Uptake & Distribution Flashcards
1
Q
Define Pharmacodynamics
A
What drug does to the body
- Mechanism of effect
- Sensitivity
- Responsiveness
2
Q
Define Pharmacokinetics
A
What your body does to the drug
- Absorption
- Distribution
- Metabolism -liver
- Excretion - kidneys
3
Q
Commonly measured parameters of injected drugs are?
A
- Elimination half-life
- Bioavailability
- Clearance
- Volume of distribution Vd
4
Q
Define the Compartmental Model
A
Divides body into two compartments that represent THEORETICAL spaces with CALCULATED volumes.
- Central
- Peripheral (reservoir)
5
Q
Which compartment has a RAPID uptake of a drug?
A
Central
6
Q
Which compartment is made up of highly perfused tissues and intravascular fluid?
A
Central
7
Q
Which compartment is the drug FIRST introduced into
A
Central
8
Q
Which organs make up the central compartment?
A
Kidney, lungs, liver, heart, brain
9
Q
How much CO does the central compartment receive?
A
75%
10
Q
How much CO does the peripheral compartment receive?
A
25%
11
Q
How much body mass does the Central compartment contain?
A
10%
12
Q
How much body mass does the reservoir contain?
A
90%
13
Q
What causes a decrease in the rate of transfer between the Central compartment and the Peripheral compartment?
A
Aging
14
Q
Why do you decrease dosage of drugs (eg Thiopental) in the elderly?
A
There is a lag due to the slowed rate of transfer between compartments leading to a greater plasma concentration in certain drugs.
15
Q
What happens when the plasma drug concentration declines below tissue drug concentration?
A
the drug leaves the tissues and re-enters the circulation
16
Q
Why do you shut off anesthetic gases/TIVA early in the obese population?
A
Fat acts as a reservoir that maintains plasma concentration and prolongs the effect of a drug.
17
Q
What effect can large or repeated doses of a drug have on redistribution?
A
Negate redistribution, prolonging duration of action by saturating inactive tissue to a point where effect depends on metabolism of the drug rather than redistribution.
18
Q
What body tissues make up the peripheral compartment?
A
Muscle groups, Fat group, Vessel-poor group
19
Q
Lungs act as a reservoir for what kind of drugs?
A
Lipophilic drugs (lidocaine, fentanyl, Demerol)
20
Q
What drugs do not cross the blood-brain barrier into the brain circulation?
A
Ionized, water soluble drugs.
21
Q
What drugs CAN cross the Blood-brain barrier?
A
Lipophilic drugs
22
Q
How do you overcome the blood brain barrier? (4 ways)
A
- Large doses of drug
- Head injury
- Hypoxemia
- Old age
23
Q
What is the Biophase?
A
Also called the “effect site”, where drugs exert their biological effect. The immediate milieu where drugs act upon the body including:
- Membranes
- Receptors
- Enzymes
24
Q
What is the biophase of muscle relaxants?
A
Muscles
25
What is the biophase of anesthetics?
The brain (effect site)
26
What is the rate constant of drug elimination from the effect site/biophase ? (I.e. rate eliminated from the brain if the drug is an anesthetic)
Ke0
27
Formula for Vd?
Vd = (Dose of IV drug) / (plasma concentration before elimination)
Eg: dose 50mg, plasma conc prior to elimination 10mg/L
(50mg) / (10mg/L) = 5L Vd
28
What is Volume of distribution Vd?
Sum of all the volumes of the theoretical compartments that constitute the Compartmental Model. How quickly does the dose occupy space.
29
Vd is influenced by? (3 things)
1. Lipid solubility (matters most)
2. Binding to plasma proteins
3. Molecular size
30
What is lipid solubility? How does it contribute to Vd?
More lipophilic = more Vd (quicker it can distribute to all spaces in the body). Matters more than protein binding.
Eg: drug is highly protein bound but super lipophilic, available drug will have a large effect.
31
How does binding to plasma protein effect Vd?
Highly bound drugs cant cross membranes (BBB) = lower Vd. Drugs that are bound to plasma proteins will UNBIND as elimination begins.
32
How does molecular size affect Vd?
Smaller size = higher Vd (can cross the BBB readily)
33
Time necessary for plasma[] of drug to decline 50% during the elimination p0hase
Elimination half time
34
Elimination half time is ______ (direct/indirect) proportional to its Vd
Directly
35
Elimination half time is _______ (independent/dependent) on the dose of drug administered
Independent
36
Time necessary to eliminate 50% of the drug from the body
Elimination half-life
37
What happens if dosing intervals are less than the elimination half times?
Drug accumulation
38
What happens when the plasma [ ] decrease doesn’t parallel its elimination from the body?
Elimination half time and elimination half life are NOT equal
39
Elimination half life is always greater than elimination half time (True/false)
True; plasma [ ] will always be less than the total body [ ]
40
If a drug undergoes 3 half-times, what percent of initial amount is eliminated?
87.5
3 half-times; 1/8 is the fraction of initial amount remaining... so 7/8 has been eliminated... 7/8 = 87.5
41
Why is the distribution phase part of the Plasma Concentration Curve so rapid?
Rapid drop as the drug goes from the central —> peripheral compartment
42
What does the Beta distribution part of the Plasma Concentration Curve represent
Elimination phase
43
Context sensitive half-time refers to ____
Discontinuing an IV infusion.
44
Define context-sensitive half-time
Time required for plasma [ ] of a drug to decrease by 50% after discontinuation of drug administration.
45
What does the context sensitive half time depend on?
1) Distribution
2) Excretion
3) Physiochemical properties (lipid solubility, size, protein binding) of the drug
4) length of infusion
46
Systemic absorption (regardless of route) depends on ___
The drug’s SOLUBILITY
47
The most convenient & most economic route is ______
PO
48
Disadvantages of the PO route in terms of drug absorption
1. Emesis
2. Destruction by enzymes (1st pass effect) or acidic gastric fluid
3. Irregular absorption w. Food or other drugs.
49
Define the First pass effect
Drugs absorbed via the GI system enter the portal venous blood flow and pass through the liver before entering the systemic circulation. Here they are extensively extracted and metabolized
50
How do drugs absorbed in the GI system get to the liver?
Via the portal venous blood supply
51
Which routes bypas the liver and prevents the first pass effect?
Sublingual, transmucosal, IV, Rectal (distal rectum), transdermal
Anything that avoids the GI system
52
Punctured nifedipine capsules & CBD oil are examples of what kind of route? What is the benefit?
Sublingual; prevent the first pass effect
53
Which route provides a sustained therapeutic plasma [ ] of a drug?
Transdermal
54
How does transdermal absorption work?
Drug enters via sweat ducts & hair follicles which function as diffusion shunts.
55
What is the rate-limiting step in transdermal absorption?
Diffusion across the stratum corners of the epidermis. Thickness and blood flow are factors reflected in the skin’s permeability for drugs.
56
Proximal vs Distal rectum
Proximal —> GI, portal system, liver = First pass effect
| DIstal —> bypasses portal system
57
Why is the rectal route unpredictable?
Distal vs proximal administration ... if the drug is too far in (proximal) then it is susceptible to the first pass effect.
58
Which route will achieve therapeutic plasma levels precisely & rapidly
IV
59
Which form (ionized/non-ionized) of a drug can diffuse across lipid cell membranes (BBB, renal, tubules, GI epithelium, hepatocytes)?
Non-ionized, lipid soluble
60
Which fraction of a drug is pharmacologically ACTIVE
Non-ionized form
61
Which form a drug will undergo re-absorption across renal tubules, absorbed from the GI tract and metabolized by liver?
Non-ionized
62
Which form of a drug is excreted by the kidneys unchanged?
Ionized
63
Why cant ionized drugs cross the lipid cell membrane?
Repelled from portion of the cell with similar charges.
64
Weak acid drug is administered to an acidic patient... should you increase or decrease the dose? Why?
Decrease dose since less ionization is happening.
65
A weak base drug is administered to an acidic patient. Should you increase or decrease the dose? Why?
Increase dose due to increased ionization of drug.
66
What does the degree of ionization depend on?
Dissociation constant pK of drug & pH of surrounding environment
67
How does ion trapping happen?
A membrane separates two different pH environments, once a drug crosses the membrane (i.e. placenta) into a more acidic/basic environment and ionizes in the new environment it wont cross back over the membrane and end up building up (in the fetus) in its ionized form (can eventually be excreted by kidneys of baby, however since the BBB may not be fully developed, the ionized form may cross the BBB when its not supposed to)
68
What protein binds to acids?
Albumin
69
What protein binds to bases
Alpha acid glycoproteins
70
Which form of a drug will readily cross the cell membrane? (Protein bound/unbound)
Unbound
71
What happens to protein binding when plasma [ ] of drug decreases?
The drug will unbind from the protein and become available
72
True/False More protein binding = longer effect
True (generally) - because if drug is protein bound, it cant cross into the liver for elimination so it stays around longer until it is unbound.
73
When can a protein-bound drug be metabolized/excreted?
Once it unbinds
74
Vd is ___ (direct/inversely) proportional to protein binding
Inversely
75
Which drugs will be markedly effected by alterations in protein binding?
Highly protein bound drugs: Warfarin, propranolol, phenytoin, diazepam
76
Define clearance
Volume of plasma cleared of drug by metabolism and excretion
77
When drug administered (in therapeutic dose ranges) is cleared at a rate PROPORTIONAL to the amt drug present in plasma... this is
1. First order kinetics
2. Zero order kinetics
First order kinetics
78
When drug administered exceeds metabolic or excretory capacity of the body to clear drugs and a CONSTANT AMOUNT of drug is cleared per unit of time (eg 2mg/hr) this is
1. First order kinetics
2. Zero order kinetics
Zero order kinetics
79
Drugs who clear via Zero Order Kinetics principle
ASA, DIlantin, ETOH
80
When hepatic extraction is higher than 0.7, the clearance of the drug will depend on_____
Hepatic blood flow
| “Perfusion-dependent elimination”
81
If hepatic extraction ratio is less than 0.3, ____ and ____ will aid in hepatic clearance
Decrease in protein binding & Increase in enzymatic activity
“Capacity - dependent elimination”
Changes in hepatic blood flow will have minimal changes in its clearance.
82
Most important organ for elimination of unchanged drugs or their metabolites
Kidney
83
Water soluble compounds are excreted ____ (more/less) efficiently by kidneys than lipid soluble drugs
More
84
Usually a drug has to be _____ or ______ to be excreted via urine
Ionized or SMALL lipophilic
Lg lipophilic drugs will be reabsorbed... unchanged drug is not excreted in urine.
85
How do you turn a lipophilic drug into a form where it can be excreted?
Metabolize it! Bio transformation from pharmacologically active into water soluble/inactive/ionized form.
86
What does it mean if a drug is X amount “excreted unchanged”
Portion will never have an effect (ionized) and will go straight to the kidneys for excretion (be aware of pats with Kidney failure!)
87
Increased water solubility ___ (inc/dec) the Vd of a drug and enhances renal excretion
Decreases
88
Why is metabolism not equal inactivation/detox of a drug?
Some metabolites are active
89
4 pathways of metabolism
1. Oxidation
2. Reduction
3. Hydrolysis
4. Conjugation
90
What happens in Phase 1 of metabolism
oxidation, reduction, hydrolysis
91
What happens in Phase II of metabolism
Conjugation
Drug interacts with endogenous substrate to form water soluble CONJUGATES —> excreted by kidney
92
Sites of metabolism
1. Plasma
2. Kidneys
3. Lungs
4. GI tract
5. Liver
93
What enzyme is responsible for metabolism of most drugs in the liver? Where is it located?
Hepatic microsomal enzymes
Located in the hepatic smooth ER
Eg: Cytochrome P-450
94
6 isozymes of cytochrome P-450 involved in drug metabolism?
CYP1A2, CYP2D6, CYP2C19, CYP2E1, CYP2C9, CYP3A
CYP: 1a2, 2d6, 2c19, 2e1, 2c9, 3a
95
What may be a reason a patient has “treatment resistant depression”? Or when cancer therapy is not working for a patient.
Patient does not have the proper hepatic microsomes isozyme (1 of the 6 CYP450) of the metabolic pathway to interact with drug (body wont react with it even if we are technically talking about metabolism)
96
How does ETOH effect the dosage other drugs in a patient who is a frequent drinker?
Must INC dose b/c ETOH is an Enzyme Inducer
Repeated exposure to ETOH will stimulate the activity of enzymes...so other drugs that follow the same pathway as ETOH will be exposed to more enzymes that break it down hence larger dosages required. Larger doses of drugs and larger doses of ETOH required for desired effect.
97
Which enzymes are involved in Oxidation, Reduction + Conjugation of drugs
Hepatic microsomal enzymes
98
Which enzymes are involved in Hydrolysis (of ester bond) of drugs?
(Also does conjugation, oxidation and reduction)
Non-microsomal enzymes
| versus hepatic microsomal enzymes that do oxidation, reduction and conjugation only
99
Which enzyme is present in Liver (mostly), plasma & GI tract?
Non-microsomal enzyme
100
Which enzymes do NOT undergo enzyme induction?
Non-microsomal enzymes
| Vs hepatic microsomal enzymes that DO
101
What is it called when you increase the concentration of receptors? Decrease?
```
Increase = up-regulate
Decrease = down-regulate
```
102
Why is it wrong to simply take someone off beta blockers after a while?
They have up-regulated their concentration of beta receptors in response to beta blockers... can cause a hypertensive crisis.
103
Taking growth hormone leads to small testes due to __
Down-regulation.
| Exogenous form of growth hormone causes the body to down-regulate the receptors.
104
State of Receptor Activation Theory states:
Non-activated receptors can be activated by the drug.
105
Receptor occupancy theory states:
The more receptors occupied by the drug the greater the effect.
106
Non-receptor drug action
When there is no receptor-drug interaction eg: chelating drugs form bonds with metallic cations. Antacids neutralize gastric acid by a direct action.
107
Agonist drug vs antagonist drug
Agonists mimic molecule and activate the SAME receptor sites causing SIMILAR effect. Eg: opioid/mu receptor
Antagonists bind to SAME receptor and change configuration of site therefore PREVENTING effect from cell signaling molecules. Eg: betablocker
108
How does chemical structure affect drugs?
Minor modifications in structure (stereochemistry) may result in drastic change in pharmacological properties. Interaction/ with biological receptors can differ greatly even to a point of no binding. Potency can be very different (ephedrine). Side effects can be different.
109
Efficacy vs Potency
Efficacy - ability of drug to produce desired effect
| Potency - relationship between effect and dose necessary to achieve effect
110
what is the median EFFECTIVE dose?
ED 50
| Dose at which 50% of people will get the effect
111
What is the median LETHAL dose?
LD 50
| dose at which 50% will die
112
How do you estimate the clinical therapeutic index?
Ratio of LD50 to ED50 will suggest how selective that drug is in producing its desired effect
113
Define a Hyper-reactive patient
People in whom a LOW dose of drug produces its expected pharmacologic effect
Eg: low dose in Asian population
114
Hypersensitivity
Allergic
115
Additive effect
When 1+1=2
| The second drug acting with first produces equal summative effect.
116
Synergistic effect
1+1=3
| Two drugs produce an effect greater than their sum
