Basic Principles of Pharm (2) Flashcards
What does Pharmacokinetics determine?
The concentration of a drug in the plasma or at the site of the drug effect (Pharmacokinetics is defined as what the body does to the drug)
Receptor Theory The maximal effect a drug can produce and the ability of a drug to activate the receptor once bound is called _________
Efficacy
Receptor Theory The amount of drug needed for a given effect is called __________
Potency
Drug potency depends on what 3 things?
Affinity to receptor Amount of drug that reaches the receptor site **Drugs with low ED50 are more potent than drugs with a high ED50
Drug Absorption What are some factors that affect absorption? ________ transport requires no energy ________ transport requires energy
Pain, Stress, Stomach Contents, drug formulation drug interaction Passive Active
Drug Absorption Drug absorption is affected by the __________ of ____________
Method of administration (IV- very fast, sublingual, inhalation)
What are the 4 principles are pharmacokinetics?
Absorption Metabolism Distribution Elimination
First Pass Effect
When drugs are circulated to the liver first, immediately after enteric absorption, before the drug enters circulation (Only part of the drug is circulated systemically)
What is distribution? What is a central compartment relative to distribution? What are the elements of the central compartment?
Once the drug enters the systemic circulation, it must be distributed. The drug suddenly becomes more dilute due to distribution in the plasma or tissues. The central compartment is the site where the drug becomes dilute within the first minute of administration. The venous blood volume of the arm, the volume of the great vessels, the heart, the lung **highly fat soluble drugs may be avidly taken up in the first passage through the lung
Drug Distribution Drugs distribute to which organs first?
To organs with a large blood supply: Heart, Liver, Kidneys, then to other organs
Drug Distribution Drugs can be ______ soluble or _______ soluble Lipid soluble drugs can cross the ______________
Water, Lipid Blood-brain barrier
Lipid Solubility The more lipid soluble an anesthetic is, the more ________ it is Lipid solubility parallels ________ _________ Agents with higher lipid solubility may last _______ because they are less likely to be cleared by blood flow
Potent Protein Binding Longer
Protein Bound VS Unbound The more highly protein bound an agent is, the more difficulty is has dissociating from the _______ ________, leading to a longer _________ of _________ Name two drugs that have no protein binding?
Sodium Channel Duration of Action Procaine and Chloroprocaine
Drug metabolism occurs in which 4 places?
Liver, Plasma, Kidneys, and Membranes of Intestines
Drug Metabolism What happens to inactive metabolites? What happens to active metabolites? What are Prodrugs?
They are excreted They exert a pharmacological action Drugs that are inactive until metabolized
Drug Metabolism Drug metabolism is affected by what 4 things?
Disease state Genetics Environment Developmental changes
Drug Elimination Drugs are eliminated mainly through the ________, but also through what other 4 outlets? The time it takes for half (50%) of the drug to be eliminated is called the drug’s ______ ______
Kidneys; Lungs, exocrine glands, skin, and intestinal tract Half Life
Drug Elimination Steady state is defined by the rate of distribution _________ the rate of excretion Drug elimination is affected by what 3 factors?
Equaling Rate of absorption Metabolism Method of excretion
Onset of Action Time interval from ___________ to __________ effect
Administration, Therapeutic
Peak Concentration __________ rate equals __________ rate
Absorption, Elimination
Duration Length of time that a drug produces a __________ effect
Therapeutic
Drug Distribution (After Systemic Absorption) _________ determines degree of diffusion Non Ionized drugs are _______ ________ Ionized drugs are ________ _________
Ionization Lipid soluble (can absorb) Lipid insoluble (cannot absorb)
Drug Distribution (After Systemic Absorption) Does pH affect systemic absorption? Weak bases end up trapped in an ________ environment (stomach) Local anesthetic become trapped in the acidic environment of the ________
Acidic Fetus
Drug Distribution (After Systemic Absorption) Does protein binding affect systemic absorption? Renal failure leads to ________ free fraction, leading to greater chance of _______ _______
Yes, more binding to plasma proteins (albumin), less Vd (Volume Distribution) Increased Drug Toxicity
Fetal Ion Trapping Local anesthetics cross the ________ and become more _________ ionized in the acidic fetus The anesthetic becomes “trapped” in fetal tissues, leading to systemic ________ in the fetus
Placenta, Ionized Toxicity
Fetal Ion Trapping This is less likely to occur with highly ________ bound local anesthetics which diffuse ________ across the placenta This is also less likely to occur with _______ local anesthetics, where rapid hydrolysis is responsible for a small quantity of drug being able to cross the placenta
Protein, Slowly Ester
Fetal Ion Trapping Which two anesthetic agents cause this to happen? What factor causes this occurrence? The non ionized form of the local anesthetic crosses the ________ ________. Once in the fetus, the drug converts to an ________ form. The ionized form cannot cross the placental barrier, thus becomes trapped.
Mepivacaine and Prilocaine (amide locals that are not highly protein bound) Fetal pH is lower (7.2) than the mother’s pH (7.4) More acidic environment = Ion Trapping Placental Barrier Ionized
Volume of Distribution (Vd) The volume of _______ body fluid into which a drug “appears” to distribute Known dose is administered IV, then ________ concentration is measured In a 70 kg adult, plasma = ____, interstitial fluid = ____, and intracellular fluid = ____
Total Plasma 3L 11L 28L
Volume of Distribution (Vd) Formula
(Vd)= amount of drug administered (mg) ——————————— Plasma drug concentration (mg/L)
Volume of Distribution (Vd) What factors affect Vd?
Lipid solubility, binding to plasma proteins, molecular size Very young or very old age (increased Vd) Liver/Kidney disease (increased Vd secondary to decreased plasma protein) Burn injury/Trauma (increased Vd)
Volume of Distribution (Vd) Non-depolarizing NMB’s bind to plasma proteins and are poorly lipid soluble They have high plasma concentration and ______ (Vd) ___________ and ____________ are highly lipid soluble (will be concentrated in tissue) and have a _____ plasma concentration and high (Vd)
Low Thiopental, Diazepam Low
Pharmacodynamics “What the drug does to the body” Study of drug _________ interaction and __________ effect
Receptor, Biological
Phase I pathway of metabolism include what actions? Which patient population loses phase I pathways first?
Reduction, oxidation, and hydrolysis Geriatric population
Phase I pathways of metabolism yields slightly ________, water soluble metabolites (active or inactive) Phase I pathway includes which 3 enzymes?
Polar Cytochrome P450 in the liver Non Cytochrome P450 Flavin-containing mono-oxygenase enzymes
Phase II pathway of metabolism includes which action?
Conjugation
Phase II pathway of metabolism yields very _______, inactive metabolites that are easily excreted by the _________.
Polar Kidneys
Phase II pathway includes what 4 enzymes?
Glucuronosyltransferases Glutathione S transferases N acetyl transferases Sulfotransferases
Following phase I, the drug may be __________, __________, it most often, ___________ Some drugs directly enter _________ __ _________ Conjugated drug is usually __________
Activated, Unchanged, Inactivated Phase II metabolism Inactive
Omeprazole inhibits _________ metabolism
Warfarin
P-450 Monoxigenases Play an important role in drug _____________ Mostly involves Phase ___ P-450 is inhibited by _________ and _________
Biotransformation Phase I Cimetidine (Tagamet) and Chloramphenicol
Glucuronyltransferase Involved in phase ____ Conjugation Located in the _________ __________
Phase II Endoplasmic Reticulum
Dose Response Curve What is potency? What 5 factors is potency dependent on?
The relative amount of drug needed to produce a given response Absorption Distribution Metabolism Excretion Affinity of Receptor
Dose Response Curve What is efficacy?
Ability of the drug to activate receptors once it is bound
Dose Response Curve What is variability?
Reflects difference between individuals in response to drug The difference in how the drug may effect elderly patients secondary to decreased CO or renal function
Dose Response Curve The slope of the curve depends on the number of _________ There is a steep slope for what type of agents? What does this indicate?
Receptors NMB’s; this means that a small change in dose produces a large change in response
Drug Variability Drug variability may be seen in the elderly due to decreased _______ and _______
Cardiac output and renal function
Chronic alcohol consumption _______ P-450, leading to a much ________ metabolism of drugs
Induces, faster
Enzyme defects such as G6PD deficiency can cause __________ with certain drugs G6PD deficiency can also cause _________ _________ with succinylcholine administration
Hemolysis Malignant Hyperthermia
Drug Clearance Volume of ________ completely cleared of drug (NOT how much drug is removed)
Plasma
Drug Clearance is dependent on what 3 factors? Which of these factors is the most important?
Hepatic Clearance Biliary Excretion Renal Clearance Renal Clearance
Renal clearance is based on which factors?
•GFR •Reabsorption and secretion by nephron ** Thiopental is completely reabsorbed •How lipid soluble metabolites are (less lipid soluble metabolites are easily excreted)
Hepatic Clearance Elimination of most drugs through the liver is primarily due to ____________ to inactive or less active metabolites Drug may be __________ (enterohepatic circulation) or excreted completely through _____ and _____ Hepatic Elimination is affected by (5 factors)?
Biotransformation Reabsorbed, Bile and Feces •Liver disease •Age •Diet •Genetics •Duration is drug administration
Clearance (CL) Relates the rate of _________ to the ________ concentration What is the elimination constant (symbol)?
Elimination, Plasma (Ke)
Clearance (CL) Formula
Rate of elimination of drug ————————————— Plasma drug concentration = (Vd) x (Ke)
Half Life Number of half-lives and their concentration
Time required to change the amount of drug in the body by 1/2 during elimination 1= 50% 2= 75% 3= 87.5% 4= 93.75%
Potency and Efficacy Pg 36 (Flood) Defined in terms of relative doses
Fentanyl reaches its peak effect 3.5 minutes after injection. Morphine reaches its peak effect 90 minutes after injection. The relative potency 3.5 minutes after injection indicates that fentanyl is far more potent than morphine **Measured 90 minutes after injection, morphine would be more potent
Potency and Efficacy Potency is more logically described in terms of concentration versus response relationship A drug with a left shifted concentration versus response curve (lower C50) is considered _____ potent A drug with a right shifted concentration versus response curve (higher C50) is considered ______ potent
More Less
Potency and Efficacy Potency should be defined in terms of a specific ________ _________ (50% of maximal effect of a full agonist) This is particularly important if the two drugs have differing __________
Drug Effect Efficacies (Hill Coefficients) Also seen as (Emax)
Therapeutic Index Classical TI classification is not helpful in anesthesia The TI is the ratio between the ______ and the _______ The larger the TI of a drug, the safer the drug is for administration
LD50 (dose of a drug required to produce death in 50% of patients) and the ED50 (dose of a drug required to produce desired effect in 50% of individuals receiving the drug)
Therapeutic Index The classic calculation of LD50 is not helpful in anesthesia for what reason? What is a more effective ratio? Why? Anesthetic drugs have a low ________ ________, Therefore requiring _________ for safe usage
We expect 100% of patients to fall asleep but for none of them to die The LD1/ED99 ratio This ratio shows a smaller margin of safety, meaning that there is appreciable risk of death, even at sub-therapeutic doses Therapeutic ratio Vigilance
Opioids Potently reduce the ______ _______ ______ (MAC) of inhaled anesthetics required to suppress movement to noxious stimuli A modest amount of opioid dramatically _______ the concentration of inhaled anesthetic needed to prevent movement Even with huge doses of opioids, some _______ component must be added to the anesthetic to prevent movement
Minimum Alveolar Concentration Reduces Hypnotic
Opioids MAC is reduced by 50% when fentanyl is at 1.5ng/mL What is the catch to this?
After this initial reduction in MAC, adding more fentanyl shows little benefit for this purpose
Routes of Administration Drugs administered IV enter ________ into the systemic circulation and have ________ ________ to the rest of the body Drugs administered orally are first exposed to the ______ and may be extensively metabolized before reaching the rest of the body
Directly Direct Access Liver
Agonist What effect does an agonist have on a receptor? What affects the magnitude of the drug?
When receptor is bound to an agonist, an effect is produced A: An agonist activates a receptor A: The amount of receptors that are bound Ex: Beta agonist (dobutamine)
Antagonist What effect does an antagonist have on a receptor?
A: An antagonist blocks the action of an agonist, preventing the agonist from binding to the receptor site and producing a drug effect Ex: Beta Blocker
Competitive Antagonism
When increasing concentrations of antagonist progressively inhibit the response to the agonist Ex: Atropine is a highly competitive antagonist at acH receptor sites, blocking acetylcholine from binding (Binding is reversible)
Noncompetitive Antagonism
When even after high concentrations of agonist cannot completely overcome the antagonism (Binding is not reversible)
Partial Agonism
Even at high doses, a partial agonist cannot cause a full drug effect **When a partial agonist is administered with a full agonist, it decreases the effect of the full agonist
Inverse Agonism
Inverse Agonists “turn off” the activity of the receptor
More on Agonism/Antagonism Why are certain states favored, rendering certain drugs more effective?
A: Receptors have multiple states and they switch spontaneously between them Ligands change the ratio of active to inactive states by favoring one of the states (Ex: Midazolam (Versed) being a full agonist, hence, causing more receptors to be in the conformation with increased sensitivity to GABA) **the antagonist does not favor either state, it just gets in the way of binding
Receptor Action -May change in response to stimuli (see below) What is up-regulation and down-regulation?
A: patient with pheochromocytoma has increased amount of circulating catecholamines. In response, there is a decrease in the amount of beta adrenergic receptors in the cell membranes Patient with lower motor neuron injury has increased amount of nicotinic aCH receptors, therefore, leading to exaggerated response to succinylcholine
Distribution After Systemic Absorption Is dependent upon (4 factors) Uptake in the lungs is ____% Lungs serve as a ________ In the CNS, _____ _____ _____ limits permeability
•Vascularity (highly vascular tissues receive maximum amount) •Lipid Solubility •Non Ionized State •Unbinding with plasma proteins 65% Reservoir Blood Brain Barrier
Drug Interactions
____ alters the rate and amount of drug absorbed in the GI tract; inhibiting ______ (ex: Grapefruit)
______ effects are when two drugs with similar effects are administered
Food, Metabolism
Additive
Drug Interactions
Potentiation ( ______ effect); where two drugs that produce the same effect are given together, and one ______ the effect of the other
_______ effect; combined response of the two drugs is less powerful that the response of either drug alone
Synergistic
Antagonistic
Metabolism of Drugs
First Order Elimination
Rate of elimination is ______ to the drug concentration (i.e. constant fraction of drug eliminated per unit time)
Cp (plasma concentration) decreases _______ with time
Proportional
Exponentially
Metabolism of Drugs
Zero Order Elimination
Rate of elimination is _____ regardless of Cp (plasma concentration)
Cp (plasma concentration) decreases ______ with time
Due to ______ of metabolic enzymes
Name some examples
Constant
Linearly
Saturation
Ethanol, Phenytoin, and Aspirin (at a high or toxic concentration)
Pharmacology of Injected Drugs
Two Compartment Model
The drug is introduced by IV injection directly into the _____ _______. The drug subsequently distributes to the ______ compartment, only to eventually return to the ______ compartment, where clearance from the body occurs
Central Compartment
Peripheral
Central
Pharmacology of Injected Drugs
Two Compartment Model
Two Phases: ______ phase - very rapid decrease in concentration due to passage of drug from _____ to _____
______ phase - ______ decline in concentration
Distribution, Plasma, Tissues
Elimination, Slower
Pharmacology of Injected Drugs
Two Compartment Model
The two compartments are _____ (drug is injected here and eliminated from here) and _____ (tissues)
Central
Peripheral
Dosage Calculations
Cp (target plasma concentration), F (bioavailability) = 1 when drug is given IV
Loading dose?
Maintenance dose?
In patients with impaired renal or hepatic function, the _____ dose remains unchanged, but the maintenance dose is _____
Loading: Cp x Vd/F
Maintenance: Cp x CL/F
Loading, Maintenance
Racemic Mixtures
Name five examples
Majority of inhaled anesthetics except for ______
Local anesthetics such as ______, ______, _____, have a center molecule _______
Thiopental, Methohexital, Brevital, Pentothal, and Ketamine
Sevoflourane
Mepivacaine, Prilocaine, Bupivacaine
Asymmetry
Enantiomers
The __ enantiomer of ketamine is more _____ than the __ form and is less likely to product _____ _____
The cardiac toxicity of bupivacaine is thought to be due to the __-bupivacaine isomer
_______, the S-enantiomer of bupivacaine, is associated with less cardiac toxicity that bupivacaine
_______ is an isomer of atracurium that lacks _______ releasing potential
S, Potent, R, Emergence Delirium
R
Levobupivacaine
Cisatracurium, Histamine
Drug Variation
The impact of interpatient ______ may be masked by the administration of ____ doses of a drug
Ex: The administration of 2-3 times the ED-95 of a non-depolarizing neuromuscular blocking drug is common practice for muscle paralysis in ___ patients
It is common practice to dose patients in proportion to ____ ____, although pharmacokinetic and pharmacodynamic principles may not support this
Variability, High
All
Body Weight
