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108 Cards in this Set
- Front
- Back
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Pharmacology
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study of substances that interact with living systems through chemical processes
beneficial or toxic effects |
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Medical Pharmacology
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science of substances used to prevent, diagnose, and treat disease
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Toxicology
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deals with undesirable effects of chemicals on living systems
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Pharmacodynamics
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Affected by individual differences in enzyme activity and genetic differences.
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Name 3 classifications of receptors
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Agonist
Antagonist Agonist/antagonist |
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What specific molecule does a drug molecules interact with?
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receptor
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What does an Agonist do?
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bind and activate the receptor in some fashion which directly or indirectly brings about the effect.
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What does an Antagonist do?
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binds to a receptor to prevent binding by other molecules; don’t activate receptors.
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What does an Agonist/antagonist do?
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bind to receptors and activate them but do not evoke as great a response as a ‘full’ agonist.
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Competitive antagonism
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Increasing concentrations of antagonist progressively inhibit response to stable concentrations of agonist
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Noncompetitive antagonism
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Even high concentrations of agonist cannot overcome the antagonism
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What is competitive antagonism?
give example (talking point) |
Once occupied by a receptor, an antagonist that can be overcome by increased concentration of agonist is competetive antagonism. Nondepolarizing muscle relaxants occupy acetylcholine receptors at the neuromuscular junction blocking the effect of acetylcholine at that receptor. The effects of the nondepolarizers can be overcome by increasing the number of acetylcholine molecules at the receptor.
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When does Noncompetetive antagonism occur?
(talking point) |
Noncompetetive antagonism occurs when increasing or high concentrations of an agonist cannot overcome or compete with the antagonist.
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What impacts duration of action?
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Depends on how long the receptor is activated
(Effect lasts only as long as the drug occupies the receptor) If covalent bond has occurred, effect may persist until the drug-receptor complex is destroyed and new receptors or enzymes are synthesized covalent bonding is strongest |
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What type of movement occurs during aqueous diffusion?
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driven by the concentration gradient of the permeation drug
a down hill movement |
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Fick's Law of Diffusion
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Flux (molecules per unit time)=
(C1-C2)x (Area x Permeability C) / thickness |
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Describe C1 and C2 related to diffusion and Fick's Law
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C1 is the higher concentration, C2 is the lower concentration, area is the area across which diffusion is occurring, permeability coefficient is a measure of the mobility of the drug molecules in the medium of the diffusion path, and thickness is the length of the diffusion path. In the case of lipid diffusion, the lipid:aqueous partition coefficient is a major determinant of mobility of the drug, b/c it determines how readily the drug enters the lipid membrane from the aqueous medium.
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What do lipids do to a drug?
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Make it more permiable
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What are the 3 barriers?
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Blood Brain
Placenta ?????? |
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What is the most limiting factor for drug permiation?
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Lipid Diffusion,
because of the large number of lipid barriers that separate the compartments of the body In the case of weak acids and weak bases, the ability to move from aqueous to lipid or vice versa varies with the pH of the medium, because charged molecules attract water molecules pKa-pH |
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by using (Henderson-Hasselbalch equation) how does pH relate to pKa regarding drug availability?
(talking note) |
This equation applies to both acidic and basic drugs. 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.
Weak acids are usually excreted faster in alkaline urine; weak bases are usually excreted faster in acidic urine. |
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A more basic drug will be in the lipid soluble form in at what pH?
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alkaline pH
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complete the sentence
The lower the pH relative to the pKa..... |
the greater will be the fraction of drug in the pronated form
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The uncharged form is
__________ lipid soluble |
more
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a weak acid will be in the soluble form at what pH?
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Acid pH
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Weak acids are usually excreted faster in
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alkaline urine
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Weak bases are usually excreted faster in
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less acidic urine
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Name 3 ways to carry products
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Special Carriers
Endocytosis Exocytosis |
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Special carriers
Exist for certain substances that are important for cell function and too large or too insoluble in lipid to diffuse passively through membranes, eg, peptides, amino acids, glucose These carriers bring about movement by active transport or facilitated diffusion and unlike passive diffusion, are saturable and inhibitable |
Exist for certain substances that are important for cell function and too large or too insoluble in lipid to diffuse passively through membranes, eg, peptides, amino acids, glucose
These carriers bring about movement by active transport or facilitated diffusion and and are Saturatable Inhabitable (unlike passive diffusion) |
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What substances must be moved by special carriers?
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peptides
amino acids glucose |
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Endocytosis
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A few substances are so large that they can enter cells only by endocytosis, the process by which the substance is engulfed by the cell membrane and carried into the cell by pinching off the newly formed vesicle inside the membrane. The substance inside can then be released inside the cell by breakdown of the vesicle membrane.
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Exocytosis
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responsible for secretion of many substances from cells.
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Do not give asthmatics
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Beta 2 blockers
or a combined Beta 1 Beta 2 |
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A drug exerts biological effects on a system through a________?
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receptor
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The more selective a drug is for a receptor results in what?
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fewer side effects
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Give examples of receptors
(specific) in the body |
alpha
beta 1 beta 2 dopamine histamine mu. |
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What is a receptor?
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biological macromolecule through which a drug exerts its effect
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What is a Ligand?
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a molecule that binds to a receptor
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What do receptors have?
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Have structural features that complimentary to the molecules that bind to them
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The strength of the interaction between a receptor and its ligand is?
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affinity
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increased affinity for a receptor means
what regarding pharmacological active-ness? |
increased pharmacological activity
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Pharmacokinetics
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Absorption, distribution, metabolism, and excretion of drugs
-What the body does to the drug Determines the concentration of drug at its sites of action (receptors) and the intensity of the drug’s effects with time and variability of drug response |
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What are Pharmacokinetics affected by ?
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Pharmacokinetics are affected by individual differences in
renal function liver function cardiac function patient age. |
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What determines the variability in drug responses between patients?
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Pharmacokinetics
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Pharmacokinetics invole
(See slide 15) |
Absorbtion
Distribution Elimination |
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Pharmacodynamics involve
(see slide 15) |
Pharmacologic Effect
Clinical Response toxicity & efficacy (toxicity not directly rt clinical response- arrow bypasses) |
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Describe Up regulation
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An antagonists may increase the number of receptors
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Describe Down regulation
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Ligand (over hours to days) induces a decrease in # of receptors
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Give a clinical example of down regulation
talking note |
beta-adrenergic receptors are chronically stimulated
in chronic Asthma treatment drugs (beta agonists) |
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Give a clinical example of up regulation
talking note |
When beta receptors are chronically blocked,
The increased number of receptors can result in an exaggerated response if the blockade is discontinued. (exaggerated hypertension resulting from discontinuation of a patient’s beta-blockade therapy) |
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Give reasons for variation in drug response
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-Age,sex,body size,disease states,genetic factors
-Simultaneous administration of other drugs -Up-regulation -Down-regulation (Ligand (over hours to days) induces a decrease in number of receptors) -Desensitization (Ligand induces a decrease in coupler efficiency) -Changes in the functional integrity of biochemical processes (e.g., post-receptor processes) -Lack of total selectivity -Bell curve -always assess risks vs benefits (careful monitoring for over extension of pharmacological effects) |
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Name 8 drug responses
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Hyperreactive
Hypersensitive Hyporeactive Tolerance Tachyphylaxis Cellular Tolerance |
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Hyperreactive
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Expected result produced by very low dose
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Hypersensitive
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Allergy or sensitivity to drug
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Hyporeactive
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Result achieved only by extremely large doses
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Tolerance
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Hyporeactivity acquired through chronic exposure to drugs
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Tachphylaxis
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Acute tolerance acquired with a few doses of the drug
OB med Marcane Epherine |
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Cellular Tolerance
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Neuronal adaptation that is integral in developing tolerance
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Additive Effect
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1+1=2
A second drug acting with first drug produces an effect equal to the sum of the drugs |
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Synergistic Effect
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1+1=3
Two drugs produce a greater effect than their summation e.g. CNS depressants (fentanyl + midazolam) |
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Give an example of the Synergistic Effect
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A synergistic effect is seen when aminoglycoside antiobiotics and nondepolarizing neuromuscular drugs are given together. The resulting NM blockade produced is greater than the added effect of each drug. (despite the inability of aminoglycoside antibiotics to produce clinically significant NMB when administered alone.
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Reality of Pharmacokinetics usually "defined" pertaining to what group?
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healthy adults w/ low fat-to-lean body ratio
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What may alter the pharmacokinetics vs the awake state?
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General anesthesia & surgery
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What tends to affect pharmacokinetics? What population will we give these drugs to?
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Changes in renal & hepatic blood flow & enzyme activity; patients w/ co-morbidities at extremes of age (maintenance dose should be adjusted downward to prevent drug accumulation.)
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What are the two basic parameters of PK?
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Clearance (Measure of body’s ability to eliminate drug)
Volume of distribution (Measure of the apparent space in body available to contain drug, apparent space) |
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What is volume of distribution?
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ratio of amount of drug in body to the concentration (C) of drug in blood or plasma
Vd = Amount of drug in body/concentration |
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Explain the volume of distribution of the central compartment. (Vdcc)
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the volume drug occupies immediately after an IV bolus before any tissue distribution or elimination occurs (usually similar to plasma volume)
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Explain the volume the drug occupies at steady-state. (Vdss)
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When the amount of drug input into body equals drug lost from body
Free drug concentrations are equalized over all body compartments (long-term IV infusion) |
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Name the three properties that will determine how much of the drug will pass from plasma into the tissues after IV administration.
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1) Capacity to bind to plasma proteins
2) Degree of ionization 3) Lipid solubility |
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The degree of ionization is key in pharmacokinetics of a drug w/ respect to what factors?
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pharmacologic activity, solubility in lipids, transfer out of the central compartment, & clearance from the central compartment.
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What constant determines the degree of ionization of the drug?
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Pka of a drug
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What factor predicts the rate of elimination in relation to drug concentration?
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Clearance (CL)
CL = Rate of Elimination / concentration thus rate of elimination = CL x C |
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What are the two major sites clearance occurs?
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Kidney & liver
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What is AUC?
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Area under the curve is the common measure of extent of bioavailability for drug by a given route.
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What does Capacity-limited elimination mean?
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-Clearance has no real meaning for these drugs & AUC is not used to describe their elimination (Ethanol, phenytoin, ASA)
-Clearance depends on the concentration of the drug that is achieved |
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What is Flow-dependent elimination?
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Readily cleared by organ of elimination by first pass – “highly extracted”
-Rate of delivery (blood flow to organ) determines elimination -Plasma protein binding & blood cell partitioning may be factors as well |
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For first-order kinetics, metabolic transformation catalyzed by what?
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Enzymes
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The rate of drug metabolism is directly proportional to what?
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concentration of free drug
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What is metabolized over time pertaining to first-order kinetics?
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constant fraction of a drug
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Zero-order kinetics dealing w/ drugs states what?
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the drugs will metabolize at a constant rate
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What are three examples of zero-order kinetic drugs?
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-ASA
-ethanol -phenytoin |
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What does first-pass elimination refer to?
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the extensive metabolism of a drug before reaching the systemic circulation & exerting its pharmacologic effects
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What drug route is absorbed from GI tract, enters portal venous blood & then passes through the liver before entering systemic circulation? What is this referred as?
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Oral; First-pass hepatic effect
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Portal blood delivers drug to what organ & what occurs here? End result of this?
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Liver (Metabolism occurs here & can excrete drug into bile)
Drug is delivered into systemic circulation |
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Where are the enzymes responsible for metabolism of many drugs located? (Be specific)
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hepatic smooth endoplasmic reticulum (microsomal enzymes) in the Liver
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What is believed to be responsible for metabolism of many drugs in the liver?
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Cytochrome P-450 system
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What are some distinguishing factors of the enzyme Cytochrome P-450?
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-Activity most likely genetic, accounting for large variation of individuals
-May be induced, increasing their activity & subsequently accelerating the rate of metabolism & clearance of some drugs |
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Which drug classically causes induction of the hepatic microsomal enzymes?
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phenobarbital
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First-pass pulmonary effect of drugs refers to uptake of what?
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basic lipophilic amines by the lung. (lidocaine, propranolol, fentanyl)
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What may influence the peak arterial concentration of certain drugs?
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First-pass pulmonary effect
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How else do lungs effect certain drugs?
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may also serve as a reservoir from which the drug is released back into the systemic circulation
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What phase pertains to changes in functional groups in drug molecule(Oxidation, Hydroxylation, De-methylation)
& sometimes may yield an active metabolite (diazepam)? |
Phase I Metabolism
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Which phase involves conjugation reactions,addition of glucuronic acid, sulfonic acid, or acetylation & larger molecular weight w/ more polar & inactive molecules (metabolites eliminated by kidney or biliary excretion)
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Phase II Metabolism
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What is the effect of first-pass hepatic elimination on bioavailability?
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Extraction Ratio (ER)
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ER = (CLliver / Q) refers to what?
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rate of elimination in relation to drug concentration [Q is hepatic blood flow (hepatic artery & portal vein)]
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What does organ clearance depend on? What do ER of 0 & 1 indicate?
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Organ perfusion; 0 = no drug clearance & 1 = entire drug is removed during one pass through the organ
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What happens If hepatic blood flow is increased?
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the ER is decreased & hepatic uptake is reduced.
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What can effect liver perfusion?
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changes in cardiac output or chronic hepatic cirrhosis
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Since only the unbound drug in plasma can be taken up into hepatocytes, what will reduce the hepatic uptake of drugs?
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Plasma protein binding & RBC binding
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What effects plasma protein binding?
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chronic renal/hepatic disease or concurrent meds
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The extent of absorption is decreased in oral routes D/T what? (limited bioavability)
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Increased hydrophilic (does not cross lipid cell membrane) & increased lipophilic (not soluble enough to cross water layer adjacent to cell) factors
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What determine the absorption rate & the clinical effectiveness of a drug?
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Determined by site of administration (IV, Inhale, IM, SC, Oral) & by drug formulation
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What part does Biliary play in excretion of drugs?
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Removes drugs & metabolites from liver into bile
Bile then released into GI tract (duodenum) & drug excreted by feces Some absorption in GI tract |
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What drug inhibits GI absorption?
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Activated Charcoal
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What part does Renal play in excretion of drugs?
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Glomerular filtration (passive filtration removes unbound drug from plasma – GFR is a key)
Tubular secretion (active transport of acid & basic drugs) Tubular reabsorption (passive or active uptake of drug from urine into plasma) |
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Time to recovery is dependent on multiple factors BUT in general, if the plasma concentration of a drug given is just above that required for awakening, recovery time would be greater or less?
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less
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What does the BIS monitor allow?
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estimation of the depth of anesthesia obtained w/ a given plasma concentration of drug for a given patient
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What is the advantage of the BIS monitor?
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The patient may be maintained at a plasma concentration just greater than that required for awakening
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