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nu 600 kinetics
Pharmacokinetics
| Question | Answer |
|---|---|
| What are the four stages in pharmacokinetics? | Absorption, Distribution, Metabolism, Elimination |
| What is pharmacokinetics? | What the body does to the drug molecules from administration to elimination |
| What is the advantage to sublingual administration? | Drug bypasses first pass hepatic effect, delivered directly to superior vena cava and taken to effect site |
| What occurs before absorption phase to drugs? | Dissolution |
| What can happen to drugs in stomach? | Destroyed by stomach acid or enzyme activity |
| What is first pass metabolism? | PO drugs enter Hepatoportal system after crossing GI membrane and are metabolized before entering systemic circulation |
| What is a high extraction ratio in relation to first pass metabolism? | Drugs are highly metabolized |
| Define bioavailability | The amount of PO drug that reaches systemic circulation |
| What is the bioavailability equation for PO drugs? | F=Amount oral/Amount IV |
| What does it mean if the bioavailability of a PO drug is 1? | No first pass effect occurred |
| What is the bioavailability of PO lidocaine? | F=100/300=.33 or 33% |
| Do IV agents experience first pass effect? | No |
| Creams, ointments, powders, sprays, drops, and transdermal patches are administered though what route? | Topical |
| Topical agents may be applied to skin or _____? | Mucous membranes |
| Fentanyl transdermal patches are designed for _______ absorption? | Systemic |
| Rectal administration is useful in these populations? | Pre-cooperative patients, pediatrics, and vomiting adults |
| Where are rectal suppositories placed to bypass the first pass effect? | Distal 1/3 of rectum |
| Rectal suppositories supplied in proximal rectum go through first pass effect through which vein? | Superior hemorrhoidal vein |
| Why may rectal administration results be unpredictable? | Fluctuations in volume of distribution, size of enema, and retention |
| Absorptive phase is absent with which administration route? | Parenteral |
| In parenteral intravenous administration, where are drugs delivered directly into? | Systemic circulation |
| Parenteral administration can cause local irritation. How might this be minimized? | Slowing infusion rate |
| Into where are epidural drugs administered? | External to the dura mater surrounding the spinal cord |
| What volume of drug may be delivered via an epidural? | 10-20 mL |
| What type of blockade is seen in epidurals? | Sensory and modest motor blockade |
| Anesthesia is provided via epidural in the following cases: | Labor and delivery, orthopedics, genitourinary, general surgical applications |
| Drugs given in the subarachnoid space, are given in the ________ space. | Spinal space |
| What is the volume of drug delivered in the subarachnoid space? | 2-4 mL |
| Drugs given via subarachnoid route are given directly into the ___. | CSF |
| What is the volume of CSF? | 150 mL |
| Drugs given into the spinal space bathe the __________. | Spinal roots |
| What type of blockade results from subarachnoid/spinal anesthesia? | Profound motor and sensory blockade and sympathetic blockade |
| Which route of administration provides constant slow absorption of the drug: Sub Q or IM? | Sub Q |
| Large or small volumes may be delivered Sub Q? | Small |
| What is the maximum amount of volume that may delivered IM to avoid excessive pain? | 5 mL |
| Sub Q and IM drugs must be nonirritating to avoid what? | Tissue necrosis |
| How do most drugs cross the tissue membranes? | Simple lipid diffusion |
| Across what must the drug diffuse to enter the cell? | Lipid bilayer membrane |
| Are cell's lipid bilayer membranes hydrophobic or hydrophilic? | Hydrophobic |
| What is absorption? | The movement of drug molecules across membranes and into the blood stream |
| What is Fick's Law? | Describes the rate of absorption of drug molecules by passive diffusion across the cell membrane |
| According to Fick's Law, what does the rate of absorption depend on? | Concentration or partial pressure of the agent, gradient across membrane, area of membrane of which a drug must be absorbed, solubility of a drug, thickness of membrane, and molecular weight and size of the drug |
| Which drugs are better absorbed in the stomach: acidic or basic? | Acidic |
| Basic drugs have more or less ionized particles in the stomach than acidic drugs? | More |
| Does the Glycocalyx increase or decrease drug absorption? | Decrease |
| Where is the Glycocalyx? | Small intestine |
| What is the Glycocalyx? | Water soluble polysaccharide layer |
| What is dissolution? | The break down of drugs into small absorbable particles for absorption |
| Why are acidic drugs absorbed well in the stomach? | Because the stomach is an acidic environment and there are more non-ionized particles |
| Highly lipid soluble drugs may bind to fat in the GI system to be absorbed via ________. | Epithelial endocytosis |
| Why are basic drugs more readily absorbed in the small intestine? | Due to bicarbonate secretions with the bile |
| What is active transport? | Transport of molecules across the membrane against the gradient. Requires ATP and is faster than passive transport. |
| What is passive transport? | Transport of molecules from high to low concentrations across the membrane. Does not require ATP and is slower than active transport. |
| What are 2 other names for the oil to water partition coefficient? | Octanol to water or octanol to buffer partition coefficient |
| In the oil/octonal to water/buffer partition coefficient, what do oil/octonal and water/buffer resemble? | Oil/Octanol resembles the lipid membrane and water/buffer resembles extracellular fluid |
| What is octanol? | 8 carbon alcohol |
| What is the oil to water partition coefficient? | The ratio of a drug's lipid solubility to water solubility at equilibrium |
| What does the oil to water partition coefficient predict? | How lipid soluble a drug is or how fast is will cross the cell membrane |
| What does a high oil to water partition coefficient mean for a drug? | High lipid solubility and the drug will cross the cell membrane faster and is more active |
| How do drugs with a low oil to water partition coefficient cross the membrane? | Transport molecules on the cell membrane |
| What is the blood-gas partition coefficient? | The partial pressure of the gas in the blood (Pa)/Partial pressure of the gas in the alveoli (PA) at equilibrium |
| True or false: Inhaled agents possess lipid solubility and some degree of blood solubility. | True |
| Do gases move from a higher partial pressure to a lower partial pressure, or lower partial pressure to higher partial pressure? | Gases move from higher partial pressure to lower partial pressure |
| Until equilibrium is reached, inhaled gases move from the alveoli to where? | Blood |
| What is the blood-gas partition coefficient of Desflurane (Suprane)? | 0.42 |
| What is the blood-gas partition coefficient of Isoflurane (Forane)? | 1.46 |
| What is the blood-gas coefficient of Sevoflurane (Ultane)? | 0.69 |
| Which agent has the highest blood-gas partition coefficient? | Isoflurane (Forane): 1.46 |
| What does a high blood-gas partition coefficient represent? | A greater amount of agent is required to be dissolved in the blood before equilibrium is reached and the agent is more lipid soluble, therefore the onset time and elimination time is slower |
| What does a low blood-gas partition coefficient represent? | A low amount of drug needs to be dissolved in the blood for equilibrium to be reached and the drug is less lipid soluble, therefore the onset and elimination time is faster |
| If the blood-gas partition coefficient is 2, what is the concentration in the blood:lungs? | 2:1 |
| Are gaseous/inhaled agents metabolized? | Minimally, if at all |
| What are ionized particles? | Charged and water soluble. Physiologically inactive. |
| What are non-ionized particles? | Uncharged and lipid soluble. Able to cross biologic barriers. |
| Do acids gain or lose protons (H+)? | Lose |
| Unprotonated acids are: charged or uncharged? | Charged or ionized |
| Non-ionized or uncharged acids are: protonated or unprotonated? | Protonated |
| After acids give away protons are they protonated or unprotonated? | Unprotonated |
| Do basic drugs lose or gain protons (H+)? | Gain |
| When a basic drug gains protons, does it become protonated or unprotonated? | Protonated |
| Is a basic protonated drug charged/ionized or uncharged/non-ionized? | Charged/Ionized |
| What is the pKa? | The pH of a solution at which a drug is 50% ionized and 50% non-ionized. The inverse/negative log of the stregnth of the acid |
| What is the primary factor that determines onset of action? | pKa |
| Are most local anesthetics weak bases or weak acids? | Weak bases |
| If Lidocaine has a pKa of 7.9 and Procaine has a pKa of 8.9, which has a faster onset of action? | Lidocaine |
| How does tissue infection effect the local anesthetic? | Because the pH is lower in the tissue there are more ionized particles of the drug when injected, therefore it is less effective. |
| What is the Henderson-Hasselbalch equation? | pH=pKa + log(UP)/(P) |
| What is ion trapping? | When the non-ionized particles of a drug cross the placental barrier into an environment with a lower pH and the particles become ionized. The ionized particles are not able to recross the placental barrier to leave and accumulate and can be toxic |
| What is distribution? | After a drug is absorbed it is transported throughout the body and may cross into tissues where it can act |
| While in the plasma, drug bind to which 2 plasma proteins? | Albumin and Alpha-1 acid glycoproteins |
| True or False: Protein bound drug is available to cross into tissue. | False, only free and unbound drug may cross into tissues |
| What is the result of highly protein bound drugs? | Less available drug for action |
| What percentage of Warfarin (Coumadin) is protein bound? | 99% |
| As unbound drugs move into tissues, what happens to the ratio of protein bound to unbound drugs? | It remains the same, known as dynamic equilibrium, and drugs unbind to maintain the ratio |
| The number of protein binding sites are: infinite or finite? | Finite |
| What is diffusional distribution? | Passive diffusion of lipid soluble drugs |
| What is diffusional distribution based on? | Relative solubility of the drug in a particular tissue, concentration gradient of drug, rate of blood flow to tissue |
| What is the normal circulation time in a healthy adult? | 60 seconds |
| In the elderly and in those with a low ejection fraction, circulation time is: increased or decreased? | Increased |
| What percentage of cardiac output does the brain receive? | 15% |
| Based on diffusional distribution, why do lipophilic anesthetic agents have a short onset time? | The brain receives 15% (large) of blood flow and has a high proportion of lipids, so the drug readily crosses the membrane |
| Where is the site of anesthetic action? | The brain |
| What is redistribution? | The movement of drugs back into the plasma to reestablish equilibrium as drugs are eliminated or distributed into the tissues |
| Why do highly lipophilic anesthetics have a short duration of action? | Redistribution. The drug leaves the brain and redistributed to fat where they are more soluble |
| What is metabolism/biotransformation? | The process of changing a lipid soluble drug into a water soluble form for elimination |
| What is the primary organ for metabolism? | Liver |
| Where are drugs metabolized? | Liver, kidneys, lungs, epithelial cells of GI tract |
| How is the lung involved in metabolism? | Conversion of Angiotensin I to Angiotensin II via Angiotensin Converting Enzyme |
| Where and how do ACE inhibitors work? | ACE inhibitors inhibit the transformation of Angiotensin I to Angiotensin II in the lungs for the treatment of HTN |
| What is an example of a non organ dependent metabolizer? | Esterases |
| What is the CYP450 series? | A family of enzymes (50+) responsible for metabolism of drugs. 6 CYP450 enzymes are responsible for 90% of drug metabolism |
| What are common phase 1 metabolism chemical reactions in the CYP450 series? | Oxidation, Reduction, Hydrolysis, Hydroxylation |
| What is the most common CYP450 phase 1 chemical reaction? | Oxidation-Reduction |
| What is another name for the CYP450 series? | Mixed function oxidase system |
| What is phase 1 metabolism? | An enzymatic process involving chemical reactions in the smooth endoplasmic reticulum of hepatocytes to convert drugs to a water soluble form for excretion |
| Is phase 1 or phase 2 an enzymatic process? | Phase 1 |
| After phase 1 metabolism what happens to the drug compound? | Compound enters the blood stream for kidney elimination or biliary excretion |
| What happens to the drug when phase 1 enzymes become saturated? | Drug builds up and half life is increased. Can be toxic. |
| How does enzyme induction affect phase 1 enzymes? | Drugs will be metabolized more quickly and half life is decreased |
| What patients may experience enzyme induction? | Drug users (illegal and prescription), heavy alcohol consumers |
| What happens when drugs inhibit the phase 1 enzymes? | Other drugs that would normally be metabolized by these enzymes will have an increased half life |
| What is phase two metabolism? | A metabolic process in which large polar molecules are attached to the drug compound for elimination through the kidney or bile |
| Phase __ is an important means for inactivating many drugs. | 2 |
| Where does phase 2 metabolism occur? | In the hepatocytes, enzymes are located in the cytoplasm and the smooth endoplasmic reticulum |
| Do all drugs go through phase 1 and 2 metabolism? | No. Some just go through 1 or 2 and some go through both |
| What is another name for phase 2 metabolism? | Conjugation reactions, biotransformation, and synthesis reactions |
| What is the most common reaction in phase 2 metabolism? | Glucuronic acid conjugation |
| What occurs in Glucuronic acid conjugation? | Uridine diphosphoglucuronic acid (UDPGA), a sugar group, attached to a drug compound to increase water solubility |
| What are examples of phase 2 synthetic/conjugation reactions? | Glucuronic acid conjugation; glutathione attachment; acylation reactions; and sulfate, glycine, and glutamine conjugations |
| What is the result of glutathione attachment in phase 2 metabolism? | Mercapturic acid derivatives for excretion |
| What type of molecules do esterases metabolize? | Esters |
| Where are esterases metabolized? | The liver |
| Where are esterases found? | Cholinergic neural synapses (acetylcholinesterase), red blood cells, hepatocytes |
| What is first order kinetics? | The rate of metabolism/elimination is proportional and dependent on drug concentration |
| In first order kinetics, an increased amount of drug will cause a(n) ________ rate of absorption (increased or decreased) | Increased |
| In first order kinetics are drugs eliminated at a logarithmic or linear rate? | Logarithmic |
| What happens when enzymes are saturated in first order kinetics? | Zero order kinetics begins |
| What is zero order kinetics? | Drugs are metabolized/eliminated at a constant rate, regardless of the drug concentration |
| Why are alcohol and heparin more likely to revert to zero order kinetics? | Alcohol is oxidized by alcohol dehydrogenase and Heparin is metabolized by heparinase and because they require specific enzymes, they are more likely to become saturated |
| Are drugs eliminated in a logarithmic or linear rate in zero order kinetics? | Linear |
| True or False: at a therapeutic drug concentration most drugs will not reach enzyme saturation and revert to zero order kinetics | True |
| What is elimination? | The process of removing drugs from the body (includes metabolism and excretion) |
| What is the primary excretory organ? | Kidneys |
| Other than the kidney, what are other means of excretion? | Lungs, breast milk, sweat, GI system: bile |
| How are drugs excreted through the GI system? | Drugs are actively secreted into the bile and excreted through the intestines |
| True or False: Lungs eliminate anesthetic agents and alcohol | True |
| True or false: Only some ingested drugs are present in breast milk | False, any drug ingested will be present in some degree |
| How do kidneys control excretion? | Filtration, Secretion, and Reabsorption |
| How are drugs filtered through the kidney? | Unbound drug is passively excreted at the glomerulus |
| How are drugs secreted through the kidney? | Actively via transport molecules at the proximal tubules |
| How are drugs reabsorbed in the kidney? | Through passive diffusion of lipid soluble drugs in the nephrons back into the blood stream |
| How is total renal excretion calculated? | Filtration + Secretion - Reabsorption |
| Of filtration, secretion, and reabsorption, which requires active transport? | Secretion |
| Why are protein bound drugs unable to be passively filtered through the glomerulus? | They are too large |
| What are four important determinants in the rate the kidney eliminates drug? | Blood flow, size, charge, and protein binding |
| Drugs with a molecular weight less than ______ are freely filtered through the glomerulus. | 5000 amu |
| What is the charge of the glomerulus pores? | Negative |
| Are negatively or positively charged drugs more easily filtered through the glomerulus? | Positive, because they are attracted to the negative glomerulus pores |
| Are ionized or non-ionized drugs easily excreted through the kidney? | Ionized (Polar/water soluble compounds) |
| How can the elimination of a non-ionized drug be increased? | By increasing percentage of ionized particles for elimination |
| How can kidney elimination of a basic drug be enhanced? | Acidifying urine to increase ionization |
| How can kidney elimination of an acidic drug be enhanced? | Alkalizing urine to increase ionization with Diomox (blocks bicarb absorption) or citric acid |
| What is the purpose of compartmental modeling? | Predict drug serum concentrations and changes in concentration |
| What is Ka? | Rate of absorptive phase of initial movement from administration site to central compartment |
| What is Ke? | Rate of elimination (metabolism and excretion) |
| What is Volume of Distribution (Vd)? | Theoretical volume in which drug is dissolved, not a true volume |
| How is volume of distribution calculated? | Dose at time zero/plasma concentration at time zero (time zero is the time required to distribute throughout the body) |
| Is volume of distribution used in the one compartment model, two compartment model, or both? | One compartment model only |
| What is the volume of distribution for Heparin? | Plasma compartment since Heparin remains in plasma |
| What does a low volume of distribution mean? | The drug remained in the plasma compartment (due to high protein binding or hydrophilic/ionized) |
| What does a high volume of distribution mean? | The drug left the plasma compartment and is in tissues |
| What happens to drugs in the one compartment model? | Initially distribute to central compartment (Vc) and then to periphery/tissues (Vt). |
| At equilibrium how do the plasma drug levels compare to the tissue drug levels in the one compartment model? | Drug levels are equal at equilibrium |
| Which drugs is the one compartment model sufficient for? | Water soluble drugs (aminogylcosides) |
| In the one compartment model, once equilibrium is reached how is it maintained? | Affinity to proteins for binding |
| Is equilibration fast or slow in the one compartment model? | Fast |
| A log scale plot of serum decay curve in the 1 compartment model would show a _______ line. | Straight |
| A log scale plot of serum decay curve in the 2 compartment model would show a _______ line. | Biphasic |
| Failure to consider the ________ phase can lead to significant error in estimates of elimination rate. | Distribution |
| How do drugs distribute in the 2 compartment model? | Drugs enter central compartment, distribute into periphery, and return to central compartment (based on dynamic equilibrium) |
| What are the 2 compartments in the 2 compartment model? | Central: intravascular fluid, highly perfused tissues Peripheral: muscle, fat, and bones |
| Which drugs are described by the 2 compartment model? | Lipid soluble anesthetics, vancomycin |
| How do the peripheral drug levels compare to the central drug levels in the 2 compartment model? | Peripheral drug levels rise more slowly and do not become as high as central drug levels |
| What is steady state? | The amount of drug being administered equals the rate of elimination at equilibrium |
| True or False: At equilibrium, when steady state is achieved the peaks are greater than the troughs. | False, peak and trough levels are equal for additional doses given |
| After how many successive equal peaks and troughs has steady state occurred? | 2 |
| How many half lives are required to reach steady state? | 4-5 |
| How many half lives are required to terminally remove a drug? | 5-6 |
| How can steady state be monitored? | BIS monitor |
| When does steady state for a Propofol infusion occur? | After 20 minutes |
| Peaks and troughs occur in the plasma concentration with: continuous infusions or intermittent dosing? | Intermittent dosing |
| What is elimination half time (T1/2)? | The time required for plasma drug to decrease by 50% |
| Elimination occurs after how many half lives? | 4-5 |
| Can elimination half time be used for continuous infusions? | No |
| Can context sensitive half time be used for continuous infusions? | Yes |
| Can elimination half time be used in 1 or 2 compartment models? | 1 only |
| What is the formula for elimination half time? | T1/2=0.693/Ke (0.693=natural log of 2) |
| What is half life of effect? | Includes the half life of the active metabolite of a parent drug |
| What drugs would you use the half life of effect to determine half life? | Diazepam, Ketamine, Morphine |
| What is context sensitive halftime? | Time necessary for drug concentration to decrease to a predetermined percentage after discontinuing an infusion of a specific duration |
| What is time to recover? | Time for plasma levels to decrease to the point where the patient will awaken |
| What is the effect of a higher infusion dose or deeper BIS sedation on time to recover? | Longer time to recover or awaken |
| What is clearance? | The rate a drug is removed from the body, plasma volume that is entirely cleared of drug per unit time |
| How is clearance (Cl) calculated? | Cl=Ke x Vd |
| What factors alter clearance? | Disease of kidney or liver |
| What is a way of writing out total clearance? | Total Cl = Cl (hepatic + renal +lungs + hair + skin) as appropriate for given drug |
| What are two things hepatic clearance is dependent on? | Perfusion and enzyme activity |
| A high hepatic extraction ratio (>0.7) of drug means the liver is dependent on what for clearance? | Perfusion |
| A low hepatic extraction ratio (<0.3) of drug means the liver is dependent on what for clearance? | Enzyme activity (capacity-dependent elimination) |
| What is ED50? | Dose that is pharmacologically effective for 50% of population |
| What is the therapeutic window? | Drug level above therapeutic plasma concentration (CPther) to exert desired effect and below plasma concentration associated with toxicity (CPtox) |
| How is therapeutic index calculated? | TI = Dtox/Dther |
| Are drugs safer with smaller or larger therapeutic indexes? | Larger |
| What are side effects? | Minor undesirable effects |
| What is toxicity? | Intolerable or life-threatening effects |
| Are therapeutic window concepts those of pharmacokinetics or pharmacodynamics? | Pharmacodynamics |
| Is local irritation more common in intra-arterial injections or intravenous injections? | Intravenous because the artery walls are less sensitive |
| What is a Depot injection? | An IM injection, usually prepared as an oil, provides slow absorption over a long period of time |
| What is the tissue-to-blood coefficient? | Relative solubility of a drug in the tissue compared with the blood |
| What is the usefulness of the tissue-to-blood coefficient? | Determining what tissues a drug enters and to what extent |
| Do liquid oral drugs require dissolution before absorption? | No, unless they contain small suspended particles requiring further dissolution |
| What are examples of molecules secreted at the proximal tubule? | Organic acids, organic bases, and conjugated metabolites |
| What is the pH of urinary fluid? | 5-8 |
| How is the loading dose calculated? | Dload = Vd x CPss (volume of distribution x steady state plasma concentration) |
| How is the infusion rate calculated for a drug? | Kin = CPss x Cl (steady state plasma concentration x clearance) |
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