1. Drug Absorption and Distribution Flashcards
1
Q
What are the two main processes that determine drug concentrations in different body compartments?
A
-Translocation of drugs
-Chemical transformation
2
Q
What is the translocation of drugs?
A
Drug movement around the body
3
Q
Give some methods of drug translocation?
A
-Bulk flow transfer
-Diffusional transfer
4
Q
Does chemical nature affect bulk flow translocation?
A
NO
5
Q
Does chemical nature affect diffusional transfer translocation?
A
YES
6
Q
What is a “compartmentalised body”
A
Body made of inter connected compartments separated by cell membranes
7
Q
What affects the ability of drugs to move between compartments?
A
-Selectivity of the membranes
-Chemical properties of the drug
8
Q
Give examples of a single layer membrane acting as a selective barrier, and what they are selective for?
A
-Epithelial barrier in GI and kidneys (Selective using transporters and channels)
-Vascular endothelium (MW selective)
9
Q
What allows drugs to exchange freely between blood and interstitium in the liver?
A
Large fenestrations (openings)
10
Q
What makes up the vascular endothelium?
A
-A monolayer of tightly joined endothelial cells
-Intercellular junctions joining these cells, including tight and adherens junctions
-Endothelial glycocalyx (acting as an additional barrier)
11
Q
What makes up the epithelial barrier in the GI tract?
A
-Single layer of polarised epithelial cells
-Intercellular junctions joining these cells, including tight and adherens junctions, and desmosomes
-Mucus layer
-Immune components
12
Q
What makes up the epithelial barrier in the kidneys?
A
-Glomerular filtration barrier, consisting of fenestrated endothelium, basement membrane and podocytes
-Tubular epithelium
-Tight junctions
13
Q
What is the function of the basement membrane in the Glomerular filtration barrier of the kidneys?
A
Size and charge selective filter
14
Q
What is the function of the podocytes in the Glomerular filtration barrier of the kidneys?
A
Form slit diaphragms for selective filtration
15
Q
What makes up the epithelial barrier in the liver?
A
-Sinusoidal endothelium, a discontinuous endothelium, with kupffer cells and stellate cells
-Space of Disse (between sinusoidal endothelium and hepatocytes)
-Tight junctions
16
Q
What makes up the epithelial barrier in the spleen?
A
-Spleic sinusoids composed of endothelial cells with slit like openings, and stave cells (forming a barrier)
-Red pulp
-White pulp
-Periarteriolar Lymphoid Sheaths (PALS)
17
Q
What do tight junctions in the CNS and placenta affect?
A
-Permeability of these barriers
-Maintaining integrity of BBB and placental barrier
18
Q
How may solutes traverse cell membranes by?
A
-Diffusion directly through the lipid
-Combination with transmembrane carrier protein
-Diffusing through aqueous pores
-Pinocytosis
19
Q
Describe how drugs diffuse through lipids?
A
-Non polar substances can penetrate cell membranes very freely (as they are lipid rich environments)
20
Q
What is the permeability of a drug through the lipid determined by?
A
PERMEABILITY COEFFECIENT (P) =
-Number of molecules crossing the membrane per unit area in unit time (J)
DIVIDED BY
-Concentration difference across the membrane (ΔC)
21
Q
What physicochemical factos contribute to permeability?
A
-Partition coefficient
-Diffusion coefficient
22
Q
What is the diffusion coefficient directly proportional to?
A
DC ∝ 1/√MW
23
Q
Why is lipid solubility important in pharmacokinetics?
A
It is an important determinant of pharmacokinetic characteristics of a drug
24
Q
What are most drugs (ionically)?
A
Either weak acids or weak bases, existing in both ionised and unionised forms
25
Is the ionised or unionised form of a drug more capable of penetrating cell membranes?
Unionised forms
26
What determines the ratio of charged/uncharged drug concentrations?
The pH of the compartment and the drug's pKa
27
How do you calculate the pKA of a weak acid?
pKa = pH + Log10([AH]/[A-])
28
How do you calculate the pKA of a weak base?
pKa = pH + Log10([BH+]/[B])
29
In what drug type is the uncharged species not sufficiently lipid soluble?
Aminoglycosides
30
What is the pH partition mechanism?
The pH of the environment influences whether the drug is predominantly ionized or non-ionized, thus affecting its ability to cross lipid membranes.
31
Give examples of how acidic and basic drugs can be affected by the pH partition mechanism?
-Acidic drugs (e.g., aspirin) are more non-ionized and better absorbed in acidic environments (e.g., the stomach).
-Basic drugs (e.g., morphine) are more non-ionized and better absorbed in basic environments (e.g., the intestines).
32
Give some important consequences of pH partition mechanisms
-Urinary acidification increases excretion of weak bases and decreases that of weak acids (and vice versa)
-Increased plasma pH causes extraction of weakly acidic drugs from CNS into plasma (and vice versa)
33
How does urinary alkalisation affect aspirin excretion?
It increases it
34
How does urinary alkalisation increase aspirin excretion?
-At normal urine pH, a proportion of salicylate is unionised and can be reabsorbed
-When urine is alkaline, salicylate is charged so much less reabsorption
35
Describe passive transport
Movement of molecules in the direction of electrochemical gradient (facilitated diffusion)
36
Describe active transport
Movement of molecules against an electrochemical gradient, coupled to an energy source by direct use of ATP or electrochemical gradient of another species
37
Give the characteristics of carrier-mediated transport?
-Saturable
-Can be inhibited (via competitive inhibition)
38
How can cisplatin be dangerous to certain individuals, and how is this problem mitigated?
-Very nephrotoxic (causing destruction of mitochondria)
-Cisplatin uptake is inhibited by an uptake blocker so there is no accumulation in the proximal tubule cells
39
Give examples of drugs and their carrier-mediated transport systems
-Levodopa: Phenylalanine transporter
-Fluorouracil: Natural pyrimidine transporter
-Iron: Carrier system in jejunum
-Calcium: Vitamin D dependent carrier system
40
Where is carrier mediated transport found and is important in drug pharmacokinetics?
-Renal tubule
-Biliary tract
-Blood brain barrier
-GI tract
41
Give some factors affecting distribution and elimination pharmacokinetics
-Binding to plasma proteins
-Partition into body fat and other tissues
42
Give some routes of drug administration
-Oral
-Sublingual
-Rectal
-Epithelial application (skin, cornea, vagina, nasal, mucosa)
-Inhalation
-Injection
43
Give some methods of injection
-Subcutaneous
-Intramuscular
-Intravenous
-Intrathecal
44
What may affect the passive transfer rate of a drug orally administered?
-GI motility
-Splanchnic blood flow
-Particle size and formulation
-Physicochemical factors
45
Give examples of how GI motility can have an effect on drug absorption
-Migraine or diabetic neuropathy can cause gastric stasis, decreasing drug absorption
-Malabsorptive states and GI disease decrease drug absorption
-Coeliac disease decreases thyroxine and digoxin absorption, but increases propranalol absorption
-Food generally decreases drug absorption
46
Where is the major site of drug absorption in oral administration
Small intestine
47
Describe how particle size and formulation may influence the rate of drug absorption
-Smaller particles increase SA available, and may dissolve quicker (increasing)
-Amorphous forms usually dissolve faster
-Immediate vs extended release formulations may increase or decrease rate
-Prodrugs are only absorbed and active when metabolised
48
Why may scientists change the size and formulation of a drug?
To control the rate of absorption, maintaining the correct dosage in a certain therapeutic window
49
Describe how physicochemical factors may affect drug absorption
-Solubility changes absorption (poorly water soluble may have slower)
-pH and pKa of a drug determine its ionisation state, with ionised drugs being less able to cross biological membranes
-Hydrophillic drugs require specific transporters (lipophilic don't)
50
Describe how drug-drug interactions may affect drug absorption
-Antacids or PPIs can increase stomach pH, affecting the ionisation state of some drugs, affecting absorption
-Drugs may affect gastric motility, affecting its absorption
-Certain drugs may bind to others, forming complexes and reducing drug absorptions of both
-Transporters may be competed for
-Drugs may inhibit or induce enzymes responsible for metabolism of others, affecting absorption
51
Give an example of a drug affecting gastric motility, therefore affecting another drugs absorption
-Codeine will reduce motility
-Reducing drug absorption
52
Give an example of a drug that forms a complex with another, preventing absorption
Tetracycline and calcium ions (eg antacids)
53
Describe the mechanism of first pass metabolism
-Drug enters stomach and small intestine, where it is absorbed into the bloodstream, from which the absorbed drug is carried via the portal vein to the liver
-Once the drug reaches the liver, it is metabolised by hepatocytes
54
Where does pre systemic metabolism occur?
In the intestinal wall and the liver BEFORE it reaches systemic circulation
55
Give some drugs that are highly extracted to the liver and undergo first pass metabolism
-Morphine
-Propranalol
-Chlormethiazole
56
Give some drugs that are not highly extracted to the liver and don't undergo first pass metabolism
-Diazepam
-Digitoxin
-Warfarin
-Paracetamol
57
What is the systemic availability of a drug?
The amount of a rug that reaches the systemic circulation in an active form
58
The rate at which a drug enters the systemic circulation depends upon?
-Gastrointestinal absorption (gastric emptying rate, motility, pH)
-Pharmaceutical factors (eg tablet vs liquid, particle size, controlled release formulations)
59
What does the extent to which a drug enters the systemic circulation depend upon?
-The rate at which it enters
-Extent of pre systemic metabolism
60
Why may the differences in absorption profile of a drug be important?
If there is a narrow therapeutic window, meaning a certain concentration of drug must be reached without going over eg analgesics
61
Why may the differences in absorption profile of a drug be unimportant?
If the therapeutic effect is based on steady state administration
62
What makes up the skin?
-3 layers:
-Hyperdermis (containing deep vascular plexus)
-Dermis (containing ascending arteriole and descending collecting venule)
-Epidermis
63
How may drugs penetrate the skin?
-Transcellularly, with lipophilic drugs passing through keratinised cells (though lipid rich membrane)
-Intercellular, with drugs diffusing through lipid layers BETWEEN keratinised cells
-Appendageal, with drugs passing through hair follicles and sweat gland ducts
64
Give examples of how skin condition may affect drug penetration?
-Hydration (moist skin absorbs drugs better as water disrupts the lipid barrier)
-Injury or damage can increase absorption
-Thinner skin (eg face) allows better drug permeation than thicker areas (palms)
65
What are the differences between topical and transdermal drugs?
-Topical: Has local effect
-Transdermal: Has systemic effect
66
Give the issues and risks associated with topical delivery of drugs
-Limited penetration with hydrophilic drugs
-Variability in absorption (thickness, hydration, temperature, damage)
-Poor patient compliance
67
Give the issues and risks associated with transdermal delivery of drugs
-Slow onset of action (may be beneficial)
-Limited penetration with hydrophilic drugs
-Adhesion issues (sweating, body movement, water exposure)
-Improper application may lead to incorrect dosing
-Variable amount and duration of drug input
68
What is transdermal administration suitable for?
-Rate controlled administration
-Non irritating, non allergenic agents whose current administration causes
1. Troublesome side effects or unreliable therapeutic action with repetitive dosing
2. Patient compliance difficulties
3. Need for frequent dosing
4. Gastric irritation with oral therapy
69
Give some therapeutic advantages of transdermal drug delivery
-Avoids first pass metabolism and unpredictable absorption due to GI variables
-Multiday continuous drug delivery
-Non invasive and painless
-Reduce risk of drug abuse or misuse
-Can be used in unconscious or emetic patients
-Sustained and controlled drug release (STEADY) with less peaks and troughs
70
Describe intravenous injection as a method of drug administration
-Fastest onset of action
-100% bioavailability
-High drug concentrations
71
What are the types of intravenous injection?
-Bolus
-Infusion
-Intermittent
72
What is Bolus intravenous injection
-A single, rapid injection of a drug into the bloodstream
-Hitting the right side of the heart, lungs and then systemic circulation
73
What is Infusion intravenous injection
-A continuous or intermittent slow infusion of a drug using an IV drip or pump
-Maintaining a steady plasma concentration over time
74
What does the rate of absorption when injecting intramuscularly or subcutaneously depend upon?
-Site of injection
-Local blood flow
-Drug formulation
75
Where are intramuscular injections delivered to?
Directly into muscle, eg
-Deltoid
-Vastus lateralis
-Gluteus medius
76
Where are subcutaneous injections delivered to?
Directly into fatty tissue layer beneath the skin
77
Where is the site of delivery for an intrathecal injection?
Subarachnoid space via a lumbar puncture needle
78
Give examples of drugs administered by intrathecal injection
-Methotextrate
-Local anaesthetics
-Opiate analgesics
79
What may inhalation drug administration be used for?
Diseases that directly affect the respiratory system eg asthma, bronchitis emphysema, lung cancer
80
How is inhalation drug administration beneficial?
-Rapid onset of action in targeted tissue
-Lower systemic side effects
-High bioavailability
-Convenient for chronic respiratory conditions
-Non invasive
81
What does drug administration by inhalation involve?
-Rapid delivery across mucous membranes of the respiratory tract and pulmonary epithelium
-Effects occur as rapidly as with IV injection
82
Which drugs is inhalation administration used for?
-Drugs that are gases (eg anaesthetics)
-Drugs that can be dispersed in an aerosol
83
What is asthma characterised by, and what are the symptoms?
-Inflammation, Mucous production and bronchospasm, all leading to:
-Shortness of breath, wheezing, tightness in the chest, coughing at night, waking at night with symptoms
84
Give some indoor and outdoor triggers of asthma
Indoor: Smoke, colds/flu, mould, fur, dust mites
Outdoor: Cold/hot weather, car exhaust, pollens, exercise, air pollution
85
What are used to treat symptoms of asthma?
β Adrenergic agonists (bronchodilators) and Glucocorticoids
86
What is the aim of β Adrenergic agonists in the treatment of asthma?
-Relax airway smooth muscle directly
-Rapid onset of action (15-30 minutes)
-Provide relief for 4-6 hours
-Little stimulation of ⍺ or β1 receptors
87
What is the aim of glucocorticoids in the treatment of asthma?
-Decrease the number and activity of cells involved in airway inflammation
-Prolonged inhalation reduce hyper responsiveness of the airway smooth muscle
88
What is a common cause of failure to respond to inhaled drugs?
Incorrect technique in the use of inhalation
89
When inhaled without an aid, how much of a drug administered actually reaches the lungs and airways?
80-90% is deposited in the mouth and pharynx or swallowed, meaning only 10-20% reaches the airways
90
What are the use of spacers in inhalation drug administration?
-A medical device used to improve delivery
-Allows medication to be suspended in air for a brief period before being inhaled, helping patients breathe in the medication more effectively
-Allowing more drug to reach the lung
91
Give some examples of delivery devices for inhaled medications
-Pressurised metered dose inhaler
-Dry powder inhaler
-Nebuliser
92
Apart from β Adrenergic agonists and glucocorticoids, what are some other inhalation treatments for asthma
-Sodium cromoglycate (prophylactic anti-inflammatory agent)
-Theophylline (Potent bronchodilator)
93
Give some physical factors affecting pharmaceutical availability?
-Tablet compression and excipients (affect rate of tablet disintegration)
-Other tablet excipients
-Form of the drug (crystalline or salt form)
-Particle size (smaller drugs dissolve quicker)
93
What factors affect a drug's bioavailability in oral dosing?
-Rate of disintegration of the tablet
-Rate of dissolution of the drug particles in the intestinal fluid
94
Describe how crystalline or salt form of a drug can affect its pharmaceutical availability
-Crystalline are more stable but dissolve slower
-Salt form increases solubility
95
What is bioequivalence?
The comparison between two pharmaceutical drugs to determine if they have
-Same bioavailability
-Produce similar therapeutic effects when administered in same dose
96
When are two drugs considered to be bioequivalent?
-Similar rate of absorption (measured by CMax)
-Similar extent of absorption (measured by AUC)
-No significant difference in safety or efficacy
97
When are two drugs considered to be therapeutically equivalent?
When they have comparable efficacy and safety
98
Why is bioinequivalence clinically significant?
Bioinequivalence can have serious clinical consequences, as changes in rates of absorption, dissolution etc can change the concentration of drug in the body (to above toxic doses)
99
Give an example of when bioinequivalence had negative consequences
Phenytoin toxicity occurred in a hospital due to a switch from calcium phosphate to lactose (increasing dissolution rate)
100
When are alterations in pharmaceutical availability important?
For drugs with narrow therapeutic index (eg phenytoin)
101
When switching from a formulation with low pharmaceutical availability to one with high availability, what may be observed?
Toxicity as non-therapeutic concentrations are reached
101
What affects systemic availability of a drug formulation?
Route of administration
102
What determines the route of administration of a drug
-Physicochemical properties of the drug
-Patient related factors (eg compliance, GI factors)
-Therapeutic factors (slow or fast onset of actions)
103
Give an example of how subcutaneous injections may be differently formulated to control absorption
INSULIN ABSORPTION
-Physical state; crystalline or non crystalline
-Zinc or protein content
-Nature and pH of the buffer suspension
104
What can affect the drug diffusion rate in an intramuscular injection formulation (and give an example)
-The vehicle in which the drug is suspended
-Eg slowed absorption by using thick oils (eg vasopressin tannate in oil)
105
Describe how plasma drug concentrations differ between intramuscular injections and oral dosing of the same drug?
-IM injections lead to a lower plasma concentration
-eg Phenytoin has half the absorption in the IM form compared to oral
106
What is the action of adrenaline in formulations of local anaesthetics?
-Causes vasoconstriction at site of injection
-Prevents the drug being carried away by circulation from site of injection
-Prolonging the effect of the anaesthetic
107
What are the benefits of sublingual, buccal, rectal and transdermal formulations of drugs?
Avoids first pass metabolism
108
What are controlled release oral formulations of drugs?
Designed to modify the rate and or location of drug release in the gastrointestinal tract
109
Give some advantages of controlled release oral formulations
-Reduced dosing frequency (improving patient adherence)
-More stable plasma drug levels
-Reduced GI irritations (enteric coatings prevent stomach upset)
-Targeted drug release
110
Give some disadvantages of controlled release oral formulations
-Higher cost than immediate release forms
-Not suitable for all drugs (eg emergency drugs)
111
Describe combination products in oral therapies
-Combination products contain two or more active pharmaceutical ingredients in a single dosage form
112
What are the criteria that must be met for oral combination therapies
-Frequency of administration of the two drugs is the same
-Fixed doses in the combination product are therapeutically and optimally effective
-No pharmacokinetic interference
113
Give some advantages of combination formulations
-Improved compliance
-Ease of administration
-Synergistic or additive effects
-Decreased adverse effects
114
Give examples of special drug delivery systems
-Biologically erodible microspheres, loaded with drugs
-Prodrugs that are metabolised to active from eg levodopa
-Antibody drug conjugates eg cancer chemotherapy
-Packaging in liposomes
-Gene therapy (viral vector for gene delivery)
-Implantable devices
115
What is drug distribution?
The process by which a drug reversibly leaves the bloodstream and enters the interstitium (extracellular fluid) and or the cells of the tissues
116
What does the delivery of a drug from the plasma to the extracellular fluid depend upon?
-Blood flow
-Capillary permeability
-Degree of binding of the drug to plasma and tissue proteins
-Relative hydrophobicity of the drug
117
What factors affect blood flow to different tissues
Non uniform blood flow, depending on
-Cardiac output
-Autonomic nervous system
-Vasoconstriction and dilation
-Local tissue demand
118
Give some examples of difference in blood flow/perfusion to different tissues
Lungs>Liver>Brain>Skeletal muscle>Adipose>Skin
119
Describe the impact of blood flow on drug distribution
-Blood flow affects how quickly and extensively a drug reaches its sight of action
-Rapid distribution to highly perfused organs
-Slow distribution to low perfused organs
120
Give examples of different drugs having distribution be affected by blood flow
-Benzodiazepines (lipophilic) accumulate in fat, causing a prolonged effect due to slow release (due to less perfusion)
-Muscle relaxants reach skeletal muscle faster during exercise due to increased perfusion
121
What aspects affect how permeable a capillary is to a drug?
-Capillary structure (type of endothelium)
-Physicochemical properties of the drug
-Transport mechanisms
122
Describe the different capillary structures and how these are permeable to drugs?
-Continuous capillaries, with tight junctions and no fenestrations (low permeability)
-Fenestrated capillaries, with small pores (moderate permeability)
-Discontinuous capillaries, with large gaps (high permeability)
123
What physicochemical properties of a drug can affect its permeability to a capillary?
-Molecular size
-Hydrophobicity
-Ionisation state
-Plasma protein binding
124
Give some plasma proteins that bind drugs
-Albumin
-⍺1 acid glycoprotein
-Lipoproteins
-Globulins
125
Describe the differences between plasma protein bound and free drugs
-Free drug is active, can cross membranes, interact with receptors and be metabolised/excreted. IS PHARMACOLOGICALLY ACTIVE
-Bound drug is inactive, acting as a reservoir
126
Give the effects of plasma protein binding on drug distribution
-Limits free drug availability
-Prolongs half life (acting as slow release reservoir)
-Affects drug elimination
-Drug drug interactions (competitive displacement, increasing free drug levels)
-Altered in disease states
127
What is the volume of distribution?
-Parameter describing the apparent space in the body available to a drug based on amount of drug in blood stream versus amount distributed in tissues
-Estimate of how extensively a drug is distributed throughout the body relative to plasma concentration
128
Give the formula to calculate volume of distribution
Vd (litres) = Dose / Initial concentration of the drug in plasma
129
How may we interpret Volume of distribution values?
-Small Vd (5-10L) signifies drug remains primarily in the bloodstream
-Moderate Vd (10-50) signifies drug is distributed into both the bloodstream and extracellular fluid
-Large Vd (50-1000+) signifies the drug is widely distributed, often into fatty tissues and organs
130
Give factors affecting volume of distribution
-Drug properties (lipophilicity, Hydrophilicity, ionisation)
-Body composition (fat and muscle mass, water content)
-Plasma protein binding (high bound = low Vd)
-Disease states (liver or renal disease)
131
Describe the differing binding capacities of drugs to albumin
-Low capacity (one drug per albumin molecule)
-High capacity (several drug molecules binding to a single albumin molecule)
132
What drugs do albumin have strongest affinity for?
-Hydrophobic
-Acidic
133
What are the two classes of drugs based on albumin binding capacity?
-Class I (Dose < binding capacity of albumin) ie most of the drug is in bound state
-Class II (Dose > binding capacity of albumin) ie most of the drug is in the free state
134
What is the clinical significance of drug-plasma protein displacement?
-Class II displaces Class I drugs from albumin
-Causing rapid increase in free Class I drugs
-Possibly reaching toxicity
135
What is the significance of drug-plasma protein displacement with regards to Vd
-If Vd is large, then change in free drug concentration is insignificant
-If Vd is small, the increase in plasma drug concentration is more profound (possibly reaching toxicity)
