Pharmacokinetic Mechanisms Flashcards
(120 cards)
1
Q
Distribution & Metabolism
A
Disposition
2
Q
Metabolism & Excretion
A
Elimination
3
Q
What is the parameter of
Absorption?
A
Bioavailability
4
Q
What is the parameter of Distribution
A
Volume of Distribution
5
Q
What is the parameter of Elimination? (metabolism & excretion)
A
Half-life
Clearance
6
Q
Diffusion / Passive transport
A
Downhill transport
Spontaneous movement across a concentration gradient
No energy required
Simple diffusion- major process for transport of most drugs
Facilitated diffusion
7
Q
Active transport
A
Uphill transport
Transport against concentration gradient
Requires energy
Primary
Secondary active transport
8
Q
Vesicular transport
A
Endocytosis
Exocytosis
Transcytosis
9
Q
Endocytosis
A
Phagocytosis - cell eating (polio & other vaccines)
Pinocytisis- cell drinking (vit A, D, E, K)
10
Q
Exocytosis
A
release contents outside the cell
11
Q
Transcytosis
A
The material internalized is transported through the cell and secreted on the opposite side
12
Q
2 types of simple diffusion
A
Transcellular- through lipid bilayer
(Nin polar, hydrophobic/lipophilic, unionized)
Paracellular
13
Q
Facilitated diffusion
A
Carrier mediated
Carrier proteins
Saturation may occur
Glucose, vits B1,B2, & B12
14
Q
Osmosis
A
Movement of solvent from a Less concentrated solution to a More concentrated solution through Pores
15
Q
Solvent drag
A
Movement of small molecules with the solvent during osmosis
(Water, sugars & urea)
16
Q
Ion-pair transport
A
Oppsitely charged molecules interact & form neutral complex that will cross cell membranes by Passive Diffusion
(4* ammonium, sulfonic acids)
17
Q
Absorption
A
Movement of unchanged drug from site of administration to syatemic circulation (central compartment)
Considers rate & extent of absorption
18
Q
Rate of absorption
A
Slow = slow onset of effect
Fast = fast onset
19
Q
Extent of absorption
A
Low= maybe ni effect
Very high= toxicity
20
Q
First pass effect
A
Metabolism of drug before it reaches the circulation
Due to CYP450 enzymes (mainly CYP3A4) (intestinal)
Hepatic (liver)- primary site of drug metabolism
21
Q
Bioavailability (F)
A
Parameter to measure absorption
Absolute & Relative bioavailability
22
Q
Absolute bioavailability
A
Compares the amount of the active drug via extravascular administration (oral, rectal, etc.) with the amount of the same drug via intravenous administration
23
Q
Relative bioavailability
A
Compares the amount of active drug via a test formulation with same drug via reference formulation when there is no intravenous formulation
24
Q
Bioequivalence
A
Compares the bioavailability of multisource (generic) with the innovator deug product
25
Peak plasma concentration
Cmax
The maximum concentration of a drug in the plasma
Usually expressed in mcg/mL
26
Time of peak concentration
Tmax
The time for a drug to reach peak plasma concentration
Expressed in hours
Useful in estimating the rate of absorption
27
Area Under Curve
AUC
Expresses the total anount of drug that comes into the systemic circulation
Usually expressed in mcg-h/mL
28
Minimum effective concentration
MEC
Minimum concentration required to produce the therapeutic effect
29
Subtherapeutic level
Plasma drug concentration below MEC
30
Minimum toxic concentration
MTC
Minimum concentration that produces adverse or unwanted effects
31
Toxic level
Plasma druc concentration above MTC
Aka maximum safe concentration (MSC)
32
Onset of action
Time required for a drug to start producing pharmacologic response
33
Duration of action
Time period for which the plasma concentration of deug remains above MEC
34
Intravenous
100% absorption
Absorption circumvented
Potentially immediate effect
Valuable for emergency
Not suitable for oily solutions or poorly soluble substances
35
Subcutaneous
75-100% absorption
Prompt form aqueous solution
Slow & sustained from repository preparations
Not auitable for large volumes
36
Intramuscular
75-100%
Suitable for moderate volumes, oily vehicles, & some irritating substances
Appropriate for self administration
37
Oral ingestion
Variable absorption due to first pass effect
Most convenient
38
Intrathecal
Produces local & rapid effects
Injection in the spinal subarachnoid space
Byoassing the BBB & blood CSF barrier
39
Inhalational
Not nasal but by mouth
Access to the circulation is rapid because the lung’s surface area is large
40
Sublingual
Venous drainage from the mouth is to the superior vena cava, byoassing the portal circulation & first pass effect
41
Factors affecting absorption
pH
Surface area
Route
42
In the stomach,
Acidic deugs are absorbed
43
In the small intestine,
Weakly basic drugs are absorbed
44
The unionized form of an acid or basic drug, if sufficiently lipid soluble is
absorbed, but the ionized form is not
45
The larger the fraction of drug is in the unionized form at a specific absorption site
the faster is the absorption
46
For drug compounds of MW >100, the process of absorption is governed by:
Dissociation constant of the drug
Lipid solubility of the unionized drug
pH at the absorption site
47
The higher the surface area,
The higher the extent & rate of absorption
48
Distribtuon
A passive process
Distribution of drugs into interstitial & intracellular fluids
-tissue or perioheral compartment
Reversible - to remove drug from the tissue (toxicity)
49
Compartment
Not a real physiologic or anatomic region but is considered a tissue or group of tissues that have similar blood flow & drug affinity
50
One compartment model
Most drugs follow this model
51
2 compartment model
*central compartment - highly perfused (heart, brain, liver,lungs)
*tissue compartment - slowly perfused
(Muscle, skin, fat, bone)
52
Volume of Distribution (Vd)
Parameter that measures distribution
The measure of apparent space in the body available to contain the drug
Low conc of drug in the blood= drug is in the tissues= high Vd= high distribution
53
Humans are 60% water
ECF: 1/3 of total body water
Interstitial fluid (80% of ecf)
Plasma (20% of ecf)
ICF: 2/3 of total body water
54
Drugs with very large MW, binds extensibly to plasma proteins, too large to move out through the endothelial slit junctions are
Effectively trapped within the plasma compartment
Vd = 4L for a 70kg man or 6% of body wt
55
Drugs with low MW & are hydrophillic can
Move through the endothelial slit junctions into intertitial fluid
But, hydrophillic drug cannot move accross lipid membranes to enter the water phase inside the cell and remain outside the cells
Vd= 14L 70kg 20% of body wt
56
Drugs with low MW & are hydrophobic can move into the interstitium through the slit junctions &
Can alao move through the cell membranes into the intracellular fluid
Vd = 42L 70kg 60% of body wt
57
Drugs that have a higher Vd have much higher concentrations in the extracellular compartment than in the plasma compartment because
They are widely distributed in the tissues
58
Calculating Vd
= amount of drug in the body (tissue) / plasma concentratio
High Vd= low metabolism
59
Methylation & acetylation makes drug more
Polar
60
Factors affecting distribution
Blood flow
Plasma protein binding
Tissue protein binding
Hydrophobicity / lipophilicity
Physiologic barriers
61
Blood flow
General amount of blood pumped by the heart
Volume of blood that curculates in the cardiovascular system
Dependent on the cardiovascular syatem
Total blood flow= mL/min (cardiac output at rest)
62
Tissue size
Amount of xenobiotic (drug) that can be stored or distributed in a tissue depends on the mass of tissue or the size of organ
63
Tissue perfusion
Magnitude differs in the body’s different region
Depends on the blood flow to that region
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Tissue diffusion
Passive transport /high to low conc
Diffusuon of drug into extravascular tissues
65
Major plasma proteins
Albumin (most abundant)
a1-acid glycoprotein (orosomucoid)
Lipoproteins
Binding to plasma proteins influences:
Distribution
Pharmacologic & toxic response
Elimination
66
Albumin
Acidic/weakly acidic compounds in ionized forms with moderate or marked lipophilicity
Phenytoin, salicylates, phenylbutazone, disopyramide, penicillins
67
a1-acid glycoprotein
Orosomucoid
Ionized basic (cationic) compounds with moderate lipophilicity
Propranolol, saquinavir, imipramine, quinidine, lidocaine
68
Lipioroteins
Neutral molecules & highly lipophillic
Chlorpromazine
69
Fraction of unbound drug
Fu
=concentration of free drug / total deug concentration
70
Drug diaplacement
Drug with the same binding site compete for interaction
71
The Displaced Drug
>95% protein bound
Small Vd (vol of distribution) <0.15L/kg
Shows a rapid onswt of therapeutic or adverse effects
72
The Displacer drug
Has a high degree of affinity as the drug to be displaced
Competes for the same binding aites
The drug/protein concentration ratio is high (>0.10)
Shows a rapid & large increase in plasma drug concentration
Adjust the dose to lower toxicity
73
Reservoir effect
Prolong action
Can cause local drug toxicity
74
Hydrophobic drugs readily
Move accross most biologic membranes
75
Hydrophilic drugs
Do not readily penetrate cell membranes & must pass through the slit junctions
76
Blood brain barrier
Most important, highly regilate or likit drug entry to the CNS
Most antibiotics like penicillins cannot penetrate BBB
Drugs to treat CNS disorder have to cross the BBB
- use levodopa for parkinsons disease instead of dopamine (cannot cross BBB)
77
Astrocytes
Firm a aolid envelope around the brain capillaries
78
Lipophilic substances
Diffuse passively
79
Polar compounds
(Glucose or akino acids)
Transported actively
Needs transporter
80
Placental barrier
Not as effective as BBB
Drugs with MW<1000Da & mod to high lipid solubility cross the barrier rapidly by simple diffusion
Ethanol, sulfonamides, barbiturates
Drugs are dangerous to the fetus during the 1st trimester (fetal organs develop)
Most drugs show teratogenic effects:
Thalidomide, phenytoin, isotretinoin, testosterone, methotrexate
81
Metabolism
Biotransformation
The conversion of drugs into more hydrophillic metabolites for elimination & termination of buologic & pharmacological activity
Generate more polar, hydrophillic, inactive metabolites that are readily excreted
In some cases, metabolites with poteny biological activity or toxic properties are generated
Can result to pharmacologic activation (prodrugs) or change in pharmacologic activity
Occasionaly yields metabolites with equal activity
Rarely leads to toxicological activation
82
Drug metabolizing organs
Liver - primary
Lungs
Kidneys
Intestine
Placenta
Adrenals
Skin
83
Drug metabolizing enzymes
Different feom enzymes that metabolize food
2 categories
Microsomal
Non-microsomal
84
Microsomal enzymes
Metabolize majority if drugs
Derived from the RER
Acts on lipophillic or lipid siluble drugs
Catalyze oxidation, reduction, hydrolysis & glucoronidation
85
Non-microsomal enzymes
Found in cytosol = aqueous /polar/ hydrophilic
Include those that are present in aoluble form in the cytoplasm and those attached to the mitochondria
Mostly performs conjugation reactions
Act on relatively water soluble substrates
86
Phase 1 metabolism
Most microsomal enzymes
Functionalization or Asynthetic reactions
A polar functional group (oh, cooh, nh2, sh) is inteoduced or unmasked (if already present) on the otherwise lipid soluble substrate
Products: primary metabolites
Oxidation - most common
Reduction
Hydrolysis
87
Microsomal mixed function oxidases
Oxidizes 2 substrates at the same time
88
Microsomal monooxygenases
Oxidizes only 1 substrate
Only 1
89
Enzyme induction
Increased drug metabolizing ability of the enzymes by drugs & other aubstances
“Inducers”
90
Phenobarbital type inducers
Includes several drugs & pesticides
91
Polycyclic hydrocarbon type inducers
Includes 3-methyl chloranthrene & cigarette smoke
92
Auto induction / self induction
Carbamazepine
Meprobamate
Cyclophosphamide
Rifampicin
93
What is the effect of enzyme induction?
Shorter duration of pharmacologic effect
Drugs will be metabolized faster
94
Enzyme inducers
Carbamazepine
Rifampicin
Alcohol (chronic intake)
Phenytoin
Griseofulvin
Phenobarbitone
Sunohonylureas (gliclazide)
95
Enzyme inhibition
Opposite of enzyme induction
Decrease srug metqbolizing activity of an enzyme
Could be direct or indirect
Usually rapid & more important than enzyme induction
96
What is tha effect of enzyme inhibition?
Prolonged effect, elimination, toxicity
Prodrug: slow onset of action, prolong activation from inactive
97
Direct inhibition
Result from interaction at the enzymatic site, the net outcome being a change in enzyme activity
98
Competitive inhibition
Structurally sane compounds compete for the same site
Reversible
99
Non competitive inhibition
Structurally unrelated compound interacts with the enzyme at a different site from the drug being metabolized
100
Product inhibition
Metabolic products compete with the substrate for the same enzyme
101
Isobiazid inhibits the metabolism of
Phenytoin
102
Indirect inhibition
Repression: decrease in enzyme content
Altered physiology: nutritional defficiency or hormonal imbalance
103
Indirect inhibition
Repression: decrease in enzyme content
Altered physiology: nutritional defficiency or hormonal imbalance
104
Factors affecting metabolism
Volume of distribution Vd
Ethnic variations
Age
Diet
Disease status
105
Metabolism is inversely related to Vd as drug elimination depends on
The amount of drug delivered to the liver
106
If a drug has a large Vd, most of the drug is in the extrapoasmic soace and is
Unavailable to the metabolizing agents
107
High Vd =
high plasma protein bound
108
Low Vd =
High metabolism
109
Keenicterus
Hyperbilirubinemia
(Chloramphenicol in newborns)
Glucuronidation is not yet developed to metabolize chloramphenicol
110
Gray baby syndrome
Cyanosis
111
Low protein diet =
Decreases metabolizing ability
112
113
High protein diet
Increases mwtabolizing ability
114
Fat free diet
Depresses CYP450 levels
Lipids are required to form microsomes
115
Alcohol
Acute alcoholism = decrease enzyme activity
Chronic alcoholism= increases enzyme activity
116
Liver disease causes
Increased half life of drugs
117
Kidney disease effects
Decreases:
Glycine conjugation
Oxidation of vit D
Hydrolysis of procaine
118
CHF & MI effects
Decreased blood flow to the liver = decreased metabolism
119
Diabetes
Decreased UDPGA & glucuronidation
120
Excretion rate =
Glumerular diltration - tubular reabsorptio + tubular secretion
