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Pharm 2060 Flashcards

1
Q

“Pharmacology” derived from…

A

Greek: pharmakon (remedy), logos (study)

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2
Q

“Pharmacology” =

A

Study of drugs

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3
Q

4 Aspects

A

How a drug is delivered
How a drug works (MOA)
Therapeutic effect
Adverse effects

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4
Q

3 Classifications:

A

Drugs
Biologics
Natural health products

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5
Q

Drug classification: antibody

A

Biologics

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6
Q

Drug classification: hormone

A

Biologics

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7
Q

Drug classification: herbals

A

Natural health products

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8
Q

Drug classification: vitamins

A

Natural health products

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9
Q

Drug classification: minerals

A

Natural health products

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10
Q

Health Canada functions under ___?

A

Food and drug act and regulations

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11
Q

What branch of Health Canada has 3 directorates?

A

Products and food branch

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12
Q

3 directorates of HC?

A

Therapeutic products directorate
Biologics and genetic therapies directorate
Natural health products directorate

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13
Q

What is the chemical name?

A

Describes the drug structure of molecule

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14
Q

Who uses chemical name?

A

Chemists; not commonly used in pharmacology

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15
Q

What is the generic name?

A

Unique name that identifies the drug

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16
Q

Who uses the generic name?

A

Most commonly used in pharmacology; should be used by health care professionals but often isn’t

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17
Q

What is the trade name?

A

Name assigned by drug company

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18
Q

Problem with using trade name?

A

Many companies may produce same drug and therefore have many trade names.

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19
Q

How many steps of approval of marketed drugs in Canada are there?

A

7

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20
Q

Approval of marketed drugs in Canada: step 1?

A

Drug discovery and preclinical testing

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21
Q

How long does step 1/pre clinical testing for drug approval take?

A

6.5 years

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22
Q

How is step 1/pre clinical testing for drug approval carried out?

A

Cultured cells, living tissue, or experimental animals.

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23
Q

Purpose of step 1/preclinical testing of drugs?

A

Evalutate biological effects, pharmokinetics, and toxicity

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24
Q

Approval of marketed drugs in Canada: step 2?

A

Clinical trial application

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25
How long does step 2/trial application of drug approval take?
30 days
26
How is step 2/trial application of drug approval carried out?
Submission of paperwork detailing all preclinical data to Health Canada
27
Approval of marketed drugs in Canada: step 3?
Phase I clinical trial
28
How long does step 3/phase I clinical trial take?
1 year
29
How is step 3/phase I clinical trial carried out?
20-100 healthy volunteers
30
Purpose of step 3/phase I clinical trial?
Evaluate phamokinetics and pharmodynamics
31
Approval of marketed drugs in Canada: step 4?
Phase II clinical trial
32
How long does step 4/phase II clinical trial take?
2 years
33
How is step 4/phase II clinical trial carried out?
300-500 patients with target disorder
34
Purpose of step 4/phase II clinical trial?
Therapeutic effectiveness, side effects and dosing information is gathered
35
Approval of marketed drugs in Canada: step 5?
Phase III clinical trial
36
How long does step 5/phase III clinical trial take?
4 years
37
How is step 5/phase III clinical trial carried out?
500-5000 patients with target disorder
38
Purpose of step 5/phase III clinical trial?
Therapeutic effectiveness verified, long term side effects assessed
39
Approval of marketed drugs in Canada: step 6?
New Drug Submission to Health Canada
40
How long does a new drug submission (NDS) take?
1.5 years
41
Components of a new drug submission?
Report detailing therapeutic effectiveness and safety. Includes results from pre clinical and clinical studies.
42
What does Health Canada issue after a successful new drug submission?
Notice of compliance (NOC) | Drug identification number (DIN)
43
Approval of marketed drugs in Canada: step 7?
Phase IV clinical trial
44
Purpose of phase IV clinical trial?
HC monitors efficacy and safety of the drug after it has been marketed. Drugs can be pulled from the market if not efficacious or safe.
45
What drug was pulled from the market in 2004?
Vioxx
46
"Pharmokinetics" =
Study of drug movement in body (what body does to drug)
47
Components of pharmokinetics:
Absorption Distribution Metabolism Excretion
48
The majority of absorption from orally ingested drugs occurs in the ___?
Small intestine
49
Pathway of orally ingested drugs?
Stomach - small intestine - portal vein - liver - systemic circulation to tissues OR bile duct to gall bladder and LI
50
Pathway of injected drugs?
Systemic circulation - tissues OR liver excretion OR kidney excretion
51
Primary site of drug metabolism?
Liver
52
Primary site of drug excretion?
Kidney
53
3 Routes of administration categories?
Enteral, parenteral, other
54
Type of administration: oral?
Enteral
55
Type of administration: rectal?
Enteral
56
Type of administration: intravenous?
Parenteral
57
Type of administration: intramuscular?
Parenteral
58
Type of administration: subcutaneous?
Parenteral
59
Type of administration: creams?
Topical/transdermal
60
Type of administration: patches?
Topical/transdermal
61
Intestinal villi form ____ against oral drugs/toxins/nutrients?
Barrier
62
Function of nucleus?
Contains genetic material/DNA
63
Function of smooth ER?
Metabolizes drugs, carbohydrates, and steroids
64
Function of rough ER?
Synthesizes proteins
65
Function of golgi?
Processes and packages proteins and lipids
66
Function of mitochondria?
Produces ATP
67
Function of cell membrane?
Separates the intracellular and extracellular environments
68
Phospholipid: head?
Polar/water soluble; phosphate
69
Phospholipid: tail?
Lipid soluble
70
3 ways to cross cell membranes:
Direct penetration Ion channels and pores Specific transport proteins
71
Necessary drug components for direct cell membrane penetration?
Lipophilic
72
Necessary drug components for transmembrane travel by ion channels and pores?
Small (molecular weight
73
Function of uptake transporters?
Transport drugs from outside the cell to inside the cell.
74
What are uptake transporters important mediators for?
Intestinal absorption, renal excretion, reaching target sites of action inside cells.
75
Function of efflux transporters?
Transport drugs from inside the cell to outside the cell.
76
What are efflux transporters important for?
Protecting cells from exposure to drugs, protection from drug absorption across intestine
77
Where are efflux transporters found? (4)
Intestine, placenta, kidney, blood brain barrier
78
What are the 5 types of drug molecules?
``` Polar Ions Quaternary ammonium compounds Ionizable molecules Lipophilic ```
79
Characteristics of polar molecules?
Water soluble, have an uneven distribution of electrical charge but have no net charge.
80
What type of molecule is water?
Polar
81
What type of molecule is glucose?
Polar
82
What type of molecule is the antibiotic 'kanamycin'?
Polar
83
How do polar molecules cross cell membranes?
Specific transport proteins
84
What are the characteristics of an ion?
Have a total number of electrons that is not equal to the total number of proteins resulting in a net charge
85
How do ions cross cell membranes?
Ion channels
86
What are the characteristics of quaternary ammonium compounds?
Have at least 1 nitrogen atom, have a positive charge at all times.
87
How do quaternary ammonium compounds cross cell membranes?
Specific transport proteins
88
What are the characteristics of ionizable molecules?
Can exist in charged (weak acid/base) or uncharged form.
89
What determines whether a ionizable molecule is charged?
pH of the surrounding environment
90
Weak acids (ionizable molecule) is ___ in an acidic environment?
Non ionized
91
Weak acids (ionizable molecule) is ___ in an alkaline environment?
Ionized
92
Weak bases (ionizable molecule) is ___ in an acidic environment?
Ionized
93
Weak bases (ionizable molecule) is ___ in an alkaline environment?
Non ionized
94
What type of ionizable molecules are the majority of drugs?
Weak bases
95
Weak bases are able to cross the membrane easier in an _____ environment?
Alkaline
96
Weak acids are able to cross the membrane easier in an _____ environment?
Acidic
97
How do ionizable molecules cross the cell membrane?
Direct penetration *ONLY when non ionized
98
How do lipophilic molecules cross the cell membrane?
Direct penetration
99
When does ion trapping occur?
Difference in pH on different sides of the membrane
100
What type of drugs experience ion trapping?
Ionizable molecules
101
What side of the membrane do ionizable molecules get trapped?
The side that they are charged.
102
When is ion trapping clinically used?
Cases of drug overdose.
103
What are the 3 areas of large capillary beds?
Kidneys, GI tract, lungs
104
What are the gaps called between capillaries?
Fenestrations
105
What types of drugs can pass through fenestrations to leave the blood?
Hydrophilic drugs (and lipophilic)
106
What area of the body does NOT have fenestrations?
Blood brain barrier
107
What type of cells line the capillaries at the blood brain barrier?
Astrocytes
108
How can drugs enter the brain?
Lipophilic OR have specific transport proteins
109
What type of cells line the capillaries NOT at the blood brain barrier?
Tissue cells
110
Drug absorption =
The movement of the drug from site of administration into the blood
111
The rate of drug absorption determines ___?
How quickly the drug effect will occur
112
The amount of drug absorption determines ___ ?
How intensive the effect of the drug will be
113
What are the 6 factors that effect rate of absorption?
``` Rate of dissolution Surface area Local blood flow Lipid solubility pH partitioning Activity of drug transport proteins ```
114
Dissolution =
Dissolving of drugs into solution (must be disintegrated then dissolved)
115
What is the greatest determinant of drug absorption?
Surface area
116
How does local blood flow effect drug absorption rate?
Areas with high blood flow maintain a concentration gradient which drives absorption
117
In what conditions can blood flow be decreased?
Heart failure, severe hypotension, hypothermia, circulatory shock
118
In what way does pH partitioning effect drug absorption?
Absorption is greater when there's a difference between pH at site of administration and the blood such that the drug is ionized in the blood (trapped in blood)
119
Per os =
By mouth (Latin) = oral administration
120
What is the most common route of administration?
Oral
121
What are the 3 advantages of oral administration?
Safe, economical, convenient
122
What is the disadvantage to oral administration?
Incomplete and/or varied absorption
123
The rate of drug absorption in the intestine will be ______ than the stomach even if the drug is ionized.
Greater
124
What is the pharmaceutical phase?
The disintegration phase and the dissolution phase that occurs after a drug is swallowed.
125
What is gastric emptying?
The movement of the stomach contents into the intestine
126
How to increase gastric emptying: stomach contents?
Empty
127
How to increase gastric emptying: water temperature?
Cold
128
How to increase gastric emptying: laying down?
Lay on right side
129
How to increase gastric emptying: osmolality?
High (tube feeding)
130
How to increase gastric emptying: GI motility?
Increased by taking pro kinetic drug
131
How to decrease gastric emptying: stomach contents?
Full/high fat meal
132
How to decrease gastric emptying: laying down?
Left side
133
How to decrease gastric emptying: activity?
Heavy exercise
134
How to decrease gastric emptying: nerve inhibitors?
Anticholinergic drug to inhibit vagus nerve
135
What is enteric coating? Purpose?
Coating on drug that prevents dissolution in acidic environment of the stomach
136
When does enteric coating dissolve?
Alkaline environment of duodenum
137
When is enteric coating useful?
If drugs are destroyed by acidic stomach OR harmful to stomach
138
What is bioavailability?
Fraction of dose that reaches the systemic circulation unchanged
139
What influences bioavailability? (3)
Drug formulation Route of administration Degree of liver metabolism
140
What has the highest bioavailability?
Aqueous solution
141
What has the lowest bioavailability?
Time release tablets
142
How are sublingual drugs delivered?
Under the tongue
143
How do sublingual drugs get absorbed?
Dissolves under tounge and is absorbed across oral mucosa. Venous drainage leads to superior vena cava.
144
What area of the body are sublingual drugs exceptionally useful for?
Heart
145
Do sublingual drugs go through first pass liver metabolism?
No
146
What type of drugs can be sublingual?
Lipophilic, uncharged
147
What characteristics must transdermal drugs have?
Lipophilic to pass through epidermis Hydrophilic to pass through extra cellular fluid Small
148
What is the advantage to transdermal drugs?
Provides constant plasma drug levels with minimal peaks and troughs
149
Why are transdermal drugs removed for periods of time?
Tolerance can develop
150
How long are transdermal [patches] removed for?
6-10 hours/day
151
What are the 5 factors that affect transdermal absorption?
``` Thickness of skin Hydration Hair follicles Application area Integrity of barrier ```
152
How does thickness of skin affect transdermal absorption?
Inversely proportional
153
How does hydration affect transdermal absorption?
Proportional
154
How does hair follicles affect transdermal absorption?
Proportional; can bypass epidermis (can be less lipophilic)
155
How does application area affect transdermal absorption?
Proportional
156
How does the integrity of the barrier affect transdermal absorption?
Proportional
157
In what skin conditions can transdermal absorption be increased?
Psoriasis, burned skin, abraded skin
158
How is a rectal suppository absorbed?
Through rectal mucosa into blood
159
When is a rectal drug helpful?
Unconscious or vomiting patient
160
Do rectal drugs get metabolized in the liver?
50% bypass liver
161
What is the disadvantages to rectal drugs?
Incomplete absorption, irritate rectal mucosa
162
What is an IV bolus?
Single dose administered over a short period (syringe)
163
What is an IV drip?
Drug is administered under continuous infusion over a prolonged period - diluted in saline
164
What is the BA of IV drugs?
100%
165
What are the 4 advantages to IV drugs?
BA 100% Precise control of drug dosage and duration of action Poorly soluble drugs can be diluted in a large volume Irritant drugs can be delivered slowly
166
What are 4 disadvantages to IV drugs?
Expensive Invasive Inconvenient Drug cannot be removed after injection (final)
167
What are 3 risks with IV drugs?
Infection Fluid overload Wrong formulation (i.e. supposed to be IM)
168
What are 'subcutaneous' drugs short formed to?
SubQ , SC
169
What are the barriers to absorption for subcutaneous injections?
Capillary wall
170
What sort of drugs should NOT be injected subcutaneously? Why?
Irritants BECAUSE severe pain/tissue sloughing
171
What are the primary determinants of rate of absorption in subcutaneous injections?
Blood flow | Water solubility
172
What are the determinants of rate of absorption in IM injections?
1. Blood flow 2. Water solubility 3. Small enough to fit through fenestrations
173
What are the advantages of IM injections? (2)
Used for poorly soluble drugs | Administer depot preparations
174
What is a depot preparation?
Drug is administered all at once but is absorbed slowly over time
175
What are the disadvantages of IM injections? (2)
Pain | Local tissue/nerve problems if done incorrectly
176
What muscle for IM injections has the highest blood flow?
Deltoid
177
What gets more blood flow - VL or glutes?
Vastus lateralis
178
What are the 3 main muscles for IM injections?
Deltoid VL Glutes
179
What type of drugs can be inhaled and absorbed by lungs?
Gaseous and volatile
180
How are pulmonary drugs absorbed?
Pulmonary epithelium into blood
181
What is the rate of absorption for pulmonary drugs?
Instantaneous
182
What is the rate of absorption of pulmonary drugs so fast?
Large lung surface area
183
What is the major advantage of pulmonary drugs?
Drug delivered right to site of action in pulmonary diseases
184
What type of drug administration route is used for general anesthetic?
Pulmonary
185
What are the 4 things drugs can do in your body?
Stored Metabolized Excreted Exert pharmacological effect
186
How many body compartments are there?
7
187
What is the interstitial space?
Extracellular fluid that surrounds cells.
188
What sort of drugs distribute into interstitial space?
Small/light | Hydrophilic
189
What is the total body water?
Fluid from interstitial space, intracellular fluid, plasma
190
What is plasma?
Non-cell containing component of blood
191
What sort of drugs distribute into plasma?
Drugs strongly bound to proteins | Large/heavy
192
What sort of drugs distribute into adipose tissue?
Lipophilic
193
Do any drugs bind to muscle tissue?
Yes. Some drugs bind tightly to muscle.
194
How are drugs absorbed in bone?
Absorb into crystal surface of bone with eventual incorporation into crystal lattice
195
Drugs can be stored and slowly released from what body compartment?
Bone
196
Where can protein bound drugs be distributed?
Trapped in plasma
197
What are the 3 drug distribution factors?
Blood flow to tissues Ability of drug to move out of capillaries Ability of drug to move into cells
198
Level of blood perfusion: liver?
High
199
Level of blood perfusion: kidney?
High
200
Level of blood perfusion: brain?
High
201
Level of blood perfusion: skin?
Low
202
Level of blood perfusion: fat?
Low
203
Level of blood perfusion: bone?
Low
204
Altered level of blood flow in neonates? Outcome?
Limited; limited/unpredictable drug distribution
205
Poor blood flow ___ limits drug distribution in adults
Rarely
206
In what circumstances can poor blood flow limit drug distribution?
Heart failure/shock Solid tumor Absesses
207
Tumour blood flow?
High outside; progressively less moving towards middle
208
What is an abscess?
Infection filled with pus
209
Abscess blood supply?
None
210
Why are abscesses so hard to treat with antibiotics?
No blood supply
211
Drug movement through fenestrations/through capillaries is ___ (speed). What is the exception?
Fast | Brain
212
What does P-GP stand for?
P glycoprotien
213
What is PGP?
Most widely studied efflux transporter
214
Why is PGP clinically significant?
Role in drug distribution
215
What are the 4 areas that PGP is found?
Liver Intestine Kidney Brain
216
What liver cells is PGP found? Where in the liver?
Hepatocytes | Bile canaliculus membrane
217
What is the function of liver PGP?
Pump drugs from hepatocytes into bile
218
What is the purpose/result of liver PGP?
PGP substate drugs are eliminated in bile
219
What intestine cells is PGP found? Where in intestine?
Enterocytes | Apical/luminal membrane
220
Where in the kidney is PGP found?
Proximal tubule; apical membrane
221
What is the function of kidney PGP?
Excrete drugs into lumen of nephron to be excreted in urine
222
Where in the brain is PGP found?
Neuronal cells at capillary endothelial cells
223
What is the function of brain PGP?
Pump drugs out of brain into blood
224
Relationship between protein bound drug and free drug?
Reversible/equilibrium
225
What happens if two drugs are present in the blood?
One drug may displace the other drug from plasma protein. Fate of free drug depends on Vd
226
What are the 2 types of plasma proteins? Which one binds the most?
Albumin** | Alpha 1 acid glycoprotein
227
Albumin has a high affinity for ____?
Lipophilic | Anionic (weakly acidic)
228
Aging decreases what plasma protein?
Albumin
229
Malnutrition decreases what plasma protein?
Albumin
230
Liver disease decreases what plasma protein?
Albumin
231
Kidney disease decreases what plasma protein?
Albumin
232
Hepatic inflammation increases what plasma protein?
Alpha 1 acid glycoprotein
233
Alpha 1 acid glycoprotein has a high affinity for ___?
Cationic (weakly basic) | Very hydrophilic
234
What may decreased albumin lead to?
Toxicity
235
What may decreased alpha 1 acid glycoprotein lead to?
Ineffective therapy
236
Aging increases what plasma protein?
Alpha 1 acid glycoprotein
237
Trauma increases what plasma protein?
Alpha 1 acid glycoprotein?
238
What increases alpha 1 glycoprotein?
Aging Trauma Hepatic inflammation
239
What decreases albumin?
Aging Malnutrition Liver/kidney disease
240
Volume of distribution represents...?
Represents the apparent volume that the drug distributes into
241
Vd =
D (total amount of drug in body) / C (plasma concentration in blood)
242
How can Vd be greater than body volume?
Extensive tissue binding
243
Amount of total body water in 70 kg person?
42 L
244
Amount of intracellular fluid in 70 kg person?
28 L
245
Amount of extracellular fluid in 70 kg person?
14 L
246
Amount of interstitial fluid in 70 kg person?
10 L
247
Amount of plasma in 70 kg person?
4 L
248
What are the two components of total body water?
Intracellular fluid | Extracellular fluid
249
What are the two components of extracellular fluid?
Interstitial fluid | Plasma
250
Drugs with small Vd are:
Highly protein bound | Large/heavy
251
Where do small Vd drugs distribute?
Plasma
252
Drugs with intermediate Vd are:
Light/small Hydrophillic Intermediate protein binding
253
Where do intermediate Vd drugs distribute?
Extracellular fluid
254
Drugs with large Vd are:
Light/small Lipophilic Minimal protein binding
255
Where do large Vd drugs distribute?
All body compartments | Mainly intracellular fluid
256
Volume requirement for large Vd?
Greater than 0.2 L/kg
257
"Metabolism" =
Enzyme mediated alteration of a drug's structure
258
Why is metabolism important?
Protection from environmental toxins and synthesized endogenous molecules
259
What is "exogenous"?
Originating from outside the body
260
What is "endogenous"?
Originating from inside the body
261
What is the primary site of drug metabolism?
Liver
262
What are the 5 sites of drug metabolism?
``` Liver Intestine Stomach Kidney Intestinal Bacteria ```
263
What is the site of alcohol metabolism?
Stomach
264
What are the 5 therapeutic consequences to drug metabolism?
``` Increase water solubility to promote excretion Inactivate drugs Increase drug effectiveness Activate pro drug Increase drug toxicity ```
265
What order kinetics do most drugs exhibit?
1st
266
What is 1st order kinetics?
Rate of drug metabolism is directly proportional to the concentration of the free drug
267
In 1st order kinetics, a constant ___ of drug metabolized per unit time?
Fraction
268
In what situation is 1st order kinetics present?
Concentration of drug is less than total metabolic capacity of body
269
What is 0 order kinetics?
Drug metabolism is constant over time
270
IN what situation is 0 order kinetics present?
Plasma drug concentration is much higher than metabolic capacity of body
271
In 0 order kinetics, a constant ___ of drug metabolized per unit time?
Amount
272
What is an example of 0 order kinetics/metabolism?
Ethanol/alcohol metabolism
273
What is 1st pass metabolism?
Oral drugs that undergo sig. metabolism period to entering systemic circulation
274
What is the result of 1st pass metabolism?
Decreased amount of parent drug in systemic circulation
275
What is the one area where 1st pass metabolism does not occur?
Kidney
276
What is the enzyme for 1st pass metabolism in the liver?
CYP
277
What is the enzyme for 1st pass metabolism in the intestine?
CYP
278
What is the enzyme for 1st pass metabolism in the stomach?
Alcohol dehydrogenase
279
After alcohol is metabolized, what does it become?
Acetaldehyde
280
What is the enzyme for 1st pass metabolism in the intestinal bacteria?
Bacterial enzyme
281
What is the extraction ratio (ER)?
Amount of metabolism that occurs on the first pass through the liver
282
What does high ER mean?
Highly metabolized in liver (1st pass)
283
What does low ER mean?
Small amount of 1st pass liver metabolism
284
What is the bioavailability of high ER drugs?
Low 1-20%
285
High ER drugs have PO doses ___ than IV doses?
Much higher
286
Small changes to hepatic enzyme activity produce ____ changes in BA in high ER drugs?
Large
287
What is the bioavailability of low ER drugs?
High 80%+
288
Low ER drugs have PO doses ___ than IV doses?
Similar
289
Small changes to hepatic enzyme activity produce ____ changes in BA in low ER drugs?
Little/none
290
Which ER group is highly susceptible to drug drug interactions?
High
291
What is the purpose of phase I metabolism? How?
Convert lipophilic drugs to more polar molecules to facilitate excretion BY introducing/unmasking polar functional groups
292
What are the 2 polar functional groups?
OH | NH2
293
What are the 3 mediators to phase I metabolism?
Cytochrome P450 enzyme = CYP Esterases Dehydrogenases
294
The metabolites formed from phase I metabolism are ___ active than the parent?
Less OR more OR equally
295
Where are phase I metabolizing enzymes found?
Smooth endoplasmic reticulum
296
The majority of drug metabolism in the body is done by ___ enzyme?
Hepatic CYP
297
What do CYPs do? How?
Oxidize drugs BY inserting 1 atom of O into the drug
298
What is the byproduct of CYP oxidation?
Water
299
How many CYP families are there?
12
300
How many of the CYP families account for the majority of drug metabolism?
3/12
301
What can decrease CYP activity?
Malnutrition
302
What is the nomenclature for CYP enzymes?
CYP (family) (subfamily) (isozyme)
303
What CYP enzyme metabolizes the largest fraction of currently marketed drugs?
CYP3A4
304
Percent of drugs metabolized by this enzyme: CYP3A4?
50
305
Percent of drugs metabolized by this enzyme: CYP2D6?
20
306
Percent of drugs metabolized by this enzyme: CYP2C9?
10
307
Percent of drugs metabolized by this enzyme: CYP2C19?
10
308
Percent of drugs metabolized by this enzyme: 2E1?
5
309
Percent of drugs metabolized by this enzyme: 1A2?
5
310
What is the purpose of phase II metabolism? How?
Increase polarity of lipophilic drugs by conjugation reaction to make more water soluble
311
What are the conjugates for phase II metabolism?
Glucuronic acid (sugar) Sulfate Acetate AA (glycine)
312
Phase II metabolites are ___ active than parent drug? Exception?
Less | Morphine metabolite
313
Where are phase II enzymes found? Exception?
Cytosol | Glucuronidation in smooth ER
314
What does UGT stand for?
UGT
315
What does GST stand for?
Glytathione S transferase
316
What does SULT stand for?
Sulfotransferase
317
What does NATs stand for?
N acetyltransferase
318
What does TMPT stand for?
Thiopurine methyltransferase
319
What phase II metabolism enzyme metabolizes the most drugs?
UGT
320
Where is UGT found?
Smooth ER
321
What does UGT do? Purpose?
Catalyze the transfer of glucuronic acid to drug | Makes more polar and more easily excreted
322
What phase II enzyme has the most human types?
GSTs
323
How many drugs does UGTs metabolize?
30%
324
How many drugs does GSTs metabolize?
25%
325
How many drugs does SULTs metabolize?
20%
326
How many drugs does NATs metabolize?
15%
327
How many drugs does TMPT metabolize?
1%
328
Where is GST enzyme found?
Cytosol | Microsome
329
What does GST do?
Catalyze transfer of glutathione to drug
330
What is glutathione?
Intracellular anti oxidant
331
If you transfer glutathione onto a reactive drug, what happens?
Becomes less toxic
332
What is SULTs found?
Cytosol
333
What do SULTs do? Why?
Catalyze transfer of sulphate group to hydroxyl group | BECAUSE more polar and more easily excreted
334
How many human types of NATs are there?
2
335
Where is NATs found?
Cytosol
336
What do NATs do? Why?
Catalyze transfer of acetyl group from acetyl CoA to a drug | BECAUSE more water soluble
337
What phase II enzyme is subject to genetic polymorphisms?
NATs and TMPTs
338
Where are TMPTs found?
Cytosol
339
What does TMPTs do?
Catalyze transfer of methyl group from 5 adensylmethionine to drug
340
Can a drug undergo multiple pathways of metabolism at the same?
YES! Some drugs can directly enter phase II metabolism.
341
What are the 4 factors that affect drug metabolism?
Age Drug interactions Disease state Genetic polymorphisms
342
What drug metabolism factors change with age?
Expression | Activity
343
What is different in babies regarding drug metabolism?
No CYP activity until 1 yr
344
At what age do babies have the same drug metabolism as adults?
2
345
What is enzyme induction?
Process where a cell synthesizes an enzyme in response to a drug or other chemical
346
What is the result of enzyme induction of CYPs?
Increased drug metabolism
347
What can increased drug metabolism lead to?
Decreased plasma concentrations | Decreased OR increased drug activity
348
What can cause enzyme induction in liver?
Smoking
349
What disease states can decrease CYP activity?
Liver disease Kidney disease Inflammatory disease Infection
350
What is a SNP?
Single nucleotide polymorphism
351
What does CYP2C9 do?
Metabolizes anticoagulant drug warfarin
352
What does CYP2D6 do?
Metabolizes codine to morphine
353
What does UGT1A1 do?
Inactivate/eliminate anti cancer drugs
354
What does NAT2 do?
Acetylates isoniazid (treat TB), caffeine, cancer causing chemicals
355
What does a SNP to CYP2C9 do? Result?
Decrease enzyme activity | Need less warfarin
356
What does a SNP to CYP2D6 do? Result?
1. Ultra rapid metabolizer UM 2. Extensive metabolizer EM = normal 3. Intermediate metabolizer IM 4. Poor metabolizer PM
357
What does a SNP to UGT1A1 do? Result?
Decrease activity | Increased risk of diarrhea and bone marrow suppression
358
What does a SNP to NAT2 do? Result?
1. Rapid acetylators | 2. Slow acetylators - more susceptible to toxicity
359
What is drug excretion?
Removal of parent drug and metabolites from body
360
What are the 4 places drug excretion occurs?
Kidney Bile Breast milk Lung
361
Healthy kidneys can limit ? of drug effects?
Duration and intensity
362
What does the nephron regulate?
``` Water Electrolytes Drug excretion Blood volume Blood pressure pH ```
363
What blood vessel brings blood to the nephron?
Afferent renal arteriole
364
What is the basic pathway of the nephron?
``` Renal artery Glomerulus Prox tubule Loop of Henle Dist tubule Collecting duct ```
365
Glomerular filtration rate =
120 ml/min/1.73m2 = 20% plasma flow
366
What is the major determinant of drug passage through glomerulus?
Size
367
If the drug remains in the blood after the glomerulus, it has a chance to re-enter the filtrate at the ___?
Proximal tubule
368
Where are the transport proteins at the proximal tubule of the nephron located?
Basolateral (blood) side
369
How does tubular secretion work? (nephron)
2 sets of transport proteins (weak acids and weak bases)
370
Rate of tubular secretion? (nephron)
Rapid/high capacity
371
Why are drugs reabsorbed in the nephron?
Filtrate concentration is higher than plasma concentration
372
What drugs are able to be reabsorbed in the nephron?
Lipophilic | Uncharged
373
What is the glomerular filtration rate in babies?
40 ml/min/1.73m2
374
What are the characteristics of drugs that are excreted in bile?
Large/heavy >300 Da Polar AND lipophilic (amiphipathic) Glucuronidated (UGT)
375
What transporters are used in biliary excretion?
P glycoprotein | MRP2
376
What does P glycoprotein transport?
Amiphipathic drugs from liver to bile
377
What does MRP2 transport?
Glucuronidated drugs from liver to bile
378
What is enterohepatic recycling?
Process where drugs in the intestine are absorbed to the liver where they undergo phase II metabolism, released back into the intestine where intestinal bacteria cleave off the conjugate and the 'parent' drug is reabsorbed again.
379
What are the 4 components of the hepato-biliary system?
Portal vein Hepatocyte Hepatic duct Bile canniculus
380
What is the bile canniculus?
Thin tube that collects bile and drugs that are excreted by the liver
381
What is the hepatic duct?
Tube that takes stuff from the liver to the gall bladder
382
What type of drug excretion is not heavily reliable on drug metabolism?
Pulmonary
383
What are the 3 factors that effect pulmonary excretion?
CO Respiration rate Drug blood solubility (inverse)
384
What percent of women take 1+ drugs in first week post partum?
90%
385
How big is the concern for secondary drug exposure to babies through breast milk?
Small
386
What type of drugs are excreted through breast milk?
Light/small Low protein binding Lipophilic
387
What is the transporter that transports drugs into breast milk?
BCRP = breast cancer resistant protein
388
What is the pH in breast milk vs. plasma?
Breast milk 6.5 | Plasma 7.4
389
What are the 3 minor routes of excretion?
Hair Saliva Sweat
390
What is the rate of hair growth?
1 cm/month
391
What are the 4 most important parameters for determining drug disposition?
Clearance Elimination half time Vd BA
392
What is clearance?
Bodies efficiency in irreversible drug elimination
393
Clearance =
Volume blood cleared PER unit time (mL/min OR L/hr)
394
Dosing rate =
Plasma concentration x clearance
395
Why is knowing elimination half time important?
Time to get to SS | How long it takes drug levels to decline after administration stops
396
Elimination half time =
0.693 x Vd ----------------- Clearance
397
How is drug concentration measured?
Plasma drug concentration (free + bound)
398
Drug duration is considered ? on a plasma time curve?
Time over minimum effective concentration MEC
399
What is it called then the rate of absorption = rate of elimination on plasma time curve?
Cmax
400
Rate of drug elimination after an IV bolus normally follows ___ order kinetics?
1st
401
Steady state range for PO drugs is ___ than IV bolus drugs?
Smaller
402
If the therapeutic range is small, when is plasma concentration tested?
Trough
403
What are 3 ways to reduce plasma drug concentration fluctuations?
Continuous IV infusion Depot preparations Change dosing interval
404
When the same dose of a drug is administered repeatedly, it takes ___ half lives to reach steady state.
5
405
Loading dose =
Target plasma drug concentration at SS * Vd
406
How many half lives does it take to eliminate 97% of drug?
5
407
After 5 half lives, how much drug has been eliminated from the body?
97%
408
After 9 half lives, how much drug has been eliminated from the body?
100%
409
What is significant about allergens and drug elimination?
Will still be irritant even when concentration very low.
410
Pharmacodynamics =
Study of what the drug does to the body
411
What type of curves are used to evaluate pharmacodynamics?
Dose response
412
What are the characteristics of dose response curves?
Monotonic | Semi logarithmic
413
How many phases of dose response curves are there?
3
414
What is phase 1 of the dose response curve?
Doses are too low to elicit clinically sig. response
415
What is phase 2 of dose response curve?
Response is graded and linear
416
Phase is phase 3 of dose response curve?
Larger dose does not lead to greater response; may cause toxicity
417
What is "efficacy"?
How effective a drug is at a given dose
418
How is maximal efficacy determined?
Maximal height on a dose response curve
419
What is "potency"?
Amount of drug required to elicit a response
420
How is potency determined?
Dose required to produce ED50 (want low)
421
How can you compare potency?
Drugs must produce same therapeutic effect
422
What is the majority of drug targets?
Receptors
423
What are the 4 drug targets?
Receptors Ion channels Enzymes Transport proteins
424
What is an example of a drug that does not act on a cellular target?
Antacids that neutralize stomach acid
425
What is the main function of receptors?
Bind to drug | Translate extracellular signals into biological responses
426
How many receptors can a selective drug bind to?
1
427
How can selective drugs still cause side effects?
Receptors may be located around the body even though you only want to target 1 specific area
428
What are the 4 types of receptors?
Ligand gated ion channels G protein coupled receptors Enzyme linked receptors Intracellular receptors
429
What type of receptors do neurotransmitters bind to?
Ligand gated ion channels
430
What type of receptor is a GABA receptor?
Ligand gated ion channel
431
When GABA binds to a GABA receptor, what moves into the cell?
Chlorine
432
What does the activation of the GABA receptor cause?
Sedation and muscle relaxaiton
433
What is the response and duration of ligand gated ion channels?
Very rapid | Milliseconds
434
How many drugs mediate their effects on G protein coupled receptors?
50%
435
What are the 3 components of a G protein coupled receptor?
7 transmembrane protein receptor G protein with 3 subunits Effector molecule/enzyme
436
Bind of a ligand to the G protein coupled receptor causes ______?
Activation of G protein which dissociates from receptor and activates effector
437
How long does the activation of a G protein coupled receptor last?
Seconds to minutes
438
Norepinephrine, serotonin and histamine all bind to what type of receptor?
G protein coupled receptor
439
Where is the enzyme catalytic site on an enzyme linked receptor?
Inside cell
440
How fast is the response to an enzyme linked receptor?
Seconds
441
What type of receptor does insulin bind to?
Enzyme linked
442
What does insulin binding cause?
Enzyme mediated phosphorylation and activation of intracellular effector = increased translocation of glucose to cell membrane
443
What are transcription factors AKA?
Intracellular receptors
444
Binding of a ligand to an intracellular receptor causes... ?
Translocation of complex to nucleus and binding to DNA
445
What happens when the ligand-receptor complex of intracellular receptors binds to the DNA?
Transcription of mRNA stimulated | Protein synthesis hours/days later
446
What type of ligands bind to intracellular receptors?
Lipophilic
447
What receptor do the steroid hormones (testosterone and estrogen) bind to?
Intracellular receptor
448
What ar the two drug receptor interaction theories?
Single occupancy | Modified occupancy
449
What is the single occupancy theory? (2)
Intensity of drug response is proportional to number of receptors occupied Maximal response when all receptors occupied
450
What is the modified occupancy theory? (3)
Intensity of drug response is proportional to number of receptors occupied Two drugs occupying receptor can have different affinities Two drugs occupying receptor can have different intrinsic activity
451
What is affinity?
Attraction that a drug has for receptor
452
Affinity is proportional to ...
Potency
453
Intrinsic activity is proportional to ...
Efficacy
454
What is intrinsic activity?
Ability of drug to activate receptor
455
After a drug binds to the receptor, it can either ____ OR ____?
Activate receptor | Prevent other ligands from binding
456
What are the 3 types of molecules that bind to receptors?
Agonist Antagonist Partial agonist
457
What is an agonist?
Molecule that binds to receptor and activates it - mimics endogenous ligands
458
What type of binding molecule is dopamine?
Agonist
459
What occurs with low dose dopamine? What receptor does it bind to?
Renal artery vasodilation = Increased urine output | Dopamine receptor
460
What occurs with moderate dose dopamine? What receptor does it bind to?
Increased CO | Beta 1 adrenergic receptor
461
What occurs with high dose dopamine? What receptor does it bind to?
Renal artery vasoconstriction = decreased urine output | Alpha adrenergic receptor
462
What is an antagonist?
Molecule that binds to receptor and does NOT activate it.
463
What condition are antagonist molecules useful?
Overdoses
464
What type of binding molecule are beta blockers, antihistamines, gastric acid reducers, and opioid receptor blockers?
Antagonists
465
What do beta blockers do?
Block binding of epinephrine to beta 1 receptor in heart = slow HR
466
What do antihistamines do?
Block binding of histamine to H1 histamine receptor in nasal mucosa = decrease allergy symptoms
467
What do gastric acid reducers do?
Block binding of histamine to H2 histamine receptors in gut = decrease gastric acid secretion
468
What do opioid receptor blockers do?
Block binding of opioids to opiate receptors = treat overdose
469
What are the 3 types of antagonists?
Competitive Irreversible Allosteric
470
What are competitive antagonists?
Binding occurs at same site as agonist; reversible based on affinity and then concentration
471
How does a dose response curve change with the presence of a competitive antagonist?
Shift right (decrease potency/affinity)
472
What are irreversible antagonists? How long do effects last?
Binding occurs at same site as agonist; irreversible Until body replaces receptor **Not common!
473
How does a dose response curve change with the presence of a irreversible antagonist?
Shift down (decrease efficacy)
474
What is an allosteric antagonist?
Binding occurs at different site than agonist - changes conformation of receptor so agonist can't bind
475
How does a dose response curve change with the presence of an allosteric antagonist?
Shift down (decrease efficacy)
476
What is a partial agonist?
Molecules that bind to receptor but have minimal ability to activate it (decrease intrinsic activity)
477
What is tolerance?
Response to agonist can decrease with prolonged exposure
478
What are the 3 types of tolerance?
Desensitization Metabolic tolerance Tachphylaxis
479
What is desensitization?
Continuous exposure to agonist causes receptor desensitization --> receptor internalization and destruction = decreased cell surface receptor expression = decreased drug effects
480
What is metabolic tolerance?
Continuous exposure to drug causes induction of drug metabolizing enzymes = decrease plasma concentrator of drug
481
What is tachphylaxis? How to prevent it?
Rapid decrease in response to drug | Have drug free time between administrations
482
How is dose response tested in phase I trials?
Animal studies
483
How is dose response tested in phase 2 trials?
Info over range of doses is determined
484
To determine interpatient variability in response to medications, we first ____?
Set an endpoint
485
What is ED50? When is it used?
Dose required to produce a response in 50% of population | Used as initial dose for therapy
486
Drugs with narrow therapeutic range should have their dose ____.
Titrated
487
How long is chronic animal testing?
6 mth - 2 yr
488
How is drug toxicity tested?
Acute and chronic testing on animals - determine doses that produce toxicity and death in multiple species
489
What is TD50?
Dose where 50% of animals experience toxicity
490
What is LD50?
Dose where 50% of animals die
491
What is the therapeutic index a measure of?
Drug safety (high = safe). High = large space between ED50 and TD50
492
How to measure therapeutic index?
TD50 LD50 -------- OR ----------- ED50 ED50
493
How many factors affect intermittent variation in response?
7
494
How does body weight and compensation affect inter-patient variation in response?
CHange Vd | Clinicians adjust drugs by body surface area
495
What is the normal body surface area of adults?
1.73m2
496
How does genetics affect inter-patient variation in response?
SNP | Genotype differences
497
How does gender affect inter-patient variation in response? (3 examples)
Can be more effective in one gender vs. other Alcohol metabolism slower in females Opioids more effective in women Heart dysrhythmia drugs in women cause long QT interval
498
How does race affect inter-patient variation in response?
Hard to define | Rousuvastatin (lower cholesterol) concentrations 2-3x higher in asian vs. Caucasian
499
How does kidney disease affect inter-patient variation in response?
Drug excretion decreased = increased half life = stronger effect = increased BA
500
How does liver disease affect inter-patient variation in response?
Decreased metabolism = increase half life
501
How can the environment affect inter-patient variation in response? (4 examples)
Cigarette smoke induces enzymes = less effective drugs Alcohol increase drug toxicity Exercise improve insulin Pesticides induce CYPs = decrease drug response
502
How many people are admitted to Cdn hospitals every year from adverse drug reactions?
185000 | 7.5% admissions
503
What are side effects? When do they occur? Example?
Secondary to main therapeutic effect of drug; expected Occur at normal doses - expected Antihistamines cause drowsiness, dry mouth, urinary retention
504
What is an allergic reaction? How does it work?
Mediated by immune system Needs prior exposure Allergen binds to IgE antibodies which cause release of chemicals/mediators
505
What are the common areas of allergic reactions symptoms on body? Uncommon?
LOOK: Stomach, bum, under arms, top of legs | DON'T LOOK: head, hands, feet
506
The intensity of allergic reactions are ___ of dosage size.
Independent
507
What is the most common drug class to cause allergy?
Penicillin
508
Sulfonamides and NSAID drugs can cause what type of ADR?
Allergy
509
What is an idiosyncratic reaction? | Where do they occur?
Rare and unpredictable Mainly due to polymorphism Occur in metabolizing enzymes and transport proteins.
510
What CYP enzymes have idiosyncratic reactions? Occurrence?
CYP2C9 15% | CYP2D6 10%
511
What are the 3 other enzymes (+2 CYP) that have idiosyncratic reactions? Occurrence?
TMPT 10% OATP1B1 15% - myopathy G6PDH - hemolysis
512
What drug caused carcinogenic effects?
Diethylstillbestrol DES
513
How are drugs tested for potential mutagens?
Ames test on bacteria
514
What are teratogenic effects?
Ability of drug to produce birth defects or infertility
515
_% of all birth defects are caused by drugs?
Less than 1
516
What part of the developing fetus is most sensitive to drugs?
CNS
517
How are pregnancy risks categorized?
A-E
518
What is a A risk pregnancy?
OK!
519
What is a B risk pregnancy?
No shown harmed effect in human but ?animal harm
520
What is a C risk pregnancy?
Animal studies = harmed fetus
521
What is a D risk pregnancy?
Human studies = harmed fetus BUT benefits outweigh risk
522
What is an E risk pregnancy?
Human studies = harmed fetus; risks outweigh benefits
523
The most common and important organ specific toxicity is observed in the ___ and ___?
Liver and heart
524
Patients taking hepatoxic drugs should be educated to look for signs of liver toxicity including: _____?
``` Jaundice Dark urine Light coloured stool Nausea Vomiting ```
525
What blood tests should you do to look for liver toxicity?
AST aspartate aminotransferase - want low | ALT alanine aminotransferase - want low
526
QT interval prolongation is a major risk for the development of...
Torsades de points
527
What is torsades de points?
Life threatening ventricular arrhythmia
528
What are opiates used for?
Analgesia
529
What is the consequence of rapid withdrawal of opiates?
``` Anorexia Irritability Nausea/vomiting Weakness Muscle spasm ```
530
What are benzodiazepines used for?
Anxiety
531
What is the consequence of rapid withdrawal of benzodiazepines?
``` Anxiety Insomnia Sweating Treamours Panic Delirium Paranoia Convulsions ```
532
What are beta blockers used for?
Decrease HR
533
What is the consequence of rapid withdrawal of beta blockers?
``` Rebound Hypertension Chest pain Heart attack Arrhythmia ```
534
What is the most common cause of adverse drug reactions?
Medication errors
535
What is it called when a medication error is caused by a health care professional?
Iatrogenic error
536
How many medication errors are due to drug name confusion?
15%
537
The abbreviation IU should be written as ___
Units
538
The abbreviation q.d. should be written as ___
Every day
539
The abbreviation q.o.d. should be written as ___
Every other day
540
The number 1.0 should be written as __
1
541
The number .5 should be written as ___
0.5
542
The abbreviation MgSO4 should be written as ___
Magnesium sulfate
543
The abbreviation MS / MSO4 should be written as___
Morphine sulfate
544
The risk of drug interactions increases ____ with the number of medications the patient takes.
Linearly
545
The most common type of drug drug interactions affect ___
Pharmokinetics
546
What are the 3 types of drug drug interaction effect?
Increased effects Decreased effects Generation of new effect
547
Ampicillin and sulbactam = example of what type of drug drug interaction?
Increase therapeutic effect
548
Aspirin and warfarin = example of what type of drug drug interaction?
Increased adverse effect
549
Clodiogrel and omepraxole = example of what type of drug drug interaction?
Decreased therapeutic effect
550
Morphine and naloxone = example of what type of drug drug interaction?
Decreased adverse effect
551
Disulfiram and alcohol = example of what type of drug drug interaction?
Generation of new effect
552
What are the 4 types of drug interactions?
Direct physical interaction Pharmacokinetic interaction Pharmodynamic interaction Combined toxicity
553
What is the most common physical drug interaction?
2 IVs mixed together that causes precipitate to form
554
Why would it be beneficial to inject epinephrine with local anaesthetic?
Epinephrine cause vasoconstriction causing anaesthetic to stay at injection site.
555
If the patient vomits 20-30 mins after administration of drug, it is likely that the drug absorption is ___.
Incomplete
556
How long after exposure to an inducer does CYP induction begin?
2-10 days
557
How long after stopped exposure to an inducer foes CYP induction stop?
7-10 days
558
Many antibiotics and anti fungals, and grapefruit juice inhibit CYP___?
CYP3A4
559
Both NSAIDS and beta blockers and decrease ___?
Renal blood flow
560
What is combined toxicity?
2+ drugs exhibit toxicity to the same organ
561
Patients on MAO inhibits must avoid foods with ...
Tyramine = old cheese, yeast, red wine, cured meat
562
What happens if patients on MAO inhibitors ingest tyramine?
Continue to release norepinephrine = hypertensive crisis

Western (14 decks)

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