BP Theme 1 Flashcards
1
Q
why do dentists need to know about principles of drug action
A
- To be able to use and prescribe drugs rationally
- Dental patients may already be taking drugs
- To keep up to date with developments in pharmacology and therapeutics
- Individual drugs will come and go but the principles will remain the same
2
Q
what is pharmacology
A
how drugs can affect the human body or the host response to a pathogen
3
Q
what 2 aspects is pharmacology split into
A
pharmacodynamics and pharmacokinetics
4
Q
what is pharmacodynamics
A
effects of a drug on the body
5
Q
what are the two elements of pharmacodynamics
A
- Molecular interactions by which drugs exert their effects because there are specific targets.
- Influence of drug concentration on the magnitude of response –> therapeutic vs toxic.
6
Q
pharmacodynamics allows us to determine the appropriate dose range for patients, why is this important
A
tell us how much drug we need to give the patient for it to work on the receptor
7
Q
pharmacodynamics allows us to Compare the effectiveness and safety of one drug to another, why is this important?
A
one receptor may need less
of 1 drug than another to exert the same effect.
8
Q
what is pharmacokinetics
A
what the body does to a drug
9
Q
what are the 4 processes of pharmacokinetics
A
absorption
distribution
metabolism
excretion
10
Q
what does absorption in pharmacokinetics involve
A
from site of administration into the blood
11
Q
what does distribution in pharmacokinetics involve
A
drug can reversibly leave the bloodstream and distribute into the interstitial
and intracellular fluids of tissues
12
Q
what does metabolism in pharmacokinetics involve
A
body inactivates the drug through enzymatic modification
13
Q
what does excretion in pharmacokinetics involve
A
drug is eliminated from the body in urine, bile or faeces –>body’s response to an
exogenous chemical is to remove it (retainment of drug may have side effects).
14
Q
what does the Study of pharmacokinetics allow us to:
A
Design and optimise treatment regimens for individuals e.g. deciding on the route
of/frequency/duration of treatment.
15
Q
why is the drug called antihistimine
A
stops histamine which causes indiscriminate immune response
16
Q
where in the nose does antihistamine work
A
H1 receptors
17
Q
is the nose the sole location for antihistimine
A
no, in the stomach as well (peristalsis and gastric acid) - receptors are different
18
Q
how does the antihistimine tablet get to the nose
A
stomach> intestines> liver >bloodstream
19
Q
why does another antihistimine tablet need to be need to be taken the next day
A
metabolised and excreted , prolonged retention causes more side effects
20
Q
what are the sources of drugs
A
naturally occurring
synthetic- insulin
biologics
21
Q
what is biologics
A
chemically produced biological entities
22
Q
how do drugs interact
A
shape- lock and key
charge distribution
23
Q
order of bond strength (weakest first)
A
vdw
hydrogen
ionic
covalent
24
Q
what else is important in drug interactions
A
hydrophobicity
ionisation (pKa)
conformation of target
stereochemistry
25
what are the 4 main targets of drug action
receptors
carries
enzymes
ion channels
26
example and drug name for receptor
B2 adrenoreceptor for salbutamol to treat asthma
27
example and drug name for ion channels
voltage gate na+ channel for lidocaine for a local anaesthetic
28
example and drug name for enzymes
transpeptidase for aspirin used as an analgesic
29
example and drug name for carriers
proton pump for omerprazole used for anti ulcer
30
what do antidotes do
e.g. acetylcysteine to treat poisoning with paracetamol (overdose)
31
what do antacids do
stop indigestion by neutralising stomach acids
32
what do laxatives do
pulls water into foetal matter e.g lactulose
33
how are receptors targets for drug action
they are the target for endogenous transmitters
34
how are enzymes targets for drug action
they are biological catalysts which facilitate biochemical . reactions
35
how are ion channels targets for drug action
they're pores which span membranes to allow selective passage of ions
36
how are carrier molecules targets for drug action
they transport ions and small organic molecules across cell membranes
37
what are the two types of chemicals that can bind to receptors
agonists and antagonists
38
what is an agonist
ligand (drug, hormone or neurotransmitter) that combines with receptors to elicit a cellular response
39
what is an antagonist
An antagonist is a drug which blocks the response to an agonist
40
how do drugs interact with ion channels
they block or modulate the opening/closing e.g. increasing frequency ion channels opens up or capacity of ion channel
41
how do drugs interact with enzymes
either inhibit or act as a false substrate
42
how do drugs interact with carriers
either transported in the place of the endogenous substrate or inhibit transport
43
what is an example of allosteric drug action at ion channels
benzodiazeopines acting on GABAa receptors - given to anxious patients
44
what is the action of benzodiazeopines on GABAa receptors
binds allosterically enhance the effect of GABA, GABA binds to ion channel, increased Cl- conductance , hyperpolarisation, decreased excitability so reduced anxiety
45
what is orthosteric binding site
normal binding site
46
what is allosteric binding site
different binding site
47
what is the normal enzymatic process for inflammation after immune activation, cell injury etc.
phospholipids in plasma membrane break down via phospholipase A2, this creates arachidonic acid which is broken down by cylcooxygenas to prostaglandin --> inflammation etc.
48
how do NSAID e.g. ibuprofen act to reduce inflammatory response
they interact with the cyclooxygenase which prevents conversion of arachidonic acid to prostaglandins
49
what is an example of an agonist
histamine acts as an agonist at the H1 receptor in the smooth muscle to increase local blood flow
50
what is an example of an antagonist
terfenadine acts as an antagonist at the H1 receptor in the smooth muscle to decrease local blood flow
51
how are receptor sub types identified
- on the basis of selectivity agonists and/or antagonists
| - cloning techniques
52
what activates receptor
bound agonist, once activates has altered physical and chem properties
53
what 4 receptor types respond to drugs
ligand gated ion channels
g-protein couples receptors
enzyme linked receptors
intracellular receptors
54
what are the two channel linked (ionotropic) receptors
ligand gated & voltage gated
55
how do ligand gated channel linked receptors work and what is an example
require agonist to open channel
| e.g. nicotinic acetylcholine receptor, actCh causes skeletal muscle to contract by opening ligand-gated channels
56
how do voltage gated channel linked receptors work and what is an example
require change in electrical charge across membrane e.g na+ channels in nerve cell membranes
57
how do local anaesthetics work
blocking voltage-gated na+ channels and stop pain
58
how do muscle relaxants work
nicotinic Ach receptor antagonists are inhibitors of the nicotinic receptor which causes muscle contraction. so we get relaxation
59
what are g-protein coupled receptors
single polypeptide chain with 7 trans-membrane helices
3 subunits- alpha, beta, gamma
2 mechanisms
60
what is an example of α/β adrenoceptors
epinephrine (will bind to the receptors)
61
what is an example of β2 adrenoceptors
salbutamol (interact with receptors as separate entity)
62
what are the different variations in α subunits
Gs, Gi, Gq and Go
63
what do the variant α subunits allow for
lots if different signalling
| dictates second msgr activation or deactivation
64
what is the action of Gs
activates adenylyl cyclase
| activates ca2+ channels
65
what is the action of Gi
inhibits adenylyl cyclase
| activates K+ channels
66
what is the action of Gq
activates phospholipase C
67
how does g-protein signal transduction work
drug binds to receptor, releases gdp, a subunit dissociates and activates adenylyl cyclase, this catalyses the formation of cAMP, cAMP activates other receptors. (when drug absent receptor reverts to its resting state
68
what is an example of g-protein signal transduction
adrenoreceptors
69
how are adrenoreceptor subunits activated
by adrenaline and noradrenaline
70
what is salbutamol
Beta 2 receptor agonist- bronchodilation- asthmatic patients
71
what is atenolol
Beta 1 receptor antagonist- ot blocks beta 1 receptors in the heart thus inhibiting the accelerated heart rate
72
what are the receptor sub types of adrenoreceptors and what is their corresponding a-subunit and effect
a1 - Gq -activates PLC- vasoconstriction
a2 - Gi- inhibits adenyl cyclase- auto-inhibition of neurotransmitter release
B1 - Gs- stimulates adenylyl cyclase- accelerated heart rate
B2 - Gs- stimulate adenylyl cyclase- bronchodilation
73
what acts on kinase linked receptors
hormones/growth hormones/steroids
74
why do kinase linked receptors take longer to occur
due to protein phosphorylation
75
what are the different forms on kinase linked receptors
receptor tyrosine kinase i.e. insulin
serine/threonine kinase
cytokine
guanylyl cyclase-linked
76
what happens when the ligand binds in kinase linked receptors
dimerization (pull 2 receptor molecules together) which activates autophosphorylation cascade
77
what is an example of a kinase linked receptor
insulin
78
how does insulin work once it binds
it activates receptor tyrosine kinase in B subunit. tyrosine residues of B subunit are auto-phosphorylated. receptor tyrosine kinase phosphorylates other proteins e.g. insulin receptor substrates
79
what are nuclear receptors
family of 48 soluble receptors intracellular based unlike others the drug must enter into the cell
80
what are examples of nuclear receptors
estrogen receptor- estradiol and tamoxifen
81
what are the 2 major classes of nuclear receptors
```
class I- endocrine ligands (steroids, hormones)
class II - ligands are lipids
```
82
where are class I nuclear receptors and what do they form
cytoplasm, form homodimers
83
where are class II nuclear receptors and what do they form
nucleus, form hetrodimers
84
what does binding to hormone response elements initiate
gene transcription changes (positive/negative)
85
outline class I nuclear receptor signal transduction
lipid soluble drug enters cell, binds to nuclear receptor, drug receptor translocated into the nucleus, drug receptor unwinds chromatin, transcription, new mRNA, new proteins, new effects
86
how many binding sites does Nachr have
hetromers- have 2 sites and homomers have up to 5 sites
87
what are the drug-receptor interactions of the future for orthosteric sites
full and partial agonists
inverse agonists
reversible competitive antagonists
irreversible competitive antagonists
88
what are the drug-receptor interactions of the future for allosteric sites
positive, negative, allosteric antagonists
89
what are the drug-receptor interactions of the future for effector regions
non competitive antagonists
| channel activators
90
what is the response when the agonist, salbutamol, binds to B2-adrenoreceptor complex
agonist-receptor complex= salbutamol-B2-adrenoreceptor complex
action=increased cAMP
effect=bronchodilation
91
specifically which G protein receptor is the B2-adrenoreceptor
Gs
92
what is the dose response curve also known as
concentration-effect curve
93
what is meant by dose
how much you give e.g. 5mg tablet
94
what is meant by concentration
how strong it is in the body, concentration in the plasma that has therapeutic effect
95
what does the sigmoidal shape for the semi-logarithmic plot of the dose response curve show us
the threshold range for concentration, the linear response, and the maximal response
96
what is a graded dose response
response of a particular system: isolated tissue, animal or patient
97
what is a quantal dose response curve
measures population based effects
98
what are the benefits of plotting a dose response curve
allows estimation of Emax
| allows estimation of EC50
99
what is meant by Emax
maximum effect given by a particular concentration
100
what is meant by EC50
dose required to produce 50% of maximal response
101
how can efficacy be determined
Emax
102
how can potency be determined
EC50
103
what is meant be affinity
the strength which an agonist/drug binds to a receptor - form a stable complex
104
how is receptor saturation measured
maximum number of binding sites (B max)
105
how can affinity be measured
ratio of association and dissociation
| k1/k-1
106
what is is k1
the rate of association of the agonist with the receptor
107
what is k-1
the rate of AR complex dissociation
108
what would the k1 and k-1 be like for a high affinity drug
large k1
| small k-1
109
what is KD
characterises affinity - physiochemical constant like Avogadros number
110
what does KD tell us
the conc of ligand at which 50% if the available receptors are occupied
111
does the KD change for a given receptor
no its the same for a given receptor and drug combination in any tissue, in any species anywhere in the universe
112
what is the relationship between Kd and affinity
inverse
| lower Kd --> greater affinity
113
what is the eq for affinity
k1/k-1
114
what is the eq for Kd
k-1/k1
115
how would you see which agonist has the highest affinity on the graph
the one with the lowest Kd (Kd determined by drawing line for 50% receptors occupied)
116
what is meant by a potent drug
those which elicit a response by binding to a critical number of receptors at a low conc (high affinity) compared with other drugs acting on the same system with lower affinity
117
what characteristics will a highly potent drug elicit
binds well, strong effect, quick effect
118
what does potency depend on
affinity of drug
efficacy of drug
receptor density
efficacy of stimulus-response mechanisms used
119
what is the relationship between ec50(dose to produce 50% max response) and potency
lower the ec50 the higher the potency
120
do agonist with a higher potency tend to have a higher affinity
yes
121
what happens if there is a linear relationship between receptor occupation and biological effect
Kd and EC50 equal e.g. 50% receptor occupation would cause 50% effect
122
why might a system said to have spare receptors
receptors can amplify signal duration and intensity which means only a fraction of total receptors for a specific ligand may need to be occupied to elicit maximal response from the cell
123
what is efficacy
describes the ability of an agonist to activate a receptor i.e. to evoke an 'action' at the cellular level.
refers to the maximum effect an agonist can produce regardless of dose
124
what is the efficacy and AR* like for a full agonist
high efficacy
| AR* very likely
125
what is the efficacy and AR* like for a partial agonist
low efficacy
| AR* less likely
126
how does a full agonist produce maximum response
by pushing eqm completely to the RHS while occupying only a small % of receptors available
127
why is a partial agonist unable to produce maximal response
even when occupying all available receptors it cant because it doesn't initiate the same signalling response a full agonist does. it falls short of maximal response the system is capable of producing
128
what does the maximum response in full agonists correspond to
the max response that the tissue can give
129
why are partial agonists beneficial
- if we dont want a max response as it may cause a problem if the full response is too large
- alleviates some of the side effects
130
what is an example of a treatment where a partial agonist is given
breast cancer treatment- giving a partial agonist will maintain the oestrogenic response but at a lower concentration
131
what is varenicline used for
nicotine receptor partial agonist for smoking cessation
132
what is tamoxifen used for
estrogen receptor partial agonists for use in estrogen dependent breast cancer.
133
what is aripiprazole used for
antipsychotic – partial agonists at selected dopamine receptors
134
why might a drug that we expect to act as a full agonist elicit the response equivalent to a partial agonist
depends on how the receptor reacts in response to the drug binding
135
what does the two state model predict
that a receptor can exist in two forms, AR and AR*
136
what is meant by constitutive activity
receptors can activate in the absence of ligand e.g. R*
137
what is the ternary complex model
```
there are 4 active states of the receptor
AR*
AR*G
R*G
R*
```
138
what is meant by RG
g protein turns the receptor on
139
what is meant by AR*G
dimerising with a G protein turns the receptor on, not the agonist
140
apart from receptors activating in the absence of a ligand (constitutive activity), what else does new evidence suggest
receptors can change state depending on GPCR function
141
what is meant by an inverse agonist
when you bind something with some level of activity it can turn down the signal of the receptor- not inhibitory and NOT ANTAGONIST!!
142
why do inverse agonists turn receptor activity down
they have a higher affinity for the AR(inactive) state than for the AR* (active state)
143
which classical competitive antagonists display inverse agonist activity
Cimetidine (H2), pirenzepine (M2), atropine (M)
144
what are examples of inverse agonists
β-carbolines on GABAA receptors – anxiogenic rather than anxiolytic
145
what do allosteric modulators do
they will change the affinity of a drug to a receptor
146
how do benzodiazpines act on GABAa receptors
BZ bind allosterically and enhances the effect of GABA
147
what effect do benzodiazapines have on KA and efficacy
increases KA for GABA
| increase efficacy of GABA
148
what are allosteric modulators- Positive (PAM)
not active aline but increase affinity and/or efficacy of endogenous agonists
149
what are examples of PAM
diazepam, propofol & isoflurane
150
what are allosteric modulators -Negative (NAM)
not active alone but decrease affinity and/or efficacy of endogenous product
151
what are examples of NAM
mGluR5 dipraglurant
152
what is desensitisation of receptors
effect of drug reduces with continual/repeated administration (tachyphylaxis)
153
what are the contributing factors to desensitisation of receptors
- Conformational changes in receptor
- Internalisation of receptors
- Depletion of mediators
- Altered drug metabolism
- Other physiological responses (homeostatic).
154
why is it difficult to measure how well an antagonist is working
because all its doing is stopping agonist
155
what receptor does the antagonist propanol bind to and what is its effect
B-adrenoreceptor
| decreases blood pressure
156
what are the general classes of antagonists
chemical
physiological
phramacological
157
what is a chemical antagonist and an example
Binding of two agents to inactive a drug (chelating agents)
| Example - protamine binds (sequesters) heparin
158
what is a physiological antagonist and an example
Two agents with opposite effects cancel each other out.
| Example – glucocorticoids and insulin
159
what is meant by an irreversible antagonist
binds with such strength receptor function doesn’t come back until the body produces new receptors
160
what can antagonists be categorised into
receptor antagonists (pharmacological) and non receptor antagonists (chemical and physiological)
161
what can receptor antagonists be split into
- active binding site (reversible & irreversible)
| - allosteric binding (reversible & irreversible)
162
why is allosteric binding non competitive
as long as you have the active site you can still have the main endogenous product binding to that receptor and turning it on, so its cannot be competitive
163
what type of antagonist is one that binds orthosterically and reversibly
competitive antagonist
164
what type of antagonist is one that binds orthosterically and non-reversibly
non competitive active site antagonist
165
what effect do antagonists have on efficacy
there will never be an active receptor so there wont be an efficacy for antagonist so AR* does not exist
166
what is a competitive antagonist
binds orthosterically and reversibly- prevents antagonist from binding
167
what shift on the agonist-response curve does a competitive antagonist cause
parallel shift to the right
168
how can a competitive antagonist be overcome
increased agonist concentration
169
what is a non-competitive (irreversible) antagonist
binds orthosterically to form irreversible covalent bonds with the receptor
170
what shift on the agonist-response curve does a non-competitive (irreversible) orthosteric antagonist cause
Causes parallel shift to right of the agonist-response curve and reduced maximal asymptote
171
what does a non-competitive allosteric antagonist cause
signal transduction rather than receptor effects
| downstream responses are blocked e.g. Ca2+ influx
172
what shift on the agonist-response curve does a allosteric non-competitive antagonist cause
reduces slope and maximum of dose response curve
173
why in the presence of a competitive antagonist does the curve have the same maximal response and the linear portions are parallel
the competitive antagonist binds reversibly with receptor which can be overcome by increased conc of agonist. the only difference is a shift to the right
174
how can the dose ratio be calculated with an agonist and antagonist
(agonist+antagonistEC50)/agonist EC50
175
what is the schild plot for competitive antagonist
How strong an antagonist is at inhibiting a receptor system
176
what does zero show on the schild plot
the conc needed to inhibit agonist by 50%
177
what is the equation for the schild plot
r-1=[B]/Kb
r=dose ratio
B=antagonist conc
Kb=antagonist dissociation constant
178
what do pA2 values show
describe the activity of a receptor antagonist in simple numbers
179
what is the relationship between pA2 and Kb
pA2=-logKb
180
when is the schild plot relevent
only if the relationship is linear and the slope of the schild plot=1
must be competitive antagonist
181
why is the dose ratio important for clinicians
- The extent of antagonist inhibition depends upon the concentration of the competing agonist which varies
- the extent of inhibition depends on the antagonist's conc (differences in metabolism or clearance influence plasma concs)
182
the dose response curve decreases, it wont hit 100%, for a irreversible antagonist, why is this
Putting in extra agonist will not bind to receptor due to antagonist binding
183
what does irreversible antagonism do to EC50
increases it
184
what is the duration of effect of irreversible antagonism related to
receptor turnover
185
what shift on the agonist-response curve does irreversible antagonism cause and why
right
| receptor reserves allow for this
186
why might the curve for irreversible antagonism be mistaken for competitive antagonism
looks like the same shift to the right however with irreversible there is a corresponding decrease in response
187
why are weak partial agonists also irreversible antagonists
they both prevented from reaching max asymptote
188
examples of competitive antagonists (most common)
cimetidine at the H2 receptor
| tamoxifen at the oestrogen receptor
189
example of irreversible antagonism (less common)
phenoxybenzamine at the a1 adrenoceptor
190
what effect does the non competitive antagonist have
blocks signal transduction events- stop receptor from having effect
E.g. Nifedipine bocks Ca2+ influx
191
what shift on the agonist-response curve does non competitive antagonism cause and why
reduces the slope and the maximal effect
| looks same as irreversible antagonist
192
what does the therapeutic index tell us
measure of risk benefit of drug
193
what is meant by a large therapeutic index
large range between the benefit of drug and its side effect
194
example of drug with large therapeutic index
penicillin
195
example of drug with small therapeutic index
warfarin
196
explain how warfarin has a small therapeutic index
Concentration range for anticoagulation is very close to the concentration range where you get side effects and the risk of bleeding.
197
why can the therapeutic index not be determined from a dose response curve alone
both the therapeutic effect and the toxic effect must be shown
198
why might a compound a compound show reasonable binding an then no result on the tissue response curve
its an antagonist- binds but has no effect
199
why might a large therapeutic index be beneficial
Clinicians can adjust the dose depending on the mass of the patient
Greater ability to manipulate drugs
200
how can you work out the potency from a binding graph and response graph
binding --> Ec50
| response--> lowest conc at which max response is achieved
201
what is the importance of being able to calculate pharmacokinetics parameters
can work out how much drug to give to patient
ensures dosage regimen results in correct plasma conc in all patients
indvidualise medication
202
how does a drug enter the plasma
Absorption
| Distribution (Tissues)
203
what does the absorption of drug involve
- transfer of exogenous compound (i.e. drug) from site of administration into system circulation
- crossing of cell membranes (passive and active)
204
what affects how rapidly compounds cross cell membranes
must be in solution
degree of ionisation (unionised absorbed better)
particle size/charge/solubility
205
what are the enteral routes of drug administration
oral
sublingual
rectal
vaginal
206
what are the parenteral routes of drug administration
```
Intravenous
Intramuscular
Subcutaneous
Transdermal
Inhaled
Intrathecal
```
207
where does the drug pass when its taken orally
stomach then small intestine
208
why is the oral route of absorption poor
stomach has thick membranes
| low pH so drugs destroyed
209
what drugs are absorbed in the Stomach
many drugs DO NOT get absorbed here
mainly weak acids
small amounts of aspirin, NSAIDS, alcohol
210
what controls the rate delivery of compounds to the SI (via sphincter muscles)
rate of gastric emptying
211
what is the site of absorption for the most exogenous compounds taken orally
small intestine
212
what compounds are best absorbed in the SI
preferentially weal bases
213
why are drugs more easily absorbed in the small intestine
large, highly permeable, vascularised surface area
214
what are the pH ranges in the SI
6(duodenum)
| 7.4 (terminal ileum)
215
what do the enterocytes of the SI contain
drug metabolising enzymes and transporters
216
what are the advantages of oral administration
safe
convenient
economical
217
what are the disadvantages of oral administration
```
irritant drugs cause sickness
not possible
vomiting patients
some drugs destroyed by gut acid/flora
intestinal absorption can be erratic
```
218
what factors affect GI absorption
gut motility
gut pH
physio-chemical interactions
particle size and formulation
219
how does gut motility affect GI absorption
decreased motility > decreased absorption (constipation )
220
how does gut pH affect GI absorption
poor absorption of strong acids and bases
221
how do physico-chemical interactions affect GI absorption
tetracycline binds to Ca rich foods
bile-acid binding resins may bind other drugs and inhibit absorption
another chemical to bind to a drug and prevent it reaching desired location (collate)
222
how does particle size and formulation affect GI absorption
slow or fast releasing
| resistant to coating
223
what is bioavailability
fraction of the administered dose which enters systemic circulation
224
what is first pass metabolism
occurs in both intestine and liver before drug reaches systemic circulation (drug can potentially degraded before it enters the systemic circulation
225
how can you measure the parameter of absorption
measure the area under the curve (AUC) with respect to time
226
what does the parameter of absorption estimate
biovavailability
227
what is the trapezoidal rule
area under each trapezoid multiplied by time then divided by the number of trapezoids
228
what is the bioavailability (f) for an IV drug and why
1
| it enters straight into the bloodstream
229
what is the bioavailability (f) for an extra-vascular dose e.g. oral
F<1
230
what are the limitations when using bioavailability
it does not consider individual variations (enzyme activity, gastric pH, intestinal motility
it does not consider rate of absorption
231
what are the parameters of absorption
Cmax and Tmax
232
what is Cmax
the maximum concentration of compound after administration
233
what is Tmax
time at which Cmax is reached
234
what is the advantage of sublingual administration
fast/rapid response
utilises venous drainage from the mouth to superior vena cava
avoids first pass metabolism
235
what are the advantages of rectal/ vaginal route
bypasses GI/hepatic first pass effects
rich blood supply
absorption may be rapid and extensive
useful when drug causes nasusea and vomiting or if patient is already vomiting
236
what is involved in the drainage from the rectum
middle and inferior rectal veins to systemic circulation
| superior rectal vein to portal
237
what are the advantages of intravenous administration
predictable, very rapid action
alternative route for drugs which are irritant by (im)
iv infusion for ill
238
what are the disadvantages for intravenous administration
difficult/pain
risk of infection
cost and safety
immediate adverse effects
239
what are the adv of subcutaneous/intramuscular administration
faster systemic effect than oral administration or local effect
kept within the peripheral tissue - more local effect
240
what is an ex of subcutaneous administration
local anaesthetic
241
when is absorption of a drug important
for all routes of administration except IV
242
what are the most important way drugs can cross cell membranes
passive diffusion through lipid
diffusion through aqueous channel
carrier mediated transport
pinocytosis- membrane invaginates something
243
what is an important determinant of absorption
lipid solubility
244
why do many drugs exist in ionised and unionised forms
they're weak acids(proton donor) or bases (proton acceptor)
245
what is the ratio of ionised: unionised determined by
pH
246
what does the degree of ionisation change with respect to
the pH of the solution - dependant on the pKa of the drug
247
what is meant by the pKa of the drug
measure of the strength of an acid/base
248
what happens when the pH of the drug = pKa
50% of the drug is ionised and 50% isn't
249
in what solution(pH) will an acidic drug need to be in to move across membranes easily and why
low pH as it will be unionised (if it was a high pH solution it would get ionised so not move across easily
250
how do you work out ionisation
do the pH minus pKa then read of the table
251
what is pH partitioning
acidic drugs accumulate in basic fluid compartments and vice versa
252
what is ion trapping
an acidic drug trapped in a basic environment so is too ionised to passively diffuse through the bilayer
253
what does distribution of a drug from the plasma into other tissues depend on
ability to cross cell membranes
blood flow to individual tissues
extent of its plasma protein binding
254
what happens equilibrium is reached between the systemic circulation and tissue
elimination process lower blood concs this lowering tissue conc
255
what is the half life in plasma also equal to
elimination half life from tissues
256
what is meant by drug distribution
the reversible transfer of drug from one location to another within the body
257
what physical structures does the drug have to pass to be distributed into the tissues
away from plasma proteins through the endothelium and into the interstitium and out into the tissues
258
what can slow down the drug distribution process into the tissues
plasma proteins and chelating agents can bind ot the drug slowing it down
259
what factors affect the rate of distribution
membrane permeability
| blood perfusion
260
what factors affect the extent of the distribution
lipid solubility
pH-Pka
plasma binding proteins
tissue binding protiens
261
how does a high molecular weight/high degree of binding to plasma proteins affect distribution
they tend to stay in the systemic circulation rather than distribute into tissues/organs
262
what are the key drug binding proteins in the plasma
albumin (HSA)
| Alpha 1 acid glycoprotein (AAG)
263
albumin is decreased in cirrhosis and malnutrition, why is this significant
can get a massive effect of the drug
264
what is the normal range of albumin
3.5-5 g/dL
265
when is Alpha 1 acid glycoprotein (AAG) elevated
cancer, inflammation
266
what is the normal range of - Alpha 1 acid glycoprotein (AAG)
0.4-1.1 mg/mL
267
which drugs are pharmacologically active
free (unbound drugs)
268
what does plasma protein binding do
increases difficulty of blood to get into the blood stream (drug bind reversibly though)
269
what does extensive plasma protein binding do and what are the therapeutic effects of this
slows drug action and elimination, prolonged therapeutic effects
270
how can tissues bind drugs
due to composition (lipid soluble drugs will accumulate in fat )
binding to cellular components (proteins, pigments, minerals)
271
why shouldn't tetracylines be used in children
they accumulate slowly in bones and teeth , have a high affinity for calcium
272
why does Chloroquine (an antimalarial drug) have high ocular toxicity
has a high affinity for melanin and is taken up by the retina, which is rich in melanin granules
273
what does volume of distribution do
Measure of the extent of distribution of drug, where in the body has that drug gone to in comparison to the volume of plasma that we have.
274
what does the dilution factor in Vd represent
relationship between the amount of compound in the body and the plasma concentration
275
how is Vd calculated
total amount of drug in the body/ drug blood plasma concentration
276
when will the Vd be small
when drugs are confined to plasma
277
when will the Vd be large
drugs accumulate outside the plasma e.g. by being stored in fat,
278
how does Vd help us calculate drug dose
plasma conc of a drug defines dose
279
how is plasma conc affected by Vd
low Vd- confined to plasma so high plasma conc
| high Vd- in peripheral tissues so low plasma conc
280
why do drugs distributed throughout body water readily cross cell membranes (high Vd)
they're lipid soluble e.g. phenytoin ethanol
281
why do drugs distributed in the extracellular compartment not easily enter cells (low Vd)
they have low lipid solubility e.g. gentamicin
282
why do drugs that are confined to the plasma compartment not cross capillary wall easily (low Vd)
too large e.g. heparin
283
why do drugs that accumulate outside of the plasma compartment easily cross cells (high Vd)
bound to tissues or stored in fat e.g. chloriquine, tricyclic antidepressants
284
what is enterohepatic recirculation (HER)
drugs that are eliminated in the bile can be absorbed in the GI tract
285
what are some drugs that undergo some degree of EHR
morphine, erythromycin, oral contraceptives, lorazepam
286
when a drug get back through the bile where does it go
stored in gall bladder and released into duodenum, can get metabolised again (enterohepatically recircualted)
287
how is HER shown graphically
as a smaller secondary peak
288
what is bioavailability
fraction of the administered dose which enters the systemic circulation
289
what is elimination
metabolism + excretion
290
what are the major excretory organs
kidneys
hepato-billiary system
lungs
291
what happens to lipophilic drugs prior to elimination
must be made more water soluble (this is the opposite of the drug getting into the body where its better if its more lipophilic!!)
292
what is metabolism
making the drug more hydrophilic so it will be removed more easily
293
what is the major site of metabolism for most drugs
the liver
294
what is involved in phase 1 of drug metabolism
activation of the drug- increasing the pharmacological activity of that product by adding on functional groups making it more hydrophilic
295
what is involved in phase 2 of drug metabolism
adding on by conjugating with another chemical/compound making the drug more hydrophilic
296
what chemical reactions do phase I reactions usually consist of
oxidation (most common)
reduction
hydrolysis
297
what are the cytochrome P450 enzyme family (CYPs)
a family of enzymes containing heme as a cofactor
298
what do P450s usually do
introduce/expose a functional group e.g. OH and decrease lipid solubility (which may in turn increase pharmacological/toxicological activity
299
what are phase 1 reactions important for
activation of pro-drug
300
what does the iron in the heme in CYPs allow for
allows group of enzymes to have a REDOX reaction
301
what are individual members of CYPs referred to as
isozymes
302
what are the main locations for CYPs
intestinal enterocytes and liver hepatocytes
303
where are there a small amount of CYPs
in the kidney, white blood cells and nasal passages
304
regardless of the organ/tissue, where in the cell are CYPs located
in the endoplasmic reticulum
305
what is involved in the basic reaction of a CYP
the addition of O2 and NADPH giving an oxidised form of the drug
306
what are most drugs in phase 1 metabolised by
CYPs
307
what compound is the exception to CYPs metabolising phase 1 reactions
ethanol metabolism
308
what is ethanol metabolised by (2 steps)
alcohol dehydrogenase to acetaldehyde
| acetaldehyde to acetic acid by aldehyde dehydrogenase
309
how can consumption of alcohol when on antibiotics cause hepatocyte damage
aldehyde dehydrogenase cannot be properly broken down so there is an accumulation of acetaldehyde
310
what is first order kinetics in drug metabolism
when the rate of elimination of drug is proportional to how much drug is in the body
311
what is involved in phase II metabolism
conjugation reactions where functional groups serve as a point of attack
312
what does adding of conjugate do
decreases pharmacological activity
313
what are the groups that can be conjugated in phase II reactions
glucuronyl, sulphate, acetyl
314
what is the most common conjugation reaction
glucuronidation reaction
315
what enzyme does glucuronidation require the addition of
transferase
| - UDP glucuronyl transferases
316
why are glucuronides usually pharmacologically inactive/rapidly excrete
due to their polar nature
317
how is paracetamol metabolised
mainly by conjugation with sulfate and glucuronic acid
only a small portion by CYP450 to a toxic metabolite (NAPQI)
318
how is the toxic metabolite of paracetamol detoxified
by glutathione (another phase 2 reaction)
319
what does NAPQI do
binds to hepatocytes and cause oxidative damage to cells
320
how is NAPQI removed
it is conjugated to eliminate the mercapturic acid from the body
321
how does alcohol affect NAPQI
it increases the amount of enzyme working to produce NAPQ
322
what happens in a paracetamol overdose
pathways of conjugation are saturated and co-factors are depleted, much more paracetamol is metabolised via CYP450
323
what happens to glucornic acid stores in paracetamol overdose
they're depleted
| less sulfation occurs
324
how does hepatic necrosis occur in paracetamol overdose
more paracetamol is metabolised by CYP450 due to depletion of glucornic acid. this route of metabolism produces more NAPQ which is toxic causing tissue damage leading to hepatic necrosis
325
what is excreted via renal excretion
urine, bile, lung, milk and sweat
326
what drugs are rapidly cleared from the blood (1 nephron transit)
penicillin
327
what drugs are slowly cleared from the blood
diazepam
328
what are the 3 major processes of renal excretion
glomerular filtration
tubular resorption
tubular secretion
329
how are water soluble drugs/metabolites excreted
excreted unchanged through the kidneys
330
how are lipid soluble drugs excreted in the kidneys
```
reabsorbed by bowmen's capsule
filtered in the glomeruli
reabsorbed on the distal portion of nephron
metabolised to more polar compounds
excretion in urine
```
331
what is the rate limiting step in glomerular filtration
size
332
what molecular weight drugs diffuse into glomerular filtrate
<20,000
333
why is plasma albumin completely held back from glomerular filtrate
68,000
334
why are highly protein drugs found at lower concs in the filtrate than plasma
because they have a high molecular weight so do not diffuse into the filtrate e.g. warfarin 98% ppb conc in filtrate and 2% in plasma
335
how do high molecular weight drugs enter the filtrate
have to undergo more metabolism
336
what factors do not affect GF
lipid solubility and pH
337
what does the rate of entry into the GF depend on
conc of drug in plasma
| molecular weight
338
where does active tubular secretion take place
proximal convoluted tube
339
what are the 2 carrier systems that can transport against an electrochemical gradient
acidic drugs and endogenous acids (penicillins and uric), organic bases e.g. morphine
340
how can active tubular secretion lead to competition between drugs
many drugs share the same transporter which can lead to competition
341
what does the volume of urine roughly equate to
1% of the filtrate
342
what occurs in passive diffusion
drug conc increases as water is reabsorbed
highly lipid soluble drugs have high tubular permeability and slowly excreted
high water soluble drugs have low tubular permeability and concentrate in urine (become trapped in the collecting duct)
343
what does the extent of absorption depend on
```
drug solubility (i.e. pKa)
pH of tubular fluid
```
344
what happens to the drug if the fluid becomes more alkaline
acidic drug ionises - less lipid soluble and reabsorption diminishes
basic drug un-ionises - more lipid soluble and reabsorption increases
345
what does it mean for the drug if it is reabsorbed more
it is held in the body for longer
346
for weak bases when is ionisation greatest
at acid pH
347
for weak acids when is ionisation greatest
at alkaline pH
348
what does pH partition impact
the rate at which drugs permeate membranes and distribution of drug between aqueous compartments
349
where do weak acids accumulate
accumulate in compartments of relatively high pH, whereas weak bases tend do the reverse
350
what conditions is a compound more rapidly excreted
in alkaline urine
351
what will urinary acidification do
accelerate excretion of weak bases and vice versa (important in overdose) - ion trapping
352
what does elimination mechanisms depend on
physiochemical properties of the compound
353
how are volatile gases eliminated
exhalation
354
how are water soluble compounds eliminated
urine
| maybe in bile
355
when will elimination mechanisms be saturated at a therapeutic dose
phenytoin
356
why does saturable elimination occur
increasing the dose will disproportionately increase concentration
357
what is clearance (CL)
elimination parameter
| -Ability of eliminating organs to remove a compound from the body per unit time
358
what is total body CL
sum of all organ CL processes
| i.e. Total CL = Hepatic CL + Renal CL + all other CL
359
what may CL be defined as
the volume of plasma (or blood) cleared of the compound per unit of time (typically expressed as L/hr in clinical pharmacokinetics, but can be any volume/time)
360
equations for CL - iv dose
L=IV Dose/〖IV AUC〗_(0→∞)
361
eq for CL- oral dose
L=(Oral dose×F)/〖Oral AUC〗_(0→∞)
362
how else can CL be calculated
CL = Ke x Vd
363
what does zero order kinetic mean
straight line - independent of how much you have e.g. alcohol
364
what does first order kinetic mean
depending on how much drug you give you will get a curve deepening on how much you give
365
how can Ke be determined
the slope of the line
366
how can elimination be calculated graphically
steepness of curve
367
what is the half life
Time it takes for concentration of drug in body to half
| • Units are time
368
what is the rule of thumb for the half life
It takes 5 half-lives for a compound to reach steady-state (rate in=rate out) after chronic exposure (no therapeutic drug present in the body) – its at the right concentration in the body
369
what do additives include
```
o pharmaceutical products
o cosmetics
o food additives
o industrial chemicals
o pesticides
o smoking
o alcohol
```
370
how do chemicals affect drugs
theyre an important factor in the pertubation of drug metabolising enzymes
371
what are 2 important mechanisms by which drug interactions occur
induction and inhibition
372
what is involved in the induction of drug metabolising enzymes
increased synthesis of enzymes (phase I and II)
| resulting in increased metabolism of inducing agent and/or other drugs
373
what are examples of drugs that act as inducers
rifampicin, carbamazepine and ethanol
374
what are enviro factors that can act as inducers
smoking and ethanol
375
what are the implications of induction
decreased drug effectiveness on chronic exposure
need to increase drug dose
multiple drug therapy - may be problems when inducer is withdrawn from regimen
376
how can inhibition occur
through inhibition of CYP system by drugs
377
what does inhibition result in
reduced rate of metabolism and increased pharmacological effect
378
does alcohol act as an inhibitor or inducer
both depending on the CYP
| ethanol act acutely to inhibit drug metabolism however
379
what is an adverse drug reaction
a harmful or seriously unpleasant event occurring at a dose intended for therapeutic effect and that calls for a reduction of the dose or withdrawal of the drug (not the same as a side effect)
380
what must drug safety take into account
the severity of the drug reaction
the disease
the therapeutic alternatives
381
what are the features that suggest a cause and effect relationship between drug administration and adverse drug reaction (e.g. if the drug causes the adverse d.r or its the patient
time sequence between taking the drug and adverse reaction
the reaction corresponds to the known pharmacology of the drug
the reaction stops on cessation of the drug
the reaction returns on restarting the drug
382
how can adverse drug reactions be monitored
MHRA- Medicines and Healthcare products Regulatory Agency
Yellow card filled out when suspected adverse reaction occurs in a patient
accumulate the evidence for/against adverse reaction
MHRA analyses this data
383
what is a side effect and why is different from an adverse reaction
They are not adverse drug reactions
Happens in a therapeutic way- the more drug, the more the side effect
Unavoidable consequence of drug administration
384
what occurs in a secondary adverse effect
Side effect that’s indirect- the original drug has caused something happening in the body with has caused an increased effect of something else in the body
385
what are risk factors that increase the chances of ADRs
```
Age
Sex
Medical history
Disease
Current medication
Ethnicity
```
386
how does age increase the chances of ADR
more expression of p450s
elderly have increased medication
pharmacokinetic factors
drop in GFR
387
how are younger children susceptible to difference in pharmacokinetic factors thus increased chances of ADR
neonates -below 6 months old- have poor glomerular filtration rate
Children above 6 months does not have many phase 2 enzymes (conjugating enzymes) are not able to change the drug. Drugs aren’t made hydrophilic so cannot be removed as easily.
388
how does sex increase ADR
Females more susceptible -pharmacokinetic factors and hormonal influences
389
how does medical history increase ADR
If ADR to one drug will be more likely to experience ADR to another drug.
If you’ve had one adverse drug reaction you’re likely to have another
390
how does disease increase ADR
Pharmacokinetic factors e.g. liver disease that influences with metabolic process increases risk
391
how does ethnicity increase ADR
intrinsic
- pharmocokinetic factors (metabolism)
- pharmacodynamic- expression of drug in the body
extrinsic
-alcohol, diet and smoking
392
what are the classification of adverse
augmented pharmacological effect- adverse effect that is known to occur from the primary pharmacology of the drug and is usually dose depend.
bizzare effects- adverse effect that are unpredictable from the pharmacology of the drug
chronic effects- occur as a result of chronic treatment of the drug
delayed effects- occur remote from treatment, either in the children of the treated patients or in the patient themselves
end of treatment effects- adverse effect occur as a result of stopping the treatment
393
what is augmented pharmacological effect
heightened response based on what you would have expected based on the pharmacology of that drug
Increased, more severe (augmented) form of physiological response than predicted
394
what are examples of augmented pharmacological effect
Bradycardia from propanol treatment with Beta blocker
- -The primary pharmacology of the B-blocker is to decrease heart rate, however if the dose is too high they can cause life threatening bradycardia (heart rate too low)
Hypoglycaemia from insulin injection
Tachycardia from muscarinic antagonist ipratropium
Common/low mortality - recoverable, withdraw of drug typically will removed adverse drug reaction
395
what are muscarinic antagonists known as
parasympatholytic
396
how does Tachycardia from muscarinic antagonist ipratropium (used for asthma- brown inhaler) occur
Tachycardia from muscarinic antagonist ipratropium (used for asthma- brown inhaler)
- Ipratropium - non-specific antagonist
- Not expecting the drug to get into the systemic circulation - if it does because it ca bind to all Muscarinic receptor’s it can bind to receptors on heart and give you tachycardia
397
what are the effect of parasympathetic activation
pupils constrict
lens of eye readjust for closer vision
airways in the lungs
constrict
heart rate decreases
blood vessels to limb muscles constrict
blood vessels to visceral organs more dilated
salivary secretions normalise
398
what is the effect of muscarinic antagonists on pupils
pupils dilate (relax of constrictor papillary muscle blurred vision)
increase in focal length of the lens (relax of ciliary muscle)
bronchodialation
increase in cardiac output
decrease in GI motility
decrease in exocrine gland secretion
399
what drugs cause the adverse drug reaction and/OR therapeutic effects shown below
- pupil dialtion
- bronchodialtion
- increased heart rate
- decreased gut motility
- decreased exocrine secretions
pupil dialtion
- ADR-atropine
- TE-tropicamide
bronchodilation
-TE-ipratropium
IHR
-ADR- ipratropium
DGM
-TE- hyoscine
DES
- ADR- iprapropium
- TE- atropine
400
what is type 2 ADR and what are examples
Unpredictable, usually have caused patient death
Examples;
•Anaphylaxis due to penicillin (beta-lactan antibiotic- breaks down structural wall of bacteria, no association with the immune system)
•Bone marrow suppression due to chloramphenicol
401
what is Northwick park clinical trial
•Phase 1 clinical trial – autoimmune, thought to be effective for leukaemia treatment
```
•ADR’s included:
Decreased blood pressure
nausea
pain
soft tissue damage (gangrene)
multi-organ failure
```
* Excess cytokine release – ‘cytokine storm’
* Super agonist- stimulated immune system so much that it effect every cell in the body
* Indiscriminate immune response
402
what is type C ADR and examples
Chronic effects (occur after prolonged treatment)
Examples
-latrogenic Cushing syndrome from chronic glucocorticoid therapy
403
what is type D ADR and examples
effects occur remote from treatment or in child of treated patient)
Examples
•Diethylstilbestrol given to pregnant mother (1940-70) results in a high incidence of vaginal cancers in offspring in their 20s
•Isotretinoin (accutane) causes birth defects
Vitamin A is a key teratogen in bone malformations of the baby
•Second cancers in response to Hodgkin’s disease treatment
404
what is type E ADR and examples
End of treatment effects (withdrawal)- should normally be different from normal course of the disease
examples
•Adrenal insufficiency after glucocorticoid therapy
•adrenal gland shrink cannot produce as much cortisol
405
what is Adrenal atrophy in response to glucocorticoid treatment
• Exogenous glucocorticoids used for anti-inflammatory or immunosuppressive therapy act on the HPA axis negative feedback system and over a period of time cause adrenal atrophy (cant switch off anymore)
On termination of treatment the atrophied adrenals cannot produce enough cortisol so this results in adrenal insufficiency
406
what is adverse drug interactions (ADI)
When one drug modifies the action of another drug.
| The modification can take the form of potentiation or attenuation
407
what the types of ADI
Pharmacodynamic interaction
| Pharmacokinetic interaction
408
what is Pharmacodynamic interaction and example
similar or opposing pharmacological effects
-Ethanol increasing the sedative effect of antihistamine drugs or certain antidepressants
409
what is Pharmacokinetic interaction and examples
one drug interferes with disposition (e.g. metabolism or excretion of drug) of the other
- Monoamine oxidase inhibitors blocking metabolism of dietary amine,
- Many drugs can inhibit CYP450 (e.g. fluvoxamine) so can interfere with metabolism of other drugs
410
what is carbamazepine metabolism
•anticonvulsive drug which needs to be metabolised into its active drug
Many drugs increase and decrease the activity of the active drug
411
why would there be different half lives for the same drug given to two different people
different metabolisms
412
why would there be different half lives for the same drug given to the same person just on separate occasions
other interactive agents (drugs) may have been taken. its acts as an INHIBITOR (inhibits drug metabolising enzymes)
413
what is meant when there is a biomodal distribution of pharmacokinetic parameters within a population
there are fast and slow metabolisers in the population
414
what are the characteristics of fast metabolisers
normal enzyme activity
lower plasma concentrations of the parent drug, higher concentrations of the metabolite
generally normal therapeutic response (therapeutic effect)
415
what are the characteristics of slow metabolisers
low enzyme activity
higher plasma concentrations of the parent drug, lower concentrations of the metabolite
may lead to exaggerated therapeutic response at normal doses
416
how do neonates have a reduced ability to metabolise drugs
have a low activity with regards to:
- CYPs, glucornyl transferase, N-acetyltransferase
- lack of conjugating activity is most important (lack of use of morphine labour)
417
how do the elderly have a reduced ability to metabolise drugs
activity declines slowly with age
- more variability in half-life of many drugs
- issues for drug development
- increased half-half of diazepam (memory impairment)
418
how to patient characteristics affect half life
Difference in CYP expression
Difference in phase 2 enzyme expression e.g. acetyl transferase
419
is the following statement correct:
| Drug A is said to have a greater affinity than drug B if drug A’s maximal effect is greater than that of drug B.
no. this is efficacy not affinity
efficacy is determined by Emax
420
is the following statement correct:
Drug A is said to be more efficacious than drug B if drug A produces its maximal effect at a lower concentration than drug B.
no this is affinity no efficacy
421
for which drugs is The intravenous route of administration is used
those Which may be easily altered in the acidic pH of the stomach.
