Chap 1 Introduction Flashcards
Define Drugs
Substances that act on biologic systems at the chemical (molecular) level and alter their functions
Drug receptors
The molecular components of the body with which drugs interact to bring about their effects
Distribution phase
The phase of drug movement from the site of administration into the tissues
Elimination phase
The phase of drug inactivation or removal from the body by metabolism or excretion
Endocytosis
Endocytosis: Absorption of material across a cell membrane by enclosing it in cell membrane material and pulling it into the cell, where it can be processed or released
exocytosis
Exocytosis: Expulsion of material from vesicles in the cell into the extracellular space
Permeation
Movement of a molecule (eg, drug) through the biologic medium
Pharmacodynamics
The actions of a drug on the body, including receptor interactions, dose-response phenomena, and mechanisms of therapeutic and toxic actions
Pharmacokinetics
The actions of the body on the drug, including absorption, distribution, metabolism, and elimina- tion. Elimination of a drug may be achieved by metabolism or by excretion
Biodisposition
is a term sometimes used to describe the processes of metabolism and excretion
Transporter
A specialized molecule, usually a protein, that carries a drug, transmitter, or other molecule across a membrane in which it is not permeable, eg, Na+/K+ ATPase, serotonin reuptake transporter, etc
Mutagenic
An effect on the inheritable characteristics of a cell or organism—a mutation in the DNA; usually tested in microorganisms with the Ames test
Carcinogenic
An effect of inducing malignant characteristics
Teratogenic
An effect on the in utero development of an organism resulting in abnormal structure or function; not generally heritable
Placebo
An inactive “dummy” medication made up to resemble the active investigational formulation as much as possible but lacking therapeutic effect
Single-blind study
A clinical trial in which the investigators—but not the subjects—know which subjects are receiving active drug and which are receiving placebos
Double-blind study
A clinical trial in which neither the subjects nor the investigators know which subjects are receiving placebos; the code is held by a third party
IND
Investigational New Drug Exemption; an application for FDA approval to carry out new drug trials in humans; requires animal data
NDA
New Drug Application; seeks FDA approval to market a new drug for ordinary clinical use; requires data from clinical trials as well as preclinical (animal) data
Phases 1, 2, and 3 of clinical trials
Three parts of a clinical trial that are usually carried out before submitting an NDA to the FDA
Positive control
A known standard therapy, to be used along with placebo, to evaluate the superiority or inferiority of a new drug in relation to the other drugs available
Orphan drugs
Drugs developed for diseases in which the expected number of patients is small. Some countries bestow certain commercial advantages on companies that develop drugs for uncommon diseases
Toxicology
is the area of pharmacology concerned with the undesirable effects of chemicals on biologic systems.
Define: Endogenous Receptors or Endogenous Agonist
Provide examptle
Drug receptor reaults in Activation of receptpr Molecule
Compound naturally produced by the body which binds to & activates that receptor
ex: agonist for Serotinin receptor is Serotinin
Many drugs found in Nature are ____ & define
Alkaloids
-are molecules the have a basic (alkanine) pH soution as a result of Amine group in their structure
Drugs vary in size from what molecular weight & give example
MW 7
ex: Lithium
to:
over 50,000
ex: Thrombolytic enzymes, antibodies and proteins
Most drugs MW is between
note: above/below
100-1000
note: MW below 100 is are rarely sufficiently selective in their actions
MW above 1000 are poorly absorbed & distributed in the body
Define: Biologicals
Protein drugs are commercially produced in Cell, Bacteria or Yest cultures using recombinant DNA technology
name Drug Receptor Bonds
- Covalent bonds (usually with irriversible action)
- Electrostatic bonds (weaker reversible electrostatic bonds between Cations & Anions)
- Hydrogen
- van der Waals
- Hydrophobic bonds (Much weaker interactions)
Drug actions are mediated through:
the effects of drug ligand molecules on drug RECEPTORS in the body
What are RECEPTORS
Ex?
Large regulatory molecules that influence important biochemical & Physiological processes
ex: Enzymes involved in gluscose metabolism (Biochemical)
ex: Ion channel receptors, neurotransmitter reuptake, transporters & Ion transporters (Physiologic)
Drug termed Agonist
when drug receptor binding results in activation of the receptor molecule
Drug termed Antagonist
Drug receptor binding results in Inhibition
define Ligand Molecule
Ex:
Types of signaling molecules and the receptors they bind to on target cells.
Ex: Intracellular receptors, ligand-gated ion channels, G protein-coupled receptors, and receptor tyrosine kinases.
Ex of Ligand Molecules
Ex: H2O Ion, NH3
& Halide Ions: F-, Cl-, Br-, CN- Cyano
Allosteric Enzymes
Has two sites
-one fitting Substrate & other the Enzyme
Substrate
Molecule upon which enzyme acts
Allosteric Inhibitors
Note: Allosteric inhibitors do not compete with the ______, and they may bind _____or_____
Substances which prevent an enzyme from changing into an active form by combiningnot with the ACTIVE SITE but with some other part of the enzyme.
- agonist drug for binding to the receptor
- reversibly
- irreversibly
Name 2 important plasma proteins with Drug binding capacity
- Albumin
- Orosomucoid (alpha 1-acid glycoprotein)
To produce useful therapeutic effects, most drugs must be able to be :
Absorbed, Distributed & eliminated
Define Permeation
movement of drug molecules into and within the biologic environment
Provide 4 processes of Permeation
- Aqueous diffusion-movement of molecules through the watery extracellular and intracellular spaces
- Lipid diffusion-is the passive movement of molecules through membranes and other lipid barriers
- Transport by special carriers -Drugs that do not readily diffuse through membranes may be transported across barriers by mechanisms that carry similar endogenous substances
- Endocytosis -occurs through binding of the transported molecule to specialized components (receptors) on cell membranes
Exocytosis
is the reverse process, that is, the expul- sion of material that is membrane-encapsulated inside the cell from the cell.
Note: Most neurotransmitters are released by exocytosis.
Important examples are transporters for ions are :
(eg, Na+/ K+ ATPase)
Important examples are transporters for neurotransmitters:
(eg, transporters for serotonin, norepinephrine)
Important examples of Transporters for Metabolites
(eg, glucose, amino acids)
Define Fick’s Law of Diffusion
Provide Equation:
Fick’s law predicts the rate of movement of molecules across a barrier
Equation:
Rate = C1 − C2 × Permeability coefficient × Area Thickness
Solubility
Aqueous solubility of a drug is often a function of the electrostatic charge (degree of ionization, polarity) of the molecule
(because water molecules behave as dipoles and are attracted to charged drug molecules, forming an aqueous shell around them)
If the pKa of the drug and the pH of the medium are known, the fraction of molecules in the ionized state can be predicted by means of _____?
Henderson-Hasselbalch equation:
Henderson-Hasselbalch equation:
When Weak bases are ion-ize they are therefore:
more polar and more water-soluble when they are protonated
When Weak acids are not ionized they are therefore
less water-soluble—when they are protonated.
- RNH3+
- RNH2
- RCOOH
- RCOO-
- protonated weak base (charged, more water-soluble)
- unprotonated weak base (uncharged, more lipid-soluble) + H+proton
- protonated weak acid (uncharged, more lipid-soluble)
- Unprotonated weak acid (charged, more water-soluble)+ H+proton
Define Bioavailability
Is the fraction of an administered dose of unchanged drug that reaches the systemic circulation
Common routes of administration and some of their features
Oral (swallowed)
Buccal and sublingual (not swallowed)
Intravenous Intramuscular
Subcutaneous Rectal (suppository)
Inhalation
Topical
Transdermal
Oral (swallowed)
Offers maximal convenience; absorption is often slower.
Subject to the first-pass effect, in which a significant amount of the agent is metabolized in the gut wall, portal circulation, and liver before it reaches the systemic circulation
Buccal and sublingual (not swallowed)
Direct absorption into the systemic venous circulation, bypassing the hepatic portal circuit and first-pass metabolism
Intravenous
Instantaneous and complete absorption (by definition, bioavailability is 100%). Potentially more dangerous
Intramuscular
Often faster and more complete (higher bioavailability) than with oral adminis- tration. Large volumes may be given if the drug is not too irritating. First-pass metabolism is avoided
Subcutaneous
Slower absorption than the intramus- cular route. First-pass metabolism is avoided.
Rectal (suppository)
The rectal route offers partial avoidance of the first-pass effect. Larger amounts of drug and drugs with unpleasant tastes are better administered rectally than by the buccal or sublingual routes
Inhalation
Route offers delivery closest to respira- tory tissues (eg, for asthma). Usually very rapid absorption (eg, for anesthetic gases)
Topical
The topical route includes application to the skin or to the mucous membrane of the eye, ear, nose, throat, airway, or vagina for local effect
Transdermal
The transdermal route involves appli-cation to the skin for systemic effect. Absorption usually occurs very slowly (because of the thickness of the skin), but the first-pass effect is avoided
Indicated by Ficks Law
the concentration gradient is a major determinant of the rate of absorption
Determinants of Distribution: Name (4)
- Size of the organ
- Blood flow
3. Solubility
4. Binding
Determant of distribution:
Size of the organ
Size of the organ—The size of the organ determines the con- centration gradient between blood and the organ.
Ex: skeletal muscle can take up a large amount of drug because theconcentration in the muscle tissue remains low (and the blood- tissue gradient high)
Determinant of Distribution: Blood flow
Blood flow—Blood flow to the tissue is an important deter- minant of the rate of uptake of drug, although blood flow may not affect the amount of drug in the tissue at equilibrium
-as a result, well-perfused tissues (eg, brain, heart, kidneys, and splanchnic organs) usually achieve high tissue concentrations sooner than poorly perfused tissues (eg, fat, bone).
Solubility (determinant of distribution)
- Solubility—The solubility of a drug in tissue influences the concentration of the drug in the extracellular fluid surrounding the blood vessels.
If the drug is very soluble in the cells, the concentration in the perivascular extracellular space will be lower and diffusion from the vessel into the extravascular tissue space will be facilitated.
Ex: some organs (such as the brain) have a high lipid content and thus dissolve a high concentration of lipid-soluble agents rapidly.
Binding (Determinant of distribution)
- Binding—Binding of a drug to macromolecules in the blood or a tissue compartment tends to increase the drug’s concentration in that compartment.
Ex: warfarin is strongly bound to plasma albumin, which restricts warfarin’s diffusion out of the vascular compartment.
Conversely, chloroquine is strongly bound to extravascular tissue proteins, which results in a marked reduction in the plasma concentration of chloroquine.
volume of distribution (Vd)
an important phar-macokinetic parameter that reflects the determinants of thedistribution of a drug in the body.
(Vd) relates the amount of drug in the body to the concentration in the plasma
Drug disposition
Drug disposition is a term sometimes used to refer to metabolism and elimination of drugs
Some drugs when given orally are metabolized before they enter the systemic circulation. This first-pass metabolism was referred to as one cause of low bioavailability.
Note: Drug metabolism occurs primarily in the liver
Elimination of Drugs
Along with the dosage, the rate of elimination following the last dose (disappearance of the active molecules from the site of action, the bloodstream, and the body) determines the duration of action
For drugs that are not metabolized, _____is the mode of elimination
excretion
First-Order Elimination
first-order elimination indicates that the rate of elimination is proportional to the concentration (ie, the higher the concentra- tion, the greater the amount of drug eliminated per unit time
Drugs with first-order elimination have a characteristic half-life of elimination that is constant regardless of the amount of drug in the body
Note: concentration of such a drug in the blood will decrease by 50% for every half-life
Most drugs in clinical use demonstrate ______
first-order kinetics.
Zero-Order Elimination
zero-order elimination implies that the rate of elimination is constant regardless of concentration
Diagram of First Order Elimination & Zero Order Elimination
Comparison of first-order and zero-order elimination.
For drugs with first-order kinetics (left), rate of elimination (units per hour) is proportional to concentration; this is the more common process.
In the case of zero-order elimination, the rate is constant and independent of concentration
Acute Toxicity (animal testing requirements)
Acute toxicity studies are required for all new drugs.
These studies involve administration of incrementing doses of the agent up to the lethal level in at least 2 species (eg, 1 rodent and 1 nonrodent).
Subacute and Chronic Toxicity (animal testing requirements)
Subacute and chronic toxicity testing is required for most agents, especially those intended for chronic use.
Tests are usually conducted for 2–4 weeks (subacute) and 6–24 months (chronic), in at least 2 species.
Teratogenesis
Teratogenesis can be defined as the induction of developmental defects in the somatic tissues of the fetus (eg, by exposure of the fetus to a chemical, infection, or radiation)
Ex’s of Drugs with Teratogenic effects
Drugs with teratogenic effects include:
- thalidomide,
- isotretinoin,
- valproic acid,
- ethanol,
- glucocorticoids,
- warfarin,
- lithium,
- androgens.
Mutagenesis
Mutagenesis denotes induction of changes in the genetic material of animals of any age and therefore induction of heritable abnormalities.
Ames test
Ames test is the standard in vitro test for mutagenicity, uses a special strain of salmonella bacteria that depends on specific nutrients in the culture medium.
Loss of this dependence as a result of exposure to the test drug signals a mutation.
Note: Many carcinogens (eg, afla- toxin, cancer chemotherapeutic drugs, bind to DNA) have mutagenic effects and test positive in the Ames test
Carcinogenesis
Ex:
Carcinogenesis is the induction of malignant characteristics in cells.
Ex: Agents with known carcinogenic effects include coal tar, aflatoxin, dimethylnitrosamine, nitrosamines, urethane, vinyl chloride, and the polycyclic aromatic hydrocarbons in tobacco smoke (eg, benzo[a]pyrene) and other tobacco products
The major clinical testing process is usually divided into ____that are carried out to provide information for a ________.
3 phases
New Drug Application (NDA)
Phase 1
A phase 1 trial consists of careful evaluation of the dose-response relationship and the pharmacokinetics of the new drug in a small number of normal human volunteers (eg, 20–100)
how are acute effects of the agent studied in phase 1 studies
In phase 1 studies, the acute effects of the agent are studied over a broad range of dosages, starting with one that produces no detectable effect and progressing to one that produces either a significant physiologic response or a very minor toxic effect.
Phase 2
A phase 2 trial involves evaluation of a drug in a moderate number of sick patients (eg, 100–200) with the target disease.
A placebo or positive control drug is included in a single-blind or double-blind design.
The study is carried out under very carefully controlled conditions, and patients are closely monitored, often in a hospital research ward.
The goal is to determine whether the agent has the desired efficacy
Phase 3
A phase 3 trial usually involves many patients (eg, 1000–6000 or more, in many centers) and many clinicians who are using the drug in the manner proposed for its ultimate general use (eg, in outpa- tients).
Such studies usually include placebo and positive controls in a double-blind crossover design
Note: If the drug successfully completes phase 3, an NDA is submit- ted to the FDA. If the NDA is approved, the drug can be mar- keted and phase 4 begins.
Phase 4
Phase 4 represents the postmarketing surveillance phase of evaluation, in which it is hoped that toxicities that occur very infrequently will be detected and reported early enough to pre- vent major therapeutic disasters.
Drug Patents & Generic Drugs (Describe Rules)
In the United States, approval of the patent and completion of the NDA approval process give the originator the right to market the drug without competition from other firms for a period of 10–14 years from the NDA approval date.
After expiration of the patent, any company may apply to the FDA for permission to market a generic version of the same drug if they demonstrate that their generic drug mol- ecule is bioequivalent (ie, meets certain requirements for content, purity, and bioavailability) to the original product
Orphan drug
Orphan drug is a drug for a rare disease (one affecting fewer than 200,000 people in the United States).
Teratogenic Effect
define:
Ex : defects
class of teratogens:
or Teratogenic Agent that can disturb the development of the Embryo or Fetus
Ex: congenital defects & malformations
Class: Radiation, maternal infections, chemicals & drugs
Phenytoin
Anti-seizure medication
Aspirin
define:
use of TX:
Blood thinner
nonsteroidal anti-inflammatory drug
- TX:* pain, fever, hedaches, infammation
- reduces:* risk of heart attack, ischemic stroke
- prevents:* blood clots
The excretion of most drugs follows ____ ____ ____, however: 3 drugs do not (name) follow ____ _____ ______ (elimination rates are constant regardless of blood concentration)
First-Order Kinetics
- Ethanol
- High doses Aspirin & Phenytoin
Zero-Order Kinetics
How to theoretically Tx Chlorpropamide or Tolbutamide overdose
Chlorpropamide &Tolbutamide are both (weak Acids) which means that it is less ionized when protonated,
Since absorption involves with permeation across lipid membranes, in theory we can treat an overdose by decreasing absorption from the gut and reabsorption from the tubular urine by making the drug less lipid-soluble.
Ionization attracts water molecules and decreases lipid solubility.
Nature of Drugs
Drugs are chemicals that modify body functions. They may be ions, carbohydrates, lipids, or proteins. They vary in size from lithium (MW 7) to proteins (MW ≥ 50,000)
