Module 01 Flashcards
(339 cards)
1
Q
drugs
A
any substance received by the biological system that is not for nutritive purposes
- influences the biological function of the organism
- chemicals, biological agents, and herbal products
2
Q
ancient civilizations shaping modern pharmacology
A
- healers existed historically in all ancient times
- records from these civilizations (greece, egypt and china) have shaped its history
3
Q
Ancient Greece
A
380 BCE - Theo wrote a textbook on therapeutics that included opium
4
Q
Serturner (German pharmmacist)
A
isolated crystals of morphine from opium and tested the pure substance on himself and three others, discovering its pain relieving capabilities
5
Q
opium
A
obtained from opium poppy (papaver somniferum)
- Pain releiving
6
Q
2 important substances of opium
A
- Morphine
- Codeine
7
Q
how much morphine does opium contain?
A
~10% morphine
8
Q
Morphine
A
- Can relieve pain of great intensity (god of dreams)
- Acetylsalicylic acid (Aspirin) and acetaminophen (Tylenol) only relieve mild to moderate pain
9
Q
how much codeine does opium contain?
A
0.5% codeine
10
Q
Codeine
A
tylenol 3 (a prescription drug)
11
Q
Ancient Egypt
A
- History was recorded on papyri - one was intended to be a textbook of drug use for medical students (Ebers Papyrus)
- Contains observations on particularly purgatives
- Recommended senna
12
Q
purgatives
A
drugs that cause bowel movements
13
Q
Ancient China
A
- Emperor Shen Nung classified all drugs according to taste (2700 BCE)
- Ex. Ma Huang classified as “medium drug”
14
Q
Ma Huang
A
Ephedrine has been isolated from Ma Huang to treat asthma
15
Q
The influence of poisons
A
all substances are poisons (not one that is not poisonous)
- the RIGHT DOSE differentiates a poison and a REMEDY
16
Q
poisons that have led to the development of drugs
A
- Curare
- Ergot
17
Q
Curare
A
- Plant-derived drug
- Used by Indigenous peoples in the Amazon rainforest in South America
18
Q
Use of Curare as a poison
A
- Indigenous people dipped their arrows in curare to use as poison for hunting
- It acts upon the voluntary muscles of the animal causing paralysis and eventually death by respiratory paralysis
19
Q
Use of Curare as a drug
A
- allopathic medicine
- anesthetists during surgery
- new derivatives are used today by anesthetists
***structure has been modified to make it safer
20
Q
how does Curare work as a drug?
A
by giving a small dose, muscle relaxation was achieved, facilitating a surgeons work
21
Q
Ergot
A
- Poisonous fungus that grows on the heads of rye, particularly during wet seasons
- Was ground together with rye in the Middle Ages, thereby finding
3 .Terrible epidemics occurred killing 20,000 people in one region in Russia
22
Q
Ergot poisoning on the nervous system
A
targets NS immediately after entering the body
23
Q
symptoms of Ergot poisoning on the NS
A
- mental frenzy
- hallucinations
- convulsions
24
Q
Erogot poisoning on the cardiovascular system
A
- constriction of blood vessels leading to fingers, toes and limbs becoming starved of their blood supply causing a burning sensation
- limbs become black and gradually die off over time (may fall off if severe)
25
Ergot poisoning on the reproductive system
1. can cause violent contractions of the uterus
2. 16th century women found out small amounts of ergot could be useful in hastening labour
3. if not used appropriately could lead to death
26
2 compounds of Ergot that have pharmacological use
1. ergotamine
2. ergonovine
27
Ergotamine
useful in treatment of migraines
- constricts blood vessels that reduce the amplitude of pulsation that cause a migraine
28
Ergonovine
1. used to arrest uterine bleeding after childbirth
2. was once used to hasten birth but could cause the parent to be injured by too rapid delivery of child (dangerous so not used for this anymore)
29
influence of religion
1. therapy was heavily influenced by religion and magic for traditional healers
2. plants containing intoxicating substances were used by traditional healers to alter consciousness and facilitate communication with their gods
30
ex. of religious drug
peyote
31
Peyote
1. peyote cactus was used to achieve a mystical state
2. contains the potent substance mescal which causes hallucinations, feeling of well-being, and distortion of perception similar to what you experience with LSD
32
LSD
lysergic acid diethylamide
- a potent hallucinogenic drug that acts on the brain
33
2 major categories of drugs
1. drugs acting on the brain
2. drugs acting against infectious disease
34
drugs acting on the brain
alter the normal chemical signalling in the brain
Ex. LSD (causes hallucinations)
35
discovery of LSD
albert hofmann 1943
- similar to ergotamine and ergonovine
36
LSD contribution to pharmacology
- the discovery of psychedelic effects of LSD supported the idea that certain mental illnesses might be due to production of potent substances in the brain that could product psychic disturbance
- derivatives of psychedelic compounds like LSD might be effective in treating certain mental illnesses such as depression, anxiety and addiction
37
1990s: Organoarsenicals (Paul Enrich)
- designed complexes of arsenic and organic molecules that selectively bounds to parasites
- this method was used for other infectious diseases and **led to cure for syphilis**
38
Syphilis
bacterial infection transmitted sexually via syphilis sore
39
1930’s: Sulfa Drugs (Gerhard Domagk)
first successful synthetic drugs for treatment of bacterial disease (called antibacterial compounds)
- antibiotics
40
antibiotics
refer specifically to chemical substances produced by microorganisms, not synthetic compounds)
41
1940’s: Penicillin (Alexander Fleming)
1. discovered the first antibiotic (penicillin)
2. occurred during the WW2
3. major use was in therapy of Gram-positive bacterial disease (diphtheria, staphylococcus)
42
Gram-positive
bacteria with thick cell walls and no outer membrane
43
1950’s: Streptomycin (Selman Waksman)
turning point in treatment of tuberculosis and Gram-negative bacterial diseases (cholera, E.coli)
44
Gram-negative
bacteria with thin cell walls and an outer membrane
45
How has historical use of chemicals contributed to the advancement of pharmacology?
Use of sulfa drugs led to the development of the first synthetic antibacterial compounds
46
Which of the historical drugs listed is still used clinically today:
morphine
47
2 key steps of the drug development process (drug discovery 3-6 years)
1. Basic research and drug discovery
2. Preclinical trials
48
3 key steps of the drug development process (drug development)
1. Clinical trials (6-7 years)
2. Health Canada review and manufacturing (0.5-2 years)
3. Post-market surveillance and phase IV clinical trials (continuous)
49
basic research and discovery of target: step 1
Identification of the Target
50
Step 1: Identification of the Target
1. a target for a new potential drug could be a receptor that when activated causes relief of pain
2. once a compound that binds well to the target is identified, it will be studied to determine its pharmacological effects at the molecular, cellular, organ and whole animal level
51
basic research and discovery of target: step 2
Studying the Target
52
Step 2: Studying the Target
if compound shows promise in initial studied, its identified as a lead compound and is studied further for safety and efficacy
53
Efficacy
the max pharmacological response produced by a specific drug in that biological system
54
Preclinical Studies
1. occurs after drug target has been discovered
2. conducted prior to testing the new drug in humans
3. range from molecular and cellular studies to tissue and whole animal studies
55
2 main categories of preclinical studies
1. pharmacology studies
2. toxicology studies
56
pharmacology studies
determine the detailed mechanism of action of the new drug
57
toxicology studies
1. determine the potential risks or harmful effects of the drug
2. studies are done to look at acute toxicity, chronic toxicity and effects on reproductive, carcinogenic, and mutagenic potential
3. studies are expensive and may take up to 6 years to complete
58
toxicology
all drugs have some toxicity at some dose in some individuals
59
clinical trials: initial steps
1. proof of safety
2. methodology of the proposed clinical trials in humans
3. investigation
60
proof of safety
pharmaceutical manufacturer must submit proof of safety and efficacy of the drug in several animal species to the government regulatory agency in particular country
61
investigation
submission is evaluated by qualified scientists in regulatory agency
62
what happens if scientists are satisfied with the submission?
permission will be given for highly qualified investigators (clinical pharmacologists) to begin investigation of the drug in humans
- very careful cause animal studies will not always predict drug behaviour in humans
63
clinical trials
performed on humans once initial steps are complete and permission is granted
64
how many compounds make it through preclinical testing and into clinical trials?
5 to 30
65
how many drugs usually make it to phase 3 clinical trials?
1 or 2
66
phase 1 clinical trials
1. carefully evaluate the absorption, distribution, elimination and adverse effects of the new drug
2. test one or two doses of the new drug to determine the tolerability of the drug
(EFFICACY IS NOT TESTED IN THIS PHASE)
67
how many people are typically included in a phase 1 clinical trial?
20-80 healthy volunteers
68
phase 2 clinical trials
looking to determine whether the drug is effective in treating the condition for which its recommended
- careful attention to safety of the drug
- conducted in patients with the disease for which the drug is designed to treat
69
how many people are typically included in a phase 2 clinical trial?
100-500 people
70
what kind of trials are phase 3 clinical trials
randomized control trials (RCTs)
71
phase 3 clinical trials
main studies for licensing and marketing of the drug
72
how many people is the drug tested on?
larger number of people (1000+) to obtain information about drug in more diverse population
73
how long are phase 3 clinical trials?
longer than phase 2 studies (months to years)
74
goal of phase 3 clinical trials
determine how safe and effective the drug is compared to no treatment (placebo) or current recommended therapy
75
location of phase 3 clinical trials
conducted at centres in many cities (multi-centred) for diversity
76
cost of phase 3 clinical trials
most expensive phase (1 million to upwards of 50 million)
77
3 stages of designing a phase 3 clinical trial
1. determining ENROLMENT prior to the study
2. ALLOCATING participants to TREATMENT groups and conducting the trial
3. monitoring and analyzing the RESULTS
78
Enrolment
1. target population
2. study population
79
target population
group of patients for whom the drug is intended
80
ex of the target population
target population for a drug to treat hypertension would be adults with clinical diagnosis of hypertension
81
study population
subset of target population that meets all required criteria
82
2 major factors that influence who can be included in study population
1. inclusion/exclusion criteria
2. consent
83
inclusion/exclusion criteria
- define characteristics of the patients to be included in the study
- determines who in and is not eligible to be part of the trial
- eliminates variables that may influence results
84
consent
- document that outlines purpose of study, procedures used, all potential risk and benefits
- at any time, participant can revoke consent and withdraw without penalty
85
treatment allocation
1. double blind design
2. randomization
3. control
86
Double blind design
neither the investigator nor the participant is aware of the treatment they are assigned to
87
Importance of double-blind design
1. bias can occur if the participant believes the drug will work
2. an investigator may be expecting positive results from the drug which can bias the results
88
Randomization
patients are assigned to the experimental treatment group (receiving new drug) or control group randomly
89
Importance of randomization
1. ensures confounding variables are distributed equally between groups
2. removes potential bias in assigning patient groups
90
Control
1. Placebo (fake drug)
2. Golds-standard drug
- efficacy and safety of experimental drug must be compared to a control drug (placebo or gold standard drug)
91
Placebo drug
1. doesn’t contain any active drug but is identical in appearance, colour, taste, and administration method
92
How do placebo drugs work?
ailment somewhat eases, because you believed it would work
93
Placebo response
can be as high as 40% in sick, anxious patients
94
Gold standard drug
drug that is accepted by the medical community as the best available treatment for the specific disease
- if this drugs is available, it is given cause it is unethical to withhold treatment if one exists
95
When is placebo used?
ONLY used when gold standard is not available
96
Results of Phase 3 Clinical Trial
1. Outcome
2. Complicance
3. Quality of Life
4. Statistics
97
Outcome of Phase 3 Clinical Trial
measures how much the drug worked must be measured and compared to see if experimental was better than control or not
- must be measured in a reliable and objective manner (same time every day, same technique, etc.)
98
Outcome example
if trial was for a drug treating hypertension, the outcome would be blood pressure so that is what you would measure
99
3 Factors that influence interpretation of a Phase 3 Clinical Trial
1. Compliance
2. Quality of Life
3. Statistics
100
Compliance
how often the patient actually took the drug when they were supposed to
- can be as low was 50 to 60%
101
Oral drug compliance
participants are asked to return their unused drugs at each clinic visit and new batch is handed out - a count of remaining tablets is an indication of overall compliance
102
IV drug compliance
measured by checking that the nurse signed off on administering the drug
103
Quality of Life
- does the drug improve QoL?
- some drugs are effective at treating diseased, but have adverse effects or be so complicated to take it may not improve QoL
104
Statistics
measured outcome for experimental drug must be compared to measured outcome for control drug
105
Health Canada Review
1. occurs after successful completion of initial phase 3 trials
2. if the drug is deemed effective and the toxicity is acceptable, it will be granted approval
106
Manufacturing of drug
manufacturers come up with a drug name (generic) and a brand name for the drug
107
Generic Name
used because a drug’s formal chemical name is too complex for general use
108
Brand Name
is given to the drug to give the company exclusive rights to market the drug for 20 years
- 20 year life of a patent (license) begins when it is filed (during preclinical development)
109
What happens when a patent on a drug is expired?
other manufacturers can make copies of the original brand name drug, and sell it under their own brand name
110
Example of generic vs. brand name
Generic: Acetaminophen
Brand: Tylenol
111
Bioequivalence (generic and brand)
original brand name drug and any generic versions of the original drug will all contain identical active ingredient in the same amount and same dosage form
112
What is the purpose of bioequivalence?
ensures all marketed drugs are as effective as original brand name and are bioequivalent
113
How do you achieve bioequivalence?
a comparative bioavailability study is conducted
- compares blood levels after administration of both the original brand name and the new brand name/generic drug to healthy volunteers under controlled conditions
114
Phase 4 Clinical Trials
Post-Market Surveillance
115
Post-Market Surveillance
surveillance of the effects of the drug is required after the drug is released for general use
- look at Adverse Reactions Reports for patterns of signals and if a problem can order changes to drug labels, add new warnings or advise that certain drugs should not be taken together
116
Purpose of post-market surveillance
risks that are delayed or less frequent than 1 in 1000 administrations may be missed in phase 3
117
Phase 3 clinical trials can employ a placebo. Which one of the statements most accurately describes a placebo?
a placebo is defined as an inert substance masquerading as a drug
118
The sound and long established way to prove or disprove a value of a new medication or treatment is a RCT. This means that…
the people who administer the drugs do not know who is receiving the new drug (because they are often double blind)
119
Several important factors when considering a drugs action
1. Drugs targets
2. Drugs response
3. Efficacy and potency
4. Therapeutic range
120
Drug targets
drugs are designed to interact with one selected target in the body
- usually receptors (BUT some drugs bind to other targets in the body)
121
Target Drug Receptors
a molecule or complex of molecules located on the outside or inside of a cell that has a regulatory or functional role in the organism
- normally bound to and activated by endogenous ligands - substances ordinarily found in the body (hormones and neurotransmitters)
122
Receptor location
determines where a drug will act and whether the response that results from the drug-receptor interaction is beneficial or detrimental
ex. activation of opioid receptors in the brain causes pain relief BUT activation of opioid receptors in the GI tract cause constipation (adverse effect)
123
Other drug targets (not receptors)
some drugs interact non-specifically with the biological system and not via receptors
ex. chemical reactions - antacids neutralize stomach acid through simple acid-base neutralization reaction
124
Cholestyramine
drugs used to lower cholesterol in the blood
125
Drugs and receptors
1. most drugs mimic the action or, or block the effect of the endogenous ligand at the receptor (by increasing or decreasing activity)
2. requires certain compatibility of fit for drug and receptor - antagonist doesn’t have same compatibility of fit so therefore can bind to it but not activate it
126
Agonists
drugs that bind to and stimulate a receptor (activates a response)
- key fit lock and can open the lock
127
Antagonist
drugs that bind to but block the response at a receptor
- blocks cellular activity
- key fit lock but cannot open the lock
128
Ligand
molecule that binds to a receptor
129
Drug Response
the intensity of the pharmacological effects produced by a drug increases in proportion to the dose (more you consume the more intense)
- dose-response relationship
130
Marijuana
cannabis product obtained from dried plants
- large doses of cannabis do impair motor vehicle performance
131
Things to consider when comparing Cannabis and alcohol
1. quantity
2. frequency
3. user demographics (what people)
4. environmental factors
132
How does a drug achieve its desired response?
many receptors need to be activated at once
133
Low doses
very little response is observed cause not many receptors are being activated
134
Threshold
a certain number of receptors must be activated before an effect will be seen
135
Therapeutic Doses
once threshold reached, a small increase in dose results in a large increase in response
136
Maximal effect
once maximal effect reached, continuing to increase the dose of drug will have no further increase in therapeutic response
137
Dose-response curve
graph of how much drug you need in the body to see a specific effect
138
Components of a Dose-response curve
1. Y-Axis
2. X-Axis
3. Low Doses
4. Therapeutic Range
5. ED50
6. Maximal Response
139
Dose-response curve - Y-Axis
1. effect of the drug
- the maximal response the body can produce is 100%
140
Dose-response curve - X-Axis
dose of the drug (plotted on a logarithmic scale)
141
Dose-response curve - Low Doses
increases in dose are not corresponding to increases in response (receptor threshold has not yet been reached)
142
Dose-response curve - Therapeutic Range
receptor threshold has been reached - dose of the drug is directly proportional to the response
- small changes in dose result in large changes in response
- linear portion of the curve - allows for accurate determination of drug effectiveness
143
Dose-response curve - ED50
the dose of drug that will result in 50% of the maximal effect
OR
the dose of drug thats effective in 50% of a population
144
Dose-response curve - Maximal Response
- max response has been reached
- further increases in dose have no effect on response level
145
Two properties of a drug that describe its ability to produce a response
1. Efficacy
2. Potency
146
Efficacy
maximum pharmacological response that can be produced by a specific drug in that biological system regardless of dose
- maximum effect matters not amount of drug needed
- NOT ADJUSTABLE
147
Example of efficacy
Drug A might produce a maximum response of 100% (high efficacy) where Drug B might only produce a 60% response at its highest dose (lower efficacy
148
Potency
dose of a drug that is required to produce a response of a certain magnitude - usually 50% of the maximal response for that drug
- refers only to the amount of drug that must be given to obtain a particular response
- ADJUSTABLE
149
Example of potency
saying Drug A is more potent than Drug B means one needs to take less of Drug A (10mg) to achieve the same effect that’s obtained from Drug B (20mg)
150
Is efficacy or potency more important clinically?
Efficacy
- the maximum effectiveness of a drug is generally what determines which drug is chosen to treat a specific condition
151
Dose-response curve and efficacy
efficacy deals with the y-axis
152
Aim of Therapeutic Range
give a dose that keeps the blood concentration of a drug above the minimum concentration that produces the desirable response, but below the concentration that produces an unacceptable toxicity
153
Steps of Administering a drug (therapeutic range)
1. after a drug is administered the blood conc. increases until it reaches the minimum conc. for therapeutic response at which point there is an onset of effect
2. blood conc. continues to increase until it peaks
3. as it is metabolized and excreted it decreases until it drops below the minimum conc. for a therapeutic response
154
Duration of action
time period when the blood conc. is above the minimum conc. for a therapeutic response
155
Therapeutic Response
difference between the minimum conc. for unacceptable toxic response and minimum conc. for therapeutic response
- the blood conc. are high enough to elicit a therapeutic response, but low enough to avoid toxic effects
156
What does the size of the therapeutic range indicate?
How safe the drug is
- wider the therapeutic range = safer the drug
157
Example of therapeutic range
antibiotics called aminoglycosides
- want the conc. to be high enough that the drug kills the bacteria, but not high enough that it damages the kidney
158
Drug A can only relieve pain of mild intensity. Drug B on the other hand, relieves pain of very marked intensity. Which has greater efficacy?
Drug B has greater efficacy than Drug A
159
The therapeutic range is best described as?
the range of blood concentrations where the drug is effective and unacceptable toxicities do not occur
160
For a drug to produce its desired effect, it must do what 3 things?
1. reach the cellular site of action at the right conc.
2. exert its effect
3. then be removed from the body
161
Pharmacokinetics:
refers to this movement of a drug intro, through, and out of the body
- “drug movement”
162
5 Key processes involved in pharmacokinetics
1. methods of administration
2. absorption
3. distribution
4. metabolism
5. excretion
163
Four key processes after administration
AMDE
164
Purpose of AMDE
determine the conc. of drug in the blood, which in turn determines the conc. of drug at the site of action
165
3 Routes of Drug Administration
1. Topical
2. Enteral
3. Parenteral
166
Topical Administration
refer to drugs that are applied directly to a particular place on or in the body
167
3 topical routes of administration
1. On the skin
2. Through the skin (transdermal)
3. Inhalation
168
On the skin - topical administration
- many drugs can be applied to the skin to treat mild to moderate severity skin conditions (eczema, acne and infections)
169
disadvantage of on the skin topical administration
drugs applied to skin for local effect can be absorbed and produce a systemic effect
- some topical steroids used to treat a skin condition can be absorbed and cause toxicities elsewhere in the body
170
Systemic
indicates something that affects the whole body or multiple organ system
171
Through the skin (Transdermal) - topical administration
application of a drug to the skin for absorption into the general circulation for a systemic effect
172
Example of transdermal - topical application
nicotine patch allows nicotine to pass into the general circulation to eventually act on the brain
173
Benefits of transdermal - topical administration
1. convenient
2. delivers steady drug supply for several days, eliminating frequent oral dosing
3. bypasses the enzymes of stomach, intestine, and liver
174
Disadvantages of transdermal - topical administration
1. expensive
2. it can cause local irritation
175
Inhalation - topical administration
can be rapidly absorbed from the lungs
- both local and systemic effects
176
Systemic effect of inhalation
gaseous anesthetics are administered by inhalation
177
Local effect of inhalation
steroids and other drugs for lung diseases are administered for local effect in the lungs
178
Benefit of local effect of inhalation
quantities of drugs are small and often less than that required for systemic effect thus avoid toxicity associated with oral administration
179
Disadvantage of local effect of inhalation
requires the proper use by patient
180
Enteral Administration
refers to administration via the GI tract
- when drug is absorbed into blood from GI tract it is first delivered to liver
181
3 Enteral routes of administration
1. mouth
2. rectum
3. sublingual (under tongue) and buccal (in cheek)
182
First bypass effect of enteral administration
liver contains enzymes that can decrease the amount of active drug left to enter general circulation
183
Mouth advantages- enteral administration
1. 90% of all drugs taken by this route
2. most convenient and least expensive way
3. non-invasive and can be self-administered
184
Mouth disadvantages- enteral administration
variable absorption between patients due to differences in intestinal motility and disease
185
Rectum advantages - enteral administration
1. can be used for systemic or local effect
2. can be used in patients who are nauseated or vomiting, or as less invasive route for those who are comatose
3. digestive enzymes of the stomach and intestine are bypassed
186
Rectum disadvantages - enteral administration
1. only a limited number of medications are suitable for rectal administration
2. absorption from the rectal mucosa is slow, incomplete and variable depending on time the medication is retained
187
Sublingual and buccal advantages - enteral administration
enzymes of the stomach, intestines, and liver are bypassed
188
Sublingual and buccal disadvantages - enteral administration
1. not all drugs are adequately adsorbed from this route
2. drug may be swallowed and then behaves as if it were taken orally
189
Parenteral Administration
refers to administration bypassing the GI tract
- drugs enter the bloodstream directly
190
3 parenteral routes of administration
1. intravenous
2. intramuscular
3. subcutaneous
191
Intravenous - parenteral administration
1. drug is placed directly into the blood and therefore has immediate effects
2. response is irreversible, which results in this route having the highest risk for drug reactions
192
What can intravenous parenteral administration be used for?
drugs that are poorly absorbed, if they can be made into a solution in purified water for injection
193
What does intravenous parenteral administration require?
1. significant human resources (ex. nursing)
2. preparation must be sterile and free of fever producing substances (pyrogens)
194
Intramuscular - parental administration
drug is injected deep into a muscle
- volume of drug is limited to 2-3 mL in an adult
195
Subcutaneous - parenteral administration
1. drug is injected into the deepest layer of the skin
2. allows for modification of drug preparations to control the timing of the release of the drug from injection site
196
Bioavailability
the fraction of an administered dose that reaches the systemic circulation (blood) in an active form
197
Bioavailability of a drug given intravenously
placed directly into the blood and is 100% bioavailable as it doesn’t require absorption
- a drug dose given by any other route will not be 100% absorbed into the blood
198
onset of action of topical administration
rapid to slow (depends on organs)
199
onset of action of mouth - enteral administration
slow (30 min to > 1 hr)
200
onset of action of rectum - enteral administration
slow and incomplete
201
onset of action of sublingual - enteral administration
rapid (1-2 min)
202
onset of action of buccal - enteral administration
intermediate (3-4 min)
203
onset of action of veins- parenteral administration
15 - 30 sec
204
onset of action of muscles- parenteral administration
10 - 20 min
205
onset of action of under the skin- parenteral administration
15 - 30 min
206
bioavailability of topical administration
5 - 100%
207
bioavailability of mouth - enteral administration
5 - 100%
208
bioavailability of rectum - enteral administration
30 - 100%
209
bioavailability of sublingual - enteral administration
30 - 100%
210
bioavailability of buccal - enteral administration
30 - 100%
211
bioavailability of veins - parenteral administration
100%
212
bioavailability of muscle - parenteral administration
75 - 100%
213
bioavailability of under the skin - parenteral administration
75 - 100%
214
Absorption
the movement of a drug from the site of administration into the blood
215
Transfer Across Membranes:
drugs can cross membranes, moving from one side (the lumen) to the other side (the interstitium) in 3 methods
216
3 methods drug can cross membranes
1. Effusion through aqueous pores
2. Diffusion through lipids
3. Active or carrier mediated transport
217
Effusion through aqueous pores
drugs with small molecular weights that are water soluble can move across membranes by..
1. first dissolving in the aqueous fluids surrounding cells
2. then by passing through the small openings between cells
- high to low concentration yes
218
Diffusion through lipids
most important method for drug movement
- drugs pass through the membrane by dissolving in the lipid portion of the membrane
- these drugs still flow down a conc. gradient
219
why is diffusion through lipids most important for drug movement?
vast majority of drugs have molecular weights greater than 150 Daltons, and therefore do not pass through aqueous pores
220
What determines the ability of a drug to cross a membrane via diffusion through lipids?
depends on its lipid solubility
221
cellular membranes
composed of a lipid bilayer structure
222
Active or carrier mediated transport
many drugs bind to proteins, termed carrier proteins or transporters, which carry molecules across a membrane
- can move down a concentration gradient but can also be an active process requiring energy to move a drug against a conc. gradient
223
What happens when the drug binds to the carrier protein?
carrier protein-drug complex moves across the membrane and releases the drug on the other side of the membrane
224
Carrier proteins for drugs role
removal of drugs and their metabolites from liver and kidney
225
Distribution
the movement of a drug from the blood to the site of action and other tissues
- the conc. of drug at the sites of distribution are in equilibrium with its conc. in the blood
225
What happens if conc. in the blood drops below conc. at any distribution site?
the drug will move from that site to the blood to maintain equilibrium
226
What does the rate at which drugs distribute in and out of a particular organ depend on?
The blood flow to that organ
- Greater the blood flow to an organ = the more rapidly drugs reach that organ and vice versa
227
What can distribution result in the termination of?
the therapeutic effect of some drugs
228
drug metabolism/biotransformation
conversion of a drug to a different chemical compound in order to eliminate it
229
products of metabolism
called metabolites and are usually devoid (lacking) of pharmacological action
230
why must drugs be water-soluble
to be eliminated from the body, by the kidneys
- most drugs must be converted to more water-soluble compounds
- **without metabolism** - some chemicals that are very lipid-soluble would never be excreted from the body
231
location of metabolism
- liver is where more occurs
- some occurs in kidney, intestines, lungs, skin, and most other organs
232
Phase 1 biotransformation reaction - purpose of reaction
add or unmask a functional group on the drug to prepare it for the addition of a large water-soluble molecule in the phase 2 reaction
233
Phase 1 biotransformation reaction - functional group
a substituent of a molecule that is responsible for the molecule’s characteristic effects
234
Phase 2 biotransformation reaction - purpose of reaction
add a large water-soluble moiety, usually glucuronic acid or sulfate to the product resulting from phase 1 biotransformation
- makes the metabolite water-soluble for excretion by kidney
235
Moiety
a part of a functional group of a molecule
236
Components of biotransformational reactions
1. Phase 1
2. Phase 2
3. P450
4. Excretion
237
P450
enzymes capable of biotransforming drugs
238
location of P450
found in most tissues, but are present in high conc. in liver
-thus, the liver is the organ responsible for the majority of drug biotransformation
239
Why is it important to consider P450s when taking multiple medications at one time?
when taking two drugs simultaneously, the drugs might compete for this enzyme
- resulting in reduced biotransformation of one or both drugs, which could lead to toxic effects
240
drug excretion
moving the drug and it’s metabolites out of the body
241
Organs involved in drug excretion
1. Kidney
2. GI tract
3. Lungs
4. Breast milk
5. Saliva and sweat
242
Kidney role in drug excretion
1. eliminates the majority of drugs
2. drugs of sufficient water solubility will be excreted in the urine
3. lipid-soluble drugs can be reabsorbed from kidney back into blood
243
GI tract role in drug excretion
some drugs can be excreted by GI tract (in feces) after they undergo biotransformation in the liver
244
Role of lungs in excretion
drugs that are volatile or in a gaseous form can be excreted by the lungs (ex. gaseous anesthetics and alcohol)
245
Role of breast milk in drug excretion
1. drugs are often found in breast milk of nursing parents
2. minor route of elimination of the drug from the parent
3. the nursing infant can be exposed to a therapeutic or toxic dose of the drug
246
Role of saliva and sweat in drug excretion
often the presence of drugs of misuse can be detected in salvia of those who have taken it
247
Half-life of a drug
time needed for the liver and kidney to remove half the drug from the body
248
What is the half-life of a drug used to determine?
how often the drug needs to be administered to keep the drug conc. in the body in the therapeutic range
- varies based on weight, gender, health, etc.
249
AMDE of an orally administered drug
1. once a drug is administered it must be absorbed from GI tract
2. enters bloodstream once crosses the SI
3. in blood the drug can be FREE or BOUND to protein
4. FREE drug can distribute throughout the body to other tissues
5. can bind to receptor to produce a therapeutic response
6. can also distribute to tissue reservoirs such as fat or muscles
7. can also distribute to unwanted sites of action, binding to receptors to elicit a response other than therapeutic response
***drug moves from high to low concentrations
250
2 processes that remove the drug from the body
1. Biotransformation
2. Excretion
250
Metabolite
usually more water-soluble than the original drug, preparing it for excretion by the kidney
251
Do all drugs require biotransformation for excretion?
NO
252
The recommended dose of a drug
amount of drug that will cause the desired effect in most people, but will not cause the desired effect in all people
- varies between individuals, so dose needs to be adjusted based on individual response
253
5 Stages after Administration
1. absorption from site of administration
2. distribution to the site of action
3. target interaction (combo with receptor or other target)
4. metabolism (or biotransformation)
5. excretion from the body
254
Factors for Drug Response Variation
1. genetic factors
2. environmental factors
3. disease states
4. altered physiological states
5. presence of other drugs
255
Genetic factors for drug response variation
genetic variability exists in the receptors to which the drug binds and in the manner in which the body handles and eliminates drugs
- some individuals are considered SLOW biotransformers and others FAST biotransformers
256
example of genetic variability in drug response variation
activity of enzymes involved in metabolism of alcohol varies from person to person due to genetic variability
257
Environmental factors in drug response variation
exposure to certain chemicals can increase the enzymes in the liver responsible for the biotransformation of drugs
- eliminate the drug more rapidly than the unexposed portion of the population
258
example of environmental factors in drug response variation
chronic alcohol use increases the amount of one if the enzymes involved in drug biotransformation
259
Other disease states in drug response variation
presence of a disease state may alter the manner in which drugs are handled by the body
260
example of other disease states in drug response variation
patients with liver disease will metabolize drugs slower than those with normal liver function
- CVD and kidney diseases too
261
Altered physiological states in drug response variation
many changes can influence drug response
- age, pregnancy, etc.
262
example with age for altered physiological states in drug response variation
1. elderly are more susceptible to drug action than young adults
2. as we age we lose some of the reserve of redundancy in neural function and drugs have a greater effect than expected
3. liver and kidney function also decrease with age, which reduces rate drug are eliminated in elderly
263
example with pregnancy for altered physiological states in drug response variation
1. the body undergoes many changes during pregnancy that effects drug response (increase in blood volume, CO, rate of renal excretion)
2. both parent and baby receive the drug
264
Other drugs presents in drug response variation
when multiple drugs are taken together, it is possible for one drug to change the biological effect of a second drug causing variability in drug response
265
the ultra-short duration of action of thiopental is due to?
conc. decreases in blood and therefore brain causing its effect to wear off
266
A drug can be given to a patient both intravenously and orally. What should be considered when selecting the most appropriate dosage for the patients situation?
- differences in bioavailability need to be carefully considered
- so patient receives appropriate dosage
267
2 Divisions of Toxic Effect of Drugs
1. Adverse effects
2. Drug-drug and drug-food interactions
268
Adverse drug reaction
any effect produced by a drug that is not the intended effect
269
Types of adverse drug reactions
1. Extension of therapeutic effect
2. Unrelated to the main drug action
3. Allergic reaction
4. Withdrawal and addiction
5. Teratogenesis
6. Adverse biotransformation reaction
270
Extension of the therapeutic effect - adverse reaction
occurs when there is too much of the drug in the blood
- happens in drug overdose
271
Unrelated to the main drug action - adverse reaction
sometimes a drug can cause effects unrelated to the intended pharmacological action of the drug (nausea)
272
Allergic reaction - adverse reaction
1. mediated by the immune system
2. an antigen-antibody combination provokes an adverse reaction in the patient
3. the reaction may be very mild (skin rash) or very severe (anaphylaxis)
273
Withdrawal and addiction - adverse reaction
unwanted physiological and psychological effects of the drug
274
Teratogenesis - adverse reaction
when a drug produces defects in the developing fetus
275
Adverse biotransformation reaction - adverse reaction
occurs when a drug is converted to a chemically reactive metabolite that can bind to tissue components and cause tissue or organ damage
276
Predicting Adverse Drug Reactions
toxic reaction is rare, only appears after prolonged use, is not detectable in animals, is unique to a particular time period
277
Factors that Make Predicting Adverse Drug Reactions Challenging
1. Rarity of occurrence
2. Length of usage
3. Detectability in animals
4. Time period specificity
278
Rarity of occurrence - predicting adverse drug reactions
toxic reaction may be rare, making it difficult to predict
279
Examples of rarity of occurrence
chloramphenicol was used before it was known that is cause fatal bone marrow damage
280
Length of usage - predicting adverse drug reactions
toxic reaction may only appear after prolonged use
281
Example of length of usage
when streptomycin was introduced for treatment of TB, it was not realized that is could cause deafness if used for too long
282
Detectability in animals - predicting adverse drug reactions
toxic effect may not be detectable in animals, so it only appears once the drug is being tested in humans
ex. headache, insomnia, nausea, and mental disturbances will not be picked up in animal testing
283
Time period specificity - predicting adverse drug reactions
toxic effect may be unique to a specific moment in time
284
Example of time period specificity
thalidomide (treats nausea) produced limb growth in the fetus, but drug testing was not done in pregnant animals
- Pregnant = specific time period
285
How do you assess drug toxicity?
Therapeutic index
286
Therapeutic index
tells you how safe the drug is
- relates to the dose of the drug required to produce a beneficial effect to the dose required to produce an undesired or adverse effect
TD50/ED50
287
Therapeutic Index and safety
Higher the TI = the safer the drug
Lower the TI = more likely toxicities will be observed
288
What does it mean is therapeutic index is low?
ED50 and TD50 are close and the individual is likely to have adverse effects
289
Toxic Dose 50 (TD50)
dose of drug that is toxic in 50% the population
290
Effective Dose 50 (ED50)
dose of drug that is effective in 50% the population
291
Drug-Drug interactions
- occur when one drug changes the effect of a second drug
- can occur at many points during the drug’s journey through the bod
292
Drug-Drug interactions during absorption
a drug can increase intestinal movement, speeding the passage of a second drug through the intestine and decreasing contact of the second drug with intestinal wall
- decreasing absorption
293
Drug-Drug interactions during metabolism
a drug can block the inactivation of a second drug in the liver, increasing the blood level and effect of the second drug
294
Drug-Drug interactions during excretion
a drug can facilitate excretion of a second drug by the kidney decreasing blood level and effect of the second drug
295
Drug-Food interactions
involve the interference of food with drugs taken concurrently
296
Tyramine
1. found in well-matured cheeses
2. can raise blood pressure and is broken down in the liver by monoamine oxidase (MAO)
297
Tyramine and drug-food interactions
1. a class of antidepressant drugs are inhibitors of MAO (break down tyramine)
2. if a patient is on this antidepressant and consumes a food with tyramine
- the tyramine won’t be broken down to inactive products
- blood pressure raising effects of tyramine will be intensified
298
Grapefruit and drug-food interactions
1. alter absorption of some drugs
2. inhibits enzymes that biotransform and inactivate drugs in the GI tract
3. results in greater amount of the active drug being absorbed than without grapefruit
4. causes higher blood levels of the drug than expected, which could lead to overdose
299
Penicillin has the ability to combine with proteins to form antigens, and a small % of the population receiving penicillin experience adverse effects. This adverse effect is properly classified as:
a drug allergy
300
The TD50 of a drug in rats was found to be 50mg/kg. The ED50 was 1mg/kg. The TI is:
50
301
Cerebral Cortex (Cerebrum
Largest part of the brain and is rich in neurons
- neurons here can be stimulated (excited) or depressed (inhibited) by drugs
302
Limbic system
1. region in the brain that integrates memory, emotion and reward
-2. contains dopaminergic reward centers - targets for commonly misused drugs and are associated with addiction
303
Functions of limbic system
with the hypothalamus, it controls emotions and behaviour
304
The Neuron
1. functional unit of the brain
2. nerve capable of generating and transmitting electrical signals
305
Neurogenesis
continuously generates new neurons
306
Neuroplasticity
constantly re-shaping the connection between neurons
307
3 Important Structures of the Neuron
1. Dendrites
2. Cell Body (Soma)
3. Axon
308
Dendrites
short and have highly complex branching patterns
309
Function of Dendrites
1. receive incoming information and accept it through receptors on dendritic membranes
2. generate an electrical current and direct it down the neuron upon receiving information from another cells
310
Cell Body (Soma)
1. largest part of neuron
2. contains a nucleus and surrounding cytoplasm
311
Cytoplasm
contains abundant pre-packages neurotransmitters which can be secreted
312
Axon
single fibre that extends from cell body and ends at a synapse
313
Function of Axon
Continues to carry the incoming information away from the dendrites and cell body by electrical pulses
- this information is then passed to subsequent neurons
314
The Synapse
1. junction between two neurons
2. area where one neuron’s axon ends and another neuron’s dendrite of cell body begins
3. how an electrical impulse is communicated between neurons
315
Synaptic transmission/neurotransmission
the passage of a signal from one neuron to another neuron
- very rapid and chemical in nature - substance is quickly released that activates the next neuron
316
Steps to synaptic transmission/neurotransmission
1. electrical impulse will travel down the axon of a neuron
2. when impulse reaches end of presynaptic neuron it causes the vesicle (with NT) to fuse with presynaptic membrane
3. this releases the NT into synaptic cleft
4. NT diffuce across synaptic cleft and bind with receptors in postsynaptic membrane
5. activation of these receptors change the permeability of the membrane, allowing Ca2+ to move into postsynaptic neuron
6. this changes electrical activity of membrane generating an AP that will travel down that neurons axon
7. this process continues until neuronal signal reaches the target organ, causing effect
317
Termination of response (synaptic transmission)
NT must be removed so other nerve impulses can be communicated
- once removed from the synaptic cleft, the postsynaptic membrane can repolarize and prepare for the next neuronal impulse
318
3 Mechanisms of Termination of the NT
1. Neurotransmitters can be taken back up into the presynaptic neuron through transports (norepinephrine)
2. the NT can be broken down by enzymes in the synaptic cleft (acetylcholine)
3. NT can be taken up into adjacent glial cells - cells that support neurons (glutamate)
319
Drugs and synaptic transmission/neurotransmission
synapse can be a target site for many drugs
- some drugs interrupt synaptic transmission
- other drugs enhance or facilitate it, thereby modifying the activity of the brain
320
6 Neurotransmitters
1. Glutamate
2. Catecholamines
3. Gamma-amino Butyric Acid (GABA)
4. Serotonin
5. Acetylcholine
6. Opioid Peptides
321
Glutamate
1. primary excitatory NT in the CNS
2. found in almost all neurons
3. important for learning
322
Glutamate Receptors
family of receptors called the Glutamatergic Receptors
323
Catacholamines
1. Dopmaine
2. Norepinephrine
324
Dopamine
1. involved in control of some hormonal systems, motor coordination and motivation and reward
2. alterations in motivation/reward systems are associated with addiction
325
Norepinephrine
1. main classes of receptors it bind to is alpha (a) and beta (B)
2. activation of these receptors leads to excitation of the cells
3. this pathway is targeted by some CNS stimulants
326
Gamma-amino Butyric Acid (GABA)
1. primary inhibitory NT in the CNS
2. many CNS depressants (benzodiazepines) enhance GABA receptor function
327
GABAergic neurons (neurons releasing GABA) and GABA receptors location
found in high concentration in the cerebral cortex
328
Serotonin
1. hyperactivity of the serotonergic system is involved in anxiety and hypo-activity has been implicated in depression
2. some CNS stimulants act by increasing serotonin at the synapse
329
Acetylcholine
produces an excitatory response
330
Receptors that bind acetylcholine (cholinergic receptors)
1. Nicotinic Receptors
2. Muscarinic Receptors
331
Nicotinic Receptors
1. found in certain regions of brain
2. can be stimulated by acetylcholine or nicotine
332
Muscarinic Receptors
1. found in many regions of the brain
2. involved in learning, memory and cognitive function
3. can be stimulated by acetylcholine or muscarine
333
Adverse effects of drugs on the cholinergic receptors
Drugs that block the action of acetylcholine at these receptors produce amnesia
- loss of these neurons is associated with Alzheimer’s disease
334
3 main classes of opioid peptides
1. enkephalins
2. endorphins
3. dynorphins
335
3 opioid receptors
1. mu
2. delta
3. kappa
***all opioid interact with these receptors
336
What is the primary excitatory NT in the brain?
Glutamate
337
Which statement most accurately describes chemical transmission?
Most synaptic transmission is chemically mediated
- an substance is quickly released that activates the next neuron
