Pharmacology Review Flashcards
1
Q
Basic pharmacokinetic principles: A drug must be absorbed, then distributed to ______ before being metabolized and excreted
A
A drug must be absorbed, then distributed to its target before being metabolized and excreted
2
Q
Basic pharmacokinetic principles: At all times, what is happening to a free drug in circulation?
A
At all times: a free drug in circulation is in equilibrium with tissues reservoirs, plasma proteins, target site (receptors)
3
Q
Basic pharmacokinetic principles: What part of the drug will have a pharmacological effect?
A
Only the fraction of drug that binds to its specific receptor will have a pharmacologic effect
4
Q
Basic pharmacokinetic principles: What can metabolism yeild?
A
active and inactive metabolites
5
Q
What is pharmacokinetics?
A
What the body does to the drug
6
Q
What is pharmacodynamics?
A
What the drug does to the body
7
Q
What are the components of pharmacokinetics?
A
Absorption, distribution, metabolism/biotransformation, elimination
8
Q
Plasma concentration & bound/unbound proteins are what type of pharmacological concepts (2)?
A
pharmacokinetics
9
Q
What are some examples of pharmacokinetic components?
A
Molecular weight, protein binding and bioavailability
10
Q
The ______ the molecular size of an agent, the better it crosses the lipid barriers and membranes of tissues.
A
smaller
11
Q
What happens to the permeability of substances as the molecular weight approaches 100-200?
A
Generally, molecules with molecular weights greater than 100 to 200 do not cross the cell membranes. Transport across the membranes can occur passively or actively.
12
Q
What is an example of an object that needs assistance getting through a membrane?
A
Example: Glucose
13
Q
What is active transport?
A
mechanisms are generally faster and require energy (ATP). Primary versus secondary (co-transport)- Difference?
14
Q
What is passive transport?
A
does not require energy and involves transfer of a drug from an area of high concentration to an area of lower concentration: facilitated versus simple diffusion. Difference?
15
Q
What are most drugs?
A
salts of either weak acids or weak bases. When introduced into the body, they behave as a chemical in solution.
16
Q
The don’t dissociate equally between unionized/ionized forms as altered by _______.
A
blood pH
17
Q
What is the ionized form?
A
The charged (ionized) form is water soluble,
18
Q
What is the nonionized form?
A
the uncharged (nonionized) form is lipophilic.,
19
Q
What is important to know about the nonionized forms of molecules?
A
Because the nonionized molecules are lipid soluble, they can diffuse across cell membranes such as the blood-brain, gastric, and placental barriers to reach the effect site.
20
Q
What happens to ionized molecules?
A
the ionized molecules are usually unable to penetrate lipid cell membranes easily because of their low lipid solubility.
21
Q
Some drugs are bound extensively to proteins in the plasma because ______________
A
of their innate affinity for circulating and tissue proteins.
22
Q
How are protein bound drugs trap?
A
The drug-protein molecule is too large to diffuse through blood vessel membranes and is therefore trapped within the circulatory system.
23
Q
What happens to heavily protein bound drugs?
A
Drugs that heavily protein-bound can compete for binding sites (displace and lead to increase in free-fraction of displaced drug)
(Finite number of binding sites, weak attraction)
24
Q
What is albumin?
A
(most abundant)- favors acidic compounds
25
What is a1 glycoprotein?
(AAG)- favors basic compounds
26
Does a protein bound drug interact with the receptor?
A protein-bound drug is not free to interact with a receptor, results in higher plasma concentration levels
27
What effect does protein binding have on drugs?
Protein-binding slows metabolism/elimination (important for some hormones)
Protein-binding proportional to lipid solubility
28
How are protein binding expressed?
Expressed in percentages (drug X is % protein-bound)
29
What does it mean to have a >90% protein bound drug?
If highly protein bound >90% which means majority not pharmacologically active so displacement can have big consequences (theoretically)
30
What can protein binding serve as? What does it create?
Protein-binding can serve as a reservoir from some drugs- diffusion gradient to unload as free form is metabolized/excreted. Creates stable distribution for some drugs/hormones
31
What is bioavailability?
Bioavailability is the extent to which a drug reaches its effect site after its introduction into the body.
32
What does the rate at which systemic absorption occur establish?
a drug's duration of action and intensity.
33
What impacts bioavailability?
The environment into which the drug is introduced also has an impact on its bioavailability. The patient's age, sex, pathology, pH, blood flow, and temperature are all factors to consider.
34
What is pulmonary first pass uptake?
the loss of some drugs after a single passage through the lung (think IV). Net result of uptake of X into lung tissue or binding to lung vasculature/tissue and back diffusion of the drug from lung tissue or vasculature into the blood
35
What is first pass hepatic effect?
The reduced bioavailability of some drugs due to immediate extraction & metabolism via the liver as drug enters portal system before reaching systemic circulation
36
What is most effected by first pass hepatic effect?
Oral
37
The rectal route bypasses the hepatic first pass ______-________%.
50-75%.
38
What are compartmental models?
Used to quantitatively describe the pharmacokinetics of a drug and predict drug concentrations in the blood and tissues with little physiologic detail
39
What is an example of a one compartment model? What does it describe?
Linear pharmacokinetics; bolus pharmacokinetics
40
What is clearance?
= fluid circulating though a clearance organ at a constant rate (k)
41
What is the equation for clearance?
Clearance=k * Vd
42
What is half-life?
directly proportional to Vd and inversely to clearance
43
What is the 2-compartment model?
the central compartment is the first to receive the drug and represent intravascular fluid and highly perfused tissue
44
What is the multicompartment model?
Expands the 1 compartmental model to explain anesthetic drugs to account for distribution to site of action
45
What is the phases of the 3 model follows?
the phases of anesthetic drugs: Rapid distribution phase Slower distribution phase, Terminal elimination phase
46
What is hysteresis?
time delay between measured concentration and effect
47
What is volume of distribution?
Vd= Dose/[Drug]plasma
Pharmacokinetic parameter describing a drug’s propensity to either remain in the plasma (central) or redistribute to other tissues
48
What is dilution/apparent volume?
The ratio of the dose present in the body and its plasma concentration when the distribution of the drug between the tissues and the plasma is at equilibrium.
49
What are many anesthetics?
highly fat soluble (lipophilic), poorly soluble in H2O- have ⬆️ Vd (ex. prop)
50
What effects volume of distribution?
Affected by molecular size, lipid solubility and plasma protein binding (also, disease state & fluid shifts (pregnancy)
51
A drug that is free, unbound to plasma proteins and lipid soluble tend to cross cell membranes more freely, thus ______ Vd with _____ plasma [ ] after injectio
large; low
52
What is zero order kinetics?
Zero order kinetics (saturation): Elimination rate is independent of concentration (can quickly become toxic)
53
Saturating the amount of drug does _________ elimination
does not speed up elimination
54
What are some examples of zero order kinetics (5)?
Coumadin, heparin, ethanol, salicylates, phenytoin, theophylline
55
What can happen quickly at therapeutic levels?
May start off at first-order at low concentrations (saturate quickly at therapeutic levels)
56
What is first order kinetics?
Concentration dependent process (most drugs): rate proportional to amount
57
What is elminiation half life?
The amount of time over which the drug concentration in the plasma decreases to 50% of its original value
58
What factors effect the elimination half life?
Kinetics= Clearance & Volume of distribution
59
What is a negligible therapeutic effect?
In general, the effect of a drug is considered to have a negligible therapeutic effect after 4-5 half-lives, or when only ~6.25% of the original dose remains in the body
60
What is steady state?
When the overall intake of a drug is at equilibrium with the elimination
61
When is steady state accomplished?
```
Accomplished at 4-5 half-lives
Steady state (infusion)=input/clearance
```
62
What is context sensitive half life?
Time required for plasma concentration to ⬇️ 50% after D/C drug iv infusion
63
What is important about context sensitive half life?
Often cannot be predicted by elimination ½ life (metabolism & elimination)
64
What determines context sensitive half life?
Volume of central compartment; rate of systemic clearance
65
What is context sensitive half life most common in?
Useful concept with infusions (accumulation)
| “Context;” duration of infusion
66
What are some examples of drugs that under go context sensitive half life?
- remifentanil (stable, short context sensitive half-time) 3 min after 3 hr infusion
- Fentanyl, dexmedetomidine, midazolam, ketamine, remifentanil, propofol
67
What is biotrnasformation?
Covert pharmacological active drugs to inactive state for elimination (lipophilic drugs to hydrophilic)
However, some have active metabolites
68
What is an example of a drug that produces an active metabolite?
morphine to morphine-6-glucuronide
69
What is a prodrug? What is an example of this
Convert a “pro-drug” into an active state (ex: codeine to morphine)
W
70
Where does biotransformation occur?
Hepatocytes are primary site (⬆️ concentration of enzymes, especially CYP 450)
Mitochondria/**ER
Others: kidneys, GI tract, lungs, plasma, placenta, skin
71
What is a phase I reaction?
include oxidation, reduction, and hydrolysis, increasing the drug’s polarity and preparing it for Phase II reactions- occurs mainly in the endoplasmic reticulum
72
What is a phase II reaction?
are conjugation reactions that covalently link the drug metabolite with a highly polar molecule, rendering it more even water soluble for excretion bile, feces, urine- occurs mainly in the cytoplasm
73
What are some enzymes involved in phase 1 reactions?
Cytochrome P450 (CYP) enzymes, Non-cytochrome P450 enzymes, Flavin-containing monooxygenase enzymes,
74
What is cytyochrome P450 enzymes?
Subclassifications to genotype and individual enzymes
| Involve both oxidative and reduction steps
75
What CYP450 metabolizes most anesthetic drugs?
CYP 3A4 (P450 3A4):
76
What is non cytochrome P450?
(Ex: monoamine oxidase, important in the metabolism of catecholamines as dopamine/NE- target for psychiatric drugs)
77
What can alter biotransformation?
by enzyme induction or inhibition
78
What is an example of induction?
phenobarbital, rifampin, phenytoin, prednisone
79
What is an example of inhibition?
grapefruit, simvastatin
80
What are enzymes of phase 2?
- Glucuronosyltransferases
- Glutathione-S-transferases (GST)- protects against oxidative stress
- N-acetyl-transferases (NAT)
- Sulfotransferases
81
What is the primary metabolic pathway of phase two?
Glucuronidation
82
What three drugs are metabolized by glucuronidation?
Propofol, Morphine and Midazolam
83
What is the active metabolity of midazolam?
active metabolite: 1-hyrdroxymidazolam
84
What is hepatic clearance?
A concept that characterizes drug elimination based on both blood flow and intrinsic clearance
85
What is the relationship of metabolism and drug concentration?
Metabolism increases proportionally with concentration as long metabolic rate <1/3 of max metabolic capacity (liver has limits- saturation)
86
What effects hepatic clearance?
Affected by liver disease, enzyme induction, flow
87
What are higher extraction ratios? What is an example of this phenomenon?
Some drugs have higher extraction ratios than others (example: propofol vs alfentanil)
What does this mean?
Drugs with higher extraction ratios (nearly 1)- flow to liver can reduce clearance; whereas flow has little influence on drugs with low extraction ratios. Anesthesia reduces blood flow to the liver thus can affect
88
What renal clearance?
Renal flood flow, glomerular filtration rate, and protein-binding affect amount of drug that enters the glomerulus for excretion.
89
What is factors of renal clearance?
Glomerular filtration
Active tubular secretion
Passive tubular reabsorption
90
What is potency?
Effective Concentration (EC50) is the dose required for an individual to experience 50% of the maximum effect.
91
What is efficacy?
the max effect that can be expected from a drug
92
What is effective dose?
Effective dose (ED50): dose of a drug required to produce a therapeutic effect in 50% of individuals
93
What is lethal dose?
LD50): dose of a drug required to produce death in 50% of patients receiving the drug
94
What is therapeutic index?
ratio between the LD50 and the ED50
95
What is LD50/ED50?
The larger the therapeutic index of a drug, the safer the drug is considered
96
What is therapeutic window?
Range of doses that produces a therapeutic response without causing any significant adverse effects in patients (toxicity)
97
What is therapeutic index?
The therapeutic window can be quantified by the Therapeutic Index
TD50
TI = -------
ED50
98
What is the TD50?
is the dose that causes a toxic response in 50% of the population
99
What is ED50?
is the dose of a drug that is therapeutically effective in 50% of the population
100
What can effect pharmacokinetics?
Bioavailability, renal/hepatic function, cardiac function, patient age
101
What is pharmacodynamics?
Enzyme activity, genetic differences and drug interactions
102
What are pharmacokinetic drug interactions?
Coadministered drugs affecting absorption, distribution, elimination of other
103
What are pharmacodynamic interactions?
Drug on drug interactions leading to synergism or antagonism of other
104
Describe the bonds of receptors from weakest to strongest.
van der Waals, hydrogen, ionic and covalent (rare)
105
What is G protein-couple receptors?
binds to extracellular substance and results in conformation change of the receptor (switch)
106
What is the process of G protein couple receptor transmission?
Signal to an intracellular molecule called a G protein comprised of a and BY subunits
- alpha dissociation from trimeric as bound GDP is exchanged for GTP
- subunits are active when bound to GTP, once GTP hydrolyzed back to GDP becomes inactive
107
What is the moa of G protein couple receptors?
To mediate intracellular effects as enzyme cascades or ion channels activation (Depending on the ligand)
108
What is an example of g protein couple receptors? What effect can opioids have on this?
Ga stimulates release of adenylate cyclase which converts ATP to 2nd messenger cAMP causing further enzymatic activities as protein kinase A> phosphorylation of glycogen to glucose (specific to epinephrine)
Opioids: decrease release of adenylate cyclase by the a subunit (decrease cAMP) and hyperpolaize a cell via ion channels through the By subunits (opioid u receptors are G protein
109
What is tolerance?
Requirement of higher doses to elicit a given response (occurs over time)
110
What effects tolerance?
increase clearance (enzyme induction),
drug receptor changes (ex. downregulation from persistent exposure (vs. sensitivity )
physical ADAPTATION
behavior tolerance
111
What is an example of a medication that promotes tolerance?
Opioids
112
What is sensitivity
where lower requirement needed (Up regulation of receptors after chronic blockade)
113
What is tachyphylaxis?
A rapid decrease in response to repeated doses (Same dose) over a short period
114
What are examples of drugs produce tachyphylaxis?
Ephedrine, local anesthetics
115
What are reasons that tachyphylaxis occurs?
Increased destruction of agonist, exhaustion of a transmitter, changes in binding (increase) of agonist to its receptors or receptor saturation
116
What does knowing about hysteresis allow us to do (3)?
Knowing about hysteresis allows us to optimize the dose, frequency and duration of exposure
117
What is classified as steady state or the goal of the third compartment model?
Basically 3 Volumes of distributions with varying clearance constants and varying rates of distribution (concentration gradients) that are occurring simultaneously until drug is removed from system. Maintaining equilibrium among the subcompartments is achieving a steady state after a bolus (goal for infusions).
118
What is the relationship between zero order kinetics and elimination half life?
the elimination half life is dependent on the initial drug concentration and rate constant
119
What is the relationship between first order kinetics and elimination half life?
half life is not dependent on concentration: constant rate (length of half life will be constant)
120
What is an example of a drug that is effected by pulmonary uptake?
Fentanyl is an example of a drug influenced by pulmonary uptake (microvascular endothelial cells), especially at lower doses (pulmonary site saturable at higher, repeated doses for fentanyl with less extraction).
121
What must steady state account for?
The steady state for oral drugs and other routes must account for fraction of bioavailability due to first pass hepatic effect (especially oral),
122
What is the rate of elimination for drugs with small central compartments and rapid clearance?
Drugs with small central compartment and rapid clearances are cleared rapidly regardless size of peripheral compartment or how long the infusion (remifentanil; propofol).
123
What is the rate of elimination for drugs with large central compartments and slow clearance?
eliminated much slower.
124
What happens to weak acids in an alkaline environment?
Weak acids excreted more rapidly in alkaline urine (alkalization created more ionized form of the drug and can’t be reabsorbed- Trapped. (example: NaBicarb given for aspirin toxicity)
125
Age ______ correlated to renal blood flow and creatine clearance
Age inversely correlated to renal blood flow and creatine clearance
126
Two drugs can have the same C50 but different ______
EFFICACY
