Basics of Pharmacology Pharmacokinetics Part I Flashcards
Pharmacodynamics, Pharmacokinetics
1
Q
6 concepts of pharmacokinetics measurementsVECBEC
A
Bioavailability Volume of distribution Clearance Elimination Context-sensitive half-time Effect site equilibration time
2
Q
What are two concepts more useful to the anesthesia providers more than elimination half-life?
A
Context sensitive half time
Effect-site equilibration time
3
Q
Define Absorption
A
Is the passage of the drugs through physiological and biological membranes before reaching the systemic circulation
4
Q
What happens when drugs are given extra-vascularly? What must take place?
A
Absorption
5
Q
Define Pharmacokinetics? List the four processes that is studies?
A
It is the quantitative study of Absorption, Distribution, Metabolism, and Excretion of the drug and its metabolites
6
Q
Pharmacokinetics is what the______does to the ______
A
Body ; drugs
7
Q
Pharmacokinetics is the relationship between the
A
Drug dose and concentration in plasma or at the site of action
8
Q
Systemic absorption depends on multiple physiochemical properties of the drug : What are 4 physio-chemical properties of the drugs that absorption depends on (2 most important first) DDMP
A
a) Drug lipid solubility
b) Degree of Ionization of the drugs
c) Molecular size
d) pKa
9
Q
The anatomy and physiology functions at the site of absorption may also affect absorption? how?
A
Cell membrane
pH at the site of absorption
Surface area at the site of absorption
Blood flow to the site of absorption
10
Q
What form of the drug can pass through the cell membrane? Ionized or non-ionized? Why?
A
NON-IONIZED: Because the non-ionized form is lipophilic.
11
Q
REMEMBER: The cell membrane is highly permeable to _______ ______substances
A
Lipid soluble
12
Q
Define passive diffusion? Is energy required from passive diffusion?
A
It is the PASSIVE movement of molecules from an area of high concentration to an area of low concentration.
NO
13
Q
What is the main process by which most drugs cross the cell membrane ?
A
Passive diffusion
14
Q
What determines the driving force of passive diffusion ? The greater the concentration , the (slow/fast) ______the movement
A
it is the difference in drug concentration between the 2 sides of the cell membrane.
15
Q
What does the Fick’s Principle or Law describes?
A
The rate of transfer of drug molecules across the membrane.
16
Q
The rate of diffusion across a membrane is calculated by which formula? Explain variables
Q/t? K? A? Cp ? Ct? D?
A
Q/t = KxAx (Cp - Ct) / D
q/t : rate of diffusion
K: Diffusion coefficient
A: Surface area of the membrane over which the drug may be absorbed
Cp - Ct is the concentration gradient , (P) plasma and (t) tissues
D: The thickness of the membrane.
17
Q
2 additional factors affecting rate of diffusion?
A
Molecular size and Blood flow
18
Q
How does solubility affect the rate of diffusion?
A
The greater the lipid solubility, the faster the rate of diffusion
19
Q
Define ACTIVE TRANSPORT? is energy needed for active transport?
A
Active transport is the movement of molecules from an area of low concentration to an area of high concentration. YES, ATP or other molecules
20
Q
What is the movement of molecules against a concentration gradient?
A
ACTIVE TRANSPORT
21
Q
Active transport requires a ________that bind to the drug and to form a _______ -______Complex that shuttles the drug across the membrane then dissociates on the other side of the membrane/
A
CARRIER, drug-carrier
22
Q
IMPORTANT: _______ _______(2) Plays an important role in ______ and _______ secretions of drugs and their metabolites.
A
ACTIVE TRANSPORT
Renal and biliary
23
Q
What is the difference between facilitated diffusion and PASSIVE Diffusion? How are they similar?
A
Facilitated diffusion requires a carrier? They both move drugs molecules from area of high concentration to an area of low concentration.
24
Q
Weak acids and weak bases are administered in solution as _______ forms of the drugs
A
SALTS
25
Characteristics of Ionized vs non-ionized drug molecules: Pharmacological effect : Ionized (Y/N) non-ionized (Y/N)
I -> NO
| NI -> YES
26
Characteristics of Ionized vs non-ionized drug molecules: SOLUBILITY
I --> WATER
| NI -->LIPIDS
27
Characteristics of Ionized vs non-ionized drug molecules: CROSS LIPID BARRIERS (BBB, GI, Placenta)
I -->NO
| NI--> YES
28
Characteristics of Ionized vs non-ionized drug molecules: RENAL EXCRETION
I -->YES
| NI--> NO
29
Characteristics of Ionized vs non-ionized drug molecules: HEPATIC METABOLISM
I -->NO
| NI--> YES
30
IMPORTANT: Identifying weak acids and bases with drug names: Weak ACID (donate/accepts)______hydrogen ions and combine with (cation/anion)
to form ________. The name of the ______is written first, followed by the name of the _________
Donate hydrogen ion
Combine with CATION
Salts
Cation is written first, followed by the salt from of the drug
31
Give 2 examples of salt form of weak acids?
sodium Thiopental
Naproxen sodium
Phenytoin sodium
Any drug starting with "sodium...." "calcium...." magnesium..."
32
IMPORTANT: Identifying weak acids and bases with drug names: Weak BASE (donate/accepts)______hydrogen ions and combine with (cation/anion)
to form ________. The name of the ______is written first, followed by the name of the _________
Accepts hydrogen ion
Combine with ANIONs
Salts
Name of the salt form of the drug is listed followed by the anions
33
3 examples of salt form of weak bases ?
Lidocaine HCL
Bupivacaine HCL
Mepivacaine HCL
34
Morphine sulfate is a weak (acid or base ) ? think about the charge of sulfate..
Base
35
What is the function of the Henderson Hasselbach Equation?
Helps predict the degree of ionization of a drug in solution, given the pH of the solution and the pKa of the drug.
36
General formula of the Henderson Hasselback Equation?
pH = pKa + log [base/acid]
37
General formula of the Henderson Hasselback Equation for weak acid?
pH = pKa + log [A-] / [AH]
38
General formula of the Henderson Hasselback Equation for weak acid?
pH = pKa + log [B] / [BH+]
39
What characteristics of the drug determines the relative amount/fraction of the drug in the ionized /non-ionized form Also affects
pH
| Absorption and the drugs onset of action
40
What are 2 examples of drugs that we cannot determine whether or not they are acids or bases based solely on their names?
Propofol
| Etomidate
41
Define pKa?
It is the pH at which, the drugs is 50% iodized and 50% non-iodized.
42
When the pH = pKa?
50% of the drug is iodized and 50% of the drug is non-iodized
43
The lower the pKa --> the _______ acid ;
Stronger
44
the Higher the pKa --> the ______base;
base
45
GENERAL PRINCIPLE
- when the pH < pKa, the ____________ or_____ form dominates
- when the pH > pKa, the Fa__________or _________form dominates
NON-IONIZED form or PROTONATED
| IONIZED FORM or UNprotonated form dominates
46
IMPORTANT: For weak ACID, when the pH is LOWER than the pKa, the __________form dominates
non-ionized form
47
IMPORTANT: For weak ACID, when the pH is LOWER than the pKa, the __________form dominates
non-ionized form (lipid soluble)
48
IMPORTANT: For weak ACID, when the pH is HIGHER than the pKa, the ___________form dominates
IONIZED form (water soluble)
49
IMPORTANT: For weak BASE, when the pH is LOWER than the pKa, the ___________form dominates
IONIZED (water soluble)
50
IMPORTANT: For weak BASE, when the pH is HIGHER than the pKa, the ___________form dominates
Non-ionized form (lipid soluble)
51
REMEMBER: The nonionized portion of the drug is more ________soluble therefore can cross the membrane
lipid
52
If a patient with has an altered pH or the tissues where the drug is being administered is altered, what will happen?
refer to pka and ph relationships in both weak acid and weak bases
53
What is the most important determinant of Drug distribution?
Lipid solubility
54
The more lipid soluble _________ (smaller, larger) volume of distribution.
The LARGER the volume of distribution
55
What is Distribution?
The passage of drugs from the bloodstream to the body tissues and organs
56
What is the VOLUME OF DISTRIBUTION? (IMPORTANT)
IMPORTANT: Relates the amount of drug in the body to the measured concentration in the plasma or blood
57
EASIER youtube definition of Volume of distribution?
How extensive the drugs is distributed to the rest of the body when compared to plasma or blood.
58
What is the formula for Vd?
Vd = Dose (Amount of Drug)/ Concentration
59
VD Definition you tube
Ratio of the total amount of drug in the body TO the CONCENTRATION In Plasma
60
Knowing the Vd allows you to estimate: (PAT)
Peak serum levels of the drug following an
IV bolus
Amount of drug in the body
The clearance of a drug
61
Vd is IMPORTANT because it determines the ________dose of the drugs required to achieve a particular ______ _______ _________immediately after the dose is administered
Loading; steady state concentration of the drug
62
Describe the relationship of Vd to Protein binding
Vd is INVERSELY PROPORTIONAL to protein binding
63
The extent of protein binding is directly related to_________
LIPID SOLUBILITY
64
As protein binding increases, drug clearance ________
| } as protein binding decreases, drug clearance ________
decreases
| increases
65
What is the major Plasma proteins that bind to ACIDIC drugs?
ALBUMIN
66
What is the major plasma proteins that bind to BASIC drugs.
Alpha 1 Acid GLYCOPROTEIN
67
Proteins plasma that bind to drug include
```
AALIE
Albumin
Alpha 1 Acid glycoprotin
Liproprotein
Immunoglobulin
Erythrocytes
```
68
For a drug metabolized by the liver, binding to plasma proteins prevents the drug from entering the __________ (what cells) resulting in
(increased/decreased )drug metabolism
decreased
69
List 4 drugs that are highly protein bound?
Propanolol
Diazepam
Phenytoin
warfarin
70
Alterations in protein binding are only important for drugs that are highly
protein bound.
PROTEIN BOUND
71
True or False: Drug metabolism can result in the formation of inactive metabolites OR active metabolites whose
pharmacologic activity is equal to, greater than, less
than, or completely different from that of the parent
drug
True
72
What is the primary organ responsible for drug metabolism
Liver
73
The majority of drugs is catalyzed by the _________ ________system
CYP 450 enzymes system
74
Most, but not all, anesthetic drugs are cleared by _________ -___________
Hepatic biotransformation
75
__________must be metabolized by several liver CYP 450 enzymes to its active metabolite
Clopidogrel
76
PRODRUGS
Inactive, until metabolized into active metabolites
77
What is the net effect of METABOLISM
the net effect of metabolism is to render drugs more POLAR, and into WATER SOLUBLE METABOLITES so that they can be excreted through the kidneys
78
When Lipid-soluble pharmacologically active drug is converted into more water-soluble and often pharmacologically inactivemetabolites. This results in:
________ (inc/Dec) vd and ______ (inc/dec)clearance by the _______ and _________
Decrease in the Vd in the body
| Increase clearance by the kidneys and liver.
79
What does the enzyme of a phase I reaction do?
It introduces the drug or expose a functional group that makes the drug more water soluble
80
What does the net effect of phase I reaction in terms of phase II and excretions
Phase I reaction prepare the drug for phase II conjugation reaction or excretion
81
Phase I reactions generally result in drug (activation/inactivation) __________although this is not always the case, for example__________
inactivation: Prodrugs
82
Enzymes responsible for phase I reactions are called
Phase I enzymes
83
What is the main enzyme responsible for phase I reactions?
Cytochrome P450 Enzymes family
84
The enzyme systems involved in phase 1 reactions are located PRIMARILY in the _______ _____(organelles)
ENDOPLASMIC RETICULUM
85
List most common enzymes in phase I reactions
Hepatic microsomal enzymes: CYP and
Flavin containing monooxygenases (FMOs)
Non-Hepatic microsomal enzyms: Alcohol dehydrogenase
86
What are the hepatic microsomal enzymes in phase I reactions
CYP 450 and FMO(flavin containing monooxygenases)
87
What are the NON-hepatic microsomal enzymes in phase I reactions
Alcohol dehydrogenase
88
Phase I Reactions all require
Oxygen
NADPH
NADPH Cytochrome p450 reductase
89
The CYP 450 oxidation reaction process splits _______one_______atom goes to form H2O and the other produces an oxidized molecule of drug (R=O)
oxygen ; oxygen
90
Examples of oxidative metabolism reactions include:
Hydroxylation (midazolam)
Deamination (remove amine (-NH3)
Desulfuration (remove sulfur (-S)
Dealkylation (remove -CH3) (Morphine -->Normorphine)
91
_________system is essential for _________ reactions
Cyp 450; reduction
92
Reduction: Occurs under_______oxygen states and CYP 450 enzymes transfer electrons directly to a substrate
low
93
Define hydrolysis?
reaction that add water to a molecule making the molecule more water soluble.
94
is CYP 450 involved in HYDROLYSIS REACTIONS
NO
95
Involved in hydrolysis reactions,name 2 enzymes and what they do?
Esterase (hydrolysis of ester bonds)
| Amidase (hydrolysis of amide bonds )
96
What are they types of Phase I reactions
Oxidation
Reduction (occurs in low oxygen states)
Hydrolysis
97
Meperidine and local anesthetics (i.e.: lidocaine HCl, cocaine HCl) all undergo what kind of reaction? ________ does it require CYP 450 enzymes?
all undergo hydrolysis reactions
98
Phase I hydrolysis of succinylcholine by_______ __________
plasma
| butyrylcholinesterase
99
Phase II conjugation reactions involve the addition of an
| _______ ________called __________agent onto another molecule
ENDOGENOUS Susbstrate; conjugating agent
100
3 examples of conjugating agents
Glucuronic acid
Glutathione
Glycine
101
What is the net effect of the binding of a conjugating agent to the drug?
The drug become highly polar and THERE IS A COVALENT BOND to facilitate excretion through kidney or bile
102
Conjugation reactions increase ______,_______,-_______ of the drugs.
Hydrophilicity, detoxification and excretion
103
What is the most common type II conjugation reaction
GLUCURONIDATION
104
Glucuronidation is an important metabolic pathway for several drugs used during anesthesia, _______ ,________,_______
propofol, morphine, and
| midazolam
105
All of the phase II reactions occur in the _______, with the exception of glucuronidation which occurs in the ________ _______
cytosol; endoplasmic reticulum
106
*****Phase II reactions generally (begin/Terminate) -_________the biological activity ofthe drug, however, there are some exceptions to this rule. Morphine undergoes a ____________reaction to form the __________ which is a more _______ opioid than morphine itself.
terminate; glucuronidation ; 6-glucuronide metabolite; potent
107
Name other phase 2 REACTIONS other than glucuronidation
| MAGS
Methylation
Acetylation
Sulfation
Glutathione conjugation
108
All phase II reactions occur in the __________while GLUCURONIDATION occurs in the ___________
Cytosol; Endoplasmic Reticulum
109
Weak acids are excreted RAPIDLY in ______(base/acidic) urine. why?
Base or ALKALINE; Because alkalinization of the urine results in more IONIZED drug that cannot be reabsorbed (reabsorption only lipid soluble ions) but can readily cross the renal membrane (Because they are ionized)
110
Renal blood flow and Creatinine Clearance is inversely correlated with _____
Age
111
Pharmacokinetics assume that plasma will
equillibrate with an effect compartment to produce pharmacodynamic activity.
112
ph of plasma ~7.4, favoring the
IONIZED FORM of the drug.
113
If you're using a local anesthetics, and the skin is inflammed? is it the same pH
Inflammed skin may have different pH
114
Ion trapping mechanism
1. Concentration difference develop on two sides of the membrane that separates fluids with different pH's
2. because of the pH difference, the degree of ionization of a drug is also different on each side of the membrane
3. the non-ionized lipid-soluble fraction of a drug equilibrates across cell membranes but the total concentration of drug is very different on each side of the membrane because of the impact of pH on the fraction of drug that exists on the ionized form.
115
Explain the ion trapping mechanism
1. Concentration difference develop on two sides of the membrane that separates fluids with different pH's
2. because of the pH difference, the degree of ionization of a drug is also different on each side of the membrane
3. the non-ionized lipid-soluble fraction of a drug equilibrates across cell membranes but the total concentration of drug is very different on each side of the membrane because of the impact of pH on the fraction of drug that exists on the ionized form.
116
Acetylsalicyclic acid is a weak organic acid with pKa of 3.5. what form of ionization will predominate at physiologic ph =7.4
Since the pH>Pka the weak acid drug Acetylsalicylic acid will exist PREDOMINATELY in it IONIZED FORM at physiologic pH
117
Base molecules in an ACIDIC environment will stay _______ and will/will not ____cross membranes
IONIZED; not
118
Base molecules in a more ALKALINE ph will become _________ and will/will not ______cross membranes
non-ionized
119
Examples of ion trapping
Local anesthetics via epidural can cross placenta. Become trapped in the fetus and accumulate because the fetus is more acidic than the mother pH .
120
Fetal pH _____ than the mother pH. can lead to ____ toxicity
lower; fetal
121
The _____ -soluble _____fraction of local anesthetics crosses the placenta is converted to the poorly lipid-soluble ________fraction in the more ______environment of the fetus.
The ionized fraction in the fetus can/cannot easily cross the placenta to the maternal circulation and thus is effectively "trapped" in the fetus But the conversion of the NON-IONIZED To IONIZED
lipid; non-ionized; ionized; acidic
Cannot; "trapped"
Maintains a gradient for continued passage of local anesthetics from mom into the fetus.
122
________ _______and fetal_______ wil most facilitate
trapping of local anesthetics in the fetus.
123
To increase urinary excretion of weak acid and weak base you do what ? why?
you need to change the urinary pH to favor the charged form of the drug .
Because the charged form of the drug cannot readily pass through biological membranes and will not be reabsorbed from the nephron.
124
Weak acids are excreted faster in ? why? what do you do then ?
ALKALINE pH; because anion form favored; ALKALINIZE the urine
125
Weak bases are excreted faster in ? why? what do you do then ?
ACIDIC pH: because cation form favored; so you ACIDIFY the urine.
126
2 drugs with LARGE FIRST PASS HEPATIC MECHANISM? what does it cause
Lidocaine
Propofol
Different IV and PO doses
127
What happens during first pass mechanism
Enzymes in the intestinal flora, intestinal mucosa, and liver can metabolize prior the medication reaching the systemic circulation
128
When drugs are given EXTRAVASCULAR what must take place for the drug to reach the systemic Circulation
ABSORPTION MUST TAKE PLACE>
129
Drugs administered intravascularly have a bioavailability of
100%
130
Oral administration is the most _______ and _______.
convenient and common
131
For most drugs, the optimum site for drug absorption after oral administration is the_______ _______ _____ why?
DUODENUM REGION OF THE UPPER PORTION of the SMALL INTESTINE
because increased surface area due to presence of MICROVILLI
Highly perfused with capillaries.
132
Route of administration with most predictable plasma concentrations
IV
133
What explains why SUBLINGUAL NTG is effective and oral NTG is ineffective
VENOUS DRAINAGE into the superior vena cava bypass the liver and AVOIDS first pass hepatic effect.
134
Sustained therapeutic plasma concentration with decreased peak and valley route____daily dose
TRANSDERMAL ;10mg
135
Transdermal absorption dependent one:
STRATUM CORNEUM THICKNESS rate limiting step accross layer
136
Drugs administered in the proximal rectum are absorbed into the _________ and distal rectum admin bypass _______
SUPERIOR HEMORRHOIDAL VEINS
| first pass effect.
137
Determinants of drug distribution include
```
Lipid solubility : more better distribution
Protein binding
Blood flow rate to the tissue
Molecular size of the drug
Degree of ionization .
```
138
It is the only the ____, _____ drug that is available to cross membranes into tissues
Free, unbound
139
Vd is the ____parameter which relates the ______ __ ______ to the Measured _________in the _________
Pk: amount of drug; concentration in the plasma
140
High protein binding limits_______ ________ to leave the plasma and penetrate organs
Protein binding
141
Highly plasma protein binding drugs are contained in plasma and have ______ Vd comared to drugs with low binding to plasma proteins
SMALLER
142
The fraction of total drug plasma that is bound to protein is determined by
Plasma concentration of drug
Affinity of binding sites for the drug
The number of proteins binding site
143
Know ______before you administer phenytoin
ALBUMIN LEVEL
144
For drug metabolized by the liver, binding to plasma proteins prevents the drugs
from entering hepatocytes resulting in decreased drug metabolism
145
For highly protein bound drug are _____molecules and they are unable to diffuse through capillaries as a result, _____ drugs is able to under _____ _______
LARGE: less drugs is able to undergo glomerular filtration
146
Drug metabolism can result in the formation of _______ _______OR _____ metabolites whose pharmacologic activity is
equal, greater than, less than or completely different from parent drug.
147
For LOW protein bound drugs changes in protein binding are not as
CLINICALLY SIGNIFICANT
148
2 drugs metabolized through HOFFMAN ELIMINATION
CISATRACURIUM
| ATRACURIUM
149
PRIMARY net effect of DRUG METABOLISM
production of more polar, water-soluble metabolites that are MORE EASILY EXCRETED From the BODY.
150
When metabolism transformed meds from lipid soluble to water-soluble what happens?
Decrease in the Vd
| Increase clearance by liver and the kidney.
151
2 drugs with active metabolites
DIAZEPAM
| MEPERIDINE
152
This drug _________Must be metabolized by several Liver CYP450 enzymes to its active metabolites
CLOPIDOGREL.
153
Pathways of drug metabolism may be divided into 2 MAJOR GROUPS of reactions
Phase I functionalization reactions
| Phase II CONJUGATION REACTIONS
154
_________ of morphine to _______ which is the ______ ______
Demethylation; NORMORPHINE; active metabolites.
