Module 1 - 11 Flashcards
1
Q
What is pharmacology (4)
A
Study of Drugs =
- route of administration
- mechanism of action
- therapeutic effect
- adverse effects
2
Q
Classification of therapeutics
A
1) Drugs
2) biological
3) natural health products
3
Q
What are drugs
A
traditional conception of medicine - chemical agents
4
Q
What are biologics
A
antibodies, hormones
5
Q
Canadian drug legislation 3 levels
A
1) Food and drugs act
2) health canada
3) health canada product and food branch
6
Q
3 branches of health canada
A
1) thereapeutic product directorate
2) Biologic and genetic therapies directorate
3) natural health products directorate
7
Q
What is a drug
A
more than a pill = chemicals
8
Q
Three types of names
A
1) chemical name
2) generic name
3) trade name
9
Q
What is the chemical name
A
describes the chemical structure of a molecule, used by chemists
- EX 7-chloro-1,3-dihydrol-1-methyl…
10
Q
Generic name + example
A
Unique name that identifies a drug. Name most used in pharmacology. Should be used by HCP.
- EX - diazepam
11
Q
Trade name
A
name assigned by a drug company. is easy to remember. Companies may make the same drug, but differet trade names exist
EX/ valium
12
Q
Stages of approval of marketing drugs
A
1) preclinical testing/drug discovery
2) clinical trial application
3) phase I clinical trial
4) phase II clinical trial
5) Phase III clinical trial
6) New drug submission (NDS)
7) Phase IV Clinical trial
13
Q
what happens in the preclinical testing/drug discovery phase
A
- cells, living tissue, experimental animals
- evaluate biological effects, pharmacokinetics, toxicity
14
Q
What happens in clinical trial application
A
submit to Health Canada, data = 30 days
15
Q
Phase I clinical trial
A
20-100 healthy volunteers, pharmacokinetics evaluated
16
Q
Phase II Clinical trial
A
300-500 people with target disorder
- evaluate therapeutic effects, side effects, dosing (2 years)
17
Q
Phase III Clinical Trial
A
- 500-5000 people with the target disorder
- therapeutic effect verrified, LT side effects (~4 years)
18
Q
New drug submission (NDS)
A
- Drug submitted to Health Canada
- therapeutic effect and safety verified via
1) notice of compliance
2) drug information number
19
Q
Phase IV clinical trial
A
post marketing surveillance
20
Q
Routes of administration
A
- enteral
- Parenteral
- topical
21
Q
Enteral administration
A
- oral or rectal
- = GI administration
22
Q
Parenteral administration
A
- IV
- Intramuscular
- subcutaneous
- = injection of medication
23
Q
Topical administraiton
A
creams and patches
= absorbed thorugh the skin
24
Q
Pharmacokinetics steps
A
ADME
- absorption
- distribution
- metabolism
- excretion
25
Oral pharmacokinetics (AMDE)
- absorption = in the small intestine
- Metabolism = in hte liver
- distribution = systemic circulaiton
- excretion = billary, renal, feces
26
Pharmacokinetics - other routes (ADME)
- Absorption - skin/blood vessel/muscle
- distribution = sstemic circulaiton
- metabolism = liver
- Excretion = renal, biliary, feces
27
Two examples of physiologic barrier to drug transportation
- intestinal villi (barrier against ingested drugs, toxins, nutrients)
- tight junctions (prevent molecules from passing between cells)
28
Cell membrane
- separates internal from exterior of cell
- affects which drugs can enter the cell
- lipid bilayer
29
nucleus
genetic material
30
mitochondria
energy source of cell - ATP
31
Rough endoplasmic recticulum
synthesis of protein
32
smooth endoplasmic reticulum
- metabolism of drugs, carbs, steroids
33
golgi apparatus
processing and packaging of proteins/lipids
34
Characteristics of the cell membrane (3)
1) phospholipid (1 polar = water soluble head and 2 fatty acid tails = lipid soluble
2) cell membrane is fluid
3) cell membrane contains proteins embeded in phospholipids
35
How can drugs cross the cell membrane
1) direct penetration of the cell
2) through ion chanels and pores
3) specific transport proteins (drug transporters)
36
Direct penetration of the cell membrane requires that drugs are
lipid soluble (cell membranes are primarily lipids)
37
Ion channels requires that drugs are...
- very small (molecular weight of less than <200 Da) as channels and pores in cell membrane are small
- the specific drug (channels are selective = why only certain small compounds can fit through them)
38
Drug transporters
carrier proteins that move drugs from one side of the cell to the other
39
2 types of cell drug transporters
- uptake transporters
| - efflux transporters
40
uptake drug transporters
move drugs from outside the cell to inside
| - mediate intestinal absorption, renal excretion, reaching target sites of action inside cells
41
Efflux transporters
- move drugs from inside of cells to outside
| - important for protecting cells and are present in intestine, placenta, kidney, blood-brain-barrier
42
Chemistry of pharmacology - types of drug molecules (5)
- polar molecules
- ions
- quaternary ammonium compounds
- ionizable molecules
- lipophilic molecules
43
Polar molecules - solubility, chemical structure, example
- H2O soluble
- uneven distribution of electrical charge but no net charge
- EX: water, glucose, kanamycin (antibiotic)
44
Ions - what, charge, can they pass through the cell membrane?, EX
- atoms or molecules where # electrons does not equal # protons
- have a net + or - charge
- due to charge they cannot directly pass through the cell membrane (very small ions can pass through channels or pores)
- EX - Na+, Cl-, Li+
45
Quatenary ammonium compounds - structure, charge, cross cell membrane?
- have at least one N atom that has a + charge at all times
| - + charge --> can't cross cell membrane
46
Ionizable molecule - structure, what, what determines charge
- exist in charged or uncharged form
- weak acids or weak bases
- pH determines whether a weak acid or base carries a charge
47
When is a weak acid ionized
in an alkaline solution
48
when is a weak acid non ionized
in an acidic environment
49
when is a weak base ionized
in an acidic environment
50
when is a weak base non-ionized
in a alkaline solution
51
Ion trapping (what, where do drugs accumulate, clinical use)
difference in pH on different sides of a membrane
= drugs accumulate om side of the membrane where they are ionized (since they can't cross back)
- sued clinically in some cases of drug overdose
52
Capilaries
- supply tissue with oxygenated blood and allow drugs and other molecules to move from blood to tissue
- have fenestrations = small holes in endothelial cells that allow molecules to pass through
53
Drug movement out of capilaries = hydrophilic
- cannot penetrate endothelial cell membrane
| - must pass thorugh fenestrations
54
Drug movement out of capilarries - lipophilic
- can penetrate endothelial cell membrane
| - can also pass through fenestrations
55
Capillaries and the BBB
- hydrophilic drugs can't pass the blood brain barrier
| - lipophilic drug = pass through cell membrane/tight junction
56
Pharmacokinetics
study of drug movement in the body (what the body does to the drug)
57
4 properties of pharmacokinetics
1) absorption
2) distribution
3) metabolism
4) excretion
58
Pharmacokinetics - absorption
- movement of drugs from site of administration of the blood
59
what determines how a drug's absorption affects the body?
1) rate of absorption = determines how quickly a drug effects will occure
2) amount of drug absorption = determines how intesnse the effect of the drug will be
60
Factors affecting drug absorption (6)
1) rate of dissolution
2) surface area
3) blood flow
4) lipid solubility
5) pH partitioning
6) activity of drug transport proteins
61
Factors affecting drug absorption - rate of drug dissolution
- drugs must dissolve before they can be absorbed
| - fast rate of dissolution = faster onset of action
62
Factors affecting drug absorption - surface area
- larger surface area = faster drug absorption
| stomach rugae have lower SA where intestinal villi have increased SA
63
Factors affecting drug absorption - Blood flow
- absorption is faster in areas with increased blood flow
| - (high blood flow creates increased concentration gradient, low blood flow creates less concentration gradient)
64
Factors affecting drug absorption - factors affecting blood flow
- exercise increases blood flow = increased drug absorption
| - heart failure, severe hypotension, hypothermia, circulatory shock = decreased blood flow, decreased absorptions
65
Factors affecting drug absorption - Lipid solubility
Lipophilic drugs are absorbed more rapidly than hydrophilic drugs (lipophilic cross cell membrane
66
Factors affecting drug absorption - pH partitioning
- drug absorption is grater where there is a difference between pH at the site of administration and the blood, where the drug is ionized in the blood
- EX - weak acid in the acidic stomach, cross membrane to alkaline bllod, weak acid ionized, and drug is stuck in blood)
67
Drug transporters + drug absorption
- uptake transporters increase absorptions
| - efflux transporters decrease absorptions
68
Routes of administration
- oral, sublingual, transdermal, rectal, IV, subQ, IM, pulmonary
69
Oral administration - advantages and disadvantages
- advantage = safety, convinient, economical
| - disadvantage = incomplete and variable absorption
70
Oral absorption - weak acids
- pH effect - drug better absorpbed in stomach
- SA effect - drug not absorbed as well in stomach
* rate of absorption will be greater in intestine even if it is ionized*
71
Gastric emptying + rate of absorption
- movement of stomach contents into the intestine
- rate of absorption is greater in intestine
- therefore anything that increases gastric emptying will increase the rate of absorption
72
Ways to increase gastric emptying
- Take meds on an empty stomach
- take med with cold water
- lying on right side after med is given
- high osmolarity feeding (tube feeding)
- taking a prokinetic drug (drug that increases GI motility)
73
Decreasing gastric emptying
- high fat meal
- heavy exercise
- lying on left side
- drugs that inhibit vagus nerve (anticholinergic drugs)
74
Enteric coating
- drugs covered with a coating that prevents their disolution int he acidic stomach
- coating dissolves in more alkaline intestine
- use - drugs that would be destroyed by acid or that would destroy stomach
75
Bioavaliability
- fraction of a dose that reaches systemic circulation
76
factors affecting bioavailibility (3)
- drug formulation
- route of administration
- degree of metabolism
77
Which formulations have the most oral bioavailibility + why
1) aqueous solution
2) syrup
3) suspension
why? no dissolution phase
78
Which formulations have medium oral bioavailibility
- chewable tablet
- granules
- capsules
79
which formulations have the least oral bioavailibility`
1) compresed tablet
2) enteric coated tablet
3) time released capsule
80
what is sublingual medication administration
placing a drug under the tongue (drug enters oral mucosa, then superior vena cava, then heart)
81
benefits of sublingual administration (2)
1) drug avoids first pass metabolism thorugh liver
| 2) useful for drugs that act directly on the heart
82
transdermal administration medication characteristics (3)
1) lipophilic
2) somewhat hydrophobic
3) small (<600 Da)
83
Transderamal preperations
- patches, ointments, sprays, lotions
84
Transdermal disadvantages
tolerance can develop unless a drug-free period is enforced
| - (constant plasma drug levels with minimum peaks or troughs)
85
Factors affecting transdermal absorbtions
- thickness of the skin (decreased absorption)
- hydration (increased absorption
- more hair follicles (increased absoption)
- application surface area (increased abospriont)
- integrity of skin barier (poor integrity is increased psoriasis)
86
rectal administration use
when a patient is unconsious or vomitting
87
metabolism after rectal administration
50% bipasses the liver
88
how rectal administration works
- drug in supository, supository dissolves and drug corsses rectal mucosa into blood
89
disadvantages of rectal absorption
incomplete absorption and may iritate rectal musosa
90
Intravenous drug administration
drugs injected into a pheripheral vein (back or hand or median cubital vein
91
type of ways to administer IV med
1) IV bolus
| 2) IV drip
92
IV bolus
a single dose administered over a short time period
93
IV drip
continuous infusion over a long time period. Drugs diluted in a vehicle (ex saline)
94
Advantages of IV administration (4)
- no absorption required = 100% bioavailibility
- allows precise control over drug dosage and duration of action
- allow adminitration of poorly soluble drugst hat must be diluted
- allows injections of drugs that are diluted in blood
95
IV disadvantages
- expensive, invasive, inconvinient
- drug cannot be removed once injected
- risk of injection and fluid overload
- risk of injecting hte wrong fomula
96
Subcutaneous
- drug is injected beneath skin into subcutaneous tissue
97
factors affecting subcutaneous absorption
- blood flow to an area
| - water solubility
98
Intramuscular medication
drug is injected directly into muscle
99
factors affecting intramuscular injection
ability of drug to pass thorugh fenestrations in capilary wall
- blood flow
- water solubility
100
intramuscular injection advantages
- poorly soluble drugs
| - aminister depot preperations (where drug is absorbed slowly over time)
101
intramuscular injeciton disadvantages
- pain
| - may cause local tissue/neve damage if injection is done improperly
102
Factor affecting rate of absorption IM
blood flow
- deltoid> vastus lateralis > gluteal
- exercise increases absorption
- heart failure, hypotension, hypothermia decreases absorption
103
Pulmonary medication administration
- gaseous + volatile drugs can be inhaled = very rapidly absorption
104
where can drugs distribute in the body? (7)
- intersitial space
- total body water
- plasma
- adipose tissue
- muscle
- bone
- other
105
What drugs distibute into intersitial space
drugs with
- low molecular weight,
- water soluble drugs
106
what drugs distribute into the plasma
drugs that bind to plasma proteins or with high omlecular weight
107
what drugs distribute into adipose tissue?
lipid soluble drugs
108
what drugs distibute into bone?
someslow release drugs
109
what drugs can distribute into other compartments?
ONLY FREE DRUGS
110
3 factors affecting drug distribution
1) blood flow to tissues
2) ability of drugs to move out of capillaries
3) ability of drug to move into cells
111
blood flow and drug distribution
- where tissues are well perfused there is faster distribution
112
which organs have greater blood flow?
liver, kidney, brain, drug distribution,
113
when does poor blood flow limit drug distribution? (4)
rarely in adult patients
- neonates
- pt with heart failure or shock
- certain solid tumours with limited blood flow
- absess
114
how a drug exits vasculature
- (not brain) it is easy for drug to leave into interstitial space due to permeability of capillary wall
- harder for drugs to enter the target organ for an effect (cell membrane)
115
P- Glycoprotein
- most widely used efflux transporter
| - p = protective = facilitates drug efflux from cells, drug excretion, protects body from exposure to drugs
116
is P-glycoprotein active or passive transport
active
117
where is P-Gp located
- liver (hepatocytes)
- intestine (enterocytes)
- kidney (proximal tubule cell)
- brain (capilary endothelial cells facing blood)
118
Plasma protein binding
in plasma the drugs can be bound to plasma proteins, or they can be free
119
is plasma protein binding reversible
yes
120
can plasma bound proteins exit capilary
no
121
what are the two main plasma proteins that bind drugs
1) albumin
| 2) alpha 1 acid glycoprotein
122
albumin and binding drugs
- lipophilic and anionic (weak acid) drugs
123
Conditions affecting albumin drug binding (5)
- malnutrition
- trauma
- aging
- liver/kidney disease
- decreased plasma alumin concentration
124
result of decreased albumin binding
- increased in free drug concentration
| - toxicity
125
Factors affecting alpha 1 acidic glycoprotein (4)
- aging
- trauma
- hepatic inflammation
- concentration of alpha in plasma
126
calculating volume of distribution
vd = d/c
where
vD = volume of distribution
D is total amount of drug in the body (dose)
C - plasma concentration of the drug (concentration)
127
Volume of distribution
represents the apparent volume that a drug distributed into
| not a physical anatomical space
128
Fluid compartments
```
intracellular fluid
extracellular fluid (plasma and intersitial fluid)
```
129
Drugs with a small vD characteristics (2)
1) highly protein bound (retained in plasma)
| 2) large molecular weight (can't pass through capillary fenestrations)
130
Small vD effects
- unable to leave vascular space
| - plasma voluem of 0.057 L/kg or 5.7% of body weight
131
Intermediate vD characteristincs
1) low molecular weight (pass through capillary)
2) very hydrophillic (can't cross cell membrane)
3) intermediate protein binding
132
intermediate vD transport out of blood vessels
- leave vascular space and enter intersitial space
- unable to enter cells
- distribute in extracelular space
- 20% of body weight
133
large vD characteristics
1) low molecular weight
2) lipophi.ic
3) minimal protein binding
134
large vD and transporting to tissues
- exit vascular space
- enter interstitial space
- enter body compartments
- distribute into greater than 0.2 L/kg
135
Drug displacement - of small vD
if drug B displaces drug A (with small Vd) the drug remains in the plasma and doesnt distribute into the tissue
aka free drug concentration increases
136
Drug Displacement - drug with a large Vd
the drug enters the tissue
- decreases the free plasma concentration
- increases the volume of distribution
137
Body composition and drug distribution (obese people)
- larger proportion of body mass as fat
| - drugs that distribute into fat will have a larger Vd
138
Body composition and age (elderly)
- elderly have a decreased muscle mass and increased fat
| - drugs that distribute into muscle will have a decreased Vd
139
Metabolism organs in the body (5)
- Liver (primary)
- intestine (eneterocytes that linegut)
- stomach (alcohol)
- kidney
- intestinal bacteria (normal flow)
140
Importance for metabolism (exogenous)
- metabolize drugs, food, coffee, alcohol, etc as they can be toxins
141
importance for metabolism (endogenous)
vitamin D synthesis, Bile acid syntehsis, cholesterol metabolism, steroid hormones, bilirubin
142
Therapeutic consequences of drug metabolism (5)
1) increase water solubility of drugs to promote their excretion
2) inactivate drugs
3) increase a drug's effectiveness
4) activate protodrugs
5) increase drug toxicity
143
protodrugs
compounds that are inactivated until metabolized
144
First order kinetics
- when the concentration of the drug is much lower than the metabolic capacity of the body (most times)
- drug metabolism is directly proportional to the concentration of free durg
- = a constant fraction of drug is metabolized per unit time
145
zero order kinetics
- when the plasma drug concentration is much higher than the metabolic capacity of the body
- drug metabolism is constant over time
146
First pass metabolism
- when a drug undergoes significant metabolism prior to entering systemic circulation (common with PO drugs)
- RESULT = a decreased amount of the parent drug enters systemic circulation
147
where can first pass metabolism occur (4)
1) hepatocytes (liver)
2) intestinal enterocytes
3) stomach
4) intestinal bacteria
148
Metabolizing enzymes in the stomach (ex alcohol)
- parent drug = alcohol
- enzyme = alcohol dehydrogenaze
- metabolite = acetahyde
149
metabolizing enzymes in the intestine
- drug-->
- enzyme = cypenzyme-->
- metabolite
150
metabolizing enzymes in the liver
many enzymes
| - primary site
151
metabolizing enzymes in the large bowel
- drug -->
- enzyme (bacterial enzyme)-->
- metabolite
152
what part of metabolism determines bioavailibility
the amount of metabolism on the first pass through the liver
153
what determines how much metabolism occurs on first pass thorugh liver?
high vs low extration ratio (ER)
154
High extraction ratio drugs and first pass metabolism
- significant first pass metabolism
155
High extraction ratio drugs and PO vs IV route
much higher PO dose than IV dose to compensate for high first pass metabolism
156
high extraction ratio and changes in hepatic enzymes
CHANGE IN HEPATIC ENZYME = LARGE CHANGE IN BIOAVALIABILITY
157
High ER drugs and drug-drug interactions
very susceptible to drug-drug interactions
158
Low ER drugs and bioavailability
high oral bioavalibility
159
Low ER drugs and changes between PO and IV route
PO dose similar to IV dose
160
Low ER drugs and changing hepatic enzyme
- small changes in hepatic enzyme have little effect on bioavalibility
161
Low ER drugs and drug-drug interactions
not very susceptible to drug-drug interactions
162
Phases 1 metabolism goal
convert lipophilic drugs to be more polar moleculs by introducing or unmasking polar functional groups (hydroxyl, OH-, amine, NH2)
163
Phase I metabolism chemical events (3)
- oxidation, reduction, hydrolysis reactions
164
phase I metabolism enzymes
cytocrome P450, enzymes, estonins, dehydrogenases
165
Phase I metabolites and effect on drug potency
- can be more active, less active, or equally active as parent drug
166
Phase II metabolism Goal
- increase the polarity of lipophilic drugs by conjucation reactions
167
Phase II metabolism potential congugates
- glucaronic acid
- sulfate
- acytel group
- amino acits
- large water soluble molecules
168
Phase II metabolism potency after metabolism
- metabolites less active than parent drug
169
Phase II metabolism (POTENCY EXEPTION)
morphine G-glucoromide is more potent than morphine
170
Goal of metabolism
make drugs more water soluble so they can be excreted
171
Where does phase one metabolism occure
smooth endoplasmic recticulum
172
where does phase 2 metabolism occur
cytosol
| - gluconidation in smooth ER
173
What are cytochrome P450 drug metabolising enzymes? (CYPs)
- predominant phase I drug metabolizing system
| - most of drug metabolism
174
how do CYP enzymes work?
insert one atom of O2 into a drug molecule producing water as a product
175
What can decrease activity of CYPs?
malnutrition (these enzymes require dietary protein)
176
How are CYPs named?
- CYP-family-subfamly-isosyme
| EX CYP3A4
177
Which CYP metabolizes the largest fraction of currently marketed drugs?
CYP34A
178
Phase II metabolic enzymes (4)
- UGTs
- GSTs
- SULTs
- NATs
179
UDD-glucorosyltransferases (UGTs) location
smooth ER
180
UDD-glucorosyltransferases (UGTs) function
- catabalize transfer of flucuronic acid (sugar) to a drug to make it more polar and easier to excrete
181
sulfotransferases (SULTS) location
- cytosol
182
sulfotransferases (SULTS) function
- catabolyze transfer of a sulfate group to a drug to make it more soluble and more easily excreted
183
Glutathione S Transferases (GSTs) location
cytosol
184
Glutathione S Transferases (GSTs) function
catabolize transfer of glutathiole molecule to a drug
| - anioxidant (makes a toxic/reactive drug metablite less toxic
185
N-acetyltransferases (NATs) location
cytosol
186
N-acetyltransferases (NATs) function
catalyze transfer of an acetyl group from acetyl CoA to a drug
187
N-acetyltransferases (NATs) variability
genetic polymorphisms
188
Thidurine methyl-transferases (TDMT) location
Cytosl
189
Thidurine methyl-transferases (TDMT) location
transfer of a methyl group from S-adenosytemethione to a drug
190
Thidurine methyl-transferases (TDMT) variations
- genetic polymorphisms
| - rarely can have dramatic effect on drug safety
191
Factors affecting drug metabolism
- age
- drug interactions
- disease state
- genetic polymorphisms
192
Age and metabolism
- young (0-6m) almost 0 hepatic activity
- metabolisms develop from 6m to 2yrs
- 2-17 normal metabolism
193
Enzyme induction and metabolism (3)
- certain CYP isotymes are susceptible to induciton by drugs = increased drug metabolism
- result
1) decreased plasma drug concentration
2a) decreased drug activity (if metabolite is inactive)
2b) increased drug activity (if metabolite is active)
194
enzyme induction and metabolism example
cigarette smoking increases drug metabolism
195
Enzyme inhibition and metabolism (3)
1) increase plasma drug concentration
2) increased therapeutic effect of drugs
3) increased drug toxicity
196
Diseases that decrease CYP activity (4)
- liver disease
- kidney disease
- inflammatory disease
- infection
197
genetic polymorphisms and metabolism
aka SNPs (single nucleotide change = ATCG)
198
Genetic polymorphism - CYP2C9.- metabolizes the drug
anticoagulant warfarin
199
Genetic polymorphism - CYP2C9.- effect on activity
polymorphism decreases enzyme activity = increased bioavalibility = increased side effect of bleeding
200
Genetic polymorphism - CYP2D6 - metabolizes
- codein to morphine (morphine is more potent)
201
Genetic polymorphism - CYP2C9.- phenotypes and effect (4)
- ultra rapid (lots of CYP)
- extensive metabolism (normal)
- intermediate metabolizers (decrased CYP)
- poor metabolizers (almost no CYP activity)
202
UGTIAI polymorphism
- polymorphism decreases its activity
| - RESULT = decrased marrow supression that could be fatal
203
NAT2 genetic polymorphism
- metabolizes ionazid, caffeine, cancer causing chemicals
- 23 SNPS
- phenotype = slow or fast
- snow acytelators = more susceptible to ionizad tocicity and are at higher risk for developing certain cancers
204
Drug Drug interactions in the elderly
on average 65+ takes 7 medications
205
common drug-drug interactions
those affecting pharmacokinetics
206
consequences of drug interactions
1) incraesed effects
2) decreased effects
3) generation of a new effect
207
Drug-Drug interactions = increased effect (2)
1) increase the therapeutic effect
| 2) increase adverse effect
208
Drug-Drug interactions - increased effect - increased therapeutic effect (ampicilin and sulbactam)
EX -
1) ampicilin the antibiotic is rapidly inactivated by bacterial enzymes
2) Sulbactam is an inhibitor of the bacterial enzyme that inactivates ampicilin
RESULT = ampicilin + sulbactam = increased therapeutic activity of ampicilin
209
Drug-Drug interactions - increased effect - increased adverse effect (warfarin and asprin)
- Warfarin = anticoagulant
- asprin = analgesic that also thins blood
- RESULT = warfarin + aspirin thins blood too much and causes bleeding (potentially life threatening)
210
Drug-Drug interactions - decreased effect
- reduce therapeutic effects
| - reduce adverse effects
211
Drug-Drug interactions - decreased effect - reduced therapeutic effect (clopidogrel and omeprazole)
- Clopidogrel = anticoagulant (is a pro drug that requires metabolic activation by CYP)
- Omeprazole = stomach ulcer drug (inhibits CYP)
- RESULT = active metabolite of clopidogrel is not formed = insuficcient anticoagulation
212
Drug-Drug interactions - decreased effect - reduced adverse effects (morphine + naloxone)
- morphine = analgesic (that when overdosed, can produce coma, resp depression, death)
- naloxone = a competitive antagonist
- RESULT = treat overdose
213
Drug-Drug interactions - generation of a new effect (disulfiram and alcohol)
- disulfiram = drug used to treat chronic alcoholism. (alc is metabolized to acetahyde then to acetic acid)
- acetahyde causes hangover (headache, nausea, vomit)
- Disulfiram inhibits the metabolism of acetadhyde (use of this drug causes patient to have very severe hangover like symptoms
214
Types of drug interactions (4)
1) direct physical interaction
2) pharmacokinetic interaction
3) pharmacodynamic interaction
4) combined toxicity
215
Direct physical interaction
direct chemical or physical interaction of 2+ drugs
| - often occurs when mixing IV solutions --> precipitate forms
216
Direct physical interaction - problems before administration
- CONSULT COMPATIBILITY CHART
| - diazepam is particularly problematic
217
Direct physical interaction problems after administration
- sodium bicarbonate followed by calcium glucanate can form a precipitate in the blood
218
Pharmacokinetic interaction
- interactions affecting absorption, distribution, metabolism, or excretion (ADME)
- most common
219
Pharmacokinetic interaction - absorption
- altered pH
- chelation/binding
- altered blood flow
- gut motility
- vomitting
- drugs that kill intestinal bacteria
220
Pharmacokinetic interaction - absorption - altered pH
- drugs that effect gastric or intestinal pH can alter drug absorption (effect ionization of some drugs)
221
Pharmacokinetic interaction - absorption - altered pH - EXAMPLE of antacids
- antacids increase gastrib pH
- incrase absorption of drugs that are weak bases
- decrease absorption of drugs that are weak acids
222
Pharmacokinetic interaction - absorption - altered pH - enteric coated drugs and antacids
- designed to pass thorugh acidic stomach without dissolution (when in alkaline environemnt)
- antacid taken = increase pH of stomach and therefore promotes premature dissolution of enteric coated drugs
- consequence = less absorption?
223
Pharmacokinetic interaction - absorption - chelation/binding
- some drugs known to bind other drugs in the intestine --> formation of insoluble complezes that can;t be absorbed
- EX - Cholestyramine (bile acid sequestrant) binds to digoxin (bile acid) preventing its absorption
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Pharmacokinetic interaction - absorption - altered blood flow
- drug decrase blood flow will decrease absorption of other drugs
- EX local anaestetic administered, it may diffuse into the blood away fron injection site
- EX2 = epinephrine is injected iwth local anestetic, it causes vasoconstriciton and decreases absorption of local anestetic so that the anestetic stays at the injection side
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Pharmacokinetic interaction - absorption - gut motility
- increase intestinal motility (ex laxatives) = decreased drug absorption
- decrease intestinal motility (ex opiate) = decreased gut motility
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Pharmacokinetic interaction - absorption - vomiting (3)
- drugs that induce vomiting will decrease the absorption of other drugs
- if vomiting occurs within 20-30 mins after taking one or more medications it is likely that absorption is incomplete
- if vomiting occurs after the drug has entered the intestine, giving another dose may produce toxicity
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Pharmacokinetic interaction - absorption - drugs that kill intestinal bacteria
- Intestinal bacteria = metabolism of some drugs
- ex antibiotics that kill intestinal bacteria = decreased deconjugation --> decreased absorption during enterohepatic recycling --> decreased plasma drug concentration
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Pharmacokinetic interaction - distribution - altering pH
- change in pH can influence ionization of other drugs
- drug sodium bicarbonate increases extracellular pH where ammonium chloride decreases extracellular pH
- pH partitioning = draw out drug from inside the cell to outside by changing its ionization (ex asprin overdose of weak acid asprin, increase extracellular pH with sodium bicarbonate will draw asprin outside of the cell and cause it to become ionized. once trapped the asprin can be eliminated
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Pharmacokinetic interaction - distribution - protein binding
- if two drugs are bound tot he same site on plasma proteins, co-administration will result in competition for binding
- drug with lower affinity for protein will become free
- may result in increased T effect, increased toxicity, increased excretion
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Pharmacokinetic interaction - metabolism - cyp induction
- some drugs increase synthesis of CYP enzymes = induction
- result = increased drug metabolism
- induction is delayed = 2-10 days following exposure to the enzyme inducer before the induction occurs
- after inducer is stopped it takes 7-10 days before the CYP enzyme levels return to normal
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Pharmacokinetic interaction - metabolism - CYP induction examples
- cigarette/marijuana smoke (one J = 5-10 cigarettes)
- rifampin - induces CYP34A
- phenobarbital
- BBQ food (induce CYP1A2)
- alc - induces CYP2E1 (severe alcoholism will decrease CYP)
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Pharmacokinetic interaction - metabolism - CYP inhibition
- enzyme inhibition = decreased metabolism of other drugs metabolized by the same enzyme
- result = increased plasma concentration of the parent drug
- exept if a pro-drug is given when CYP enzymes are inhibited (decreased metabolic activation)
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Pharmacokinetic interaction - metabolism - CYP inhibitors example
- antibiotics and antifungals inhibit CYP3A4
- HIV protease inhibitors inhibit CYP3A4
- omeprazole inhibits CYP2C19
- selective seretonin reuptake inhibitors (SSRIs) inhibid CYP2D6
- fluvozamine - inhibits CYP1A2
- grapefruit juice - inhibits CYP3A4
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Pharmacokinetic interaction - excretion = altered blood flow
- drugs that decrease renal blood flow = decreased glomerular filtration = decreased renal excretion = increased plpasma drug concentrations
- EX non-steroidal anti-inflammatory drugs (NSAIDS) = renal vasoconstriction
- EX2 = beta blockers act on heart to decrease cardiac output (indirectly decreases renal flow)
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Pharmacokinetic interaction - excretion - altered pH
- change pH of renal tubular filtrate --> alter drug excretion
- pH partitioning and ion trapping
- USE = drug overdose (overdose on amphetamine, a weak base = acidify filtrate with ammonium chloride = prevent reabsorption in the blood = increased renal excretion of amphetamine)
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Pharmacokinetic interaction - excretion - tubular
- mediated by transporters at prozimal tubule
- if a drug blocks the transporter, it may block another drug from being secreted into the tubule lumen = decreased renal excretion and increased plasma concentration
- EX antibioti penecilin and probenecid (causes renal penecilin excretion to decrease + blood penicillin to rise)
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Pharmacodynamic interaction (2) types
1) interactions that occur at the same receptor
| 2) interactions that occur at separate sites
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Interactions that occur at the same receptor (3)
- usually drug interactions that occur at the smae receptor = antagonist blocking action of an agonist (inhibitory)
- result = decreased therapeutic action, or decrease toxicity in overdose situations
- EX = overdose of morphine....use a competitive antagonist to reverse the symptoms
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Pharmacodynamic interaction - interactions that occur at separate sites (2)
- drugs that have different mechanisms can interact if they produce the same physiologic response
- EX MORPHINE (ACTS ON OPIOD RECEPTORS) AND DIAZEPAM (ACTS ON BENZODIAZAPINE RECEPTOR) --> CNS depression
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Combined toxicity - drug-drug interaction
- two drugs that cause toxicity should not be administered together
- EX acetaminophen and alcohol - both are hepatotoxic and when used together can increase amount of liver damage
