Uptake and distribution of Iv Agents Flashcards
1
Q
whats pharmacokinetics comprised of?
A
- absorption
- distribution
- metabolism
- excretion
- “what the body does to a drug”
2
Q
Whats Pharmacodynamics comprised of?
A
- mechanism of effect
- sensitivity
- responsiveness
- “what a drug does to the body”
3
Q
Pharmacokinetics parameters are?
A
a. elimination half-time
b. bioavailability
c. clearance
d. volume of distribution (Vd)
4
Q
Does the body compartmental model divide the body into 2 namely?
A
yes in this the model that we use,but it could be 3 or 4.
Our model is 1.Central 2.Peripheral
5
Q
Characteristics of Central compartment
A
- highly perfused tissues
- the rapid uptake of drug
mechanism of drug is as follows: - drug first introduced into the central compartment distributes to the 2nd compartment and returns to the central compartment for clearance
- kidney, liver, lungs, heart, brain
- receives 75% of the CO
- represents only 10% of the body mass
6
Q
Characteristics of the peripheral compartment
A
large calculated volume
- extensive uptake of drug
rate of transfer between compartments decreases with aging, leading to greater plasma [ ] in certain drugs (thiopental).
7
Q
How is iv drugs distributed between the central and the peripheral compartments after absorption
A
- Following systemic absorption of a drug,
the highly perfused tissues (heart, brain, kidneys, liver) receive a large amount of the total dose of drug.- As the plasma concentration of the drug decreases below that in these tissues, drug leaves and is redistributed to less well-perfused sites, i.e. muscle and fat.
- With continuing elimination of drug, the plasma concentration declines below that in tissues, drug leaves tissues to re-enter the circulation.
8
Q
What are the 3 ways in which drug distribution or action is unintentionally prolonged
A
- Tissues that accumulate drug preferentially act as a reservoir to maintain the plasma concentration and prolong the effect.(Fat).
- Similarly, large or repeated doses saturate inactive tissue negating redistribution, again prolonging duration of action, as now reduction of the effect depends on metabolism rather than redistribution.
- Lung uptakes basic lipophilic drugs (lidocaine, fentanyl, Demerol) and acts as a reservoir to release drugs back into the systemic circulation.
9
Q
state body tissue Compartment numbers
A
Body Mass Blood Flow
(percent of (percent of
70-kg cardiac
adult) output)
Vessel-rich group 10 75
Muscle group 50 19
Fat group 20 6
Vessel-poor group 20 <1
10
Q
What do the Lungs do with Lipophilic drugs
A
Lung uptakes basic lipophilic drugs(lidocaine, fentanyl, Demerol) about 75% and acts as a reservoir to release drugs back into the systemic circulation.
11
Q
In the CNS distribution, How does the blood-brain barrier affect ionized drugs and in what scenario cand the BBB be overcome
A
- The blood-brain barrier prevents ionized, water-soluble drugs from crossing the barrier into the brain circulation.
Blood-brain barriers can be overcome with large doses of drug, in head injury and hypoxemia.
12
Q
What is the Effect site(Biophase) in relation to IV drug
A
Drugs exert their biological effect at the “biophase,” also called the “effect site”.
It is the immediate milieu where the drug acts upon the body, including membranes, receptors, and enzymes, brain. etc
13
Q
What is Keo
A
This the rate constant of the drug elimination from the effect site
14
Q
What is the volume of distribution
A
This is the sum of all the volume of the compartments.
calculated:
VD= Dose of Iv Drug/Plasma concentration before elimination.
15
Q
Name the physiochemical characteristics that influence VD
A
- Lipid solubility: Highly lipophilic drugs are distributed quickly
- Binding Characteristics: Drugs that have a high propensity to bind to protein may not be distributed quickly
- Molecular size: Large molecular-sized also have difficulty passing through for distribution
16
Q
What is Elimination half time
A
The time necessary for the plasma concentration of drug to decline 50% during the elimination phase.
E1/2t of a drug is directly proportional to its Vd.
formula= 1/2’‘n
17
Q
Elimination half-time is independent of the dose of drug administered,true or false
A
True
18
Q
What occurs if dosing intervals are less than the elimination half times?
A
Drug accumulation.
19
Q
Elimination half-time and elimination half-life are not equal when the decrease in the drug’s plasma concentration does not parallel its elimination from the body. True or False
A
True
20
Q
The time necessary to eliminate 50% of the drug from the body.
A
Elimination half-life.
21
Q
what is α-distribution phase
A
from central compartment to peripheral
22
Q
what is a β-elimination phase
A
from central compartment to liver and kidneys for elimination
23
Q
what is context-sensitive half time
A
The context-sensitive half-time is the time required for blood or plasma concentrations of a drug to decrease by 50% after discontinuation of drug administration.
Refers to discontinuing an infusion.
24
Q
What does systemic absorption of a drug depend on
A
Depends on drug solubility
25
advantages of po route
economical and most convenient
26
disadvantages of po route
- Emesis
- Destruction by enzymes or acidic gastric Fluid
- Irregular absorption with food or other drugs
27
What is drug first-pass effect
Drugs absorbed from GI system enter the portal venous blood and pass through the liver before entering the systemic circulation for delivery to tissue receptors. Here they are extensively extracted and metabolized.
28
How does absorption happen with sublingual and transmucosal route
Rapid onset: bypasses the liver and prevents first-pass effect
29
How does absorption happen with transdermal route
- Absorption occurs along sweat ducts and hair follicles that function as diffusion shunts.
30
advantages of the transdermal route for drug absorption
- Provides sustained therapeutic plasma concentration of drug.
31
what factors may affcet the rate of absorption via the transdermal route
Rate-limiting step is diffusion across the stratum corneum of the epidermis.
thickness and blood flow are factors reflected in the skin’s permeability for drugs.
32
Disadvantages of transdermal route per absorption
Contact dermatitis
33
How does absorption happen with rectal route
- Proximal rectum: transport to the portal system via superior hemorrhoidal veins, thereby, first-pass effect.
- Distal rectum – bypasses portal system.
34
What is the benefit of iv route admin with absorption
Achieve therapeutic plasma levels precisely and rapidly.
35
Explain the ionization in drugs
Most drugs are weak acids or bases present in both ionized and non-ionized forms.
36
How do non-ionized drugs affect their absorption?
Non-ionized drugs are usually lipid-soluble and can diffuse across lipid cell membranes i.e. BBB, renal, tubules, GI epithelium, hepatocytes.
This fraction of drug is therefore pharmacologically ACTIVE, undergoes re-absorption across renal tubules, is absorbed from the GI tract and is metabolized by the liver.
37
How do ionized drugs affect their absorption
-Ionized fraction of the drug is poorly lipid-soluble, can not penetrate lipid cell membranes, and is repelled from portions of the cell with similar changes. They are excreted by the kidneys unchanged.
Does this mean that drugs that are excreted by the kidneys are ionized?
38
what does the degree of ionization depend on?
It depends on its dissociation constant (pK) and the Ph of the surrounding fluid.
- Changes in Ph can result in a large degree of ionization, i.e. acidic drugs are highly ionized at alkaline pH, and
Basic drugs are highly ionized at acidic PH
------->The degree of ionization of a weak acid or base is determined by the pK of the drug and pH of its environment
When the pK of a drug equals the pH of the surroundings, 50% ionization occurs; that
is, equal numbers of ionized and unionized species are present.
----->A lower pK reflects a stronger acid;
a higher pK corresponds to a stronger base.
---->Drugs with different pK values will diffuse across membranes at different rates.
------>The pH of the biologic fluid in which the drug is dissolved affects the degree of ionization and, therefore, the rate of drug transport
39
what is Ion trapping?
Concentration difference of total drug can develop on two sides of a membrane that separates fluids with different pHs.
EXAMPLE: Placenta
Ion trapping occurs when a drug that is a weak acid or weak base moves between fluid
compartments with different pHs, for example, when a drug given orally is absorbed
from the stomach contents (with a pH of 1 to 2) to plasma with a pH of 7.4. The drug
will tend to accumulate in the fluid compartment in which it is most highly ionized,
i.e., weak acids will tend to accumulate in the fluid with the higher pH and weak bases
in the fluid with the lower pH
40
How does protein binding affect Drug absorption
serum albumin binds- acidic drugs,
α1-acid glycoprotein binds-basic drugs
Only free or unbound fraction of drug is easily and readily available to cross cell membranes.
41
How is the volume of distribution related to protein binding capacity of a drug
Vd is therefore inversely proportional to protein binding
42
is the rate of metabolism and excretion of unbound drug increased or decreased in plasma
It's metabolized more easily and readily
43
Examples of drugs that are high protein bound are?
(warfarin, propranolol, phenytoin, diazepam) are markedly effected by alterations in protein binding
44
What is clearance?
This is the volume of plasma cleared of drug by metabolism or by excretion
45
What is first Order kinetics in relations to clearance
Almost all drugs administered in the therapeutic dose ranges are cleared at a rate proportional to the amount of drug present in the plasma.
The elimination of most drugs at therapeutic doses is “first-order,” where a constant fraction of drug is eliminated per unit time;
that is, the rate of elimination depends on the concentration of drug in the plasma and is equal to
the plasma concentration of the drug multiplied by a proportionality constant:
Rate of elimination from body (mass/time) =
" Constant × [Drug]plasma(mass/vol)
Because the rate of elimination is given in units of mass/time and concentration is
in units of mass/volume, the units of the constant are volume/time. This constant is
referred to as the “clearance” of the drug
46
What is Zero-order kinetics
This is where a constant amount of drug is eliminated per unit time.
In this case, the mechanism by which the body eliminates the drug (e.g., metabolism by hepatic enzymes, active secretion in the kidney) is saturated. The rate of drug elimination from the body is thus constant and does not depend on plasma concentration.
e.g-Asp, Dilantin, EtOH.
47
What is hepatic clearance of a drug?
Hepatic blood flow and hepatic extraction ratio. If hepatic extraction for a drug is high (greater than 0.7) the clearance of the drug will depend on hepatic blood flow.
This is termed: “perfusion – dependent elimination”
General extraction by the liver occurs because of the liver’s large size (1,500 g) and high blood flow (1mL/g/min).
1. The extraction ratio is the amount of drug removed in the liver divided by the amount of drug entering the organ; a drug completely extracted by the liver would have an extraction ratio of 1. Highly extracted drugs can have a hepatic clearance approaching
1,500 mL/min.
48
What is capacity dependent elimination
If the hepatic extraction ratio is low (less than 0.3)
a decrease in protein binding or
an increase in enzyme activity will increase hepatic clearance.
Changes in hepatic blood flow will have minimal changes in its clearance
49
The most important organ for elimination of drugs and their metabolites that is unchanged
Kidney
50
What organ excretes more efficiently water-soluble drugs more than lipid-soluble drugs
Kidney
51
What is the reason that lipid-soluble drugs do not get excreted by the kidneys much
Highly lipid-soluble drugs are reabsorbed such that little or no unchanged drug is excreted in the urine
52
What is Drug metabolism or Biotransformation
conversion of pharmacologically active, lipid-soluble drugs into water-soluble and often inactive drugs
53
What does increased water solubility do to the Vd and excretion
Increased water solubility reduces the Vd for a drug and enhances its renal excretion.
Metabolism is not always synonymous with inactivation or detoxification as some metabolites of certain drugs are active.
54
what is First-order kinetics
This is the most Most common
| - A constant fraction of available drug is metabolized in a given time period.
55
What is zero-order kinetics during metabolism
The plasma concentration of the drug exceeds the capacity of metabolizing enzymes.
- Metabolism of a constant amount of drug per unit of time.
- Examples: ETOH, ASA, Dilantin.
56
What are the pathways of drugs metabolism
1. Oxidation
2. Reduction
3. Hydrolysis
4. Conjugation
57
Biotransformation reactions are divided into 2 namely
```
Phase 1(Non-synthetic): Oxidation, Reduction, and Hydrolysis
phase 2:(Synthetic) Conjugation.
```
58
What is phase 1 in Biotransformation
involve enzyme-catalyzed biotransformation of the drug
without any conjugations. Phase I reactions include oxidations, reductions, and hydrolysis reactions; they frequently introduce a functional group (e.g., -OH) that serves as the active center for sequential conjugation in a phase II reaction.
59
What is phase 2 in biotransformation
```
conjugation reactions, which involve the enzyme-catalyzed combination of a drug (or drug metabolite) with an endogenous substance.
Phase II reactions require a functional group—an active center—as the site of conjugation with the endogenous substance. Phase II reactions require energy indirectly for
the synthesis of “activated carriers,” the form of the endogenous substance used in the
conjugation reaction (e.g., uridine diphosphate-glucuronate).
Finally, Parent or metabolite drug reacts with an endogenous substrate to form water-soluble conjugates
```
60
What are the sites of drug metabolism
```
Plasma
Kidneys
Lungs
GI Tract
Liver – hepatic microsomal enzymes are responsible for the metabolism of most drugs.
```
61
In the liver which enzyme is responsible for the metabolism of most drugs
Hepatic microsomal enzymes,CYP450
| located in the hepatic smooth ER.
62
What is Cytochrome p -450
| CYP-450
Cytochrome P-450: is a large number of different protein enzymes involved in oxidation and reduction and conjugation of a large number of drugs.
This enzyme system is the one most frequently involved in phase I reactions in the liver.
63
What reactions does the CYP-450 catalyze
aromatic and aliphatic hydroxylations; dealkylation at nitrogen, sulfur, and oxygen atoms; heteroatom oxidations at nitrogen and sulfur atoms; reductions at nitrogen atoms; and ester and amide hydrolysis.
64
What are the forms of CYP-450 that exist
There are six well-characterized forms, or isozymes, of the cytochrome P-450 system involved in drug metabolism in humans: CYP1A2, CYP2D6, CYP2C19, CYP2E1, CYP2C9, and CYP3A
65
what are the 3 subfamilies of the CYP-450 that are responsible for the metabolism of majority clinically used drugs
CYP2C, CYP2D, and CYP3A
66
Which of the CYP-450 drug is responsible for metabolism of over 50% of clinically important drugs.
CYP3A4.
67
Why should grapefruit be avoided in reference to the CYP3A4 enzyme?
Drugs or other agents
(e.g., components of grapefruit juice) that inhibit this enzyme or induce its levels may cause untoward effects of numerous drugs based upon their altered
metabolism that in turn alters plasma and tissue levels via effects on absorption or elimination.
68
How is the nomenclature for CYP 450 written
The nomenclature is as follows, the letters CYP stand for Cytochrome P-450, the first number denotes genetic family, the second letter describes the genetic subfamily and finally the second number stands for the specific gene/isozyme
69
what is the mechanism of action for the CYP-450
the drug is oxidized and oxygen is reduced to water.
Reducing equivalents are provided by nicotinamide adenine dinucleotide phosphate (NADPH), and generation of this cofactor is coupled to cytochrome P-450
reductase.
70
What is induction of CYP450 in the process of drug metabolism
Induction is brought about by drugs and endogenous substances, such as hormones, also chemicals. Any given drug preferentially induces one form of cytochrome P-450 or a particular set of P-450s.
(2) When caused by drugs, induction is pharmacologically important as a major
source of drug interactions. A drug may induce its own metabolism (metabolic
tolerance) and that of other drugs catalyzed by the induced P-450.
(3) Induction can be caused by a wide variety of clinically useful drugs (drug-drug interactions), such as quinidine, phenytoin, griseofulvin, phenobarbital, troglitazone,
omeprazole, rifampin, carbamazepine, and St. John’s wort, and by environmental
agents such as tobacco smoke.
(4) Some of the same drugs that induce CYP3A4 can induce the drug efflux transporter P-glycoprotein (e.g., rifampin, St. John’s wort).
71
What is the Inhibition of CYP-450
Competitive or non-competitive (clinically more likely) inhibition of P-450
enzyme activity can result in the reduced metabolism of other drugs or endogenous substrates such as testosterone.
(2) Inhibition can be caused by a number of commonly used drugs, including cimetidine, fluconazole, fluoxetine, and erythromycin or environmental or dietary agents
(e.g., grapefruit juice), and is another major source of drug-drug interactions.
(3) Some of the same drugs that inhibit CYP3A4 can inhibit the drug efflux transporter P-glycoprotein (e.g., amiodarone, clarithromycin, erythromycin, ketoconazole)
72
What is the enzyme Glucoronyl transferase
Glucuronyl transferase is a set of enzymes with unique but overlapping specificities that are involved in phase II reactions.
(2) It catalyzes the conjugation of glucuronic acid to a variety of active centers,
including $OH, $COOH, $SH, and $NH2.
b. Location and induction
.
73
What is the location and function of Glucoronyl Transferase
(1) Glucuronyl transferase is located in the endoplasmic reticulum.
(2) It is the only phase II reaction that is inducible by drugs and is a possible site of drug interactions
74
What are the Non-Microsomal enzymes
- Metabolize drugs mostly by conjugation and hydrolysis
To a lesser degree also by oxidation-reduction
- Present in: liver mostly, plasma, GI tract
- Is responsible for hydrolysis of drugs that contain ester bonds (succhs, emolo)
- Do not undergo enzyme induction
- Determined genetically
75
The most common mechanism by which drugs exert pharmacologic effect is?
Interaction with specific macromolecules in the lipid bi-layer of cell membranes called receptors.
76
How do the concentration regulators act?
Can increase (up-regulate) or decrease (down-regulate) in number in response to specific stimuli
77
what is the state of receptor activation theory
Non-activated receptors are converted to active by the drug by binding to Ligands.
78
what receptor occupancy theory
The more receptors occupied by the drug the more effect.
In the classic theory of receptor occupancy, the drug effect is proportional to the number of receptors occupied by the drug. The maximal effect occurs when all receptors are occupied
79
What are the non-receptor drug actions
Mechanisms other than receptor-drug interactions
i.e. chelating drugs form bonds with metallic cations that may be found in the body.
(Antacids neutralize gastric acid by a direct action).
80
What are Agonist drugs
Agonist drugs mimic cell signaling molecules by activating the same receptor sites and causing similar effects.
81
What are Antagonist drugs
Bind to receptors as well and change the configuration of the agonist site or bind to it, preventing effect from cell signaling molecules
82
what effect does the chemical structure of a drug have on the cell in relation to its affinity?
The affinity of a drug for a specific macromolecular component of the cell and its intrinsic activity are intimately related to its chemical structure.
changes in the stereochemistry of the drug may result in major changes in pharmacological properties.
83
Some facts about stereochemistry
Interaction with biological receptors can differ greatly between two enantomers, even to the point of no binding.
Some isomers may cause side effects or entirely different effects than its mirror image.
Some isomers may have little to no effect.
84
What is the Efficacy of a drug
The ability of a drug to produce the desired therapeutic effect
85
what is the potency of a drug
The relationship between the therapeutic effect of a drug and the dose necessary to achieve that effect.
86
Whats ED50
Median effective dose
87
Whats LD50
Median Lethal dose
88
what's the significance of the ratio of ED50: LD50
This indicates the therapeutic index of a drug for that effect.
This suggests how selective a drug is in producing its desired effects
This is used to estimate the clinical therapeutic index
89
Whats Hyper-reactive in relation to drugs
People in whom an unusually low dose of a drug produces its expected pharmacologic effect
90
Hyper-sensitivity
People who are allergic
91
Additive drug effect
The second drug acting with the first will produce equal to the sum of both.
1+1=2
92
Synergetic effect
Two drugs interact to produce an effect greater than their sum.
1+1=3!
93
What does context sensitive half time depend on?
It depends on distribution and excretion.
| Depends on physiochemical properties of the drug, and length of infusion
94
Does context-sensitive half time depend on?
It depends on distribution and excretion.
| Depends on physiochemical properties of the drug, and length of infusion
95
Systemic absorption, regardless of the route of drug administration, depends on?
Drug’s solubility.
96
If a drug has an esterase link, where will it get metabolised
In the plasma. Adenosine
97
In the presence of enzyme inducers like alchohol.
| what happens to metabolism.
Metabolism becomes faster
