Semester 1 Exam Deck Flashcards
1
Q
What is the overall goal of medicine design?
A
To get the right drug to the right place at the right dose at the right rate
2
Q
What is ADME? Why is it important?
A
ADME stands for:
- Absorption
- Distribution
- Metabolism
- Excretion
Its important because lists the ways in which a drug’s properties can influence the way it is processed by the body.
3
Q
Why is thermodynamics relevant to biopharmaceutics?
A
Many processes associated with drug absorption are dictated by thermodynamics:
Formation of micelles (and vesicles)
Partition of membranes
Solubility
4
Q
What is the difference between a drug and a medicine?
A
Drug = Active pharmaceutical ingredient (API)
Medicine = The combined package of drugs and their associated delivery system
5
Q
What is the dosage form? Why is it significant?
A
The dosage form describes the physical form of the medication as it is produced and administered.
It is significant as it affects the onset action of the active ingredient.
6
Q
What is a drug delivery system (DDS)?
A
A method or process by which a drug is delivered
7
Q
List the steps of drug absorption via the GI tract
A
Dosage form dissolves in the GI tract, forming a solution
Absorbed into the superior and inferior mesenteric veins
Feed into the portal vein of the liver WHERE THE DRUG IS LIKELY METABOLISED
The remaining drug is then sent around the body
8
Q
Describe the different absorption pathways in the GI tract
A
Paracellular - Absorbed in between epithelial cells
Transcellular - Absorbed through epithelial cells via various types of membrane absorption
9
Q
What’s the difference between biopharmaceutics and pharmaceutics?
A
Biopharmaceutics - The study of the interaction between a medicine and associated biological systems
Pharmaceutics - The study of developing medicines
10
Q
Define bioavailability. What does a high bioavailability mean?
A
A measure of the quantity of a drug which reaches its site of action and the rate at which it gets there
A high bioavailability means that a given drug is reaching its site of action quickly and efficiently
11
Q
In what way are “fractions” relevant to the mindset of bioavailability?
A
The bioavailability of a drug is dictated by its absorption across multiple membranes.
At each of these membranes only a fraction of the drug is absorbed due to factors of metabolism and rate of absorption.
By thinking of the size of these fractions we can determine the bioavailability of a drug.
12
Q
What is the generally accepted method of measuring drug bioavailability? Are there exceptions?
A
By determining drug concentration in the systemic circulation.
Yes, medications such as eyedrops won’t end up in the blood thus their bioavailability must be determined else how.
13
Q
Pharmacokinetics Vs Pharmacodynamics?
A
Pharmacokinetics - What the body does to the drug
Pharmacodynamics - What the drug does to the body
(Think about how kinetics often refers to the metabolism of the drug)
14
Q
What are the features of a plasma concentration Vs time graph for oral administration?
A
Initial lag in concentration of drug from administration (due to absorption)
Concentration then rapidly increases
Concentration slowly drops
Markers for minimum therapeutic concentration, minimum toxic concentration and peak concentration
15
Q
What is an efflux pump?
A
A transmembrane transport protein that extrudes toxic substances from within cells
16
Q
What is a patent’s lifetime?
A
20 years, can be extended by up to 5.
17
Q
What is the difference between a patent lifespan and marketing lifespan? Why is this significant?
A
Patent lifespan defines the period during which a sole company has rights to produce a drug.
Marketing lifespan defines the time during the patent’s life where the drug can be sold on the market by said sole company.
This is important since in the small marketing life of a given drug, the parent company aims to recuperate the money spent on R&D, then some more in order to turn a profit.
18
Q
Why is it important that drug companies have mixed portfolios?
A
Ensures that said companies can gain back money lost on failed or unpopular projects
19
Q
What is a blockbuster drug?
A
A drug which reaches over $1 billion per annum
20
Q
What is the blockbuster drug model? Why is this model relevant?
A
Aim to produce blockbuster drugs above all other drugs. In doing so you can pay for the R&D of other drugs. Rinse and repeat.
Relevant because this is the model that almost every major modern-day pharmaceutical company follows.
21
Q
What was the Generic Era of drugs? Why is this significant?
A
The period from the 90’s to the 00’s where governments promoted the use of generics over name brands.
This is significant as it reduced the market share of large pharmaceutical companies and their control over the industry.
22
Q
What is a generic drug? Why are they significant to hospital organisations (such as the NHS)?
A
A drug which is bioequivalent to a name brand (identical in dose and route of admission)
They flood the markets after a name brand’s patent expires
They are significant to hospital organisations since they can save money (up to roughly 80%) whilst maintaining efficacy
23
Q
Why are epilepsy generic medicines sometimes less effective, if not harmful, for patients?
A
They can have slightly different rates of absorption which affects the action of the drug.
24
Q
What are the three types of systems that we come across in thermodynamics?
A
Isolated system - Exchange of neither matter nor energy
Closed system - No exchange of matter but exchange of energy
Open system - Exchange of both matter and energy
25
Define work (thermodynamics)
The transfer of energy in an ordered fashion
26
Define enthalpy
The heat energy change within a system. Can be expressed as a relative or an absolute (change in heat energy values or absolute heat energy change).
27
Define entropy. How can we perceive it?
The amount of disorder within a system. Can be perceived as the probabilities of a form existing.
28
Where is thermodynamics relevant in pharmacology?
During the drug discovery process:
- Solubility
- Partitioning
- Melting point
These three factors relate to the ADME of a drug.
Drug receptor interactions:
-Toxicity predictions
Thermodynamic calculations can predict how strongly a drug can bond to a receptor, thus determining if it will enhance cellular activity too much (becoming toxic)
29
Why is drug dissolution important?
Drugs must first be dissolved before they can be absorbed by the body
30
Define liberation
The release of a drug from its administered form
31
What are the four distinct types of drug release in oral dosage forms?
Osmotic pump tablets: Suspension forms within tablet and is slowly released
Coated tablets: Coating dissolves to allow the tablet to dissolve and disintegrate
Coarse or fine granules: Drug can dissolve or further disintegrate (particularly if coarse)
Drug suspension: Already aqueous, sometimes contains granules to saturate suspension (0th order reaction)
32
What is the significance of disintegration in large drug particles?
Disintegration decomposes the large particles into smaller pieces. In doing so surface area is increased allowing for more dissolution to occur.
33
What are the two steps in crystal to liquid drug dissolution?
1. Surface drug molecules are solvated, forming a stagnant DIFFUSION LAYER
2. Drug molecules then diffuse across the diffusion layer into the BULK DISSOLUTION MEDIUM
34
What are the key parameters of the Noyes-Whitney Equation
- dm/dt = dissolution rate
- Effective surface area
- Molecular weight
- Solubility
- Various GI tract variables
35
Why is transcellular the major and paracellular the minor absorption pathway for small molecules?
Rate of paracellular absorption is restricted by the tight intimate connections between cells (little room to diffuse). Transcellular absorption is favoured since there are a wide variety of channels and methods by which drugs can enter cells.
36
What type of drugs do travel via the paracellular pathway?
Small, light (<1,000) hydrophilic solutes
37
How can larger protein based drugs be absorbed?
Endocytosis; they are internalised by the plasma membrane. However, this pathway is very minor.
38
What is flux?
The net flow of particles in a given direction. The driving force of diffusion.
39
What is the significance of Fick's First Law (what does its equation illustrate)?
The equation of Fick's First Law illustrates that the further a system is from equilibrium, the faster it moves towards it.
40
What are the key parameters in the Stokes-Einstein Equation?
- Local environmental conditions of the particle
- Properties of the medium (viscosity etc.)
- Properties of the diffusing particle
41
What are the steps to the passive diffusion of a drug across epithelia? What factors affect the rate of diffusion?
1. Drug diffuses to the epithelium (aqueous)
2. Diffuses across the epithelium (lipid)
3. Through the epithelium (aqueous)
The thicker the membrane the slower the flux, the greater the conc. gradient the better the flux.
42
Define lipophilicity. How is it measured?
The capability of a drug to dissolve in lipids
Measured by the partition coefficient which quantifies the distribution of a drug between an aqueous and lipid (often octanol) phase
43
Why is lipophilicity important?
It determines how much of the drug will end up distributed between the aqueous phase and the lipid membrane, thus determining roughly how much of the drug will crossing the epithelium.
44
Why is acid base theory relevant to drug development and pharmacology overall?
Many drugs are weak organic acids/bases or salts.
Thus, the dissociation of the drugs affects their dissolution and bioavailability.
45
Define amphiprotic
A substance that can act as either an acid or a base
46
What is the most common amphiprotic solvent? Why is it relevant?
The most common amphiprotic solvent is water.
Importantly, water reacts with weak acids or bases to produce conjugate acid-base pairs as part of their Bronsted-Lowry chemistry
47
Why is pKa used when comparing acid/base strength?
It defines the strength of an acid/base independent of its concentration, on a sheer molecular level.
48
Define polyprotic
A substance capable of accepting or donating multiple protons.
49
What are the key differences between polyprotic and monoprotic substances?
Polyphonic can donate or accept multiple protons, thus multiple equilibria equations (each with their own pKa/pKb).
50
What information can be derived from the pKa of an acid/base?
Lower pKas suggest stronger, more polyprotic acids. Vice versa applies.
51
Why do strong acids/bases have a propensity to fully dissociate?
- Their reactions are virtually irreversible
- Their conjugate bases/acids are so weak that they have no effect on the corresponding acid's/bases action
52
Why are weak acids considered weak?
They only partially dissociate in solution, release much fewer protons than a strong acid (at the same conc.)
53
What is an electrolyte?
A compound that ionises in aqueous solution. They can be weak or strong.
54
What are non-electrolytes?
Substances that do not yield ions when dissolved in water
55
What is the common ion in a buffer? What is its purpose?
The ion shared between the acid/base and the salt.
It soaks up additional protons/hydroxoniums as the "acting portion" of the buffer.
56
How can a buffer be formed?
Weak acid/base + conjugate salt
Strong base/acid + weak acid/base (to form a solution of weak acid/base + salt)
56
How can you derive the Henderson Hasselbach equation from the buffer equation?
- Rearrange for [H+]
- Take -Log10 of both sides
57
What is the relationship between electrolytes and acids/bases?
All acids/bases count as electrolytes as they ionise (to some degree in solution)
58
Why are acetate buffers so common?
They remain functional as pKw changes. Thus, they can be used at a variety of temperatures.
59
Why are acidic buffers preferred?
They are less prone to being affected by temperature changes in their ability to maintain pH (of a solution)
59
What does buffer capacity measure?
The magnitude of the resistance a buffer provides to pH changes
60
Why is drug stability important?
- Unstable drugs can metabolise into toxic byproducts
- Can lead to loss of active product via metabolism
- Can affect solubility and bioavailability of drug
61
What are the common mechanisms of drug degradation?
- Hydrolysis
- Oxidation
- Other pathways
62
What types of drugs are susceptible to hydrolysis? How is this susceptibility tested?
Drugs with groups such as esters, amides and lactam groups. To test the likelihood they undergo a UV test.
63
Oxidation degradation mechanism Lecture 11
64
Other pathways of drug degradation Lecture 11
65
What are the 4 routes of degradation?
Direct: A degrades to B (one constant)
Dynamic Equilibrium: A forms B and vice versa (2 associated constants)
Competitive: A degrades to B OR C (2 separate constants)
Sequential: A degrades to B, then B to C (2 separate constants)
66
What is the order of a reaction? Why is it important?
The sum of the powers in a rate equation?
It defines the kinetic rules the reaction abides by, very useful in modelling reactions.
(Can be 0th order or fractional)
67
Why is experimental data necessary to confirm the rate equation? How is this data gathered?
Though the rate equation can resemble the reaction, it doesn't always.
The order of each reactant is determined individually in experiments, then combined with the other reactant data to determine the overall reaction order.
68
How do you determine the rate of a first order reaction?
Calculate the gradient of the LOGGED reaction line. Use a computer for maximal accuracy.
69
What information can we gather from the rate constant?
The theoretical reactivity of a substance or overall reaction
70
Why are zero order kinetics technically theoretical? By what mechanism do they actually occur?
Zero order kinetics depends on a constant supply of drug (to maintain initial value).
In reality, this occurs by having particles of solid drug within drug suspension to constantly replenish the suspension. This is maintained until the reservoir of solid drug runs out, at which point the reaction is modelled after first order kinetics.
71
What occurs when the solid particles of a 0th order suspension are fully solubilised?
The reaction is now modelled as first order
72
What reactions are often modelled by second order kinetics?
Bimolecular reactions
73
What is the ideal ration for second order kinetics?
t1/2 = 19*t95%
74
What methods can be used to determine reaction order?
- Substitution method
- Shelf-life method
- Graphical method
75
What effect does pH have on rate equations? Where is this effect most prominent?
The presence of H+ and OH- can immensely effect the rate of many reactions particularly hydrolytic reactions.
76
What equations illustrates the relationship between temperature and the rate of a reaction?
Arrhenius equation
77
What is the pre-exponential factor?
A variable to describe the frequency of molecules that possess reactive conditions (collision energy, orientation etc.).
78
What is the purpose of stability testing?
To provide a more efficient alternative to observing the stability of a product over its entire shelf-life before it can reach the open market.
79
How do we accelerate the stability testing process?
We vary the temperature and humidity at which the medicine is stored.
80
What protocols are followed in stability testing?
1. Temperature and humidity
2. Storage time before sampling
3. Number of batches sampled
4. Number of replicates in a batch
5. Suitable light challenge
6. Details of the assay
81
What are the requirements of a good drug?
- Efficacy
- Chemical stability
- Solubility
- Oral bioavailability
- Appropriate pharmacokinetics
- Favourable safety profile
82
Why is lipophilicity the key physical parameter in drug development?
Enough lipophilic character is needed to partition the cell membrane, but not so much that it can't partition back out, in order for the drug to have any effect in the body.
83
What factors affect LogP and lipophilicity? How can the Log P of a drug be modified?
Underpinned by chemical structure of the drug. Some groups are lipophilic, some are hydrophilic.
The lipophilicity of a drug (and thus its LogP) can be modified by the addition of hydrophilic or lipophilic groups to bring its LogP value into the appropriate range.
84
How does pH influence the lipophilicity of a drug?
pH can cause drugs to ionise, in doing so their lipophilicity is affected, potentially pushing it out of the ideal range (LogP≤5)
85
Describe the relationship between ionised drugs and HYDROphilicity
Ionised drugs have increased hydrophilicity, reduced membrane permeability
Unionised drugs have decreased hydrophilicity, increased membrane permeability
86
What's the difference between LogP and LogD?
LogP only accounts for the partitioning of neutral unionised species
LogD ALSO accounts for charged species
87
What bonds must be broken for desolvation to occur?
Where/when does desolvation occur?
Hydrogen bonds between the drug and water must be broken for a drug to desolve.
This occurs when a drug enters the lipid plasma membrane.
88
State Lipinski's Rule of Five
Poor oral absorption is likely if two or more of the following criteria are broken:
- Molecular weight is ≤500
- LogP is ≤5
- # of H bond donors ≤5
- # of H bond acceptors ≤10
89
State Lipinski's Rule of Five
Poor oral absorption is likely if two or more of the following criteria are broken:
- Molecular weight is ≤500
- LogP is ≤5
- # of H bond donors ≤5
- # of H bond acceptors ≤10
90
State Lipinski's Rule of Five
Poor oral absorption is likely if two or more of the following criteria are broken:
- Molecular weight is ≤500
- LogP is ≤5
- # of H bond donors ≤5
- # of H bond acceptors ≤10
91
What four variables are measured in Lipinski's Rule of Five?
Molecular weight
LogP (lipophilicity)
H bond donors
H bond acceptors
92
Where is Lipinski's Rule of five applicable?
Applicable for passive transcellular diffusion
93
What types compounds break the rule of 5 but are still absorbed?
- Antibiotics
- Natural compounds
- Semi-synthetics
94
How can we optimise the effect of pH on lipophilicity?
- Change the pKa functional groups on the molecule to change the resultant lipophilicity
95
What is a pro-drug? How can they be used to improve lipophilicity?
A pro-drug is a molecule that metabolises to form an active drug molecule. By designing a lipophilic pro-drug (by adding lipophilic groups) that degrades into an active drug once its absorbed, we can improve the lipophilicity of a drug where it is essential and thus improve its bioavailability.
96
What organs make up the GI tract?
- Mouth
- Oesophagus
- Stomach
- Small and large intestine
- Anus
97
What accessory organs are associated with the GI tract? What role do they all share?
- Salivary glands
- Liver
- Gallbladder
- Pancreas
They all secrete substances into the GI tract
98
What is the mesentery tissue? What is its function?
The tissue that surrounds all GI tract organs.
It holds them in place and provides access to blood vessels and lymphatics.
99
What key components make up the mouth? What are their functions?
- Teeth (mechanical digestion)
- Tongue (sense of taste)
- Mucous membranes (secrete saliva to protect and lubricate)
- Pharynx and epiglottis (to prevent food from reaching airway, swallow reflex)
100
What are the two movement stages involved in swallowing?
1. Initial voluntary movement, "choosing" to swallow
2. Involuntary movement of the food bolus down the oesophagus
101
What are the main layers of the stomach wall? What functions are they responsible for?
- Mucosa (Layer of mucous that protects other layers from damage)
- Submucosa (Layer of glands and blood vessels that secrete enzymes and mucous)
- Muscularis (Layer of smooth muscle responsible for emptying stomach contents)
102
What are the main functions of the stomach?
- Secrete peptidases for protein digestion (and pathogen breakdown)
- Defense against foreign pathogens via stomach acid
103
What are the 3 "main" regions of the large intestine?
Ascending, parallel and descending colons
104
What are the 3 main regions of the small intestine? What is the function of each section?
- Duodenum (Receives stomach contents and uses contents from gallbladder and pancreas to digest)
- Jejunum (Responsible for folate uptake)
- Ileum (Longest section, absorbs most of the nutrient)
105
From macro to micro list the structures responsible for the small intestine's surface area
Small intestine > Intestinal folds > Villi > Epithelial cells > Microvilli
106
What are the crypts of Lieberkuhn? What are the functions of the cells its comprised of?
A functional unit in the small intestine responsible for its immune response as well as protection and repair.
Comprised of:
- Paneth cells (immune functions)
- Stem cells (intestinal regeneration)
- Goblet cells (secrete mucous)
107
What's the primary function of the large intestine?
To conserve water and ions which may have been lost from earlier sections of the GI tract epithelium
108
What are the main functions of the salivary glands?
- Lubrication (mucous)
- Protection (lysozymes and thiocyanate)
- Digestion (amylase and lipase)
109
What is the role of thiocyanate in the mouth?
To prevent the build up of the toxic compounds hydrogen peroxide and hypochlorite
110
What is the main function of the liver for the GI tract?
Produces and excretes bile into the gallbladder, important in emulsifying fats for absorption.
111
What is the main function of the gallbladder?
Concentrating reservoir for bile from the liver. Releases the bile into the duodenum of the SI.
112
What are the main functions of the pancreas?
Makes enzymes to digest the main food groups
Produces insulin and glucagon
113
What are the 6 functions of the overall GI system?
- Ingestion
- Secretion
- Movement
- Digestion
- Absorption
- Excretion
114
What two types of movement are a part of the GI system? Describe them.
Segmentation: Food squashed into sections so that enzymes can digest the food (before it moves on)
Peristalsis: Movement of a food bubble down the GI tract via sequential contraction of the smooth muscle tissue
115
Where in the GI tract does ingestion and secretion occur?
Voluntary ingestion of food at the mouth in the form of eating and swallowing, involuntary secretion of saliva in response to sight and smell of food.
116
What are the two main forms of digestion?
Mechanical digestion: Physical process of breaking down food into smaller particles
Chemical digestion: The use of enzymes or other chemicals (stomach acid) to break down food
117
In what processes does mechanical digestion appear in the GI system?
- Peristaltic contractions
- Mastication (chewing)
118
How is the swallowing reflex triggered?
Food bolus stimulates pressure receptors in the throat and pharynx.
Signals to swallowing centre of the brain to swallow.
119
What are the 3 phases of swallowing?
- Oral
- Pharyngeal
- Oesophageal
120
How does motility appear in the stomach?
Mixing and churning motion to form chyme
Peristalsis to empty the stomach contents into the small intestine
121
What is chyme?
A semi-fluid pulpy contents that are formed by and expelled from the stomach
122
Why is the stomach significant to oral drug administration?
In the stomach the drug starts to properly mix and dissolve
Low pH can affect the drug's ionisation
Rate of gastric emptying can influence drug absorption
123
How does the rate of gastric emptying influence drug absorption?
If the stomach empties too quickly then the drug won't have enough time to dissolve
If the stomach empties too slowly then the drug is in contact with acidic contents for too long (affecting ionisation)
124
How does motility appear in the small intestine? What allows this motility to occur?
- Segmentation to mix contents
- Peristalsis to move contents
This motility is possible due to the bands of smooth muscle tissue in the lining of the small intestine
125
Describe the muscle contractions that occur in peristalsis
Contraction of ringed muscle behind bolus, contraction of longitudinal muscle alongside bolus.
126
Describe the relation between the ENS and the motility and environment of the intestines?
Two sections: Submucosal and myenteric plexus.
Submucosal - Maintains chemical conditions optimal for absorption
Myenteric - Maintains optimal velocity and intensity of muscular contractions (and other muscle functions)
127
How does the ENS control peristalsis? Can this process be influenced?
Sensory neurons detect the presence of food by the degree of stretch
Thus, causing motor neurons that innervate the smooth muscle tissue to contract or relax
Yes, it can be influenced by neurotransmitters
128
What are the respective effects of the SNS and PNS on the ENS
Sympathetic inhibits ENS (have sympathy)
Parasympathetic stimulates
129
What are the effects of ENS stimulation? What about when inhibited?
Increased peristalsis, blood flow, secretion and absorption. When inhibited, vice versa occurs.
130
Describe the relationship between intestinal motility and drug absorption
The greater the transit time the greater the drug absorption (directly proportional)
131
What is the migrating motility complex?
A recurring motility pattern that occurs between meals. It cleans the GI tract from the stomach to the large intestine.
132
What is haustral shuttling? Why does it occur?
Segmentation that moves back and forth through the large intestine.
It allows us to reabsorb water more efficiently.
133
What is mass movement?
A series of coordinated contractions that propel the contents of the large intestine towards the rectum.
134
What are the two forms of motility in the large intestine?
- Haustral shuttling (segmentation)
- Mass movement (peristalsis)
135
What process in the GI tract causes constipation and diarrhoea respectively? Why might this occur?
Constipation: Weak mass movement
Diarrhoea: Hyperactive mass movement
Some conditions such as Parkinson's affect the muscle contractions.
136
Outline the timeline for vomiting
- Increased salivation
- Relaxation of lower oesophageal sphincter (for food to come up)
- Contraction of the diaphragm and abdominal muscles
- Opening of the upper oesophageal sphincter (expulsion)
137
What can cause vomiting to occur?
- Toxins or potent drugs
- Eating too much or too quickly
138
What purpose does the kidney's outer capsule serve?
Separates kidneys concentration gradients from the rest of the body
139
Describe the structure of the kidney
Nephrons make up the cortex and medulla which drains urine out of the blood supply in.
Urine is sent to the central renal pelvis where it then goes through the ureter.
Surrounded in an outer capsule
140
How many nephrons does a kidney contain? What purpose do they serve?
About 1 million nephrons. They are the functional unit of the kidney that filters waste out of the blood
141
Describe the overall process of filtration in the nephron
1. Blood enters through the glomerulus
2. Water and nutrients are forced into the Bowman's capsule via ultrafiltration
3. Nutrients are reabsorbed in the proximal convoluted tubule
4. Loop of Henle maximises the reabsorption of water by acting as a countercurrent multiplier
5. More nutrients are reabsorbed in the distal convoluted tubule
6. Collecting duct reabsorbs last bits of water. concentrating the urine
142
Describe the overall structure of the nephron (follow the pathway)
Glomerulus is enclosed in the Bowman's capsule. Capsule flows into the proximal convoluted tubule, then loop of Henle, distal and finally the collecting duct.
143
What are the 3 main functions of the nephron?
1. Glomerular filtration
2. Tubular secretion
3. Tubular reabsorption
144
Describe the process of glomerular filtration. Explain why this occurs
Water and dissolved nutrients are forced out of the glomerulus (the blood stream) into Bowman's capsule.
This occurs because the afferent arteriole is larger than the efferent arteriole. This increases pressure within the glomerulus forcing contents out of the blood.
145
What is tubular secretion?
The process by which arterioles surrounding the tubules secrete waste into said tubules
146
What is tubular reabsorption
The process by which arterioles reabsorb useful substances such as water and dissolved compounds from the tubules
147
Describe how the structure of the glomerulus relates to its function
Blood vessel walls are one cell thick, increasing porosity.
Podocytes and basement cells surrounding the vessel prevent the filtration of larger particles (RBCs or plasma proteins, PREVENTS PROTEIN BOUND DRUGS FROM BEING FILTERED)
148
What molecules do filter between the podocytes and what molecules don't?
Do:
- Water
- Salts
- Glucose
- Amino acids
- Urea
- Uric acid
- Creatine
- Small drugs
Don't:
- Cells
- Proteins
- Protein-bound drugs
- Anything >8nm
149
What is the glomerular filtration rate?
The volume of fluid filtered from the glomeruli to bowman's space per unit time
150
How is the glomerular filtration rate (GFR) modified by the body?
By adjusting the blood pressure either side of the glomerulus
151
Why do the kidneys modify the GFR?
To maintain a water and salt balance (there are other ways)
152
Describe the relationship between GFR and water/salt excretion
Increased GFR increases water/salt excretion. Proportional relationship.
153
What is the interstitial space?
The space in between tubules. It is involved in the concentration gradients for reabsorption from the tubules.
154
How is Na+ reabsorbed into the proximal tubule cells?
Na+ is co transported with other molecules and also counter-transported against H+ to bring Na+ into the tubule cells.
155
How is Na+ transferred from proximal tubule cells to the body (interstitial space)?
Na+ is pumped into the interstitial space by antiporter Na+/K+ pumps. K+ is recycled to the interstitial space by ion channels.
156
In which section of the loop of Henle does Na+ reabsorption occur?
The ascending portion of the loop of Henle.
157
How is Na+ reabsorbed into Loop of Henle's tubule cells from the tubule?
Na+ is cotransported with K+ and Cl- by NKKCs. K+ is recycled back into the tubule by an ion channel.
158
What is a NKCC?
A Na-K-Cl Co transporter
159
How do ions reabsorbed into the loop of Henle tubule cells transfer into the interstitial space?
Na+ is antiported by a Na+/K+ pump. K+ is recycled by K+ ion channels. 2Cl- ions move via ion channels.
160
How is Na+ reabsorbed in the collecting duct? Describe the movement of K+ too.
Na+ is drawn into the tubule cells, diffusing down its conc. gradient via Na+ channels. Na+ then antiported into the interstitial space by Na+/K+ pump (which maintains the Na+ conc. gradient for the channel). K+ moves in the opposite direction
161
Describe the effect of aldosterone on salt reabsorption.
Aldosterone promotes salt reabsorption.
Does so by increasing expression of ion channels and Na+/K+ pump in the membrane.
162
How long does it take for aldosterone to increase the amount of salt reabsorption in the collecting duct? Why does it take this amount of time?
Takes hours to occur.
This is due to the amount of time required for gene expression to substantially effect the number of channel proteins synthesised.
163
Where is water reabsorbed in the nephron?
In the descending portion of the loop of Henle
164
How is water reabsorbed in the loop of Henle?
1. Descending loop is permeant to water, ascending loop isn't.
2. Ascending loop reabsorbs salts, makes low water concentration interstitial fluid
3. Water diffuses down conc. gradient into the interstitial fluid
(The longer the loop the greater the countercurrent multiplier for water reabsorption)
165
Describe how blood flow around the loop of Henle ensures that concentration gradients are maintained.
Blood flow around the loop is counter to the flow through the loop.
Filtered blood (low in salt) encounters ascending loop where it absorbs salt.
Salt-rich blood then encounters descending loop where it absorbs water.
The balance of water and salt maintains concentration gradients.
166
Describe how water is reabsorbed in the collecting ducts.
Water diffuses through aquaporins from the tubules into the tubule cells into the interstitial space (two membranes with aquaporins).
167
How long does it take for vasopressin to increase water reabsorption? Explain why.
Vasopressin modifies the rate of water reabsorption within minutes.
This is because when vasopressin binds to its receptor, aquaporin-rich vesicles fuse with the cell membrane to rapidly increase the number of channels for reabsorption.
Unlike with the protein channels from aldosterone's response, the aquaporins are already made and just need to be inserted.
168
What is the other common name for vasopressin?
Anti-diuretic hormone (ADH)
169
What is proteinuria? Why does this happen?
High levels of protein in urine. Happens when kidney is damaged and its function is diminished.
170
What is the body's buffer system?
Carbonic acid/carbonate buffer system?
171
What enzyme is responsible for the carbonic acid/carbonate buffer system?
Carbonic anhydrase
172
How does the kidney regulate pH?
By regulating the carbonate as part of the body's buffer system.
173
Why do the kidney's reabsorb carbonate ions from their tubules?
Since carbonate is essential to the body's buffer system, loss of carbonate would impact the buffer. Instead of replacing the carbonate, the kidneys reabsorb it.
174
Describe how carbonate is reabsorbed in the nephron.
Protons are transported from tubule cells into the tubule, reacting with carbonate ions to form carbonic acid.
Carbonic acid forms water and carbon dioxide which diffuses into the tubule cell.
In the tubule cells it reforms carbonic acid thus producing carbonate ions which are transported into the interstitial space.
175
How are excess protons from carbonate reabsorption secreted?
Diffuse into the tubule where they bind with phosphates in order to maintain the conc. gradient out of the tubule cells.
176
How does glutamine metabolism generate carbonate ions?
Filtered glutamine is reabsorbed into tubule cells.
Glutamine is metabolised into ammonium and carbonate ions.
Ammonium is secreted into the tubules and secreted whilst carbonate ions are transported into the body.
177
Define alkalosis
When the body becomes more alkaline, loses protons, pH increases.
178
Define acidosis
When the body becomes more acidic, gains protons, pH decreases.
179
Why must body pH be so tightly balanced? What pH range does a healthy body maintain?
Since many processes are dependent on pH it must be controlled.
7.35-7.45 = pH of the blood
180
How do the kidneys respond to acidosis?
- Excess protons in the tubule cells
- More protons diffuse into tubule
- More carbonate ions taken up as a result
- More protons bind to phosphate for elimination
- More glutamine is metabolise to release carbonate ions
Thus increasing the amount of carbonate in the body, mitigating the acidosis.
181
How do the kidneys respond to alkalosis?
- Less protons in the tubule cells
- Less protons diffuse into tubule
- Less carbonate ions taken up as a result
- Less glutamine is metabolised to release carbonate ions
Thus decreasing the amount of carbonate in the body, mitigating the alkalosis.
182
How does urine pH effect drug excretion?
Most drugs are either weakly acidic or basic.
In alkaline urine, acidic drugs are ionised. Vice versa applies.
Ionised drugs are less likely to be reabsorbed thus increasing excretion.
183
How can modifying urine pH increase aspirin excretion?
- Aspirin metabolises into salicylic acid
- IV infusion of sodium bicarbonate releases carbonate ions into the blood
- Carbonate ions make their way to the urine where they ionise the salicylic acid
- Ionised salicylic acid no longer reabsorbed
184
What is the biological process of elimination? How can something be eliminated by the body?
The removal of a substance or termination of its biological action.
It can be metabolised or excreted.
185
Define the two types of metabolism
Anabolism: Build up
Catabolism: Breakdown
186
What types of molecules does the liver metabolise? How does it eliminate them?
The liver metabolises lipophilic molecules, forming polar products which can then be excreted in the urine.
187
Describe phase 1 reactions in the liver
- Catabolic reaction
- Introduces a functional group as a point of conjugation for phase II
- Product often reactive
- Carried out by hepatic microsomal enzymes on smooth ER of hepatocytes
188
Why do phase 1 reactions mainly apply to lipid soluble molecules?
Since the reaction is carried out by enzymes on the smooth ER, the molecules must be able to enter cells. Thus, likely requiring some degree of lipid solubility.
189
What is the cytochrome P450 monooxygenase system?
- A family of haem enzymes located on the smooth ER of hepatocytes
- Possess species and inter-individual variation
190
Why is the genetic variation in the cytochrome P450 monooxygenase system significant?
The variations found in the enzymes implicates drug testing and drug response from patient to patient
191
Describe the P450 cycle
DH = Drug
- P450 combines with the drug
- Fe3+ iron in the P450 is reduced to Fe2+
- This combines with the released e-, O2 and a proton to form FeOOH-DH
- Combines with another proton to form water and (FeO)3+ DH
- FeO3+ extracts a hydrogen ion (isn't oxygen being extracted?), releasing DOH and regenerating P450
192
Describe phase II reactions in the liver
- Anabolic, involve conjugation
- Product is often inactive
- Hydrophilic conjugates are secreted into bile where conjugation is move and molecule is reabsorbed (enterohepatic recirc.)
193
What is conjugation? What is a conjugation point?
Conjugation refers to the attachment of a substituent group
A conjugation point is a location on a molecule where a substituent group can be attached
194
Where else can phase I and II reactions occur?
In the kidneys and the lungs
195
How do stereoisomers differ in their metabolism? Why is this significant?
Stereoisomers are metabolised differently. This has potential for a large range of drug interactions and effects of polymorphisms.
196
What is first pass metabolism?
The process by which a drug given orally must first pass through the liver where it is metabolised by hepatic microsomal enzymes before it enters systemic circulation.
197
Why are drugs given by IV exempt from first pass metabolism?
Since they directly enter systemic circulation they have an effect before they are metabolised in the liver unlike drugs delivered orally.
198
How would first pass metabolism be impacted in patients with decreased GI/liver function?
In the case of decreased GI function: Less of the drug would make its way into the blood stream and would therefore be less bioavailable once metabolised.
In the case of decreased liver function: Less of the drug would be metabolised and more would enter systemic circulation. Thus making the drug more bioavailable.
199
What are prodrugs?
Drugs which only become active once metabolised by microsomal enzymes
200
What common agent(s) can induce CYP450 function?
- Brussel sprouts
- Smoking
- St Johns Wort
201
What common agent(s) can inhibit CYP450 function?
- Grapefruit juice
202
What are enzyme inducer/inhibitor drugs? Why are they significant?
Drugs which increase/decrease the activity of CYP enzymes.
In doing so they can affect the metabolism of other compounds/drugs
203
What is the main aim of phase I and II reactions?
To decrease lipid solubility and enhance renal elimination
204
Define bioavailability
A quantitative measure of the amount of drug that reaches its site of action and of the rate at which it gets there
205
What does LADME stand for?
- Liberation
- Absorption
- Distribution
- Metabolism
- Excretion
206
Why does drug release/liberation oppose its membrane transport?
Drug release is dependent on its capability to dissolve (hydrophilicity) whereas membrane transport is dependent on its lipophilicity.
207
State the Noyes-Whitney equation
dC/dt = ((D*S)/h)*(Cs-Cb)
Where
Cs = Solubility of drug
S = Surface area of the particle
208
How can the solubility (Cs) of a weakly acidic/basic drug be predicted?
It can be predicted given the:
- pH of the solution
- pKa
- Solubility of free (unionised) drug
209
What is the main pathway of drug absorption? How does this influence drug design?
The main pathway of drug absorption is passive diffusion
Thus, most drug design aims to optimise lipophilicity, in order to partition into and then out of the lipid bilayer
210
What is the flux equation?
J = C*v*A
Where
J = Flux
C = Concentration
v = Velocity
A = Area
211
What is Fick's first law equation? NEEDS TO BE EDITED, INCOMPLETE
J = ((A*D*K)/∆x)*(C1-C2)
Where
J = Flux
A = Surface area
D = Diffusion coefficient (diffusivity)
∆x = Membrane thickness
K = Partition coefficient
C1-C2 = Difference between drug's concentrations on either side of the membrane
212
What does the partition coefficient (K) quantify? Can you define this as an equation?
The distribution of a drug between membrane and aqueous phases which it separates
K = Coil/Cw
213
What oil is often used as a standard for calculating the partition coefficient of a drug?
Octanol
214
What is the difference between K and P?
No difference. They both represent the partition coefficient (be careful though K doesn't always).
215
How does drug ionisation and pH partition affect the absorption of weakly acidic/basic drugs?
Ionised versions of drugs (A- and BH+) are more hydrophilic, reducing membrane transport of a given species.
216
What is the pH partition hypothesis? Why isn't it always applicable?
A drug will accumulate on the side of the membrane where pH favours ionisation.
Doesn't take into account a variety of factors associated with absorption.
217
State Lipinski's Rule of Five
1. Molecular weight ≤ 500
2. log P ≤ 5
3. No more than 5 hydrogen bond donors
4. No more than 10 hydrogen bond accceptors
(All units in the rules are multiples of five)
218
How has gastric transit influenced medicine design?
Gastric acid degrades certain drugs. To allow oral administration, gastro-resistant dosage forms have been developed.
Pepsin completely degrades polypeptide drugs so they must be administered by other means.
219
Where are oral drugs principally absorbed?
The small intestine
220
How do meals influence gastric emptying rate?
The larger the meal the quicker the initial rate of gastric emptying
221
What order can be used to model gastric emptying?
Zero order
222
How do fatty acids influence emptying rate?
Reduce emptying rate proportional to conc. and chain length
223
How do triglycerides influence emptying rate?
Reduce emptying rate. Unsaturated more than saturated.
224
How do carbs and AAs influence emptying rate?
Reduce rate in a conc.-dependent manner (relative to osmotic pressure)
225
Describe the gastric transit of a gastro-resistant dosage form. How does this impact its absorption?
Won't break down in gastric acid, so can't pass through pylorus due to size. Must wait for house-keeper wave to pass through.
Therefore, lag-time between when drug is taken and SI absorption.
226
Describe the gastric transit of a suspension/powdered dosage form. How does this impact its absorption?
Drug is rapidly decomposed into gastric fluid, dissolving into the solution. Drug rapidly passes via the pylorus.
Therefore, little lag-time between when drug is taken and SI absorption.
227
What is an excipient?
Any component besides the API in a medicine. Often used to improve administration of the API.
228
How can we improve the membrane permeability of a drug?
- Modifying a drug with lipophilic groups to allow it to partition easier
- Developing a prodrug that can partition easier and then metabolise to form the active drug
229
What is enterohepatic recycling?
The process by which drugs can be eliminated by biliary secretion only to be absorbed again in the SI.
230
What are the 3 main factors that the amount of drug absorbed depends on?
- The amount released from the dosage form
- The amount metabolised (stomach, intestines and liver)
- The amount that permeates through the GI membrane
231
How can a drug be transported across the GI membrane?
Via:
- Paracellular transport
- Diffusion
- Facilitated diffusion
- Drug transporters
232
What is an efflux pump? What is its purpose?
A membrane protein that pumps a given molecule outside of a cell. This allows for the efflux pump to eliminate/reduce the presence of potentially toxic molecules inside the cell.
233
How can efflux pumps explain the resistance of tumour cells to anticancer drugs?
Drug is pumped out of the tumour cells faster than it is transported in, preventing it from reaching a therapeutic level.
234
What is the function of P-Glycoprotein (PGP)? What effect does this have on drugs?
PGP is a typical efflux pump that is found in many different tissues.
PGP is responsible for the poor bioavailability and low CNS conc. of numerous drugs.
235
Why are P-Glycoprotein (PGP) inhibitors so important when administering chemotherapeutic drugs?
They prevent PGP from pumping chemotherapeutic drugs out of epithelial cells after they're absorbed. In doing so they improve the oral bioavailability of the drug in question.
236
Why is food a significant consideration for drug absorption?
Presence of food can improve or worsen the absorption of the drug and thus impact its bioavailability. For this reason some drugs must be taken with food or during fasting conditions.
237
What drugs can most easily permeate the oral mucosa? How do they permeate?
Small lipophilic drugs, they do so via passive diffusion.
238
What are the benefits of the buccal pathway for drug absorption?
There is a good supply to the oral mucosa making absorption efficient. It also bypasses hepatic first-pass metabolism.
239
Why can't insulin be orally administered?
Insulin would be completely degraded
