Drug Information and Nomenclature
A. Drug Classification
OTC drugs: Adequate directions can be written for the layman and they’re safe for the not-so-careful customer.
B. Prescription Drugs
Adequate directions can not be written for the layman. Directions are intended for the physician, and the proper and successful use of these drugs is the responsibility of the physician.
C. Drug Names
Chemical name- designates the precise chemical composition and structure
Trade name- registered name of the drug used by the owner of the copyright
Nonproprietary name- given to a drug when usefulness is demonstrated, in theory there could be an unlimited number of names
Generic name- nonproprietary name recommended by the USANC, used in the compendia, and used on the manufacturer’s label
General Principles of Drug Actions
I. Nature of Drug Effects: Drugs alter biological function in four general ways:
A. Modes of Action
1. Nonspecific chemical/physical interactions (ex. acid/base, osmotic agents, etc.)
2. Altering enzyme levels or activity
3. Antimetabolites act as bogus analogs of natural metabolites to produce a non-functional molecule in a target cell (ex. Sulfa drugs)
4. Receptor mediated effects- receptors are sites on cells where drugs interact and initiate events that produce the pharmacological effect. Drugs are either agonists(produces an effect), antagonists(binds but cannot produce an effect but prevents the other molecules from binding), and partial agonists(bind and produce smaller response than an agonist, and when added in the presence of a “full”agonist, can dec. the response)
NOTE: The actions of all drugs are considered conceptually to act through receptors.
B. Response to a Drug
Two factors determine response to a drug:
1. Amount of drug that reaches the receptor(dependent on dose, route of administration, adsorption, protein binding in plasma, tissue distribution, metabolism, and excretion)
2. Nature of interaction of drug with receptor(affinity and effectiveness to promote uptake)
C. Selectivity
Ability of drug to produce effect at one site. Most drugs are not perfectly selective. Measure of selectivity is degree to which drug produces desired therapeutic effect w/o producing side effects.
D. Potency
Drug activity relative to a given reference standard. Potency is determined by two factors:
1. Amount of drug that reaches receptor
2. Affinity of the drug for the receptor
E. Efficacy
Magnitude of the response produced with a maximum dose. It is affected by several parameters:
1. Number of drug-receptor complexes formed
2. Ability of the drug to initiate the effect at the receptor site
3. Status of the target cell
II. The Dose Response Relationship- The Graded Dose Response Curve
A. Description and Parameters
Graded dose response curves illustrate the relationship between drug dose and the intensity of the pharmacological effect for an individual. Magnitude of the response is plotted on the y-axis and the log of the drug dose is plotted on the x-axis. Important parameters include:
1. Threshold- the minimally effective dose
2. D50- dose of drug that produces half-maximal effect
3. Maximally effective dose
4. Efficacy- referred to as intrinsic activity
5. Slope
B. Uses of the Graded Dose Response Curve
1. Compare potency- the lower the D50, the more potent the drug
2. Compare efficacy- the greater the response, the higher the efficacy
3. Mechanism of action- if two drugs act by the same receptor mechanism, DR curves parallel
4. Used to indicate the nature of drug antagonists:
a. competitive antagonist- binds to the receptor of the agonist and shifts the DR curve for an agonist to the right(inc. D50) w/o dec. the efficacy
b. non-competitive antagonist- binds to a different site than the agonist and prevents the agonist from binding or the receptor from being activated. It will dec. the efficacy w/o affecting potency(D50) of the agonist.
c. Irreversible inhibitors- act like that of non-competitive antagonists
III. The Quantal Dose Response Relationship
A. The Quantal DR curve relates dose of a drug to frequency with which a response will occur. The dose of the drug which yields half-maximal effect is referred to as ED50 (the dose of a drug that produces a therapeutic response in half the population). TD50 is the dose of a drug that produces a toxic effect in half the population. If the toxic effect is death then the term is LD50.
B. Use of the Quantal DR Curve for Safety Evaluation
The greater the difference between the TD50 and the ED50, the safer the drug. Therapeutic index is a measure of these terms. TI=TD50/ED50, and the larger the TI, the safer the drug. In general, selective drugs have very large therapeutic indices. Also, Quantal DR curves deal with the incidence of effectiveness and toxicity in the entire patient population.
Drug Absorption
I. Routes of Drug Administration
Drugs may be administered by mouth, parenterally, topically, or by inhalation.
1. Enteral
a. Oral
The oral route is convenient, economical, and the safest mode of drug administration. It is also the most common route. Daily fluctuations of the GI environment produced by food and the rate of gastric emptying make it the most unpredictable and slowest route in terms of both amount and rate of drug absorption. Drugs that are altered by digestive enzymes cannot be used by this route. Also, since all drugs that go through the stomach and the intestine pass through the liver on their way to the general circulation, drugs that are altered or destroyed by the liver must be given in larger doses.
b. Oral mucosa
Drugs administered by this route enter directly into the systemic circulation and bypass the liver, which is clinically useful when prescribing drugs that cannot be given orally b/c of first pass metabolism in the liver.
c. Stomach
Weakly acidic drugs are absorbed by the gastric mucosa to a modest degree. Alcohol is rapidly absorbed here. Basic drugs are not absorbed here.
d. Intestine
The SI is the principle absorptive organ. Complete absorption may occur here b/c of the large SA even though local pH may not favor absorption. Weak bases with high pKa are absorbed here b/c of the higher pH. Even acidic drugs are absorbed here because of the large SA. A small fraction of the unionized drug(lipid soluble) is absorbed, pushing ionized drug into unionized to equilibrate, and that is absorbed and so on. Most drugs pass into the circulation in their unionized lipid soluble form, but some can pass via transporters.
e. Rectum
Absorption is rapid and hepatic first pass metabolism is less than that of oral. Used when the patient is vomiting, noncooperative, or unconscious. Retention is unpredictable.
1. Parenteral
Parenteral refers to drug administration that does not involve the alimentary canal. The three major routes are subcutaneous, intramuscular, and intravenous.
a. Subcutaneous and intramuscular route is rapid since it bypasses the epithelial barrier. The rate of absorption does depend on the vascularity and blood flow at the site of administration. Intramuscular injection is generally more rapid only in the event of muscular activity. Irritating drugs cannot be given by this route b/c of possible tissue damage. Both sites may be used for sustained therapy which are slowly released for absorption. Main disadvantage- equipment, skill, and sterility.
b. The intravascular route eliminates the need for absorption into the blood and is the most rapid route for administration of drugs. Used for emergencies and when absolute control of the amount administered is essential. It is the most hazardous route, since once administered, there can be no recall. It is dangerous and can cause embolism due to injection of air or infection.
2. Specialized Routes of Administration
a. Inhalation
Very rapid due to large SA and number of capillaries lining the alveoli.
b. Intraperitoneal
c. Intra-arterial
d. Bone Marrow
Can be viewed identically as IV, used in children and the elderly when difficulty finding veins.
e. Intrathecal
Drugs which do not pass the BBB can be given in the spinal subarachnoid space.
3. Topical or Local Administration
Very useful in the practice of dermatology and ophthalmology.
a. Skin
Absorption through the skin is dependent upon lipid solubility. Occlusive dressings are used to enhance absorption by maintaining an elevated temperature and humidity, but can promote fungal/bacterial growth.
b. Mucosal Membranes
Suppositories are composed of the drug and a base which melts at body temperature.
Drug Absorption
I. Routes of Drug Administration
Two key parameters governing absorption are lipid solubility and blood flow.
II. Bioavailabilty
Bioavailability is defined as the fraction of administered dose that reaches the bloodstream unaltered. In the case of IV administration, bioavailability is equal to 1. For the same drug, bioavailability may vary among different preparations.
III. Transport of Drugs Across Biological Membranes
Movement across biological membranes generally represents the primary obstacle to drug absorption into the blood stream and distribution to the tissues. Passive diffusion is the most common mode of drug transport.
IV. Diffusion of Uncharged Drugs across the biological membrane
Rate of diffusion of uncharged molecule depends on concentration gradient across the membrane, SA of the membrane, diffusion coefficient of the drug, the inverse of the membrane thickness, and the partition coefficient of the drug(measure of lipid solubility and is the most important factor).
V. Diffusion of Weak Acids and Bases
A. Only the unionized species can diffuse across the membrane, therefore the degree of unionization is important for determining diffusion.
B. Ionization is determined by the pK of the drug and the pH of the fluid in which it is dissolved.
The Henderson Hasselbach equation gives us: pH – pK = log [A]/[HA]
When the pK=pH, the acid is one-half ionized.
VI. Absorption of Drugs Following Oral Administration
A. Stomach
1. Since gastric contents are generally acidic, weak acids are absorbed to a significant extent. Most bases are unable to be absorbed because they are in their ionized state.
2. Ion trapping is the phenomenon that applies to the distribution of weak acids/bases b/w fluid compartments of different pH that are separated by a semi-permeable membrane. The drug will tend to accumulate on the side of the membrane where it is most extensively ionized.
3.
B. Intestine
1. Since the pH of the intestine is more alkaline, most acids will be ionized and unable to be absorbed effectively. Bases will be less ionized and thus more readily absorbed.
2. Effect of the surface area: due to the large SA of the intestine, it is the major site of absorption for both acids and bases.
3.
C. GI Blood Flow
Blood flowing through the GI tract continually maintains the concentration gradient across the epithelial surface. The absorption of lipid soluble molecules is thus blood flow dependent.
D. First Pass Metabolism
E. Gastric Emptying
Fats, other foodstuffs , diseases, and physiological status can alter gastric emptying. Drugs taken on an empty stomach are more rapidly absorbed in the intestine.
F. Bioavailabilty
Since only dissolved drug is absorbed, the rate of disintegration and dissolution is a major determinant of bioavailability. Interactions with other drugs, food, inert ingredients can also affect bioavailability of orally administered drugs.
Binding of Drugs By Plasma Proteins
Drugs in the plasma exist in a free form or bound to proteins. Drugs bound cannot distribute outside the plasma compartment. The extent of drug binding to plasma proteins is highly variable. Serum Albumin can bind many different drugs, especially organic acids and lipophilic drugs. Alpha 1-acid glycoprotein binds many basic drugs. Protein binding of many drugs can have many consequences:
1. Decreased tissue distribution
2. Decreased rates of metabolism and therefore longer half lives
3. Drug-protein complexes have high molecular weights and therefore can’t be filtered and eliminated by the kidney which also causes longer half lives
4. Drug-Drug interactions by binding to the same site on a plasma protein. Ex. Drug A could displace Drug B from its bound state on the protein, increasing Drug B’s free concentration in the plasma and causing overdose. However, this is unlikely since all the displaced drug does not remain in the plasma but distributes to various tissues effectively reducing its plasma concentration. Secondly, free drug is more readily filterable by the kidneys and biotransformed by hepatocytes. Finally, most drugs have a volume of distribution much greater than plasma levels.
Drug Distribution
The distribution of a drug to a tissue is determined by: (1) blood flow to that site, (2) ability to cross the capillary wall, (3) and its ability to cross the cell membrane.
I. Importance of blood flow for drug distribution
The initial rate of drug distribution is heavily dependent on the relative rate of blood flow to various tissues; however, at equilibrium, the amount of drug in that tissue is related to the mass and properties of that tissue and the properties of the drug.
Drugs enter more highly perfused tissues first, then over time can redistribute to less perfused tissues.
II. Blood Brain Barrier
Lipid soluble drugs can enter the CNS rapidly. Placing a charged or polar functional group on the molecule can keep it from entering the CNS. At the same time, charged molecules for CNS treatment can present difficulties.
III. Redistribution of Drugs
The distribution of a drug within tissues may change over time. Ex. 1. Brain 2. Muscle 3. Fat. If the drug is very lipophilic, it may remain in fat for a long time. Ex. Thiopental- redistribution from brain eventually to adipose tissue actually terminates the action of the drug.
IV. Volume of Distribution
Volume of distribution-the volume of bodily fluid in which a drug appears to distribute. The larger the number, the more widely distributed in bodily fluids. (For a 70kg. Adult: plasma= 3L, extracellular water=12L, total body water=41L).
A. Distribution Following IV Dosing
Once a drug is administered IV, its concentration in the plasma decreases rapidly because of two factors:
1. Drug distributes out of the plasma and into bodily tissues and spaces
2. Elimination of the drug by liver, kidney, and other mechanisms
Even though both are occurring, this is referred to as the distribution phase.
After distribution from the plasma compartment to the tissues is completed, “re-equilibration” occurs from the tissues back to the bloodstream as decreases in plasma concentration is due primarily to biotransformation and elimination(excretion in urine). This is referred to as the elimination phase.
Drugs that observe this distribution pattern are said to obey the two compartment model.
However, for some drugs, the initial distribution phase of the drugs is so rapid, separate distribution and elimination phases are not observed, just the elimination phase. This is the one compartment model.
B. Calculation of Vd
For a one compartment model drug: Give IV dose and draw blood sample immediately to determine concentration of drug in plasma. Concentration = IV dose/Vd and Vd = IV dose/Plasma Concentration
For a two compartment model drug, IV dose is given and blood is drawn at time intervals. The drug concentration is plotted as a function of time and back extrapolated to where it intersects the y-axis at time zero to determine drug concentration in plasma IF the drug had distributed immediately. This value for drug conc. along with IV dose can be used to calculate Vd.
C. Utility of Vd
A very high Vd may indicate the drug is sequestered in tissues like bone or adipose tissue. A very low Vd may suggest the drug extensively binds plasma proteins and cannot leave the plasma compartment. It is also used to calculate the loading dose of a drug.
Drug Elimination From The Body And Termination Of Action
Mechanisms of Drug Elimination: The action of a drug is terminated by enzyme catalyzed conversion to inactive compound and/or elimination via the kidney, bile, or other routes.
Rate of Drug Elimination from the Body: Most drugs are eliminated at a first order rate.
Rate of elimination(mass/time) = Constant(vol/time) x [DRUG]plasma(mass/vol)
The Constant is referred to as the “CLEARANCE” of the drug, and represents the capacity of the body to remove a drug.
In zero order, the rate at which the body eliminates the drug is constant and does not depend on plasma concentration.
Specific Organ Clearance is the capacity of an individual organ to eliminate a drug via either metabolism(liver) or excretion(kidney).
Rate of elimination of organ = CLorgan x [DRUG]plasma perfusing organ
Whole Body Clearance is the capacity of the entire body to eliminate the drug by all mechanisms and is equal to the sum all specific organ clearances.
Plasma Clearance is essentially the same term as clearance.
Drug Biotransformation Fundamental Concepts:
1. All drugs undergo metabolism or biotransformation. Consequences of metabolism are
decreased pharmacological activity, conversion to more polar intermediates and thus more readily eliminated, production of metabolites of different potency, production of toxic metabolites
2. Most undergo a variety of biotransformations
3. Metabolism of drugs occur via specific enzyme systems
4. The liver is the major organ involved in biotransformation
5. Biotransformation of drugs is variable and can be affected by many factors(genetics, age, nutrition, etc.)
Types of Biotransformation Reactions
The four major types of reactions involved in biotransformation are oxidations, reductions, hydrolases, and conjugations.
I. Classification of Reaction
A. Non-synthetic or Phase I reactions: Include oxidations, reduction, and hydrolysis rxn. All involve the enzyme catalyzed biotransformation of a drug
B. Synthetic or Phase II reactions: Conjugation rxn. Which involve the enzyme catalyzed combination of a drug with an endogenous substance at an active site.
C. Sequential Biotransformation: Phase I rxn. introduces active site into 1st metabolite followed by a Phase II conjugation rxn.
Biotransformations almost always produce metabolites which are more polar than the parent molecule increasing ease of excretion. This is especially true for conjugation rxns. that introduce highly charged functional groups like glucuronic acid, sulfates, acetic groups, methyl groups, glutathione, etc.
Enzymes that Catalyze Drug Biotransformation Reactions
I. Cytochrome P450 Monooxygenase
General Features
P450 is a family of proteins which catalyze the biotransformation of drugs. There is much variability in types and levels of P450 between individuals in a population. This helps explain the variations in responses to drugs within a population. In a typical monooxygenase rxn., one atom of O ends up in the oxidized metabolite, one in the formed water molecule, and NADPH is converted to NADP+.
A. Cellular and Subcellular Localization
Highest activity of P450 is in the liver. Other tissues with high activity are adrenal, ovaries, and testes, because of involvement in steroidogenesis. P450′s are located in the ER and catalyze lipophilic drugs best.
B. Regulation of P450 Levels
P450 levels can be altered by drugs and hormones, and regulation occurs primarily at the transcription level. Some drugs inc. synthesis of P450s and thus their own metabolism or the metabolism of other drugs. One example is the induction of P450 and glucuronyl transferase.
C. P450 Nomenclature
Ex. CYP3A2= CY-cytochrome P-P450 3-family A-subfamily 2-individual enzyme
An individual drug may be metabolized by any one or combination of P450s. CYP3A subfamily of enzymes is thought to account for 50% of all the clinically important drug interactions based on metabolism. Specifically, CYP3A4 alone accounts for 1/3 of activity in the liver. Food can effect the P450 activity that is also present in the small intestine. For ex., grapefruit juice inhibits CYP3A4 in the S.I. so greater conc. of drug can enter into the plasma. Another source of variable drug metabolism is the existence of genetic polymorphisms for several P450s.
II. Glucuronyl Transferase
A. General Features
1. Most common synthetic (phase II) reaction
2. Conjugates glucuronic acid to -OH, -COOH, -NH2, and -SH
3. Requires an active center and energy in the form of UDP-glucuronic acid
4. Located in the ER and is induced by drugs
5. Multiple enzymes with unique but overlapping specificities
III. Biliary Elimination and Entero-Hepatic Cycling
Liver cells may excrete the drug into the bile which can then be reabsorbed by the S.I. This may occur repeatedly until the drug is finally passed in the feces or eliminated by hepatic metabolism or renal excretion. Phase II reactions and the formation of glucuronides are charged metabolites and generally are not reabsorbed in the S.I. unless enzymes in the gut wall or bacteria deconjugate the metabolite to reform the parent drug.
Pharmacological Consequences of Drug Biotransformation
The most common consequence is a decrease in pharmacological activity. Drugs are metabolized in a series of rxns. until the metabolite is polar enough to be excreted(ex. Conjugation rxn.). Some metabolites formed by Phase I rxns. may have pharmacological or toxicological activity. Reactive or toxic metabolites are so because they form adducts with nucleic acids and protein components of liver cells.
Factors Which Influence Drug Metabolism
I. Drug disposition: route of administration, distribution, plasma binding, biliary excretion, etc.
II. Duration of administration: repeated administration may produce metabolic tolerance and shift of DR curve to the right
III. Administration of other Drugs
A. Decreased response of drug A due to enzyme induction by drug B
Any drug metabolized in the liver should be considered a potential inducer of drug metabolism. Ex. Barbiturates, anticoagulants, anticonvulsants, rifampicin
In this case, drug B will cause a shift to the right of the DR curve for drug A.
B. Increased response due to inhibition of a drug metabolizing enzyme
This can occur via the competitive type mechanism, where two drugs bind to the active site of the same P450 and inhibit the biotransformation of the other, or by a non-competitive mechanism where one drug inactivates the enzyme by binding to somewhere other than the active site. Ex. Cimetidine binds hepatic P450s
C. Altered response due to Physiological or Pharmacological factors(Endocrine, Nutrition, Liver damage)
D. Species differences
Most drugs are tested in animal models, but the metabolism of the drug may differ significantly.
E. Age and Developmental Status
The very young or the elderly may be more sensitive to drugs because of underdeveloped or decreased levels of drug metabolizing enzymes.
F. Genetic factors
Pharmacogenetics
Pharmacogenetics is the study of hereditary variation in the response to drugs.
I. Drug Metabolism Influenced by Multiple Genetic Loci
Genes at a number of genetic loci affect metabolism of a drug. The variation in a population will exhibit a unimodal distribution curve b/c there will be a progression from very low to very high metabolism.
II. Drug Metabolism Controlled by a Single Genetic Locus with 2 Alleles
Drug metabolism is controlled by a single locus, but there are two alleles that code for two different forms of the same enzyme. Ex. AA or Aa dominant genotype- fastest; aa homozygote recessive- slow. This results in bimodal distribution
A. N-acetylation of Isoniazid(tuberculosis), Procainamide(anti-arrhythmic) and Hydralazine(vasodilator)
All three drugs exhibit a bimodal distribution of metabolic phenotypes and all 3 contain a N atom which undergoes acetylation by N-acetyl transferase(NAT) as a major biotransformation. There are two forms of NAT, fast and slow. Slow acetylators can develop polyneuritis from taking Isoniazid and Lupus like symptoms from taking Procainamide and Hydralizine.
B. Hydrolysis of Succinylcholine by Plasma Cholinesterase
Succinylcholine is a neuromuscular relaxing drug used in surgery. It is administered continuously b/c the drug is metabolized quickly by plasma cholinesterases. 1 in 2500 have an altered form of this cholinesterase and cannot metabolize the drug for hours. They awake to find themselves paralyzed and mechanically ventilated.
C. Sparteine-Debrisoquine Biotransformation
Poor metabolizers of these drugs have a single P450 with high Km or low affinity binding, and require reduced doses to prevent toxicities.
III. Pharmacogenetic Variations not based upon Drug Metabolism
Altered structure and function of receptors, amount or affinity of plasma proteins, and glucose-6-phosphate dehydrogenase deficiency affect the response to drugs. G-6-P DH is the first enzyme in the PPP. The PPP is responsible for making NADPH, which reduces oxidized glutathione. Glutathione is oxidized when it reduces disulfide bonds formed in RBC membranes due to oxidizing agents and drugs. Disulfide bonds in RBC membranes weaken the membrane and induce lysis which can lead to an anemic state. Ex. Of drugs are sulfonamides, chloramphenical, and anti-malarials.
IV. Genetic Predisposition to Cancer
It is believed that certain types of cancers are related to drug metabolizing enzymes. The current thinking is two fold.
(1) Some enzymes rapidly metabolize chemical carcinogens to non-toxic or less toxic substances
(2) It is not the environmental chemical, but rather an activated metabolite formed by the enzyme that is actually the carcinogen
Excretion of Drugs
I. Sites of drug excretion
Kidney-the primary site
Rate of excretion from the kidney is dependent on three processes:
1. Filtration at the glomerulus 2. Secretory rate of drug from plasma to glomerular filtrate
2. Reabsorption rate from filtrate back to plasma
Other routes of excretion include feces, saliva, sweat, tears, milk, or lungs.
II. Renal excretion
A. Filtration
Plasma binding reduces filtration of a drug. Note: if a drug is filtered, and it is not secreted nor reabsorbed, it will have a renal clearance equal to the GFR (125-130ml/min).
B. Secretion
Secretion of drugs takes place primarily in the proximal convoluted tubule. Secretion is an active process mediated by non-specific transport systems for organic acids and bases. Because of non-specificity, different drugs may compete for secretion by the same transport system. Binding of drugs to plasma proteins does not affect secretion b/c transport systems have a higher affinity for the acids or bases.
C. Reabsorption
Reabsorption of drugs is primarily by passive diffusion. Reabsorption, like absorption, depends on lipid solubility, degree of ionization, and concentration gradient b/w urine and plasma.
1. The reabsorption of an ionizable drug can be altered by changing the urinary pH
2. The principles of ion trapping apply
III. Renal Clearance of Drugs
Definition: Clearance (ml/min) = (U) x (V) / (P)
Clearance is the ratio of the elimination of a substance to the concentration of the substance in plasma. Its numeric value is the same as the volume of plasma that will be cleared of the drug per unit time. Variations in renal function among patients is assessed by comparing creatinine clearance and can be used to determine drug dosage. Also, the value for renal clearance can give an idea of how the drug is cleared. IF it is 130 ml/min, then the drug is just filtered only (similar to inulin). If it is 650 ml/min, then it is filtered, secreted, but not reabsorbed (similar to PAH).
Receptor Structure and Function
I. Introduction
Most drugs produce their effects via interactions with specific receptors.
A. Definition of Receptor
Receptors are naturally occurring chemical sites on or within cells which interact with drugs and initiate the sequence of events leading to target cell response. Most receptors are proteins.
B. Receptor Sub-types
The physiological function of receptors is to mediate the responses of hormones, neurotransmitters, etc. In many cases, a single substance uses several receptors. Ex. Ach and nicotinic and muscarinic receptors
C. There is a quantitative relationship b/w receptor occupancy and pharmacological response.
D. Features of Receptors
1. Specific tissue distribution
2. Characterized pharmacologically; important for distinguishing b/w different receptor subtypes
3. Number and property of receptors may vary with disease states and physiological status. Also, receptors may exist in an active or desensitized state. Dynamic
4. Receptor-Drug interaction are normally reversible b/c involve non-covalent bonds
II. Receptors and Receptor Systems
The receptor site provides the specificity for recognizing and binding a particular agonist or antagonist.
Afterwards, the transduction of the signal resulting from the drug-receptor interaction occurs via conformational changes in proteins that interact with the receptor. Finally, amplification occurs via second messenger systems which have distal effects on protein kinases. Changes in any one of these components has significant effects on the pharmacological response to a drug and can affect the DR curve for that drug.
III. Drug Receptor Interactions and Pharmacological Responses
Simple Occupation Theory- there is a direct relationship between receptor occupancy and pharmacological response over the entire range of receptor occupancy.
A. Drug-Receptor Binding
Drug-Receptor interactions are governed by the law of mass action. Formation of the DR complex is second order and dissociation is first order.
Kd is a constant which is a measure of the affinity of the receptor for the drug.
Kd= [Drug] x [Receptor] / [Receptor-Drug]
A low value of Kd indicates high affinity which means it does not take much drug to occupy the receptor.
B. Drug Receptor Interactions and Biological Responses
Occupancy of a receptor by an agonist must activate the receptor to initiate a response. This activation step is distinct from binding. Common mechanism of receptor system for signal transduction and amplification:
1. opening/closing of ion channels
2. direct receptor mediated phophorylations
3. direct receptor mediated activation of gene transcription
4. second messenger pathways
Most of these changes are thought to occur as the result of conformational changes produced in the receptor upon drug binding.
C. Drug Agonists, Antagonists, and Partial Agonists
1. Agonist- drug can bind to the receptor and produce a full response at a high enough dose. Receptors may have differing affinities for agonists which is why drugs have different potencies, toxicities, selectivities, and thus different DR curves. Remember, other major factor determining potency besides affinity is the amount of drug reaching the receptor-dependent upon drug’s pharmacokinetic properties.
2. Antagonist
a. Competitive, reversible antagonist bind to the same receptor site as an agonist. The site can only occupy one at a time. The effect is to shift the DR curve of the agonist to the right. The effect of the antagonist can be overcome at sufficiently high doses of agonist.
b. Non-competitive, reversible antagonists bind to the receptor at a site distinct from the agonist binding site. This inactivates the receptor and thus reduces the maximum response obtained by an agonist no matter how high the dose of agonist, but the potency of the agonist remains the same.
c. Irreversible Antagonist- bind covalently to receptors to cause permanent inactivation.
d. Distal Effectors/Inhibitors- Increase or decrease the magnitude of response of a drug by interfering with pathway b/w receptor and final response w/o affecting potency.
3. Partial Agonist- Affinity may be less than, equal to, or greater than its affinity for a full agonist, but once bound it elicits a partial rather than a full response. When administered with a full agonist, it will blunt the effects of a full agonist.
Specific Receptor Systems
Be familiar with the specific receptors, their signal transduction pathways, and prototypical agonists and antagonists for adrenergic and cholinergic receptor types.
I. Cholinergic Receptors
A. Acetylcholine Has Multiple Effects
Ach will stimulate contraction in both skeletal muscle and smooth muscle and is dose dependent.
B. Effects of Muscarine and Nicotine
Muscarine cause intestinal smooth muscle contraction but not skeletal muscle contraction. Conversely, nicotine can cause contraction of skeletal muscle in doses that do not cause smooth muscle contraction. Therefore, there are two subtypes of cholinergic receptors: muscarinic and nicotinic receptors.
C. Effects of Atropine and Curare
Receptor subtypes can also be distinguished on the basis of actions of antagonists. Atropine blocks Ach at muscarinic sites only. Curare blocks Ach only at nicotinic sites. Hence, atropine is termed a selective muscarinic antagonists and curare is a selective nicotinic antagonist.
D. Structure-Activity Relationship of Cholinergic Receptors
Distinct sets of structure-activity relationships have indicated that the binding sites on the two receptor subtypes for Ach and its analogs are different, ie. One can use different structures to selectively activate or antagonize these two receptors even though both utilize the same endogenous substance.
E. Further Subclassification of Nicotinic and Muscarinic Receptor Subtypes
1. Nicotinic Receptor Subclassification
Curare is a more potent antagonist at the neuromuscular junction than at ganglionic sites. In contrast, hexamethonium is more potent at the ganglia. Thus, there at least two subtypes of nicotinic receptors. Ng occur in autonomic ganglia and Nm are the nicotinic receptors at the neuromuscular junction.
2. Muscarinic Receptor Subclassification
The use of other drugs like pirenzapine has revealed that multiple subtypes of muscarinic receptors exist.
At least 5 different muscarinic receptors have been identified, labeled m1-m5, using molecular cloning.
F. Summary of Pharmacological Agents which Interact Selectively with Cholinergic Receptors
1. Parasympathomimetics- agonists that interact with muscarinic receptors in end organs innervated by the ANS.
2. Atropine Like Blockers-competitive antagonists at muscarinic receptor sites.
3. Muscle Relaxants- drugs with curare-like actions that are competitive antagonists at nicotinic receptors at skeletal muscle.
4. Ganglionic Blockers- antagonists that exhibit some selectivity for Ach receptors at ganglionic sites.
5. ACE inhibitors- Ach is degraded by AchE at the post-junctional membrane. ACE inhibitors block the degradation of Ach and thus the effect is generally like that of an agonist.
G. Molecular Pharmacology of Cholinergic Receptors
1. Structure and Function of the Nicotinic Receptor- an example of a ligand-gated channel, allows Na+ to flow into target cell and cause depolarization.
2. Structure and Function of Muscarinic Receptor- Mechanism of signal transduction for these receptors:
(1)activation of phospholipase C which generates signals that elevate Ca++ levels (2) inhibition of adenylyl cyclase (3) in the heart, activation of K+ channel
II. Adrenergic Receptor Systems
A. Introduction
Adrenergic receptors mediate the actions of endogenous catecholamines. In the ANS, receptors are primarily post-synaptic. A number of different adrenergic receptors exist. Each subtype exhibits a given ability to be preferentially activated by naturally occurring and synthetic catecholamines.
B. Classification of Alpha and Beta Adrenergic Receptors
1. Differentiation of alpha and beta receptors
Done by Ahlquist in 1948 by measuring responses of different tissues to 5 distinct catecholamines. He ranked ordered the potency of the 5 drugs, and the rankings in each case exhibited one of only two patterns. Therefore he postulated there must be only two receptor types.
2. Subclassification of Beta Receptor Subtypes
15 different drugs were used in the same method of experiment as Ahlquist and two type of beta receptors were discovered.
3. Subclassification of Alpha Receptors
Alpha1- located post-junctionally and initiate excitatory post-synaptic events.
Alpha2- mainly pre-synaptic, activation inhibits the release of NE(negative feedback)
C. Molecular Mechanisms of Receptor and Drug Action
Three components that mediate the actions of drugs that interact with adrenergic and muscarinic receptors:
1. Receptor- binds the agonist or antagonist, then initiates drug action via interacting w/ transduction part
2. Transduction – both receptors utilize G proteins, active w/ bound GTP, intrinsic GTPase activity, several G-proteins exist: Gs stimulate and inc. activity, Gi inhibit or dec. activity of effectors
3. Effector System- Primarily the adenylyl cyclase and phospholipase C enzymes
Both types of Beta receptor subtypes 1 and 2 are linked to elevation in cAMP. CAMP activates Protein Kinase A and phophodiesterases dec. cAMP levels.
D. Alpha Receptors and Muscarinic Receptors
1. Alpha2 and M2 receptors have an inhibitory effect on cAMP levels via a Gi protein.
2. Alpha1 and M1 and M3 receptors stimulate phospholipase C activity which makes IP3 and DAG. IP3- release of Ca++ from intracellular stores. DAG-activates Protein Kinase C
III. Steroid Receptor Systems
A. Steroid Receptors
The activities of naturally occurring steroids and their synthetic analogs are mediated by a nuclear receptor system that activates transcription of specific genes. Once the receptor-hormone complex is formed, it interacts with specific regulatory sequences referred to as hormone responsive elements. The receptors also bind other regulatory proteins referred to as Co-Activators and Co-Repressors that can regulate transcription catalyzed by the RNA polymerase complex. These multiple interactions regulate transcription of the hormone regulated genes. Steroid receptor proteins have at least two domains: (1) a steroid binding domain (2) a DNA binding region.
Multiple receptors exist for a given class of steroid (estrogen, progesterone, glucocorticoid, etc.). There are two forms of estrogen and progesterone receptors. Estrogen receptors are distinct proteins coded for by distinct genes and are termed alpha and beta. They have differing tissue distribution and ligand binding affinities. Alpha is found primarily in the uterus while beta is found in the ovaries. The progesterone receptors arise from a single gene, but due to alternative translational start codons, two different forms termed A and B are made.
B. Effects of the Same Steroid on Different Tissues
The ratio of different forms of receptors for a steroid may vary in different tissues. In addition, different tissues appear to contain different complements of co-activators and co-repressors for a particular receptor, and these can selectively affect the manner in which different tissues respond to a steroid. Tissue selective steroids may be developed in the future. Benefits- hormone replacement therapy in postmenopausal women w/o side effects like breast cancer or endometrial hyperplasia.
C. The Same Tissue May Respond to Different Steroids
In these cases, the response is mediated by hormone specific receptors. There are also case where the transcription of a specific gene is regulated by more than one steroid. The transcription of the gene is regulated by distinct hormone responsive elements (ex. an estrogen HRE and a progesterone HRE).
D. Role of Metabolism in Steroid Hormone Action
Metabolism may be important in the action of two classes of steroid receptors, androgen and mineralcorticoid-glucocorticoid receptor system.
Many of the effects of Testosterone (T) are due to the metabolite, Dihydrotestosterone (DHT) formed by the enzyme 5 alpha-reductase. This metabolite has a higher affinity for the androgen receptor. Both glucocorticoids and mineralcorticoids bind well to the mineralcorticoid receptor, but mineralcorticoid target tissue contains an enzyme that degrades glucocorticoid so it cannot activate the mineralcorticoid receptor and produce an inappropriate response.
Integrated Responses of Target Cells- It is important to remember that the response of a tissue to a given drug, hormone, or neurotransmitter, can be quite different depending upon the status of the tissue, what other signals are impinging on it, what its pathological condition is, etc.
Pharmacokinetics
I. Introduction
Pharmacokinetics is the study of the magnitude of drug effects as a function of time. Plasma and tissue levels of drug are not exactly the same, but tissue levels and plasma levels of a drug vary in parallel. The ultimate goal of pharmacokinetics is to maintain plasma levels of drug in the proper therapeutic range, i.e., above the minimal effective concentration but below the toxic level.
II. General Approach
The approach will be to consider the development of dosing strategies in the following order:
(1) What loading dose of a drug must one give to initially obtain the desired plasma level of a drug?
(2) What maintenance dose of a drug must one give to maintain a desired plasma level of a drug?
If we administer drug at a maintenance dose rate equivalent to the elimination rate, the amount of drug in the body will remain constant.
Elimination Rate = Clearance x [Drug]plasma
Maintenance Dose Rate = Clearance x [Drug]plasma
(3) When you stop administration of a drug, how long does it take to be eliminated from the body?
Answer: We must ask how the conc. of drug in the plasma changes w/ time after drug administration is discontinued and drug is only being eliminated.
(4) In most cases we do not administer drugs by i.v. infusion, but rather by injections or tablets. How does one know the time table to administer these doses?
Answer: We must ask how long does it take for the concentration of drug in the plasma to decrease from desired plasma conc. to the minimum effective concentration.
(5) How does one determine the dose and time interval to use when administering discrete doses?
Answer: Select the plasma conc. of drug you think will be effective and use the clearance to calculate the maintenance dose rate.
(6.) How long will it take for the drug to reach the desired plasma conc.?
Answer: Depends on how fast the drug is eliminated. If elimination of a drug is first order, it takes 5 halve lives to reach the desired steady state level.
III. Calculation of the Initial Loading Dose
Assuming I.V. dosing and all drug reaches plasma:
Loading Dose(mass) = Vd(volume) x desired [Drug]plasma(mass/vol)
One can give a loading dose by any route of administration, but one must consider the bioavailability of the drug by the route of administration. If you give a dose orally, it has a bioavailability of .5 or 50% of the drug. In this case:
(Loading Dose)orally = (Vd x desired [Drug]plasma) / F
where F is the fractional bioavailability.
IV. Calculation of Maintenance Dose
Assuming I.V. dosing and all drug reaches plasma:
Maintenance Dose Rate(mass/time) = Clearance(vol/time) x desired[Drug]plasma(mass/vol)
If one administers the drug by another route, one must consider the bioavailability:
Maintenance Dose Rate= (Clearance x desired[Drug]plasma) / F
For example, say the maintenance dose rate is 1.25 mg/hr. One can give this dose by i.v. at this rate or a 10mg pill every 8 hrs. I.V. dosing will keep a constant drug plasma level while the tablet will cause peaks and troughs.
V. Kinetics of Drug Elimination
A. Background
First Order Elimination – a constant fraction of drug is eliminated per unit time.(ex. Renal filtration)
In a typical Michaelis-Menten Plot- the first order phase is where the rate of the rxn. is directly proportional to the substrate conc. and can be represented by the equation: Rate = k x substrate
Zero Order Elimination – a constant amount of drug is eliminated per unit time(ex. Renal secretion)
In a typical Michaelis-Menten Plot- the zero order phase is where the rate of the rxn. is constant and independent of the substrate concentration. There are two important differences from the first order range:
1. The amount of substrate metabolized is not proportional to substrate concentration, rather the amount of substrate metabolized is constant
2. The same absolute amount of substrate is metabolized per unit time.
When the drug conc. is low enough so elimination mechanisms are NOT saturated, drug elimination is first order. When they do become saturated, then drugs are eliminated by zero order.
B. Drug Elimination after a Single i.v. dose in a One Compartment Model
Scenario: Administration of a single dose of drug equilibrates rapidly b/w plasma and body tissues. Elimination of the drug follows first-order kinetics and thus a constant fraction of the drug will be eliminated form the plasma per unit time: Rate of Loss of Drug from Plasma = k x [Drug]plasma
Note:
1. A constant fraction of drug is eliminated each hour
2. The absolute amount of drug eliminated per unit time varies as the plasma drug level decreases
3. A plot of the log of the drug remaining in the plasma vs. time will be linear
4. The slope of a plot of the ln of drug remaining in the plasma vs. time will yield -k or the elimination rate constant
5. The elimination rate constant can be used to calculate the plasma decay curves for a drug. If you determine the concentration of a drug in the plasma at any given time and you know k, you can determine what the drug concentration will be at any subsequent time.
a) ln [drug]plasma = ln[drug]0 – (k x time)
b) log[drug]plasma = log[drug]0 – (k/2.303 x time)
C. Other Routes of Administration
If a single dose is administered by another route, a plot of the plasma concentration of drug vs. time will be bell shaped. This is due to the absorption phase which is not present after i.v. administration. Once the absorption phase is complete, points 1-3 above will be valid.
D. The Concept of Half-Life
The half-life of a drug is the time required for the plasma conc. to dec. by one half. As long as elimination remains first order, the half life of a drug will remain constant. A drug will almost be totally eliminated from the plasma within 5 half lives. This will be true for any dose of drug as long as elimination is first order. It is important to remember that the half life and the rate constant are inversely proportional.
t ½ = 0.69 / k
E. Single Dose Pharmacokinetics/Two Compartment Model
In most cases, i.v administration of a drug does not lead to a linear plot of log of drug in plasma vs. time but rather a bi-phasic curve. There is a rapid dec. in plasma conc. of drug referred to as the distribution phase followed by a linear decline in the log of drug in plasma vs. time known as the elimination phase.
For drugs which show both distribution and elimination phases, pharmacokinetic variables are obtained from the elimination portion of the curve.
F. Zero Order Elimination
If the mechanisms for eliminating a drug become saturated, then a fixed amount of drug is eliminated per unit time. Under these circumstances, the log of the drug in plasma will not decline in a linear fashion with time, and the half life for drug elimination will not be constant. This has several important consequences:
1. If amount of drug administered per unit time is greater than that which is eliminated, toxicity may occur
2. After administration is stopped, it may take longer than 5 half lives to eliminate most of the drug
VI. Kinetics of Drug Accumulation and Attainment of Steady State
A. Continuous Infusion
In practice, the only way to reach an absolutely invariant steady state level is via continuous drug infusion. The plasma conc. of drug will be directly proportional to the dose rate. With continuous infusion at any dose rate, steady state plasma levels will be reached in 5 half lives, as long as the drug exhibits first-order elimination.
B. Attainment of Steady State with Multiple Dosing
When a drug is administered in multiple doses, the plasma conc. will exhibit peaks and troughs, but as long as elimination is first order,, an average steady state plasma level will be reached in 5 half lives. If you need to measure a steady state blood level, wait 5 half lives before drawing a blood sample for analysis.
C. Factors Affecting Steady State Plasma Levels
The average steady-state drug conc. in plasma is given by the equation:
CPavg = [ (Dose Rate)(F)] / [(Clearance)(Dosing Interval)]
Or
CPavg = (1.44) (t ½) (F) (Dose)
(Vd) (Dosing Interval)
Note: If you dose on the half life, the amount of drug in the body will be 1.5 times the amount of a single dose if F=1, and CPavg = 1.5 x Dose/Vd.
D. Fluctuations in Plasma Levels
Except for continuous infusion of a drug at a constant rate, all other routes of administration will lead to peaks and troughs in plasma drug levels. There are three general patterns for different types of drugs after an avg. steady state level is reached:
Dosing Interval Much Longer than Half-Life- Considerable variation in peaks and troughs. Drugs are given this way when they have short half lives or significant toxicities.
Dosing Interval In the Range Of Half Life- Ratio of peak to troughs is close to 2:1.
Dosing Interval Much Shorter Than Half Life- Little difference b/w peak and trough
E. Effects of Varying Dose and Dosing Intervals(assuming first order elimination)
Changes In Dose w/ Constant Dosing Interval- Inc. or dec. the dose will raise or lower the plasma conc. accordingly, but will not change time to reach steady state nor variation b/w peaks and troughs
Changes In Dosing Interval w/ a Constant Dose- A higher plasma level will result and there will be less fluctuations in plasma levels. It will still require 5 half lives to reach steady state.
3. Decreasing Fluctuations in Plasma Levels by Dec. both Dose and Dosing Interval- Cpavg will remain unchanged, but the amount of fluctuation b/w peaks and troughs will be reduced. It still requires 5 half-lives to reach steady state
4. Loading Dose- can be used to rapidly reach the desired drug conc. in plasma, but be cautious when doing this via i.v. so to avoid toxicity.
F. Multiple Dosing Under Conditions of Zero Order Elimination
One cannot obtain a steady state plasma level unless the dose administered per unit time is exactly equal to the amount of drug per unit time. If a higher dose is administered, you will always get drug accumulation.
Liver Ý HDL, ß LDL, ß Cholesterol, Ý TG, Ý Free cholesterol, ß Lipoprotein A
Arterial Wall Ý relaxing capability
Estrogen
Heart Ý Coronary Blood Flow
Ý Arterial Pulsality Index ionotropic effects