Pharmacology (Chapt. 4)

jasmine's version from 2015-10-19 21:23


Question Answer
3 Major factors that determined drug distribution 1) Blood flow to tissues; 2) The ability of a drug to exit the vascular system; and 3) The ability of a drug to enter cells. Regional blood flow is rarely a limiting factor in drug distribution due to most tissues are well perfused; however, abscesses and tumors lack blood supple within
Most drugs do not produce effects where? Blood
Why is it important for drugs to leave the vascular system? So drug actions can occur and undergo metabolism and excretion; Drugs leave the blood at capillary beds
Blood Brain Barrier Refers to the unique anatomy of capillaries in the CNS; Only drugs that are lipid soluble or have a transport system can cross this to a significant degree due to tight junctions between the cells that compose the walls of most capillaries in the CNS;
P-Glycoprotein Included in pumping drugs out of cells, this pumps drugs back into the blood thereby limiting drug access to the brain
Albumin Most abundant protein in plasma; It always remains in the blood stream Drugs can bind to it, and it is reversible-hence drugs may be bound or unbound; It is too large to squeeze through pores in the capillary wall, and no transport system exists by which it might leave
Unbound Free Drug Molecules Can leave the vascular system
Bound Molecules Too large to fit through the pores in the capillary wall
Drugs can form... Reversible bonds with various proteins in the body that results in the ability to bind or unbind to some proteins such as albumin
An Important consequence of protein binding Restriction of drug distribution; Bond moles cannot read their sites of action, metabolism, or excretion
What can happen when drug molecules compete for binding sites? Albumin has only a few sites to which drug molecules can bind; Drugs with the ability to bind albumin will compete for those sites. As a result, one drug can displace another causing free concentration of the displaced drug to rise. Increasing levels of free drug can increase intensity of drug responses, creating a toxicity environment
Factors that determine the ability of a drug to cross cell membranes are the same for... the passage of drugs across all other membranes, namely lipid solubility, the presence of a transport system, or both; Some drugs must enter cells to reach their sites of action, and practically all drugs must enter cells to undergo metabolism and excretion
Many drugs produce their effects by Binding with receptors located on the external surface of the cell membrane; These drugs do not need to cross the cell membrane to act
Most drug metabolism that takes place in the liver is performed by what? The hepatic microsomal enzyme system, known as the P450 system, referring to cytochrome P450, a key component of this enzyme system
Cytochrome P450 A group of 12 closely related enzyme families. 3 Types are CYP1 (CYP1A2), CYP2 (CYP2D6), and CYP3 (CYP3A4) that metabolize drugs. The other 9 metabolize endogenous compounds (i.e., steroids, fatty acids)
6 possible consequences of therapeutic significance to drug metabolism 1) Accelerated renal excretion of drugs; 2) Drug inactivation; 3) Increased therapeutic action; 4) Activation of “prodrugs”; 5) Increased toxicity; and 6) Decreased toxicity
Most important consequence of drug metabolism Promotion of renal drug excretion
Renal Drug Excretion The kidney is unable to excrete drugs that are highly lipid soluble; Conversion of lipid-soluble drugs into more hydrophilic (water-soluble) forms takes place with metabolic conversion accelerating renal excretion of many agents
Prodrugs A compound that is pharmacologically inactive as administered and then undergoes conversion to its active form within the body
Factors that influence the rate drugs are metabolized Age, Induction of drug-metabolizing enzymes, first-pass effect, nutritional status, and competition between drugs
Age influencing drugs Liver does not develop to its full capacity to metabolize drugs until about 1 year after birth
Induction Process of stimulating enzyme synthesis
2 Therapeutic consequences for Induction By stimulating the liver to produce more drug-metabolizing enzymes, a drug can increase the rate of its own metabolism, thereby necessitating an increase in its dosage to maintain therapeutic effects. It also can accelerate the metabolism of other drugs used concurrently, necessitating an increase in their dosages
Remember If the capacity of the liver to metabolize a drug is extremely high, that drug can be completely inactivated on its first pass through the liver
Competition between drugs in metabolism When two drugs are metabolized by the same metabolic pathway, they may compete with each other for metabolism, and may thereby decrease the rate at which one or both agents are metabolized. If metabolism is depressed enough, a drug can accumulate to dangerous levels
3 Steps to renal drug excretion Glomerular Filtration, Passive Tubular Reabsorption, and Active Tubular Secretion
Glomerular Filtration Starting place; Moves drugs from the blood into the tubular urine; Protein-bound drugs and/or large drugs cannot do this such as drugs bound to albumin that remain behind in the blood
Passive Tubular Reabsorption Lipid-soluble drugs move back into the blood through concentration gradient. Polar and ionized drugs remain in the urine to be excreted; Conversion of lipid-soluble drugs into more polar forms reduces passive reabsorption of drugs and thereby accelerates their excretion
Active Tubular Secretion This has active transport systems that “pump” drugs from the blood to the tubular urine to be excreted
2 Types of Active Tubular Secretion Pumps One for organic acids and one for organic bases
Factors that modify renal drug excretion pH-Dependent Ionization; Competition for Active Tubular Transport; and Age
pH-Dependent Ionization Ions are not lipid soluble, drugs that are ionized at the pH of tubular urine will remain in the tubule to be excreted
Competition for Active Tubular Transport This can delay renal excretion, thereby prolonging effects
Age factor in Active Tubular Transport The kidneys in newborns are not fully developed until a few months after birth. Infants have a limited capacity to excrete drugs
Non-Renal Routes of Excretion Breast milk, bile, lungs, sweat and aliva
Breast Milk Excretion Lipid-soluble drugs have ready access to this, whereas drugs that are polar, ionized , or protein bound cannot enter n significant amounts
Bile Excretion This excretes into the small intestine and then leaves the body in the feces; In some cases, drugs entering the intestine in bile may undergo reabsorption back into the portal blood. This reabsorption, referred to as enterohepatic recirculation, can substantially prolong a drug’s sojourn in the body
Lund Excretion Major route by which volatile anesthetics are excreted
Sweat and Saliva Excretion Small amounts of drugs can appear in these, however these routes have little therapeutic or toxicologic significance
Time Course of Drug Responses Regulation of time at which rug responses start, the time they are most intense, and the time they cease---absorption, distribution, metabolism, and excretion---In most cases, this pertaining to drug action bears a direct relationship to the concentration of a drug in the blood
Important It is a practical impossibility to measure drug concentrations at sites of action; There is a direct correlation between therapeutic and toxic responses and the amount of drug present in plasma; therefore, plasma drug concentrations can be determined, as it is highly predictive of therapeutic and toxic responses
Dosing Objective Commonly spoken of in terms of achieving a specific plasma level of a drug; It is to maintain plasma drug levels within the therapeutic range
Narrow Therapeutic Range Drugs that are difficult to administer safely; More dangerous than drugs with the opposite range; Patients taking drugs in this range are more likely to require intervention for drug-related complications
Wide Therapeutic Range Drugs that are not difficult to administer safely; Less dangerous than drugs with the opposite range
What are 2 Plasma Drug Levels Minimum effective concentration and Toxic concentration
Minimum Effective Concentration (MEC) The plasma drug level below which therapeutic effects will not occur; To be of benefit, a drug must be present in concentrations at or about this
Toxic Concentration It occurs when plasma drug levels climb too high; The level at which effects begin is called this; Doses must be kept small enough so that this is not reached
Therapeutic Range A range of plasma drug levels, falling between the MEC and the toxic concentration. When is this, there is enough drug present to produce therapeutic responses yet not so much that toxicity results
What is or are most responsible for causing plasma drug levels to fall Metabolism and excretion, and these processes are the primary determinants of how long drug effects will persist
What is or are responsible for causing plasma drug levels to rise Absorption; responses cannot occur until plasma drug levels have reached the MEC; there is a latent period between drug administration and onset of effect, and the extent of this delay is determined by the rate of absorption
Half-Life No matter what the amount of drug in the body may be, half (50 percent) will leave during a specified period of time (what this is)
What does the actual amount of drug that is lost during one half-life depend on? How much drug is present; The more drug that is in the body, the larger the amount lost during one half-life
What does the half-life of drugs determine? The dosing intervals (i.e., how much time separates each dose); For example, for drugs with a short half-life, the dosing interval must be correspondingly short. Drugs with a long half-life, a long time can separate doses without loss of benefits; Morphine provides a good example: The half-life of morphine is approximately 3 hours. By definition, this means that body stores of morphine will decrease by 50 percent every 3 hours regardless of how much morphine is in the body. If there is 50 mg of morphine in the body, 25 mg (50 percent of 50 mg) will be lost in 3 hours, that is, during an interval of one half-life; However, the actual amount lost is larger when total body stores of the drug are higher
Factors that determine the rate and extent of accumulation The process by which plateau drug levels are achieved; time to plateau; Techniques for reducing fluctuations in drug levels, Loading doses versus maintenance of doses; and Decline from plateau
The process by which plateau drug levels are achieved Repeated doses will cause a drug to build up in the body until a steady level has been reached; If a second drug dose is administered before all of the prior dose has been eliminated, total body stores of that drug will be higher after the second dose than after the initial dose; As succeeding doses are administered, drug levels will climb even higher; the drug will continue to accumulate until a state has been achieved in which the amount of drug eliminated between doses equals the amount administered.
Plateau Drug Levels When the amount of drug eliminated between doses equals the dose administered, average drug levels will remain constant and this will have been reached
Example of Plateau Drug Levels Upon giving the first 2 g dose per day, total body stores go from zero to 2 g. Within one day, or one half-life, body stores drop by 50 percent, from 2 g to 1 g. Day two: the second 2 g dose is given, causing the body stores to rise from 1 g to 3 g., and body stores again drop by 50 percent, or half-life, from 3 g to 1.5 g. Next day, a third 2 g dose is given, causing the body stores to rise from 1.5 g to 3.5 g. to only again drop by 50 percent, the half-life from 3.5 g to 1.75 g. Once again next day dose give, and rises and drops its half-life. When body stores reach 4 g, body stores will simply alternate between 4 g and 2 g; average body stores will be stable, and plateau will have been reached.
Time to Plateau When a drug is administered repeatedly in the same dose, plateau will be reached in approximately four half-lives; As long as dosage remains constant, the time required to reach plateau is independent of dosage size; Put another way, the time required to reach plateau when giving repeated large doses of a particular drug is identical to the time required to reach plateau when giving repeated small doses of that same drug; The height of the plateau would be greater with large doses, however the time required to reach plateau would be the same
3 Techniques for reducing fluctuations in drug levels 1) Administering drugs by continuous infusion (plasma levels can be kept nearly constant); 2) Administer a depot preparation (releases the drug slowly and steadily); and 3) Reduce both the size of each dose and the dosing interval (keeping the total daily dose constant; i.e., 1 g doses every 12 hours instead of 2 g doses every 24 hours-the result would be total daily dose remaining unchanged, as would total body stores at plateau)
Peak Concentration As when a drug is administered repeatedly, its level will fluctuate between doses. The highest level is referred to as this, and must be kept below toxic concentration
Trough Concentration As when a drug is administered repeatedly, its level will fluctuate between doses. The lowest level is referred to as this, and must be kept above MEC
Loading Doses For drugs whose half-lives are long, achieving a plateau could take days or even weeks; When plateau must be in equivalent more quickly, a large initial dose can be administered. This large initial dose is called this. After high drug levels have been established with this, plateau can be maintained by giving smaller doses
Maintenance Doses Smaller doses that maintain the plateau after it has been established by an initial large dose
Remember When a loading dose is administered followed by maintenance doses, the loading dose does not reach plateau. Rather, the loading dose rapidly produce a drug level equivalent to the plateau level for a smaller dose.
Decline from Plateau When drug administration is discontinued, most (approximately 94 percent) of the drug in the body will be eliminated over an interval equal to about four half-lives
Important to Note The concept of half-life does not apply to the elimination of all drugs; A few agents, most notably ethanol (alcohol), leave the body at a constant rate, regardless of how much is present