Introduction to Pharmacology Dr. SA Ziai. Pharmacology Pharmacology can be defined as the study of substances that interact with living systems through.

Introduction to Pharmacology

Dr. SA Ziai

Pharmacology

• Pharmacology can be defined as the study of substances that interact with living systems through chemical processes, especially by binding to regulatory molecules and activating or inhibiting normal body processes.

• These substances may be chemicals administered to achieve a beneficial therapeutic effect on some process within the patient or for their toxic effects on regulatory processes in parasites infecting the patient.

Toxicology

• Toxicology is the branch of pharmacology that deals with the undesirable effects of chemicals on living systems, from individual cells to humans to complex ecosystems

History of Pharmacology The Ebers papyrus, written in Egypt in the 16th century B.C., lists the extensive pharmacopia of that civilization. Included in this are: beer, turpentine, myrrh, juniperberries., poppy, lead, salt and crushed precious stones. Also included were products derived from animals, including lizard's blood, swine teeth, goose grease, ass hooves and the excreta from various animals. The effects of many of these drugs on patients of antiquity can only be imagined.

History of Pharmacology From ancient China comes evidence of that culture's extensive efforts to heal through the use of natural products. The Pen Tsao, or Great Herbal, comprised forty volumes describing several thousands of prescriptions.

Galen’s Influence on Medicine lasted >1500 years… present day language reflects Galen’s influence:

“phlegmatic personality” … “a bilious person” “melancholy” … “in good humor”

Some of Galen’s “remedies” for righting these imbalances were based on ancient practices (e.g. bloodletting)By 1737, 73 per cent of patients at the British Royal Infirmary experienced bloodletting as part of their treatment…popularity peaked in the early 19th century through the use of leeches

Precursors to “Scientific” Drug Development

“Chymical remedies” – 16th century remedies based on ideas of the Swiss physician Philippus

Aureolus Theophrastus Bombastus von Hohenheim (1490-1541), better known as

PARACELSUS -- he held Galen in contempt

Started in 1623, the “medicinal garden” of Oxford University was growing over 600 native plants and over 1000 plants from all over the world by 1650

• Around the end of the 17th century, and following the example of the physical sciences, reliance on observation and experimentation began to replace theorizing in medicine

• Materia medica—the science of drug preparation and the medical use of drugs—began to develop as the precursor to pharmacology.

• In the late 18th and early 19th centuries, François Magendie, and later his student Claude Bernard, began to develop the methods of experimental physiology and pharmacology.

• Advances in chemistry and the further development of physiology in the 18th, 19th, and early 20th centuries laid the foundation needed for understanding how drugs work at the organ and tissue levels.

History of Pharmacology

• Paradoxically, real advances in basic pharmacology during this time were accompanied by an outburst of unscientific claims by manufacturers and marketers of worthless "patent medicines."

• Not until the concepts of rational therapeutics, especially that of the controlled clinical trial, were reintroduced into medicine—only about 60 years ago—did it become possible to accurately evaluate therapeutic claims.

• Unfortunately, manipulation of the legislative process in the United States has allowed many substances promoted for health—but not promoted specifically as "drugs"—to avoid meeting the Food and Drug Administration standards

• During the last half-century, many fundamentally new drug groups and new members of old groups were introduced.

• The last three decades have seen an even more rapid growth of information and understanding of the molecular basis for drug action.

Pharmaceutical Industry

• Much of the recent progress in the application of drugs to disease problems can be ascribed to the pharmaceutical industry and specifically to "big pharma," the multibillion-dollar corporations that specialize in drug discovery and development.

August 10, 1897: Felix Hoffmann, a chemist working at Farbenfabriken vorm. Friedr. Bayer & Co., recorded in his laboratory logbook that he had succeeded in acetylating salicylic acid into a chemically pure and stable form of acetylsalicylic acid (ASA). (easier to “stomach” in its acetylated form)…

Within the same month (in fact only two weeks later Felix Hoffmann in acetylates morphine into diacetylmorphine…

Pharmacogenomics

• or pharmacogenetics is the study of the genetic variations that cause differences in drug response among individuals or populations.

• Gene therapy• knockout mice• Knockdown• Knockin

The Nature of Drugs

• Agonist• Antagonist• Receptor• Chemical antagonist• Hormones• Xenobiotics• Poisons "the dose makes the poison" Paracelsus• Toxins

The Physical Nature of Drugs

• Drugs may be solid at room temperature (eg, aspirin, atropine), liquid (eg, nicotine, ethanol), or gaseous (eg, nitrous oxide).

• A number of useful or dangerous drugs are inorganic elements, eg, lithium, iron, and heavy metals.

• Many organic drugs are weak acids or bases.

• To interact chemically with its receptor, a drug molecule must have the – appropriate size – electrical charge– shape– atomic composition

Drug Size

• The molecular size of drugs varies from very small (lithium ion, MW 7) to very large (eg, alteplase [tPA], a protein of MW 59,050).

• However, most drugs have molecular weights between 100 and 1000

• To have a good "fit" to only one type of receptor, a drug molecule must be sufficiently unique in shape, charge, and other properties, to prevent its binding to other receptors.

Drug Reactivity and Drug-Receptor Bonds

• Drugs interact with receptors by means of chemical forces or bonds. These are of three major types:

• Covalent– Aspirin, DNA-alkylating agents

• Electrostatic – Ionic, hydrogen bond, van der waals

• Hydrophobic

Drug Shape

Dissociation Constants (Kd) of the Enantiomers and Racemate of Carvedilol.

Form of Carvedilol αReceptors (Kd, nmol/L) βReceptors (Kd, nmol/L)

R(+) enantiomer 14 45S(–) enantiomer 16 0.4R,S(±) enantiomers 11 0.9

Enantiomers

• Transport• Duration of action• As a result, many patients are receiving drug

doses of which 50% or more is less active, inactive, or actively toxic.

Intrinsic efficacy is independent of affinity for the receptor.

Agonists, Partial Agonists, and Inverse Agonists

• Constitutive activity• Full agonists• Partial agonists

– Pindolol• Intrinsic efficacy• Neutral antagonism• Inverse agonists

Competitive & Irreversible Antagonists

• The degree of inhibition produced by a competitive antagonist depends on the concentration of antagonist.

• Clinical response to a competitive antagonist depends on the concentration of agonist that is competing for binding to receptors.

Irreversible antagonists advantages and disadvantages.

• The duration of action of such an irreversible antagonist is relatively independent of its own rate of elimination and more dependent on the rate of turnover of receptor molecules.

• If overdose occurs, however, a real problem may arise

• Duration of Drug Action– The action may persist after the drug has

dissociated – Drugs that bind covalently to the receptor site

• Acetylcholinesterase inhibitors

Macromolecular Nature of Drug Receptors

• Regulatory proteins• Enzymes• Transport proteins • Structural proteins

Concentration-Effect Curves & Receptor Binding of Agonists

Potency & maximal efficacy• Potency refers to the

concentration (EC50) or dose (ED50) of a drug required to produce 50% of that drug's maximal effect

• Potency of a drug depends in part on the affinity (Kd) of receptors for binding the drug and in part on the efficiency with which drug-receptor interaction is coupled to response.

Potency & maximal efficacy• The clinical effectiveness of a

drug depends not on its potency (EC50), but on its maximal efficacy and its ability to reach the relevant receptors

• This ability can depend on its route of administration, absorption, distribution through the body, and clearance from the blood or site of action

Quantal Dose-Effect Curves

Quantal Dose-Effect Curves

• median effective dose (ED50): the dose at which 50% of individuals exhibit the specified quantal effect

• median toxic dose (TD50): the dose required to produce a particular toxic effect in 50% of animals

• median lethal dose (LD50): If the toxic effect is death of the animal

• therapeutic index: One measure, which relates the dose of a drug required to produce a desired effect to that which produces an undesired effect and in animal studies it is usually defined as the ratio of the TD50 to the ED50

Graded vs. quantal dose-effect curve

• Both curves provide information regarding the potency and selectivity of drugs; the graded dose-response curve indicates the maximal efficacy of a drug, and the quantal dose-effect curve indicates the potential variability of responsiveness among individuals.

Receptor-Effector Coupling

• Coupling: The transduction process that links drug occupancy of receptors and pharmacologic response

• Coupling efficiency is also determined by the biochemical events that transduce receptor occupancy into cellular response

Spare Receptors• Spare receptors: nonlinear occupancy-response coupling• Myocardial cells are said to contain a large proportion of

spare adrenoceptors.• Β-adrenoceptor activation promotes binding of guanosine

triphosphate (GTP) to an intermediate signaling protein and activation of the signaling intermediate may greatly outlast the agonist-receptor interaction

• In such a case, the "spareness" of receptors is temporal• The receptors may be spare in number

Signaling Mechanisms & Drug Action

Intracellular Receptors for Lipid-Soluble Agents

• Steroids – Corticosteroids– Mineralocorticoids– Sex steroids– Vitamin D

• Thyroid hormone• Lag period of 30 min. to

several hrs• Persist for hrs or days

Ligand-Regulated Transmembrane Enzymes

Protein tyrosine kinaseSerine kinaseGuanylyl cyclase

Ligand-Regulated Transmembrane Enzymes

• Insulin• Epidermal growth factor (EGF)• Platelet-derived growth factor (PDGF)• Atrial natriuretic peptide (ANP)• Transforming growth factor- β(TGF-β)

– Inhibitors (eg, trastuzumab, cetuximab)– Other inhibitors are membrane-permeant "small molecule"

chemicals (eg, gefitinib, erlotinib)• many other trophic hormones • Receptor down-regulation (endocytosis of receptors)• EGF and cancer

Cytokine Receptors

Janus-kinase (JAK) familySTATs (signal transducers and activators of transcription)

Cytokine Receptors

• Growth hormone• Erythropoietin• Interferons• other regulators of growth and differentiation

Ligand- and Voltage-Gated Channels

• The natural ligands are acetylcholine, serotonin, GABA, and glutamate.

• Time in milliseconds• Phosphorylation and

endocytosis

G Proteins & Second Messengers

G Proteins & Second Messengers

• Norepinephrine may encounter its membrane receptor for only a few milliseconds.

• GTP-bound Gs may remain active for tens of seconds

• The duration of activation of adenylyl cyclase depends on the longevity of GTP binding to Gs rather than on the receptor's affinity for norepinephrine.

G Protein Receptors for Effector/Signaling PathwayGs

β-Adrenergic amines, glucagon, histamine, serotonin, and many other hormones

↑Adenylyl cyclase→ ↑cAMP

Gi1, Gi2, Gi3

α2-Adrenergic amines, acetylcholine (muscarinic), opioids, serotonin, and many others

Several, including: ↓Adenylyl cyclase→↓ cAMP Open cardiac K+ channels→↓ heart rate

Golf

Odorants (olfactory epithelium) ↑Adenylyl cyclase→↑cAMP

Go

Neurotransmitters in brain (not yet specifically identified)

Not yet clear

Gq

Acetylcholine (muscarinic), bombesin, serotonin (5-HT1C), and many others

↑Phospholipase C→↑IP3, diacylglycerol, cytoplasmic Ca2+

Gt1, Gt2

Photons (rhodopsin and color opsins in retinal rod and cone cells)

↑cGMP phosphodiesterase→↓ cGMP (phototransduction)

G Proteins and Their Receptors and Effectors

GPCRsserpentine

Receptor Regulation

Receptor Regulation

The activated GRK phosphorylates serine residues in the receptor's carboxyl terminal tail.

    β-arrestin binding accelerates endocytosis of receptors

A receptor phosphatase is present at high concentration on endosome membranes

Cyclic Adenosine Monophosphate (cAMP)

• Mobilization of stored energy (the breakdown of carbohydrates in liver or triglycerides in fat cells stimulated by β-adrenomimetic catecholamines)

• conservation of water by the kidney (mediated by vasopressin)• Ca2+ homeostasis (regulated by parathyroid hormone)• Increased rate and contractile force of heart muscle (β-

adrenomimetic catecholamines)• Regulates the production of adrenal and sex steroids (in

response to corticotropin or follicle-stimulating hormone)• Relaxation of smooth muscle, and many other endocrine and

neural processes.

cAMP

Competitive inhibition of cAMP degradation is one way caffeine, theophylline, and other methylxanthines

Calcium and Phosphoinositides• Triggered by GPCRs & Tyrosine

kinase• At least nine structurally distinct

types of protein kinase C have been identified

• IP3 is inactivated by dephosphorylation

• DAG is either phosphorylated to yield phosphatidic acid, which is then converted back into phospholipids, or it is deacylated to yield arachidonic acid

Cyclic Guanosine Monophosphate (cGMP)

• cGMP signaling in only a few cell types• In intestinal mucosa and vascular smooth

muscle, the cGMP-based signal transduction mechanism closely parallels the cAMP-mediated signaling mechanism

• ANP & NO• Nitroglycerin and sodium nitroprusside • Sildenafil

cGMP

Interplay among Signaling Mechanisms

• cAMP and IP3 counteract each other in smooth muscle contraction

• cAMP and phosphoinositide second messengers act together to stimulate glucose release from the liver

Phosphorylation: A Common Theme

• Amplification : the attachment of a phosphoryl group to a serine, threonine, or tyrosine residue powerfully amplifies the initial regulatory signal by recording a molecular memory

• Flexible regulation: differing substrate specificities of the multiple protein kinases regulated by second messengers provide branch points in signaling pathways that may be independently regulated

• Inhibitors of protein kinases have great potential as therapeutic agents, particularly in neoplastic diseases