. Many were skilled in the use of local herbal substances to holistically treat the mind, body, and soul of people in their community. They were focused more on natural substances including plant, mineral, animal, and human sources. They were considered practitioners of magical arts associated with their cultural belief systems. Usually little or no recorded information can be found to depict and understand the knowledge and practice of such people. However, in ancient Egypt, pharmacological knowledge was recorded on papyrus. Two examples are Ebers Papyrus from 1550 BC, and the Edwin Smith Papyrus from the 16th century BC. Ancient mummies in Egypt and parts of Sudan included a kind of beer infused with tetracycline, an antibiotic. These early healers were known by many names in parts of the world where their practices influenced transitions toward modern day pharmacology. • African Continent: Babalawo, Adahunse, Oniseegun, Abia ibok, Dibia, Boka, Sangoma, Nganga • Asian Continent: Wu Yi, Zhubo, Kashaf, Pharmakeia, Sihr, jhakri, Dayan, Kitsune, Hanja, Curandero, Bomoh, juju, isangoma • European Continent: Sorcerer, Wizard, Pellers, Hexenmeister, Maghiardzha, De Kloka
Chapter 3 Pharmaceutical drugs
Recorded Transition toward modern pharmacology Hippocrates (460e377 BC) • • • • • •
•
Considered the founder of western medicine Transformed medicine from superstition and magic into a healthcare system based on a scientific uniform of clinical protocol Created the Hippocratic Corpus, which includes his lectures, medical notes, books, essays, and research Taught physicians to be calm, honest, understanding, smart, and serious Taught physicians to keep separate detailed record of observations and clinical diagnosis and treatment methods for each patient Developed a homeopathetic theory that a human body has the power to heal itself based on the four humors: blood, black bile, yellow bile, and phlegm Observed that the disease can be classified as family inheritance, natural environment, lifestyle, and food habits; acute, chronic, endemic, and epidemic; and would either subside or increase, leading eventually to the death of the patient
Islamic medicine During the middle ages, pharmacology advanced further because of innovations in botanical sciences and chemistry. • The first state-regulated pharmacies were established in Baghdad in AD 754 under the Abbasid Caliphate. zi Rhazes (AD 865e915) promoted • Muhammad ibn Zakarıya Ra the use of chemical compounds in medicines. • Abu al-Qasim al-Zahrawi Abulcasis (AD 936e1013) wrote the Liber Servitoris, which described how to make simple medicinal recipes from which complex drugs could be created. • Sabur Ibn Sahl (died AD 869) initiated the order of a pharmacopedia with detailed instructions about drugs for various diseases. • Al-Biruni (AD 973e1050) wrote the Kitab al-Saydalah (The Book of Drugs). He discussed the role of the pharmacist, properties of various medicines, and how to use them. • Ibn Sina (Avicenna) wrote The Canon of Medicine, which described 700 medicines with recipes, actions, and indications. • Al-Maridini of Baghdad and Cairo and Ibn al-Wafid (AD 1008e1074) wrote texts on uses of medicines, which later were printed in Latin as De Medicinis Universalibus et Particularibus, by Mesue and as the Medicamentis simplicibus by Abenguefit.
27
28
Chapter 3 Pharmaceutical drugs
• Peter of Abano (AD 1250e1316) translated and added a supplemental section of information in the text De Veneris, which was written by Al-Maridini. • Al-Muwaffaq (AD 842e910) wrote The Foundations of the True Properties of Remedies. The text described distinction and uses of sodium carbonate and potassium carbonate and poisonous elements such as arsenic, copper, and distillation of seawater for drinking.
Modern history Originating in the 19th and 20th centuries, pharmacology developed many techniques and study designs for creating and testing new drugs. • François Magendie: In 1809 he presented his work to the Paris Academy. It involved the convulsant action of strychnine, a constituent of nux vomica, on the spinal cord of dogs. • Friedrich Wohler: By 1828, he had challenged the vital force theory by synthesizing urea from inorganic substances. This led to developing organic chemistry. • Oswald Schmiedeberg (1838e921): He is recognized as the founder of modern pharmacology. • Claude Bernard: In 1842, he discovered that alkaloid constituents in curare plants interrupt the stimulation of muscle by nerve impulses at the neuromuscular junction. • Jean-François Heymans: In 1842, he worked with a harvested heart from a mammal while Claude Bernard experimented with stimulation of nerve impulses. • Karl Ludwig: In 1840 he invented a kymograph, which records motion or pressure, which was used as a crude device to monitor blood pressure. • Arnold Berthold: In 1849, he transplanted testicular tissue into a rooster to prove it would induce growth of the comb. His method initiated the study of male sex hormones. • Edgar Allen and Edward Doisy: In 1924, they used rats in three studies. The first was to remove the ovaries from rats to study estrogen. The second was to inject them with Freund’s adjuvant, which is a serum of dead bacteria, to study antiinflammatory agents. The third was to test the effects of gastric secretion by forming a vagally denervated Heidenhain pouch, which has an opening through the abdominal wall. Oswald Schmiedeberg (1838e921) • •
He obtained his medical doctorate in 1866 with a thesis on the measurement of chloroform in blood. He became professor of pharmacology at the University of Strasburg and studied chloroform and chloralhydrate.
Chapter 3 Pharmaceutical drugs
•
• • •
During his 46-year tenure at University of Strasburg, he trained most of the scientists who became professors at other German universities and around the world. He was responsible for the development of the German pharmaceutical industry up to World War II. In 1869 he showed that muscarine had the same effect on the heart as electrical stimulation of the vagus nerve. In 1878, he published Outline of Pharmacology. In 1885, he introduced urethane as a hypnotic.
John Jacob Abel (1857e938) • • • •
•
An American biochemist and pharmacologist Studied under Oswald Schmiedeberg In 1890, he became the first chair in pharmacology at the University of Michigan. In 1893, he began research at Johns Hopkins University: • 1898: isolation of epinephrine from adrenal gland extracts • 1919: isolation of histamine from pituitary extract • 1926: preparation of pure crystalline insulin His student, Reid Hunt, discovered acetylcholine in adrenal extracts in 1906.
The development of drugs for categories of heart and vascular diseases requires study and design of constituents to act on cell receptors and signaling pathways. Drugs have a narrow or wide therapeutic index or therapeutic window, which is the ratio between the desired effect to toxic effect.
Therapeutic index Narrow index: The desired effect occurs at or close to a toxic dose. The drug is difficult to administer to the patient because it requires close monitoring; for example, antibiotics, warfarin, aminoglycosides, and so on. Wide index: The desired effect occurs below the toxic dose. The drug is easier to administer to the patient because it requires less or no direct monitoring.
Active pharmaceutical ingredient The pharmacokinetics of the drug is also known as the active pharmaceutical ingredient (API). When studying the API, scientists are interested in the LADME: • Liberation: How the API is released from the medication (dissolving, etc.) • Absorption: How the API is absorbed (mouth, skin or intestine)
29
30
Chapter 3 Pharmaceutical drugs
• Distribution: How the API is spread through the organism • Metabolism: How the API is converted into active, toxic, or inactive ingredients once inside the body • Excretion: How the API is eliminated from the body, through either breath, skin, urine, bowels, and so on. Screening of candidate compounds and mode-of-action studies may focus on specific tissues, organs, or systems or on actions, such as antihistaminic or anticonvulsant. As knowledge of human biochemistry and molecular biology advances, pharmacology zeroes in more often on enzymatic action and receptors. Clinical pharmacology: focuses on principles and methods in the medical clinic and toward patient care and outcomes. Cardiovascular pharmacology: focuses on the effects of drugs throughout the cardiovascular system. Pharmacogenetics: focuses on the different responses to drugs based on genetic variation. Pharmacogenomics: focuses on the genomics technologies to personalize new drugs and old classifications. Posology: focuses on drug dosage based on age, sex, weight, genetics, elimination rate, and time of administration.
Further reading Titsingh I. Annales des Empereurs du Japon. 1834:434. Levey M. Early Arabic Pharmacology. Leiden: E. J. Brill; 1973. Kremers E, Sonnedecker G. Kremers and Urdang’s History of Pharmacy. Amer. Inst. History of Pharmacy; 1986:17. ISBN 0-931292-17-4. Oldham FK, Kelsey FE, Geiling EMK. Essentials of Pharmacology. Philadelphia: Lippincott; 1955. Sneader W. Drug Discovery: The Evolution of Modern Medicines. New York: Wiley; 1985. Oldham FK, Kelsey FE, Geiling EMK. Essentials of Pharmacology. Philadelphia: Lippincott; 1955. Sneader W. Drug Discovery: The Evolution of Modern Medicines. New York: Wiley; 1985. Holmstedt B, Liljestrand G. Readings in Pharmacology. New York: MacMillan; 1963. Leake CD. An Historical Account of Pharmacology to the Twentieth Century. Springfield, IL: Charles C. Thomas; 1975. Holmstedt B, Liljestrand G. Readings in Pharmacology. New York: MacMillan; 1963. Hadzovic S. Pharmacy and the great contribution of Arab-Islamic science to its development. Med Arh. 1997;51(1e2). ISSN: 0025-8083:47e50. OCLC 32564530. Ellis L. Archaeological Method and Theory: An Encyclopedia. Taylor & Francis; 2000:443e448. ISBN 978-0-8153-1305-2.
Chapter 3 Pharmaceutical drugs
Borchardt JK. The beginnings of drug therapy: ancient mesopotamian medicine. Drug News Perspect. 2002;15(3). ISSN: 0214-0934:187e192. https://doi.org/ 10.1358/dnp.2002.15.3.840015. PMID 12677263. Al-Ghazal SK. The valuable contributions of Al-Razi (Rhazes) in the history of pharmacy during the middle ages. J Int Soc Hist Islam Med. October 2003; 2(4). ISSN: 1303-667X:9e11. OCLC 54045642. Abdullahi AJ. Trends and challenges of traditional medicine in Africa. Tradit Complement Altern Med. 2011;8(S):115e123.
31
Pharmacology is the study of the interactions that occur between a living organism and any natural, synthetic, or endogenous substance on the organism that exerts a biochemical or physiological effect on the cell, tissue, organ, or organ system, and with a normal or abnormal effect. This involves: 1. Drug composition and properties 2. Synthesis and drug design 3. Molecular and cellular mechanisms 4. Organ/system mechanisms 5. Signal transduction/cellular communication 6. Molecular diagnostics 7. Interactions 8. Toxicology 9. Chemical biology therapy, medical applications, and antipathogenic capabilities Modern pharmacology as a biomedical science was developed during the 19th century. It has evolved by continuous study of biological mechanisms, biochemistry, and genetics to adapt medicines into more effective tools against pathogenic factors and disease. The purpose is to provide tools for prevention, treatment, and personalized medicine. Pharmacology involves two distinct areas of study: Pharmacodynamics: the effects of chemicals on a biological system of receptors. Herbal, Bio-nutrient and Drug Titration According to Disease Stages in Integrative Cardiovascular Chinese Medicine. https://doi.org/10.1016/B978-0-12-817580-4.00003-2 Copyright © 2020 Elsevier Inc. All rights reserved.
25
26
Chapter 3 Pharmaceutical drugs
Pharmacokinetics: the effect of the biological system dynamics of absorption, distribution, metabolism, and excretion of biological systems on a drug. The creation of stable drugs for use involves the cooperation between scientists of various disciplines and purposes. First, the medicinal chemist creates a medicinal compound. Next, pharmacologists test existing substances for medicinal stability and develop new medicines. The criteria for determining substances for medicinal use involve: • Screening for desired activity of the constituents • Determining mode of action for indications • Quantifying drug activity for the indicated use The pharmacologist approves the compound for successful physiological activity and therapeutic effect. Next, toxicologists and microbiologists test for indication and dosage. Healthcare clinicians provide the cohorts for collecting evidence and experience of therapeutic effects.
Ancient influence on western medicine pharmacology During the times of antiquity, healers from various indigenous cultures around the world were collectively called, “witch doctors”. Many were skilled in the use of local herbal substances to holistically treat the mind, body, and soul of people in their community. They were focused more on natural substances including plant, mineral, animal, and human sources. They were considered practitioners of magical arts associated with their cultural belief systems. Usually little or no recorded information can be found to depict and understand the knowledge and practice of such people. However, in ancient Egypt, pharmacological knowledge was recorded on papyrus. Two examples are Ebers Papyrus from 1550 BC, and the Edwin Smith Papyrus from the 16th century BC. Ancient mummies in Egypt and parts of Sudan included a kind of beer infused with tetracycline, an antibiotic. These early healers were known by many names in parts of the world where their practices influenced transitions toward modern day pharmacology. • African Continent: Babalawo, Adahunse, Oniseegun, Abia ibok, Dibia, Boka, Sangoma, Nganga • Asian Continent: Wu Yi, Zhubo, Kashaf, Pharmakeia, Sihr, jhakri, Dayan, Kitsune, Hanja, Curandero, Bomoh, juju, isangoma • European Continent: Sorcerer, Wizard, Pellers, Hexenmeister, Maghiardzha, De Kloka
Chapter 3 Pharmaceutical drugs
Recorded Transition toward modern pharmacology Hippocrates (460e377 BC) • • • • • •
•
Considered the founder of western medicine Transformed medicine from superstition and magic into a healthcare system based on a scientific uniform of clinical protocol Created the Hippocratic Corpus, which includes his lectures, medical notes, books, essays, and research Taught physicians to be calm, honest, understanding, smart, and serious Taught physicians to keep separate detailed record of observations and clinical diagnosis and treatment methods for each patient Developed a homeopathetic theory that a human body has the power to heal itself based on the four humors: blood, black bile, yellow bile, and phlegm Observed that the disease can be classified as family inheritance, natural environment, lifestyle, and food habits; acute, chronic, endemic, and epidemic; and would either subside or increase, leading eventually to the death of the patient
Islamic medicine During the middle ages, pharmacology advanced further because of innovations in botanical sciences and chemistry. • The first state-regulated pharmacies were established in Baghdad in AD 754 under the Abbasid Caliphate. zi Rhazes (AD 865e915) promoted • Muhammad ibn Zakarıya Ra the use of chemical compounds in medicines. • Abu al-Qasim al-Zahrawi Abulcasis (AD 936e1013) wrote the Liber Servitoris, which described how to make simple medicinal recipes from which complex drugs could be created. • Sabur Ibn Sahl (died AD 869) initiated the order of a pharmacopedia with detailed instructions about drugs for various diseases. • Al-Biruni (AD 973e1050) wrote the Kitab al-Saydalah (The Book of Drugs). He discussed the role of the pharmacist, properties of various medicines, and how to use them. • Ibn Sina (Avicenna) wrote The Canon of Medicine, which described 700 medicines with recipes, actions, and indications. • Al-Maridini of Baghdad and Cairo and Ibn al-Wafid (AD 1008e1074) wrote texts on uses of medicines, which later were printed in Latin as De Medicinis Universalibus et Particularibus, by Mesue and as the Medicamentis simplicibus by Abenguefit.
27
28
Chapter 3 Pharmaceutical drugs
• Peter of Abano (AD 1250e1316) translated and added a supplemental section of information in the text De Veneris, which was written by Al-Maridini. • Al-Muwaffaq (AD 842e910) wrote The Foundations of the True Properties of Remedies. The text described distinction and uses of sodium carbonate and potassium carbonate and poisonous elements such as arsenic, copper, and distillation of seawater for drinking.
Modern history Originating in the 19th and 20th centuries, pharmacology developed many techniques and study designs for creating and testing new drugs. • François Magendie: In 1809 he presented his work to the Paris Academy. It involved the convulsant action of strychnine, a constituent of nux vomica, on the spinal cord of dogs. • Friedrich Wohler: By 1828, he had challenged the vital force theory by synthesizing urea from inorganic substances. This led to developing organic chemistry. • Oswald Schmiedeberg (1838e921): He is recognized as the founder of modern pharmacology. • Claude Bernard: In 1842, he discovered that alkaloid constituents in curare plants interrupt the stimulation of muscle by nerve impulses at the neuromuscular junction. • Jean-François Heymans: In 1842, he worked with a harvested heart from a mammal while Claude Bernard experimented with stimulation of nerve impulses. • Karl Ludwig: In 1840 he invented a kymograph, which records motion or pressure, which was used as a crude device to monitor blood pressure. • Arnold Berthold: In 1849, he transplanted testicular tissue into a rooster to prove it would induce growth of the comb. His method initiated the study of male sex hormones. • Edgar Allen and Edward Doisy: In 1924, they used rats in three studies. The first was to remove the ovaries from rats to study estrogen. The second was to inject them with Freund’s adjuvant, which is a serum of dead bacteria, to study antiinflammatory agents. The third was to test the effects of gastric secretion by forming a vagally denervated Heidenhain pouch, which has an opening through the abdominal wall. Oswald Schmiedeberg (1838e921) • •
He obtained his medical doctorate in 1866 with a thesis on the measurement of chloroform in blood. He became professor of pharmacology at the University of Strasburg and studied chloroform and chloralhydrate.
Chapter 3 Pharmaceutical drugs
•
• • •
During his 46-year tenure at University of Strasburg, he trained most of the scientists who became professors at other German universities and around the world. He was responsible for the development of the German pharmaceutical industry up to World War II. In 1869 he showed that muscarine had the same effect on the heart as electrical stimulation of the vagus nerve. In 1878, he published Outline of Pharmacology. In 1885, he introduced urethane as a hypnotic.
John Jacob Abel (1857e938) • • • •
•
An American biochemist and pharmacologist Studied under Oswald Schmiedeberg In 1890, he became the first chair in pharmacology at the University of Michigan. In 1893, he began research at Johns Hopkins University: • 1898: isolation of epinephrine from adrenal gland extracts • 1919: isolation of histamine from pituitary extract • 1926: preparation of pure crystalline insulin His student, Reid Hunt, discovered acetylcholine in adrenal extracts in 1906.
The development of drugs for categories of heart and vascular diseases requires study and design of constituents to act on cell receptors and signaling pathways. Drugs have a narrow or wide therapeutic index or therapeutic window, which is the ratio between the desired effect to toxic effect.
Therapeutic index Narrow index: The desired effect occurs at or close to a toxic dose. The drug is difficult to administer to the patient because it requires close monitoring; for example, antibiotics, warfarin, aminoglycosides, and so on. Wide index: The desired effect occurs below the toxic dose. The drug is easier to administer to the patient because it requires less or no direct monitoring.
Active pharmaceutical ingredient The pharmacokinetics of the drug is also known as the active pharmaceutical ingredient (API). When studying the API, scientists are interested in the LADME: • Liberation: How the API is released from the medication (dissolving, etc.) • Absorption: How the API is absorbed (mouth, skin or intestine)
29
30
Chapter 3 Pharmaceutical drugs
• Distribution: How the API is spread through the organism • Metabolism: How the API is converted into active, toxic, or inactive ingredients once inside the body • Excretion: How the API is eliminated from the body, through either breath, skin, urine, bowels, and so on. Screening of candidate compounds and mode-of-action studies may focus on specific tissues, organs, or systems or on actions, such as antihistaminic or anticonvulsant. As knowledge of human biochemistry and molecular biology advances, pharmacology zeroes in more often on enzymatic action and receptors. Clinical pharmacology: focuses on principles and methods in the medical clinic and toward patient care and outcomes. Cardiovascular pharmacology: focuses on the effects of drugs throughout the cardiovascular system. Pharmacogenetics: focuses on the different responses to drugs based on genetic variation. Pharmacogenomics: focuses on the genomics technologies to personalize new drugs and old classifications. Posology: focuses on drug dosage based on age, sex, weight, genetics, elimination rate, and time of administration.
Further reading Titsingh I. Annales des Empereurs du Japon. 1834:434. Levey M. Early Arabic Pharmacology. Leiden: E. J. Brill; 1973. Kremers E, Sonnedecker G. Kremers and Urdang’s History of Pharmacy. Amer. Inst. History of Pharmacy; 1986:17. ISBN 0-931292-17-4. Oldham FK, Kelsey FE, Geiling EMK. Essentials of Pharmacology. Philadelphia: Lippincott; 1955. Sneader W. Drug Discovery: The Evolution of Modern Medicines. New York: Wiley; 1985. Oldham FK, Kelsey FE, Geiling EMK. Essentials of Pharmacology. Philadelphia: Lippincott; 1955. Sneader W. Drug Discovery: The Evolution of Modern Medicines. New York: Wiley; 1985. Holmstedt B, Liljestrand G. Readings in Pharmacology. New York: MacMillan; 1963. Leake CD. An Historical Account of Pharmacology to the Twentieth Century. Springfield, IL: Charles C. Thomas; 1975. Holmstedt B, Liljestrand G. Readings in Pharmacology. New York: MacMillan; 1963. Hadzovic S. Pharmacy and the great contribution of Arab-Islamic science to its development. Med Arh. 1997;51(1e2). ISSN: 0025-8083:47e50. OCLC 32564530. Ellis L. Archaeological Method and Theory: An Encyclopedia. Taylor & Francis; 2000:443e448. ISBN 978-0-8153-1305-2.
Chapter 3 Pharmaceutical drugs
Borchardt JK. The beginnings of drug therapy: ancient mesopotamian medicine. Drug News Perspect. 2002;15(3). ISSN: 0214-0934:187e192. https://doi.org/ 10.1358/dnp.2002.15.3.840015. PMID 12677263. Al-Ghazal SK. The valuable contributions of Al-Razi (Rhazes) in the history of pharmacy during the middle ages. J Int Soc Hist Islam Med. October 2003; 2(4). ISSN: 1303-667X:9e11. OCLC 54045642. Abdullahi AJ. Trends and challenges of traditional medicine in Africa. Tradit Complement Altern Med. 2011;8(S):115e123.
31