1
Q
Define pharmaceutics
A
Area of study that provides the scientific foundation for the design, development, formulation, maufacture, stability, effectiveness, acceptable delivery and appropriate use of pharmaceutical dsage forms and drug delivery systems
2
Q
Define dosage form
A
Form in which the drug is taken: tablet, syrup, ointment, etc.
3
Q
Define drug delivery system
A
Includes products that are designed to provide optimal control over the release of a drug to achieve enhanced safety or efficacy
4
Q
Name some considerations regarding the formulation of a drug that is stable, efficacious, attractive, easy to administer and safe
A
- The therapeutic indication of the drug
- The profile and psychological characteristics of the inteded patient
- The bioavailability of the drug substance
- The compatability of medicinal and non-medicinal ingredients with one another
- The stability and physiochemical properties of he drug
- Anticipated adverse drug effects
5
Q
The product should be manufacteured with appropriate measure of:
A
Quality control
6
Q
The product should be packaged in a container that keeps the product:
A
Stable
7
Q
The product should be labeled to promote:
A
Correct use
8
Q
The product should be stored under conditions that contribute to:
A
maximum shelf life
9
Q
Define ‘drug’
A
Any substance, other than food, intended for use in the diagnosis, mitigation, treatment, cure of prevention of disease in humans or in other animals
10
Q
Name two examples of early drugs
A
- The sumerian tablet
- The Eber’s papyrus
11
Q
Who introduced the scientific viewpoint to science?
A
Hippocrates
12
Q
What are the two broad steps of new drug devel.?
A
- Identify the cause and process of a disease
- Design molecules capable of interfering with that process
13
Q
Name some priorities in selecting diseases for a new drug
A
- The disease affects the developed world
- The disease is widespread
- If there are drugs already on the market for the disease, what are their advantages & disadvantages
- A market advantage for a new drug can be ID
- The profits from marketing a new drug should outweigh the cost of developing and testing that drug
14
Q
What is the binding site?
A
A hollow or canyon on the surface of the molecular target which allows the incoming drug to sink into it
15
Q
What are the main molecular drug targets?
A
- Proteins (enzymes, receptors, transport proteins…)
- Nucleic acids (RNA, DNA)
Proteins are the most important
16
Q
What is tubulin?
A
- The only structural protein that serves as a drug target
- Molecules of this protein polymerize to form small tubes called microtubules
- The protein is critical to cell division
17
Q
Why is tubulin critical to cell division?
A
In preperation for division:
* The cell’s microtubules depolymerize to produce tubulin
* Tubulin re-polymerizes to form spindles
* Spindles seperate the 2 new cells
* Spindles act as a framework for transferring the parent cell’s chromosomes to daughter cells
18
Q
Tubulin is used as a drug target to treat which disease?
A
Cancer
19
Q
Describe the effects of the taxane family of drugs on tubulin and name two of these taxane drugs
A
Taxanes bind to microtubules and stabilize them, therefore inhibiting depolymerization:
* Taxol (paclitaxel)
* Docetaxtoere (docetaxel)
20
Q
Describe the effects of the vinca family of drugs on tubulin and name two of these vinca drugs
A
Vinca bind to tubulin and inhibit its polymerization process
* Vincristine
* Vinblastine
21
Q
What drug targets are the most important in biopharm research?
A
Receptors
22
Q
Describe the general anatomy of a receptor
A
- Embedded in cell membrane with part of the structure facing the outside, also located intracellularly
- Surface contains hollows, ravines, etc.
- One area of the surface posesses the matching shape to house the incoming chemical messenger molecule or drug (binding site)
- Endo. ligand leaves the receptor once it has activated it and triggered a reaction intracellularly
23
Q
How do drugs target receptors?
A
Drugs mimic the endo. ligand and bind to receptors when the drug’s molecular structure is similar in shape
24
Q
When a drug with a similar shape as the endo ligand binds to the receptor, it can be an:
A
- Agonist: same effect as endo ligand
- Antagonist: drug produces no effect but prevents the receptor’s natural messenger from binding and inducing expected effects (blockers)
25
What is a sub-category of antagonist?
Beta-blocker: bind to adrenoreceptors in the heart and block adrenaline from activation, thus reducing workload and preventing heart failure
26
What are the possible outcomes concerning the amount of drugs at the action site?
* The cell's receptors ma or may not become fully saturated with the interacting drug
* When the receptors are saturated, the effects of the specific interactions are maximized
* Any additional drug present ( as in the circulatory system) and not participating in the interaction may serve as a reservoir to replace the drug molecules released from the complex
* Two drugs may compete for the same binding sites, with the drug having the stronger bonding attraction for the site generally prevailing
* Already bound moleules of the more weakly bound drug may be displaced from the binding site and left free in the circulatory system
27
The key purpose of the clinical trials is to:
Establish a safe and effective dose
27
What are the criteria for the safe and effective dose established during clinical trials?
* Characteristics of the drug substance
* Dosage form and its route of admin
* Patient's: age, body weight, general health status, pathologic conditions, concominant drug therapy, sex, race
28
In a normal distribution sample, a drug dose will provide:
* Little effect in a portion
* Average effect in most individuals
* Greater than average effect in another portion
29
The dose that would produce the desired effect in most individuals is considered
* The drug's usual adult dose
* The likely starting dose for a patient
30
What is the minimum effective concentration (MEC)?
## Footnote
When there is a correlation between blood serum concentration and the presentation of drug effects
An average blood serum concentration that represents the minimum concentration that can be expected to produce the drug's desired effects in a patient
31
What is the minimum toxic concentration (MTC)
## Footnote
When there is a correlation between blood serum concentration and the presentation of drug effects
Second level of serum concentration of drug.
Drug serum concentrations above this level would be expected to produce dose-related toxic effects in the average individual
32
For what reason are drugs manufactued in a dosage form?
So that one dose is in a managable size
* Most current drugs are very potent, of low dosage, and administered in milligrams
* When the dose of the drug is small, additionnal ingredients may be needed to make the drug larg enough to pick up
33
Name some common families of non-medicinal ingredients found in tablet formulations
* Diluents
* Binders
* Disintergants
* Lubricants
* Glidants
* Colouring agents
* Flavouring agents
34
# What is the use of:
Diluents?
Increase bulk
35
# What is the use of:
Binders?
Hold powders together
36
# What is the use of:
Disintergrants
Aid in breaking up the tablet
37
# What is the use of:
Lubricants
Decrease adhesion to punch/die
Decrease friction to punch/die and facilitate tablet ejection
Recuce punch/die wear
38
# What is the use of:
Glidants
Improve flow properties of powders
39
# What is the use of:
Colouring agents
Impart colour
40
# What is the use of:
Flavouring agents
Desired flavour
41
How are formulations protected from destruction by atmospheric oxygen or humidity?
Use of coated tablets or sealed ampuls
42
How are drugs protected from the destructive influence of gastric acid after oral admin?
Enteric-coated tablets
43
How are biterness, saltyness or offensive flavours or odors of a drug substance concealed?
Use of capsules, coated tablets of flavored syrups
44
What are the three types of stability considered when making a drug?
* Chemical
* Physical
* Microbiological
45
What does chemical stability of a drug entail?
The drug retains its chemical structure throughout its shelf life. Drugs in solution are more susceptible to structure altering chemical reactions
46
What does physical stability of a drug entail?
The product retains the original physical characteristics especially in the initial appearance and uniformity. Avoid precipitation and settling for a suspended drug, which may be difficult to re-disperse
47
What does microbiological stability of a drug entail?
The dosage form must be sterile and resist microbial growth
48
What is a first-order rate reaction?
When the loss of drug is directlt proportional to the concentration remaining with respect to time (units are reciprocal time, time^-1
49
How is the stability projection for shelf life (t90) calculated?
Time required for 10% of the drug to degrade with 90% of the intact drug remaining
50
To enhance the stability of drugs, we increase the stability against what types of reaction?
* Hydrolysis
* Oxidation
51
# To help prevent hydrolysis
How do we reduce or eliminate water from the pharmaceutical system?
Use of solid dosage form:
* Apply water-proof protective coating
* Keeping drug in a tightly closed container
Use of liquid dosage form:
* Replace water with glycerin, propylene glycol and alcohol
* Use anhydrous vegetable oils
* Suspending drug in a non-aqueous vehicle
* Drug supplied to pharmacist in a dry from and reconstituted by adding a specified volume of purified water just before dispensing
52
What is a route of administration? How are they categorized?
Route by which a drug is administered
Categorized according to the general location of the intended effect to be produced
53
What are the two main locations of intended effect for routes of administration?
Systemic drug efect: from admin site to a different site of action at a different location, potentially interacts with all body tissues
Site-specific effects: drug is administered to the tissue in need of drug therapy (local drug therapy)
54
Name systemic routes of administration
* Intravenous
* Intramuscular
* Subcutaneous
* Sublingual
* Buccal
* Oral
* Rectal
* Vaginal
* Transdermal
* Nose
* Lungs
55
What is the onset of administration via the intervenous route?
within 60s
56
What is the onset of administration via the intramuscular route?
15-30 minutes for aq. sol
57
What is the onset of administration via the subcutaneous route?
15-60 minutes for aq. sol
58
What is the onset of administration via sublignual route?
1-3 minutes
59
What is the onset of administration via the buccal route?
2-3 minutes
60
What is the onset of administration via the oral route?
30-60 minutes
61
What is the onset of administration via the rectal route?
30-60 minutes
62
What is the onset of administration via the vaginal route?
Slow for systemic effects
63
What is the onset of administration via the transdermal route?
1-4 hours
64
What is the onset of administration via the nasal route?
Within 10 minutes
65
What is the onset of administration via the pulmonary route?
Within 5 minutes
66
What is pre-formulation?
Series of studies carried out prior to formulating a drug dosage form, to collect basic information on the physical and chemical characteristics of all medicinal and non-medicinal ingredients in consideration of the physiological aspects of the intended patients.
It also provides the framework for the drug substance's combination with non-medicinal ingredients
67
The magnitude of a response to a drug depends on:
The concentration of the drug reaching the site of its action
68
What are some physicochemical factors taken into account during pre-formulation?
* pH and pKa
* Solubility
* Dissolution
69
Most drugs currently used are organic molecules that behave like:
weak acids or weak bases according to the Bronsted acid-base theory
70
What is the key implication of drugs being weak acids/bases?
The drugs are partially ionized in the human body
Their ionized and un-ionized forms coexist in solution, which would affect the drug's
* Solubility
* Pharmacokinetics
* Drug-receptor interaction
71
The extent of ionization of a drug is of primary importance in drug formulation as it affects:
* Solubility
* Pharmacokinetics (absorption, distribution, eliminatiom)
72
Define solubility
The maximum concentration of a substance that may be completly dissolved in a specific solvent at a specific temperature
Generally expressed in mass of solutes per the volume of solvent
Determines the appropriateness to be used as a medicinal agent
73
How does solubility impact pre-formulation?
Guides the formulation, administration, and absorption of a drug substance
74
How does solubility affect diffusion?
It is the driving force for absorption by diffusion across a membrane:
* The highest concentration a drug can acheive in the biological fluid provides the high point of the concentration gradient
75
What is the importance of aqueous solubility for drugs?
* Critical for therapeutic efficacy
* Necessary for entrance into systemic circulation
* Biological fluids that act as solvents for drugs in the body are aqueous
* The inonized salt form is more soluble than the unionized acid
76
What determines the ability of a drug to dissolve in aqueous bodily fluids?
The number of functional groups capabale of forming hydrogen or ionic bonds
77
How can solubility of a drug be improved?
Chemical manipulation of:
* The drug substance
* The solvent
78
What is the drug salt?
The chargedm water soluble form of the drug, wether solid or liquid dosage form
79
What is the proportion of drugs that are weak bases? Weak acids?
75%
20%
80
Most drugs that are weak acids/bases are prepared using:
Their salt, as to be absorbed
A drug must be in solution in the aq. body fluids
81
How are drug salts prepared?
Reaction of:
* Weak base with strong acid
* Weak acid with strong base
82
Dissolution rate can affect what aspects of therapeutic response?
* Onset
* Intensity
* Duration
The dissolution rate can also control the overall bioavailability of the drug
83
What are the 4 main way the body deals with administered drugs?
Absorption
Distribution
Metabolism
Excretion
84
What is the key principle of absorption?
For a drug to be absorbed, it must first be dissolved in the fluid at the absorption site
85
By what mechanism can solute molecules and ions cross the bi-layer membrane?
* Passive diffusion
* Facilitated transport
* Active transport
86
What is passive diffusion?
Passage of drug molecule through a membrane that does not actively participate in the process:
* By random molecular motion
* Driven by the concentration gradient
Involves most drugs
Hydrophillic compounds cross the membrane by filtration, through water-filled pores in the membrane
87
When passive diffusion is driven by the concentration gradient, the rate of diffusion depends on:
* Drug's concentration
* Drug's affinity with the lipid bilayer
88
Enounce Fick's first law. What does it apply to?
The rate of diffusion across a membrane is proportional to the difference in drug concentration on both sides of the membrane
It applies to passive diffusion
89
Which mecanism of membrane transport requires transport proteins?
* Facilitative transport
* Active transport
90
Which mechanisms of membrane transport can lead to saturation?
* Facilitative transport
* Active transport
91
Which mechanisms of membrane transport can go against the concentration gradient?
* Active transport
92
Which mechanisms of membrane transport is energy dependant?
* Active transport
93
What are some possible sources of energy of active transport?
* Light
* Oxidation reactions
* ATP hydrolysis
* Co-transport of other solute
94
What is the primary role of drug transporters?
Transport endogenous substances across the cell membrane
Facilitate movement of moleules across the cell membrane
95
Name two transporter superfamiles
* ATP-binding cassette (ABC) family
* Solute carrier family (SLC)
96
What are the two large drug transporter classifications according to transport direction?
* Efflux: pump substrate out of cell (P-gp)
* Influx: transfer substrate into cell (PepT1)
97
What are two large drug transporter classifications accoring to pharmacokinetics?
* Absorptive transporter: transfer substrate toward the systemic circulation
* Secretory transporter: transport substances from the systemic circulation
98
What are two large drug transporter classifications accoring to energetics?
* Active transporter - requiring energy: primary and secondairy
* Passive transporter - does not require energy: facilitative transport
99
Where are drug transporters located?
Mostly in tissues with barrier functions (intestine, kindey, liver and brain)
100
Drug transporter are located mostly in tissues with barrier functions. What is a cell characteristic at these locations?
Cells at the bordder are polarized:
* Plasma membrane has 2 discrete regions with different functions: apical and basolateral domain
101
What is the function and the location of P-gp transporters?
Efflux pump for xenobiotic compounds with broad substrate specificity, which is responsible for decreased drug accumulation in multidrug resistant cells and often mediates the development of resistance to anticancer drugs
Found in many tissues (especially those with barrier functions)
102
What is the function and the location of MRP1 transporters?
MRP1 transports glucuronides and sulfate-conjugated steroid hormones and bile salts. It also transports drugs and other hydrophobic compounds in presence of glutathione
Found in the lungs, testis and intestine
103
What is the function and the location of BCRP transporters?
Xenobiotic tranporter, which contributes to multidrug resistance. It serves as a cellular defense mechanism in response to mitoxantronc and anthracycline exposure. It also transports organic anions, steroids and certain chlorophyll metabolites
It is found in the placenta, brain, liver and intestine
104
What is the primary cause of the failure of chemotherapy?
* Resistance if the tumour to drugs
* Resistance to chemotherapy is caused by multidrug resistance transporters (MDR)
105
Following absorption into the blood circulation, the drug may be: (1)
Boud to blood proteins, especially albumins
* These molecules are considered inactive and may serve as reservoir
* Will not be subject to metabolism and excretion
Conditions such as malnutrition reduce the levels of plasma albumin, and thus a lower dose may cause an overdose, since less drug will be binded to proteins
106
Following absorption into the blood circulation, the drug may be: (2)
Transferred into the fluid bathing in the tissues
* Considered as active as it'll interact with the intended target faster
* May accumulate in cells according to their permeability and chemical & physical affinities
* Will be subjugated to metabolism and excretion
107
What is a compartmental model?
Models which simulate the exten of the distribution of a drug to different tissues, which compartmentalize the physiologic systems of the body
108
Following absorption, drugs and all other absorbed substances are transferred:
To the liver via the hepatic portal vein
109
Which organ is considered the first and primary centre on metabolism?
The liver
110
Define metabolism
Biotransformation through which a xenobiotic or endobiotic compound is enzymatically transformed into a generally more polar, water-soluble, and excretable metabolite.
Major process by which foreign substances, including drugs are eliminated from the body
111
During metabolism, a drug may be bio-transformed into a pharmacological form that is:
* Active
* Inactive
* Both
112
During metabolism, drugs undergo:
Full, partial or no biotransformation
113
Most metabolic biotransformations take place in:
the liver
114
What is a prodrug?
Drug in which the administered drug is pharmacologically inactive while its metabolite is active
115
An inactive metabolite is usually:
* More water soluble
* More ionized
* Less capable to bind to blood proteins & tissues
* Less capable of penetrating cell membranes
* Less toxic
116
What is cytochrome P450?
Family of enzymes that metabolize compounds into a form that is easier for the kidney to excrete in urine
117
What are the three main groups of CYP450?
CYP1, CYP2, CTP3
118
What is the reaction carried out by P450?
* Type 1: changing lipophilic substances into hydrophilic metabolites (mainly by oxidation, attaching an oxygen atom, for example as ah OH)
119
Describe first-pass metabolism
All drugs absorbing from the digestive system pass thorugh the liver and are metabolized before entering the circulatory system
120
Descrie pre-systemic metbolism
Prior to reacing the liver, enteral drugs are metabolized in the wall of the gut by P450, hereby affecting the amount of drug reaching the liver
121
What are factors that influence metabolism?
* Species differences: difficult to extrapolate effects of a drug from one species to another
* Interindividual variations: genetic factors e.g cytochrome P450 mutations
* Age: ability to metabolize drugs is low in neonates & the elderly. liver blood flow is reduced by aging at about 1% per year
* Diet: ex. production of polycyclic hydrocarbons by the charcoal broiling of beef affects theophylline, which enhances hepatic metabolism and shortens plasma half life; large quantities of grapefruit juice...
* Other drugs
* Disease state
122
What is the main excretion organ of the body?
The kidneyrs
123
What is the general function of the kidneys?
Remove unwanted materials from the blood whil conserving the useful materials such as glucose, salts and amino acids
124
How are drugs with large molecular weight eliminated?
By the liver in the bile (mixture of cholesterol, acids and pigments)
Drugs are carried into the digestive syste via the bile duct and eliminated as feces
125
Bile salts are involved in a recycling process called:
The enterohepatic recirculation between the intestine and the liver
126
Define pharmacokinetics
The study of how a drug reaches its target, and what happens to it during that journey. It elucidates the time course of drug concentration in the blood and tissues
127
The absorption phase of a drug includes:
* Absorption
* Metabolism
* Excretion
128
The disposition phase of a drug includes
* Absorption
* Distribution
* Metabolism
* Excretion
129
Define elimination in the context of a drug
An irreversible process by which the drug is removed from the body
Elimination is a product of metabolism and excretion
130
Define excretion in the context of a drug
Terminates the activity and presence of drugs and their metabolites in the body
131
Through which routes can excretion take place?
* Kidneys
* Anus
* GI tract
* Lungs
* Sweat glands (including breast milk)
132
What is the criteria for a generic drug to be on the market?
Must contain the same medicinal ingredients as the brand name drug, and are considered bioequivalent to the reference product. Non-medicinal ingredients may be different
Must provide studies showing that the different non-medicinal ingredients have not changed the quality, safety or effectiveness of the generic drug
133
How does a generic product prove that the drug performs similarly to the brand name?
Level of a medicinal ingredient in the blood of healthy human volunteers is measured in the generic vs. name brand
This is called a comparative bioavailability study
Generic drug must show that it delivers the same amount of medicinal ingredient at the samerate as the brand name drug.
BPS 4
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