The nature of drugs, drug development and regulation (Katzung, Ch 1. Trans 1-2, wkbk) Flashcards
Deals with the absorption, distribution, and elimination of drugs
Pharmacokinetics
Concerns the actions of the chemical on the organism
Pharmacodynamics
True or False
All substances can under certain circumstances be toxic
True
True or False
The chemicals in botanicals (herbs and plant extracts, “nutraceuticals”) are different from chemicals in manufactured drugs because there is much greater proportion of impurities in manufactured drugs
False
** There is much greater proportion of impurities in botanical drugs
REMEMBER
The molecular size of drugs varies from very small (lithium ion, MW 7) to very large (eg, alteplase [t-PA], a protein of MW 59,050). However, most drugs have molecular weights between 100 and 1000.
The lower limit of this narrow range is probably set by the requirements for specificity of action. The upper limit in molecular weight is determined primarily by the requirement that drugs must be able to move within the body. Drugs much larger than MW 1000 do not diffuse readily between compartments of the body.
**In the case of alteplase, a clot-dissolving enzyme, the drug is administered directly into the vascular compartment by intravenous or intra-arterial infusion.
Three major types of drug-receptor bonds
Covalent, electrostatic and hydrophobic
This type of drug-receptor bond is very strong and in many cases not reversible under biologic conditions
Covalent bond
Example:
- Covalent bond formed between the acetyl group of acetylsalicylic acid (aspirin) and cyclooxygenase, its enzyme target in platelets, is not readily broken
- DNA alkylating agents used in cancer chemotherapy to disrupt cell division in the tumor
True or false
Electrostatic bonding is much more common than covalent bonding in drug-receptor interactions
True
- Electrostatic bonds vary from relatively strong linkages between permanently charged ionic molecules to weaker hydrogen bonds and very weak induced dipole interactions such as van der Waals forces and similar phenomena.
- *Electrostatic bonds are weaker than covalent bonds
This type of bond is important in the interactions of highly lipid-soluble drugs
Hydrophobic
True or False
Drugs that bind through weak bonds to their receptors are generally more selective than drugs that bind by means of very strong bonds.
True
** This is because weak bonds require a very precise fit of the drug to its receptor if an interaction is to occur. Only a few receptor types are likely to provide such a precise fit for a particular drug structure
In the Ra conformation (active form), a receptor can activate downstream mechanisms that produce a small observable effect, even in the absence of drug. This is termed as_______
Constitutive activity
REMEMBER
The receptor is able to assume two conformations. In the Ri conformation, it is inactive and produces no effect, even when combined with a drug molecule. In the Ra conformation, the receptor can activate downstream mechanisms that produce a small observable effect, even in the absence of drug (constitutive activity).
In the absence of drugs, the two isoforms are in equilibrium, and the Ri form is favored.
REMEMBER
The receptor is able to assume two conformations. In the Ri conformation, it is inactive and produces no effect, even when combined with a drug molecule. In the Ra conformation, the receptor can activate downstream mechanisms that produce a small observable effect, even in the absence of drug (constitutive activity).
Conventional full agonist drugs have a much higher affinity for the Ra conformation and mass action thus favors the formation of the Ra–D complex with a much larger observed effect.
REMEMBER
The receptor is able to assume two conformations. In the Ri conformation, it is inactive and produces no effect, even when combined with a drug molecule. In the Ra conformation, the receptor can activate downstream mechanisms that produce a small observable effect, even in the absence of drug (constitutive activity).
Partial agonists have an intermediate affinity for both Ri and Ra forms. Conventional antagonists, according to this hypothesis, have equal affinity for both receptor forms and maintain the same level of constitutive activity.
REMEMBER
The receptor is able to assume two conformations. In the Ri conformation, it is inactive and produces no effect, even when combined with a drug molecule. In the Ra conformation, the receptor can activate downstream mechanisms that produce a small observable effect, even in the absence of drug (constitutive activity).
Inverse agonists, have a much higher affinity for the Ri form, reduce constitutive activity, and may produce a contrasting physiologic result.
Binding of a drug to a nonregulatory molecule such as plasma albumin will result in no detectable change in the function of the biologic system, so this endogenous molecule can be called _____
Inert binding site
** Such binding is not completely without significance, however, because it affects the distribution of drug within the body and determines the amount of free drug in the circulation. Both of these factors are of pharmacokinetic importance
A weak acid is best defined as a neutral molecule that can reversibly dissociate into an anion (a negatively charged molecule) and a proton (a hydrogen ion)
A weak base can be defined as a neutral molecule that can form a cation (a positively charged molecule) by combining with a proton
REMEMBER
The protonated form of a weak acid is the neutral, more lipid-soluble form, whereas the unprotonated form of a weak base is the neutral form
Inspection confirms that the lower the pH relative to the pKa, the greater will be the fraction of drug in the protonated form. Because the uncharged form is the more lipid-soluble, more of a weak acid will be in the lipid soluble form at acid pH, whereas more of a basic drug will be in the lipid-soluble form at alkaline pH
REMEMBER
Almost all drugs are filtered at the glomerulus. If a drug is in a lipid-soluble form during its passage down the renal tubule, a significant fraction will be reabsorbed by simple passive diffusion
If the goal is to accelerate excretion of the drug (eg, in a case of drug overdose), it is important to prevent its reabsorption from the tubule. This can often be accomplished by adjusting urine pH to make certain that most of the drug is in the ionized state. Thus, weak acids are usually excreted faster in alkaline urine; weak bases are usually excreted faster in acidic urine
An inactive precursor chemical that is readily absorbed and distributed which must be converted to the active drug by biologic processes inside the body
Prodrug
For a drug given orally to produce an effect in the central nervous system, it must pass through barriers that include the tissues that make up the wall of the intestine, the walls of the capillaries that perfuse the gut, and the blood-brain barrier, the walls of the capillaries that perfuse the brain
Therefore drugs that enter the CNS must be lipid-soluble
Aqueous diffusion of drug molecules is usually driven by the concentration gradient of the permeating drug, a downhill movement described by Fick’s law. Drug molecules that are bound to large plasma proteins (eg, albumin) do not permeate most vascular aqueous pores.
If the drug is charged, its flux is also influenced by electrical fields (eg, the membrane potential and—in parts of the nephron—the transtubular potential)
This property of drug determines how readily the molecule moves between aqueous and lipid media
Lipid-aqueous partition coefficient
- *In the case of weak acids and weak bases (which gain or lose electrical charge-bearing protons, depending on the pH), the ability to move from aqueous to lipid or vice versa varies with the pH of the medium, because charged molecules attract water molecules.
- *The ratio of lipid-soluble form to water-soluble form for a weak acid or weak base is expressed by the Henderson-Hasselbalch equation
Before clinical testing:
(1) Identification or elucidation of a new drug target
(2) Rational design of a new molecule based on an understanding of biologic mechanisms and drug receptor structure
(3) Screening for biologic activity of large numbers of natural products, banks of previously discovered chemical entities, or large libraries of peptides, nucleic acids, and other organic molecules
**Steps (1) and (2) are often carried out in academic research laboratories
This phase of drug development involves a variety of assays at the molecular, cellular, organ system, and whole animal levels to define the pharmacologic profile, i.e., the activity and selectivity of the drug. The type and number of initial screening tests depend on the pharmacologic and therapeutic goal
Preclinical trial – drug screening
**The desired result of this screening procedure (which may have to be repeated several times with congeners of the original molecule) is a lead compound
In this phase of CLINICAL TRIAL, the effects of the drug as a function of dosage are established in a small number (20–100) of healthy volunteers. If the drug is expected to have significant toxicity, as may be the case in cancer and AIDS therapy, volunteer patients with the disease participate rather than normal volunteers
Phase 1
REMEMBER
Phase 1 trials are done to determine the probable limits of the safe clinical dosage range. These trials may be nonblind or “open”; that is, both the investigators and the subjects know what is being given.
Alternatively, they may be “blinded” and placebo controlled. Pharmacokinetic measurements of absorption, half-life, and metabolism are often done. Phase 1 studies are usually performed in research centers by specially trained clinical pharmacologists
In this phase of CLINICAL TRIAL, the drug is studied in patients with the target disease to determine its efficacy (“proof of concept”), and the doses to be used in any follow-on trials. A modest number of patients (100–200) are studied in detail. A single-blind design may be used, with an inert placebo medication and an established active drug (positive control) in addition to the investigational agent.
Phase 2
**Phase 2 trials are usually done in special clinical centers (eg, university hospitals). Phase 2 trials have the highest rate of drug failures, and only 25% of innovative drugs move on to phase 3
In this phase of CLINICAL TRIAL, the drug is evaluated in much larger numbers of patients with the target disease usually thousands to further establish and confirm safety and efficacy.
Phase 3
**Using information gathered in phases 1 and 2, phase 3 trials are designed to minimize errors caused by placebo effects, variable course of the disease, etc. Therefore, double-blind and crossover techniques are often used. Phase 3 trials are usually performed in settings similar to those anticipated for the ultimate use of the drug.
This phase constitutes monitoring the safety of the new drug under actual conditions of use in large numbers of patients
Phase 4
Philippine FDA-registered herbal medicines
Lagundi – Vitex negundo L; used as an anti-histaminic (anti-asthmatic, expectorant and anti-inflammatory)
Sambong – Blumea balsamifera; used in urinary tract pain and burning, to increase urinary output in edema, or as a preparation before laser treatment of kidney or bladder stones
Akapulko – Cassia alata L; used as an antifungal, anti-lice and; anti-scabies
Tsaang gubat – Carmona retusa (Vahl) Masam; used in acute diarrhea, biliary colic and; gastric/intestinal colic from acute gastroenteritis
Yerba buena – Menthacordifolia opiz; used in the symptomatic relief of mild to moderate pain secondary to circumcision, episiotomy, skin biopsy and; dental extractions
Cardinal Concepts in Pharmacology
- No drug can create a new effect
- At most a drug can modulate intrinsic physiologic function
- Can potentially alter the rate at which a bodily function proceeds
Refers to the percentage of an active drug in a drug product that enters the systemic circulation at a certain rate
Bioavailability
It is a measure of whether the bioavailability (BA) of a certain drug product is closely similar to the BA of the indicator drug
Bioequivalence
Sources of drugs
- plant sources
- animal sources
- microbes
- Earth/soil
- human sources
PLANT SOURCES
a. Alkaloids
b. Glycosides
c. Oils
d. Gum
e. Resin: rosin-like substance usually formed by the oxidation of volatile oils; most are used as cathartics (pine rosin)
f. Tannins: complex principle found widely distributed in plants; has astringent action and is used in the treatment of burns, diarrhea and hemorrhoids (tannic acid)
PLANT SOURCES
Alkaloids – basic organic substances containing carbon, hydrogen, nitrogen, and oxygen; occurs in almost all parts of plants but are most often found in seeds, roots and leaves
Atropine [anti-muscarinic] Vinblastine Vincristine [anti-cancer] Quinine [anti-malaria] Quinidine Reserpine Scopolamine Cocaine Ephedrine Caffeine Colchicine [anti-gout] Morphine [analgesia] Theophylline [treatment for asthma] Theobromine
PLANT SOURCES
Glycosides – ether-like combinations of sugar with some other organic substances
Digoxin [for congestive heart failure] Digitoxin Coumarin [anticoagulant] Salicin [anti-inflammatory] Hesperidin Rutin Quercetin
