Basic Principles Of ADME Flashcards
1
Q
What does pharmacokinetics focus on in a drug’s journey through the body?
A
- what the body does to the drug, including absorption, distribution, metabolism, and elimination (ADME).
2
Q
What does pharmacodynamics focus on in a drug’s journey through the body?
A
- what the drug does to the body, including its target site interaction, effects and clinical outcomes.
3
Q
What is the definition of pharmacokinetics ?
A
- study of the time course and movement of a drug through the body
- including absorption (into the body)
- distribution (around the body)
- elimination (out of the body)
4
Q
What 2 factors limit a drug’s ability to access it’s target ?
A
- metabolism = body inactivates enzymatically
- excretion = body gets rid of the drug via kidney or in the faeces
5
Q
Why do we need pharmacokinetics?
A
- ensure that a drug is administered at the correct dose
- to reach the target site at a concentration high enough to cause an effect
- but low enough to avoid side effects.
6
Q
What knowledge does a drug PK give us?
A
- Which dose to give
• Which administration route to choose
• How often to give a dose (frequency)
• Which administration formulation to choose for a drug
7
Q
Where do we gain information about a drug’s pharmacokinetic (PK) data?
A
- through experiments done as part of drug development research
• Certain types of data are required for a drug to get approved by an authorised body (UK: MHRA, US: FDA, EU: EMA)
8
Q
What are the three stages of drug development that provide pharmacokinetic data?
A
- drug discovery
- preclinical experiments
- clinical trials
9
Q
Drug discovery
A
- Identify target site
• New drug synthesis
10
Q
Preclinical experiments
A
- In vitro (cell model) and in vivo (animal model) experiments
• Testing drug activity
• First PK and PD data (IC50, LD50, side effects, efficacy)
11
Q
3 phases of clinical trials ?
A
- Phase I: Safety and Dose range identification (small number of participants), PK, PD, Dose range
• Phase II: Safety, Efficacy, Dose range, target disease population (higher number of participants)
• Phase III: Efficacy and Comparison, (bigger number of participants)
12
Q
What is phase 4 of a clinical trial ?
A
- drug approval
- observation
- 10-15 years
13
Q
What does ADME stand for ?
A
- Absorption
- Distribution
- Metabolism
- Elimination
14
Q
What is absorption ?
A
- drug is absorbed from the body (drug enters the blood flow)
15
Q
What is distribution ?
A
- Once a drug reaches the blood stream, it will get distributed across different compartments in the body
16
Q
What is metabolism ?
A
- Being distributed, the drug will reach sites, where it is metabolised (in its active or inactive form)
17
Q
What is excretion ?
A
- Drug is excreted from the body and passed out via
excretion organs (liver, kidney, skin, lungs)
18
Q
What is the definition of drug absorption ?
A
- mass transfer process that involves the movement of unchanged drug molecules from the site of administration into the blood stream
19
Q
How are drugs transported across membranes ? (4)
A
- Active transport
• Passive diffusion
• Facilitated passive diffusion
• Endocytosis
20
Q
What do cell membranes consist of ?
A
- phospholipids (PL) with hydrophobic tail and hydrophobic tail, harbouring a phosphate group
- many integral proteins in the membrane
21
Q
What does it mean when integral proteins are amphipathic ?
A
- have polar and non-polar groups
22
Q
What is the cell membranes consist permeable to ?
A
- small non-polar molecules
23
Q
What molecules are cell membranes not permeable to ?
A
- High polarity
• High molecular weight
• Conformational freedom
24
Q
What are the 4 uptake transporters ?
A
- Simple diffusion
• Facilitated diffusion
• Active transport
• Transcytosis / different forms of Endocytosis
25
What route does simple diffusion follow ?
- Transcellular route is used spontaneously
• No involvement of any membrane protein
26
What is the slowest step of the absorption process ?
- diffusion
- Large molecules will diffuse more slowly than smaller ones
27
What is the equation for the rate of drug absorption during simple diffusion?
28
What type of kinetics does simple diffusion follow?
- Simple diffusion follows first-order kinetics
- where the rate of absorption is proportional to the remaining concentration of the drug at the absorption site.
29
Is simple diffusion linear or non-linear?
- linear = rate of absorption proportional to drug concentration
30
What is facilitated diffusion?
- a form of passive mediated transport where drugs cross a biological membrane via specific transmembrane integral proteins without energy input.
31
What are the two types of transmembrane proteins involved in facilitated diffusion?
- channel proteins and carrier proteins.
32
What does the number of molecules transported depends on ?
- the number of proteins
33
How do channel proteins function ?
- Form open pores in membranes
• Small molecules also pass between adjacent cells
connected as tight junctions
34
How do carrier proteins function ?
- Bind specific drugs and as a consequence undergo
conformational changes that allows molecules to pass through
35
What types of molecules are commonly transported via facilitated diffusion?
- molecules such as sugars, amino acids, and nucleosides
36
What is required for a drug to pass through facilitated diffusion?
- Only drugs with similar structures to those naturally transported (e.g., levodopa, methyldopa, tyrosine, 5-fluorouracil) can pass through facilitated diffusion.
37
What are the 3 different active transporters?
-Uniport,
- Antiport
- Symport
38
What is uniport active transport?
- mediates the transport of a single drug or substance across the membrane
- facilitating the movement of substances that are already thermodynamically favored
39
How does uniport active transport differ from passive diffusion?
- allows non-diffusible substances to be transported across the membrane at a much higher rate than passive diffusion
- without the substances interacting with the hydrophobic core of the membrane.
40
Example of a uniport active transporter
- GLUT1 glucose carrier (large 12 alpha helix membrane protein)
41
What is antiport active transport?
- Antiport active transport involves the movement of one substance in one direction while another substance is moved in the opposite direction
- both against their concentration gradients.
42
Example of an antiport active transport system?
- 3Na+/Ca2+ antiporter in cardiac muscle cells
- where 3 Na+ ions are exchanged in to transport one Ca2+ ion out against its concentration gradient.
43
What is symport active (co-transport)?
- the ability to transport two different substances simultaneously in the same direction across a membrane.
44
Example of symport active cotransporter
- 2Na+/ Glucose Symporter
- Movement of Na+ driven by Na+ concentration gradient and inside negative membrane electric potential
- N- terminal end couples Na+ binding and glucose transport -> conformational changes
45
What are the key parameters that influence drug absorption?
1. Physicochemical properties of the drug (e.g., hydrophilic, lipophilic, size, acidity)
2. Pharmaceutical dosage form (e.g., sustained release forms)
3. Anatomical and physiological characteristics (e.g., body weight, age, sex)
4. Administration route (e.g., systemic or topical)
46
What does the plasma concentration versus time curve represent?
- represents the relationship between plasma drug concentration and time after a single oral dose
- showing both the rate and extent of absorption.
47
What is typically plotted on the axes of a plasma concentration versus time graph?
• X-axis: Time after drug administration
• Y-axis: Plasma drug concentration (C_p)
48
What is a drug dose?
- a drug dose is a specific, measured amount of a drug (in mg or µg) administered to achieve a specific plasma concentration.
49
What is plasma concentration?
- the amount of drug that reaches the bloodstream, gets distributed in the body, thus achieves a specific plasma concentration
- This specific plasma concentration reaches the target site and has a pharmacologic effect
50
Absorption phase
- absorption>elimination
- rise in plasma concentration
51
Elimination phase
- elimination>absorption
- decreased plasma concentration
52
Drug Exposure
Exposure = plasma or blood concentrations vs time
53
What are some common routes of drug administration?
- Intravenous
• Oral
• Intramuscular
• Subcutaneous
• Transdermal
• Inhaled
• Intrathecal
• Sublingual
• Rectal
• Vaginal
54
Typical concentration-time profiles in plasma
after various routes of administration
- look at slide 25
55
What does DL represent in pharmacokinetics?
- Initial Dose, which is the amount of drug given at the start of therapy to achieve a desired plasma concentration.
56
What is Cp in pharmacokinetics?
- Plasma Concentration, which is the concentration of the drug in the bloodstream at a given time.
57
What does Cmax indicate?
- maximum plasma concentration
- absorption = elimination
58
What is Tmax ?
- time to reach maximum plasma concentration
59
What isVD ?
- Volume of distribution
60
What does AUC represent?
- Reflects actual body exposure to drug after
administration of a dose
- Expressed in mg*h/L
61
What factors determine the AUC ?
- Determined by dose
- clearance
- bioavailability
62
What is bioavailability ?
- amount of drug reaching circulatory system from delivery system used
63
Bioavailability for Oral administration
- bioavailability depends on the absorption rate
64
Bioavailability for intravenous administration
- bioavailability is 100% as it isadministered directly into circulation
65
Bioavailability factor (F)
- the ratio of the Area under the Curve (AUC) of an orally and intravenously administered drug
66
What are the key factors that influence drug bioavailability?
1. Lipid solubility and chemical form of the drug (e.g., salt factor).
2. Formulation and bioequivalence.
3. Physicochemical properties of the drug.
4. Co-administration of other drugs.
5. Presence of comorbidities affecting absorption sites (e.g., diarrhoea, vomiting).
6. Susceptibility to gastric acid and digestive enzymes.
7. Degree of metabolism in gut mucosa and the First-Pass Effect.
67
What is bioequivalence ?
- Sometimes the same drug is produced by different companies in a different formulation
• Bioequality ensures that all the drug formulation on the market have the same bioavailability
68
What is drug distribution ?
- Reversible mass transfer of a drug from one location to another within the body
69
What is drug distribution dependent on ?
- dependent on blood flow
- more lipid soluble the drug is, the higher the chances of reaching the target
70
What must drug pass through?
- must pass through capillary walls and into interstitial fluid to be able to interact with cell surface receptors
71
Factors that influence distribution
- Large molecules are more difficult to cross membranes than smaller ones
- Polar molecules will face difficulties to move through simple diffusion
- Degree of ionization • Charge of molecules will depend on ionisation and the pH of environment
72
How does exercise impact drug distribution?
- cardiac output increases 5 to 6 times
- enhancing perfusion and therefore accelerating drug distribution to tissues
73
How do concomitant diseases, like heart failure, affect drug distribution?
- patients with heart failure, reduced perfusion means slower drug distribution
- causing a delayed peak response and slower onset of drug effects.
74
How do concomitant diseases, like heart failure, affect drug distribution?
- patients with heart failure, reduced perfusion means slower drug distribution
- causing a delayed peak response and slower onset of drug effects.
75
How does a decrease in renal clearance impact drug excretion?
- Reduced renal and hepatic perfusion can delay drug excretion
- leading to prolonged drug presence in the body and possibly increased side effects.
76
What impact does shock have on drug distribution?
- In shock, reduced blood flow to tissues leads to decreased drug distribution,
- making drug effects slower and less predictable.
77
Ionic drug binding
- Association of ions of opposite charge by the transfer of electrons from one to another
• Bounds are weak -> easily broken through the induction of a different ion with a greater affinity
• Example: phenytoin sodium (weak acid, ↑ pH ionizes, ↓ pH forms a salt and preticipates)
78
Hydrogen drug binding
- strongest bound
• Determines the way a drug interacts with target molecule, metabolic enzymes, transport proteins
• Determines the degree of binding to plasma proteins (e.g. albumin)
• Binding is reversible, concentration dependent and subject to competition with other drugs/ substances
79
What plasma proteins are involved in drug binding?
Drugs can bind to:
1. Albumin
2. Lipoproteins
3. α1-acid glycoprotein
80
What is the nature of plasma protein binding?
- Plasma protein binding is reversible and, at therapeutic drug concentrations, is unlikely to become saturable.
81
Which plasma protein binds most weak acids?
- Most weak acids bind to albumin.
82
How many binding sites does albumin have for drugs?
- Albumin has 2 binding sites for drugs.
83
How does α1-acid glycoprotein bind to drugs?
- α1-acid glycoprotein binds cationic drugs at physiological pH (e.g., propranolol).
84
What is the significance of unbound drugs?
- Only the unbound drug can leave the plasma compartment, diffuse across membranes, and enter target organs to exert its pharmacological effect.
85
What is the typical Fu for highly plasma protein-bound drugs?
- For highly plasma protein-bound drugs, Fu is typically <5-10%.
86
How does co-administration with other drugs or substances affect plasma protein binding?
- Co-administration with another drug or endogenous substances (e.g., urea, bilirubin, free fatty acids)
- can lead to competition for binding sites, reducing the proportion of bound drug and increasing the unbound fraction.
87
How can liver disease or old age affect unbound drug levels?
- decreased plasma protein synthesis (e.g., in liver disease or old age) can increase the unbound fraction of the drug
- leading to more active drug available for action.
88
How does pregnancy or illness like inflammatory diseases affect plasma protein binding?
- Pregnancy and illnesses such as inflammatory diseases or cancer can increase α1-acid glycoprotein levels, which affects the plasma protein binding of drugs.
89
What does the Volume of Distribution (VD) describe?
- describes how well a drug is distributed in the body by relating the serum concentration of the drug to the dose.
90
How is the Volume of Distribution (VD) defined?
- the volume of fluid required to contain the total dose of a drug in the body at the same concentration as it is in the plasma.
91
What is VD measured in?
Litres
92
VD varies with body weight
- VD should be calculated for each patients in individualized therapy
93
Volume of Distribution depends on plasma protein binding
- Drug with a low VD, are currently highly bound to plasma proteins
