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Don Pharm Lecture

SIUE-Don's pharm lecture #1

The study of substances that interact with living systems through chemical processes. Pharmacology. Used to prevent, diagnose, and treat disease.
What are the two areas of study in Pharmacology? Pharmacodynamics and Pharmacokinetics.
Pharmacodynamics Study of the biochemical and physiological effects of drugs.
What area of study in pharmacology explores what a drug does to the body? Pharmacodynamics. Ex. Beta blocker Esmolol-slows down heart rate.
Pharmacokinetics The study of the time course of substances and their relationship with an organism or system.
What area of study in pharmacology explores what the body does do a drug? Pharmacokinetics
What are the two categories of pharmacokinetics? Absorption and Disposition- distribution, metabolism and elimination.
This describes the amount of drug which gets into the system (bloodstream) following administration. Absorption
Describe the nature of drugs A substance that causes a change in biological function through chemical rxns. Usually deals with specific chemicals interacting w specific molecules(receptor molecule or target tissue).May also deal w rxns bt other drugs, interactions w water molecules.
What qualities must a drug posses for interaction w molecules to occur? Size, shape, electrical charge, atmoic composition, ability to reach site of action, ability to be inactivated over a reasonable time period.
When referring to drug size, what unit of measurement are we talking about? Molecular weight. Mass of one molecule of that substance.
Most drugs have the molecular weight between what two numbers? 100-1000
Why do we not care if t-PA has a molecular weight of 59,050? Because we are giving it IV and want it to act intravascularly. We do not care that it cannot cross membranes bc of it's MW because the site of action is where it is given.
How does drug size affect the action of the drug? Smaller MW usually is less selective meaning it can effect many tissues or organs (atropine). Larger MW decreases diffusion across membranes.
What is the first step in the principle of pharmacokinetics? The drug must be able to reach it's target tissue. Direct application-topical ointment, IV administration (t-PA).
What are the other principles of pharmacokinetics? Absorption and disposition (distribution, metabolism, and elimination)
What is required of a drug unless it is delivered directly to its target tissue? Permeation. 4 primary mechanisms. Aqueous diffusion, lipid diffusion, special carriers, and endocytosis & exocytosis.
What is Fick's Law of Diffusion and what is it explaining? (C1-C2)X(A X Perm. Coeff)/thickness. The greater concentration on one side the more will cross over. Thicker membrane it will take longer to cross.
Usually driven by a concentration gradient across epithelial and endothelial lining. If drug is charged; also influenced by electrical fields. Aqueous diffusion.
Aqueous Diffusion Usually driven by a concentration gradient. Across epithelial and endothelial lining. If drug is charged; also influenced by electrical fields.
What is the most limiting permeating factor? Lipid barriers. Large number of lipid barriers in the body.
What determines movement across membranes? Lipid:aqueous partition coefficient. Involved the henderson-hasselbalch equation(lipid soluble vs. water soluble form of a drug).
A drug molecule gains or loses electrons depending on what? pH
How does the pH of a medium affect a drug? The pH of a medium affects ability to move bt aqueous and lipid areas.
What type of molecule attracts water? A charged molecule
Is water charged or uncharged? Charged
Acids want to give up what? H+ ions
Bases want to take on what? H+ ions
Chemical equilibrium is achieved through? Reversible reactions-closed system? If not closed system have to take into account the surrounding medium.
Dynamic equilibrium Closed system. Reaction is continuously happening but with the same results ratio(ex. 1:5 ionized to unionized) Position of equilibrium.
What happens when a drug expires? There is no longer dynamic equilibrium. Changes the action of the drug and becomes unstable. May be more or less effective. Have no way of knowing unless drug is taken.
Henderson-Hasselbalch Equation Electrostatic charge of ionized molecule attracts water dipoles. Creates polar, water soluble complex(lipid insoluble). Ionized drugs decreases ability to cross lipid soluble membrane. pH affects proton action-ion trapping.
What happens when electrostatic charge of ionized molecules attracts water dipoles? Creates polar, water soluble complex. Lipid insoluble.
What decreases the ability of a drug to cross a lipid soluble membrane? When a drug is ionized.
Weak acid A neutral molecule that can dissociate up H+. Anion=negatively charged molecule, or proton=H+ ion.
Weak base Neutral molecule that can form a cation. Positively charged molecule + free proton.
When a weak acid is in its neutral form is it protonated or unprotonated? Protonated- it has H+ attached. Neutral means it is not an ion.
A weak acid that is protonated is unionized and lipid soluble.
When a weak base is in its neutral form is it protonated or unprotonated? Unprotonated- it does not have H+ attached. Neutral mean it is unionized and lipid soluble.
If a weak acid is 70% protonated how much crosses BBB? 70% crosses BBB.
Weak acid C8H7O2COOH is what form? Neutral (unionized)(protonated)(lipid soluble)
Weak acid C8H7O2COO- + H+ is what form? Ionized (unprotonated)(not lipid soluble)
Weak base C12H11CIN3NH2 is what form? Neutral (unionized)(unprotonated)(lipid soluble)
Weak base C112H11CIN3NH3+ is what form? Positive (ionized)(protonated)(not lipid soluble)
What is to be known first about a drug to determine ionization in a particular medium? If it is a weak acid or weak base.
What are the general rules of weak bases? 1)Nitrogen with 3 groups (NH3).2)Negative ions (except Cl-,Br-,HSO4- sulfate, and H2PO4- phosphate).3)Hydroxide OH (remember bases attract H+ ions)
Weak Acid general rules 1)Begin w H. 2)Most positive ions (cation). 3)COOH at end (carboxyl groups in acids).4)Nitrogen with 4 groups (NH4+) ammonium.5)Gives up H+ easily.
Acid environment Low pH, excess protons, rxns favor movement to the left.
Alkaline environment High pH, favor movement to the right.
Weak acids excreted faster through what type of urine? Alkaline urine
Weak bases excreted faster in what type of urine? Acidic urine.
Most bases are what type of molecules? Amine containing molecules. Timethylamine (CH3)3N, contain nitrogen. Nitrogen usually associated w 3 atoms + unshared pair of electrons. The 3 atoms may vary but contain carbon & hydrogen.
Weak bases that have a quaternary amine has what property? It is permanently charged. Water soluble=not lipid soluble.
Quaternary amines The first 3 can reversibly bind to proton-(more lipid soluble or less) Unshared pair of electrons, protonated or unprotonated. Unprotonated weak base=lipid soluble. This action is dependent on pH.
Special carriers are needed when? Drugs are large or lipid insoluble. Ex. peptides, amino acids, glucose. Some drugs may resemble these drugs and use special carriers.
This process is saturable and can also be inhibited? Active transport or facilitated diffusion.
An example of endocytosis in which a drug gets engulfed by a cell is... Iron and Vit B. B12 needs intrisic factor to get absorbed. Iron needs transferrin.
An example of exocytosis.... Neurotransmitters. This protects them from cytoplasm metabolism.
What are the three major interaction or bonds between drugs/receptors? Covalent, electrostatic, and hydrophobic.
Covalent bonds Strong bonds, not readily broken, may last after free drug has been cleared. ex. DNA alkylating agents used in chemotherapy.
Electrostatic bonds More common than covalent, ionic molecules w hydrogen bonds, weak dipole interactions (van der waals forces)
Van der Waals forces Intermolecular forces related to polarization of molecules into dipoles. Non-uniform distributions of positive and negative charges on the various atoms.
Hydrophobic bonds Weak bonds, bt lipid soluble drugs and lipids of cell membranes, generally more selective, also short acting.
What can permit binding to a site? Drug shape. Chirality (asymmetry)-sterioisomerism, enantiomers. May have two different receptor sites; however, one enantiomer may be 100X more potent.
How can enzymes by steroselective? They can break down one isomer of a drug but not the other isomer.
Mimics action of another drug/chemical? Agonist
Agonist can mimic the action of another drug/chemical by.. bind to a receptor, activate receptor (may be direct or indirect).
Example of indirect and direct action of agonist. Indirect- activating coupling molecules that enhances the release or action of another molecule that has the direct effect. Direct- opening ion channels.
Agonist that inhibit. Mimics the action of a drug. Blocks actions of molecules responsible for terminating the action of an endogenous agonist agent.
Partial agonist Evoke a lesser response at receptor sites.
The ability to bind to a receptor Affinity. The higher the affinity constant, the lower the drug concentration needed to produce desired response.
Affinity constant Drug/receptor concentration that produces 50% occupancy of receptors.
Efficacy The ability to achieve a response. The capacity of agonist to produce affect.
Antagonist Bind to receptor-prevents binding of other molecules. Reduce the effects of other molecules on the body. Have affinity for a receptor but no efficacy. Competitive or noncompetitive.
Antagonist/Competitive Two molecules with similar structure but different actions. Compete for same receptor site. One causes an action and the other causes no action. Agonist vs. antagonist.
Is it possible to reach the desired effect by increasing the concentration of either the competitive antagonist or the drug being competed with at the receptor site? Yes it is possible.
Propranolol An example of competitive antagonist. B adrenoceptor antagonist. Blocks basal norephinephrine. Exercise or stress increases release of norephinephrine and overcomes propranolol= increased HR
Antagonist/non-competitive Two different molecules bind to different receptor sites on the same effector molecule- there is no competition. One activates and the other inhibits.
What is a distinguishing feature of a non-competitive antagonist? It is non-surmountable: you can't change the action by increasing concentration of agonist.
This type on antagonist can be ineffective if the other molecule/drug's concentration is increased. Competitive antagonist
What happens with drug antagonism? Give an example. One drug binds to another drug causing it to become inactive. Protamine=cations at physiologic pH. Heparin=anion at physiologic pH. Bind together making heparin unavailable for interactions.
The duration of a drugs effect is terminated when? When the drug leaves the receptor.
If a drugs effect is not terminated when the drug leaves the receptor what could be the cause of its persisting effect? Activation may persist after drug dissociation if coupling of molecules is present.
What type of bond is associated with a long lasting drug effect? Covalent Bond. It lasts until complex is destroyed and new receptors synthesized.
What mechanism prevents excessive activation? Desensitization- inactivation of ion channel. Receptor changes shape to agonist and it becomes less effective.
Receptors can do what? They can be selective in choosing ligands (drug molecules)-more specific receptor. They can alter function after binding w drug molecules (regulatory).
What are binding sites? Can you give an example? Molecules within the body in which bind to drugs, but are not receptors. Ex. Plasma albumin
Two types of changes in which receptors are capable of? Down regulation and internalization
Down regulation of receptors Desensitization, agonist induced, decrease in number of receptors.
Internalization of receptors Taken into cell from plasma membrane. Some are degraded by lysosomes. Some are returned to membrane unchanged.
What are the three general mechanisms of desensitization Receptor phosphorylation, receptor internalization or sequestration, receptor downregulation.
This type of desensitization is agonist dependent correlated with respect to time and dose. Receptor phosphyorylation. Leads to decreased affinity of receptors and attenuated receptor function.
An example of receptor phosphorylation Phosphorylation by g-protein coupled receptor kinases increases the affinity of receptor binding to a arrestin molecule. Prevents further signal transduction.
Internalization or sequestration Temperature sensitive. Results in reversible sequestration of receptors into an intracellular membrane. Either recycle to the cell surface of enter the endolysosomal pathway and eventually be degraded.
During internalization or sequestration when the receptor goes into the intracellular membrane, what is significant of this? The density inside the cell membrane is lower than the plasma membranes. The intracellular membrane is also inaccessible to some hydrophillic antagonist.
What type of desensitization is a steady state level of receptor protein decreasing? Receptor downregulation (slow phase). Another name is homologous receptor downregulation.
Is it possible for one drug to only cause on effect? NO! Only in theory.
Therapeutic vs toxic is determined by... Dose, clearance, pH, binding (# target receptors & inert sites), depends on what action you are expecting.
Volume of distrubution The measure of the apparent space in the body available to contain a drug. VD= total amount of drug in the body/drug blood concentration
Refers to the extent of a drug's extravascular distribution at equillibrium. Volume of distribution. Hypothetical volume- quantity of drug if its concentration in the entire volume were the same as that in the plasma.
Volume of distribution is a constant relationship between the amount of drug in the body and... The plasma concentration at equilibrium.
The volume of distribution is dependent on what? The size of the patient. Closely correspond to body weight (sometimes ideal body weight) not to body surface area.
What type of Vd occurs when there are high concentrations in the plasma? Low Vd. Low lipid solubility and extensive binding to plasma proteins.
What type of Vd occurs when there are low concentration in the plasma? High Vd. High lipid solubility and little binding to plasma proteins.
What measures the ability of the body to eliminate a drug? Clearance. Rate of elimination/concentration
Does pharmacological effect parallel plasma levels? No. Two compartment model
Renal and hepatic elimination are dependent of? Central circulation. Two compartment model- also states that a drug must return back from peripheral circulation.
Half-life (t1/2) time required to decrease the amount of drug in body by 1/2 during elimination.
Half-time time necessary for the plasma concentration of a drug to decrease to 50% during the elimination phase.
Half-time is directly proportional to __ and inversely proportional to __? Directly to Vd and inversely to clearance.
5 half times = __% elimination? 96% elimination
First order kinetics (clearance) Administered drugs are cleased from the circulation at a rate proportional to the amount present in plasma. Same percent every time.
Zero order kinetics Clearance of drugs that exceeds metabolic or excretory capacity of the body. A constant amount cleared regardless of concentration.
What is "context sensitive" halftimes in which is pertinent to anesthesia? The length of time required for the drug plasma concentration to fall 50% after continuous infusion.
Elimination is done by which organs? Kidney, liver, lungs, blood, muscle.
Liver regarding clearance First pass metabolism. Portal blood, PO meds.
Hepatic clearance has two ways of elimination, what are they? Capacity dependent elimination-low hepatic extraction ratio <0.3. Relies on enzymes % other methods. Perfusion dependent elimination-high hepatic extraction ratio >0.7 dependent on hepatic blood flow.
What happens through biliary excretion? Liver breaks down drug. Metabolites excreted in bile into GI tract. Then metabolites are reabsorbed and eliminated in urine
In what type of clearance are ionized drugs excreted more efficiently? Renal clearance because they can't be reabsorbed. Elimination capabilities=serum creatinine levels.
What are the three process of renal clearance? Glomerular filtration, active tubular secretion, passive tubular reabsorption.
What are some factors in which effect renal clearance? Glomerular filtration rate, protein binding, ionized metabolites, urine pH- weak acids excreted more rapidly in alkaline urine.
Drug metabolism characterists The same characteristics that allow a drug to reach a target tissue easily also inhibit excretion.
Lipophilic drug properties Lipophilic drug is easily reabsorbed through renal tubular membranes.
Hydrophilic molecules are required for elimination from the body because why? They are more polar inactive molecules and are readily excreted.
Biotransformation is also called? Metabolism
What does biotransformaion produce? Produces more polar, hydrophilic, biologically inactive molecules. Sometimes metabolites retain biological activity.
What could potentially happen when an inactive metabolite retains some of its biological activity? It may become toxic.
What are the four basic pathways of metabolism? Which belong to Phase I and Phase II? Oxidation, reduction, hydrolysis, conjugation. Phase I- oxidation, reduction, hydrolysis. Phase II-conjugation.
In what phase in which drugs are transformed do they lose pharmacological activity? Phase I
What type of drugs are converted to phase I reactions to biologically active metabolites? Prodrugs. An example is anzimet-once metabolized it becomes zofran.
In phase I reactions how do drugs lose their pharmacological activity? Their functional group are introduced or exposed to (-OH, -NH2, -SH)-makes more water soluble or allows to enter phase II.
What are phase I enzymes? Cytochrome P-450, noncytochrome P-450, flavin containing monooxygenase enzymes.
In phase I, reaction products may... be directly excreted in the urine. React with endogenous compounds to form water soluble conjugates--> phase II.
In what phase does the parent drug participate in conjugation reactions? Phase II
In a phase II reaction what happens? Parent drug conjugates to form covalent linkage bt a parent compound functional group & glucuronic acid, sulfate, glutathione, amino acids, & acetate. Makes water soluble
Conjugates are highly polar water soluble, generally inactive (exception to morphine glucuronide metabolite--more potent analgesic then parent compound), & rapidly excreted in the urine.
Extended released High molecular weight conjugates that are excreted in the bile. Conjugate bond may be cleaved by interstitial flora. Parent drug released back into the systemic circulation. Delayed parent drug elimination and prolongation of drug effect.
What is the principle organ for biotransformation? Liver
What are the other organs involved with biotransformation metabolism? GI tract, lungs, skin, kidney
During biotransformation Sequence I, where is most of the metabolism occurring? The liver, where it is first transported.
Biotransformation: Sequence I Oral administration, absorbed intact(small intestine), transport 1st to the liver(portal system)-->extensive metabolism 1st pass effect.
Where does most of the metabolism take place in biotransformation Sequence II? Intestinal metabolism-contributing to overall 1st pass effect.
Biotransformation Sequence II Oral administration, absorbed intact(small intestine), extensive intestinal metabolism.
Cytochrome 450 system aka mixed function oxidase system. Drug metabolizing enzymes located in lipophilic, hepatic, endoplasmic reticulum membranes. Smooth ER contains enzymes responsible for drug metabolism.
Where is the primary site for cytochrome 450 system? Liver
Cytochrome P450 oxidase undergoes what type of reaction? Phase I reaction
Cytochrome P450 oxidase phase I redox reaction. Chemical processes in which atoms have their oxidation # (oxidation state)changed.
What is oxidation number? Charge of an element if all the electron pairs that were shared with the central atom were removed.
In oxidation-reduction process (redox), oxidation=__, reduction=__? Oxidation=loss of an electron. Reduction=gain of electron
What are the two important micorosomal enzymes of Cytochrome P450 oxidase? 1)Flavoprotein--NADPH cytochrome P450 reductase. 2)Cytochrome P450--terminal oxidase.
1st: When binding of a substrate to a P450 what happens? Lowers the redox potential.
When a substrate binds to a P450 and lowers the redox potential what does this then allow? Allows for transfer of an electron form its redox partner, NADH or NADPH.
In phase I reactions what is happening? Introduction or exposure of a functional group to (OH-,NH2-, SH-)
Reaction products may do what? Be directly excreted in the urine. React w/ endogenous compounds to form water soluble conjugates (phase II)
When may cytochrome P450 enzyme be induced? Following repeated administration exposure to certain drugs. 2 Processes-1)increase enzyme synthesis rate 2)reduced enzyme degradation rate.
P450 enzyme inhibition occurs when? 1)There is binding to the cytochrome component-mechanism of action:competitive inhibition 2)Catalytic inactivation of cyt(cytochrome) P450-metabolized by a cyt P450;metabolites complex w cyt heme-iron:producing a complex that is catalytically inactive.
What is an example of P450 enzyme inhibition? Tagament-binds to heme iron of cytochrome P450 and makes P450 unavailable. Reduced metabolism of co-administered drugs.
Could giving one does of a competitive inhibitor (tagament)of P450 cause it to become inhibited? Nope
In phase II, where are the non-microsomal enzymes located? Primarily formed in hepatic (liver), also plasma and GI tract.
In phase II, the nonspecific esterases in liver, plasms, GI tract hydrolyze drugs containing what? What are some examples? Nonspecific esterases hydrolyze drugs containing ester linkages such as succinlycholine, mivacron, ester local anesthetics.
Conjugation reactions Usually detoxification reactions that are usually more polar, easily excreted, and typically inactive.
What are the types of conjugation? Glucuronidation, acetylation, glutathione conjugation, sulfate conjugation, methylation
This type of conjugation uses glucuronic acid Glucuronidation
Glucuronidation requires what enzymes and then what happens? Requires cytochrome P450 enzymes. Glucuronic acid conjugated to lipid soluble drug results in lipohilic glucuronic acid derivative that is pharmaologically inactive, and MORE water soluble(than parent compound)=excretion.
Certain conjugation reactions can form toxic reactive species; What is an example of this? Hepatotoxicity from acetaminophen
How is acetaminophen excreted therapeutically? Therapeutic doses of acetaminophen are excreted by glucuronidation + sulfation to conjugates. 95% are excreted this way. Cyt P450 depending glutathione (GSH) conjugation patheway. 5% excreted this way.
What happens when high doses of acetaminophen are taken? What pathways are now being relied on? Glucuronidation and sulfation pathways become saturated very rapidly. Cyt P450 dependent pathway now is more important-hepatoxic, reactive, electrophilic metabolites are formed.
AUC is what? Area under the curve; i.e., the drug level vs. time curve.
Clearance can be thought of as... The volume of plasms that appears to be entirely cleared of drug per unit time. Most useful in determining dosage regimens (rate of continuous infusion to maintain a given plasma level)
Cpi is what? initial plasma drug concentration. quantitatively characterized extent of tissue distribution. Important in determining loading dose. An "apparent" volume. In a multicompartmental model, vd=sum of all individual compartment volumes.
Cl=__, Vd=__, T1/2=__, clearance=Dose/AUC; Dose/Cpi; (0.693Vd)/Cl
T1/2=(0.693Vd)/Cl Time required for drug concentration to decrease by 50%. Not a fundamental pharmacokinetic parameter. Not as useful as Cl or Vd. In a multicompartmental model there are as many T1/2 as there are compartments.
Context sensitive half time Time necessary to achieve a 50% decrease in plasma concentration after termination of a continuous infusion. Tells us how long will it take the pt to wake up, & when should I turn off my infusion.
TIVA how do you do it? Just infuse faster than Cp x Cl until desired effect (clinical signs). Then slow rate to Cp x Cl.
Propofol Cl- clearance 20-30 ml/kg/min. = loss of consciousness. Cp-50 2.5-3.5 mcg/ml. 1.2-1.6 & orientated. 3 mcg/ml x 30 ml/kg/min=90 mcg/kg/min
Created by: ngawlik
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