Basic Pharmacology theme 2 Flashcards
(408 cards)
1
Q
What is the sensory nervous system ?
A
afferent towards the spinal chord
2
Q
What is the autonomic nervous system ?
A
controls smooth muscle outside of voluntary control
efferetn
3
Q
What is the somatic nervous system ?
A
voluntary motor control
of skeletal muscle
efferent
4
Q
What are some sympathetic effects ?
A
pupils dilate lens adjusted fro far vision respiratory rate increases- bronchodialtion HR increaaes Blood vessels to muscles dilate blood vessels to organs constrict
5
Q
What are some parasympathetic effects ?
A
pupils constrict lens adjusted for close vision airways constrict HR and respiratory rate decrease saliva increaes
6
Q
What are the neurotransmitters in the sympathetic nervous system ?
A
preganglionic- acetylcholine
postganglionic- noradrenaline
7
Q
What are the neurotransmitters of the parasympathetic system ?
A
both preganglionic and postganglionic use acetylcholine
8
Q
Which neurotransmitters act on the somatic nervous system ?
A
acetylcholine acts on the NMJ
9
Q
What are the sympathetic system exceptions ?
A
sweat glands- acetylcholine in preganglionic
Adrenal glands- acetylholine in postaganglionic
10
Q
What are the fundamentals oof neurotransmission ?
A
synthesis storage release - exocyotic receptor interaction termination
11
Q
What are the steps in Ach synthesis ?
A
choline precursor made to Ach via choline acetyltransferase
12
Q
How is Ach stored and released ?
A
stored in vesicles
allows vesicular release in conjunction with action potentials
vesicles fuse with membrane and Ach released into synapse
13
Q
What is the receptor interaction of Ach ?
A
acts on receptors on post synaptic membrane
muscarinic or nicotinic
14
Q
How is Ach terminated ?
A
after acting on receptor
Ach disassociates via acetylcholinesterase into choline and acetate
15
Q
What are the 2 classes of Ach receptor ?
A
muscaranic
nicotinic
16
Q
What are muscarinic receptors ?
A
located on postganglionic parasymapathetic synapses
on parasmpathetic organs
GPCRs with slow response
17
Q
What are nicotinic receptors ?
A
neuronal type- acts on brain and autonomic ganglia
muscule type- acts on NMJ- excitatory
ligand gated ion channels - fast repsonse
18
Q
Where are nictonic receptors located ?
A
sympathetic, parasympathetic and somatic systems
19
Q
Where are muscuranic receptors located ?
A
present in parasympathetic system only
mainly parasympathetic fibers
20
Q
What will muscarinic agonists do ?
A
increase pupil cosntriction
contract ciliary muscle
decrease CO
increase GI motiity
21
Q
What are muscarinic agonists called ?
A
paraympathomimetics
22
Q
What do muscarinic antagonists do ?
A
increase CO
decrease GI motility
pupil dialtion
decrease sweating
23
Q
What are muscarinic antagonists called ?
A
parasympatholytics
24
Q
What are the clinical uses of muscarinic agonists ?
A
pilocarpine
treat glaucoma- build up of tumour in eye- agonist will lead to sphincter muscle contraction- increase drainage
treat xerostomia
25
What are the clinical uses of muscarinic antagonists ?
pupil dilation before surgery
decrease respiratory secretions before oral procedures
adjunct to anaesthesia
resucitation in bradycardia- increase HR
used in asthma to cause bronchodilation
motion sickness - decrease gut motility
26
Where are neuronal type nicotinic receptors located ?
parasymapthetic and sympathetic ganglia
agonists will bind to both systems leading too autonomic confusion
neuronal nicotinic agonists arent useful
27
What do neuronal nictonic antagonists do ?
lead to loss of sympathetic and parasympathetic reflexes
| neuronal antagonists dont have good therapeutuc value
28
Where are muscle type nicotnic receptors located ?
in the NMJ
29
What doe stimulation of a muscle type nicotinic receptor lead to ?
depolarisation
| skeletal muscle fibre contraction
30
What will a nicotnic muscle type receptor agonist do ?
causes initial depolarisation
| and EPP
31
What is a depolarising block ?
giving a synthetic muscle type muscarnic agonist means the drug is not metabolied rapidly by acetylcholinesterase
the fibre is persistently depolarised resulting in loss of further electrical excitability
it is used for paralysis before surgery
32
What will a muscle type nicotinic receptor antagonist do ?
hyperpolarisation
inhibition of EPPs
muscle fibre relaxation
33
Which drugs can effect Ach release ?
botulinum toxin
causes autonomic and motor paralysis
toxin is injected locally to treat muscle spasm and in botox
34
What does acetylcholinestarase do ?
metabolises Ach into choline and acetate
| termination of Ach
35
How can Ach termination be inhibited ?
an anticholinesterase
| incrases Ach transmission at parasympathetic postanglionic synapses
36
What is the effect of anticholinesterases at the NMJ ?
increase muscle tension
| twitiching and at large doses lead to depolarising block
37
Where in the PNS does NA act as a neurotransmitter ?
NA acts on postganglionic fibres of the sympathetic system
38
What is NA synthesis ?
precursor tyrosine
converted to DOPA by tyrosine hydroxylase
DOPA to DA by DOPA decarboxylase
DA to NA by DA beta hydroxylase in vesicle
39
What is the storage and release of NA ?
stored in vesicle until action potential
| release vesicles by exocytosis
40
What is NA receptor interaction ?
alpha or beta receptors
41
What is the termination of NA ?
taken back up
| NA converted to amines via monamine oxidase
42
What are the 2 classes of NA receptors ?
alpha
| beta
43
What are the alpha noradrenergic family of receptors ?
alpha 1
| alpha 2
44
Where are the alpha 1 and 2 noardrenergic receptors located ?
organs and targets of the sympathetic system
45
What type of receptor are the Alpha 1 and 2 noradrenergic ?
GPCR
| slow response
46
What are the beta noradrenergic receptors ?
3 types- Beta 1
| beta 2 and beta 3
47
Where are the beta adrenergic receptors located ?
effector organs and targets of the sympathetic system
48
What type of receptor are the beta adrenergic ?
GPCRs
| slow responses
49
What are sympathetic effects mediated by alpha 1 receptors ?
pupil dilation- radial muscle contracts
blood vessels to visceral organs and skin constrict
brain activity increases
50
What are the sympathetic effects mediated by the alpha 2 receptors ?
presynaptic receptors
negative feedback system for NA and other neurotransmitter release
NA released from the presynaptic synapse acts on terminal receptro on the presynaptic neurone
feedback turns off further NA
51
Do alpha 2 receptors only control NA release ?
no they can be autoreceptors affecting NA release from their own neurone
they can be heteroreceptors affecting Ach release from other neurones
52
What are sympathetic effects mediated by beta 1 receptors ?
HR increases
| force of contraction increases
53
What are sympathetic effects mediated by beta 2 receptors ?
bronchodialtion
cilary muscle relax - lens for far vision
blood vessels to limbs dilate
54
What are sympathetic effects medaited by beta 3 receptors ?
increase lipolyisis
| breakdown of TAGs to fatty acids
55
What are the effects of adrenaline ?
a noradrenergic agonist
1- given locally with LA- vasoconstriction- increase LA effects- injection as destroyed by stomach
2- intramuscular adrenaline to treat anaphlyctic shock
56
How can adrenaline be used to treat anaphlyactic shock ?
anyphalactic shock is cardio collapse and bronchospasm
it hits alpha 1, beta 1 and beta 2 receptors
alpha 1- smooth muscle constriction
beta 1- cardiac stimualtion
beta 2- bronchodialtion
57
What is clonidine ?
alpha 2 agonist
58
What do alpha 2 receptors normally do ?
inhibit further NA release via negative feedback
59
What are alpha 2 agonists used for ?
hypertension - stop noradrenerigc transmission
| also has central effect- for morphine withdrawal- stops more NA
60
What is dobutamine ?
beta 1 agonist
61
What do beta 1 receptors do ?
increased cardiac force and rate
62
What will a beta 1 receptor do ?
treat heart failure
63
What is salbutamol ?
beta 2 agonist
64
What do beta 2 receptors do ?
bronchodilation
65
What will beta 2 agonists do ?
lead to bronchodilation so use for asthma
66
What is clenbuterol ?
Beta 2/3 agonist
67
How was clenbuterol used ?
as a beta 2 agonist to treat asthma
| but shows affinity for beta 3 which leads to increased lipolysis which is a side effect
68
What is prazosin ?
alpha 1 antagonsist
69
What do alpha 1 receptors do ?
smooth muscle vasoconstriction
70
What will an alpha 1 antagonist do ?
block vasoconstriction
| used to treat hypertension as decreased vascular resistance
71
What is a side effect of using alpha 1 antagonist ?
orthostatic and postiral hypotension
| due to loss of sympathetic reflexes
72
What is tamuloson ?
alpha 1 antagonist
73
How can an alpha 1 antagonist treat urianary problems in prostate hyperplasia ?
block vasconstriction leading to relaxation of smooth muscle
74
What is propanolol ?
beta 1 and 2 antagonist
75
What do beta 1 receptors do ?
increase CO
76
What do beta 2 receptors do ?
mediate bronchodilation
77
What can we use beta 1 antagonists for ?
to decrease CO in angina
| in hypertension
78
What is the effect of blocking beta 2 receptors ?
would lead to bronchocosntriction - not useful and fatal in asthmatics
79
What is atenolol ?
beta 1 antagonist
80
What do beta 1 receptors mediate ?
increased CO and force
81
What will a beta 1 antagonist do ?
treat angina and hypertension
82
What is the problem with beta 1 anathonists ?
removal of the antagonist can cause hypersensitivty
| as receptors are supersensitive
83
What is timolol ?
beta 2 antagonist
84
What can we use beta 2 antagonists for ?
treat glaucoma
| antagonism will lead to ciliarmy muscle contraction and reduced intraocular pressure
85
What is the symapthetic innervation of salivary glands ?
alpha 1
beta 1
beta 2
86
What is the indirect innervation of salivary glands ?
vascular adrenergic
87
What do beta 1 receptors in saliva glands lead to ?
stimulate protein secretion
88
What do alpha 1 receptors in saliva glands lead to ?
water electrolyre secretions
89
What does clonidine do ?
inhibits NA release leading to xerostomia
90
How can we use drugs to affect NA synthesis ?
```
can use false substrate of meDOPA
leads to meDA via DOPA decarboxylase
leads to meNA by DA beta hydroxylase
meNA has lower affinity fot NA receptors
decrease in NA transmission- use for hypertesnion
```
91
How can we use drugs to effect NA storage ?
reserpine disrupts storage of NA in synaptic vesicles
less NA available for release- treat hypertension
lots of side effects tho
92
How can we use drugs affecting NA release ?
NA release subject to inhibitory control by presynaptic alpha 2 receptors
clonidine is alpha 2 agonsit- inhibit NA release
treat hypertesnsion
93
How can we use drugs to effect NA uptake ?
termination of NA action happens via reuptkae
NA uptake blocked by uptake inhinitors
prolongs action of NA in synapse
Reboxetine
94
How can we use drugs affecting NA metabolism >?
NA degraded to amines via monoxamine oxidase
block MO so more NA for release availble
blocker of MO- tranylcypramine
95
What is the problem with MO inhibitors ?
block amine metabolism
amines not degraded
displace NA from the terminal sympathetic system
excess NA released - hypertension
96
What are noxious stimuli sensed by ?
nociceptors
97
What is nociception ?
the process by which noxious stimuli are transmitted to the CNS
98
What is pain ?
a combination of sensory and emotional componenents
99
How are most nociceptors triggered ?
by chemical stimuli
100
Which stimuli cause actue pain ?
thermal and mechanical
101
What does a primary neuron do ?
stimulus acts on a primary neuron which goes to the dorsal horn of the spinal chord- synapses in the layers of the dorsal horn
102
What are the afferent pain fibres ?
C fibres
A delta
A beta
103
What are the properties of C fibres ?
Non myelinated - low conduction velocity
Nociceptor/thermo and mechanoreceptor
dull pain- synpase in upper layers of the dorsal horn
104
What are the properties of A-delta fibres ?
myelinated
rapid conduction velocity
nociceptor/mechanoreceptor
sharp pain
105
What do secondary neurones do ?
to the thalamus via the brainstem
106
What do teritiary neurones do ?
from the thalamus to the cingulate cortex, limbic system and the somatosensory cortex
107
What are the descending pathways that tun off the noxious response ?
limbic system
periaqueductal grey
rostral ventromedial area
108
What are chemical mediators ?
substances that stimulate the pain endings in skin
109
What are examples of chemical mediators ?
5-HT
Bradykinin
metabolites of intermediate metabolism- lactic acid
capsacnin
110
What are eicosanoids ?
substances like prostaglandins, prostacyclins which are inflammatory mediators that enhance the pain producing effects of other agents
111
How do the eicosanoids work ?
they increase the sensitivity of pathways to bradykinin
112
What effect does Nitric oxide have on pain transmission ?
nitric oxide increases C fibre activity
113
Which molecules increase C fibre activity ?
Chemical mediators
NGF
Neuropeptides
114
What are NGFs, mediators and neuropeptides a result of ?
inflammation
115
What is the role of enkephalins and GABA ?
reduce pain transmission
116
What is the basic mechanism of NSAID action ?
reducing the chemical mediator release
117
What do opioids do ?
stop neuropeptide release
118
What do opiates do ?
increase the descending inhibitory pathways
| through 5-HT and NA
119
What are the properties of NSAIDs ?
analgesic
anti inflammatory
anti pyretic
anti platelet
120
What does anti pyretic mean ?
can decrease elevated body temeperature
121
What is the mechanism of NSAID action ?
inhibiting prostaglandin (an ecosanoid) production by inhibitng COX fucntion
122
What is COX ?
cycloxygenase
123
What are the 2 forms of COX ?
COX1- enzyme expressed in most tissue
| COX 2- induced in activated inflamamatory cells
124
What do NSAIDs do to the 2 forms of COX ?
therapeutic effects of NSAIDs are due to inhibition of COX2
| Unwanted effects of NSAIDS are due to inhibition of COX1
125
Why is COX2 easy to target ?
due to its structure
| has a large side pocket which can be bound to by functional groups
126
What is the prostaglandin synthetic pathway ?
```
phospholipids in the membrane
phospholipase A2
arachidonic acid- ecosanoids
COX
intermediates
ecosanoids
```
127
What are 3 examples of NSAIDs ?
aspirin
ibuprofen
paracetamol
128
How does aspirin work as an analgesic ?
decreased prostanoid synthesis
| less sensitisation of nociceptors to mediators
129
What are the characteristics of aspirin ?
analgesic
anti inflammatory
anti platelet
anti pyretic
130
How does aspirin reduce temperature in a fever ?
prostaglnadins produced by pathogens alter the thermostat
| aspirin decrease prostalglandins synthesis and changing of the thermostat
131
What is the ADME of aspirin ?
oral
hydrolysed rapidly by esterases
short half life- give in high doses
interactions with warfarin can prevent drug metabolism
132
What are the characteristics of ibuprofen ?
anlagesic
| anti pyretic
133
What is the ADME of ibuprofen ?
oral, topical and rectal
| rapid absorption
134
What are the characteristics of paracetamol ?
analgesic and anti pyretic
135
What is the ADME of paracetamol ?
safe and effective at a therapeutic dose
oral, rectal or IV admin
quick C max so need regularly
136
What are the cautions with paracetamol ?
hepatotoxicity in alcohol overdose
137
What are the forms of opioids ?
morphine analogues
| synthetic derivatives
138
What are opioid neurotransmitters ?
enkephalins
endorphins
dynorphins
139
What are the 3 types of opioid receptors ?
U
delta
K
140
What is the U opioid receptor reesponsible for ?
analgesic effects of opioids
141
How do opioid analgesiscs act ?
agonists of the U receptor
stimulate receptor though GPCR
inhibit adenylyl cyclase
hyperpolarisation leads to reduced excitability
142
What are the therapeutic effects of opioids ?
analgesia
euphoria
sedation
143
Why do opioids have to be given in high doses ?
have extensive first pass metabolism
144
What do we use strong opioids for ?
morphine
| moderate/severe pain
145
What do we use weak opioids for ?
cough suppressive
moderate pain
diarrhoea
146
What are the adverse CNS effects of opioids ?
drowsiness
sedation
respiratory sedation
nausea
147
What are the adverse effects on the PNS of opioids ?
constipation
histamine release
pinhole pupils
148
What is morphine used for ?
most valuable fro severe pain relief
| terminal care
149
What is pethidine used for ?
rapid onset
| more lipid soluble than morphine
150
What is dextropropxyphene used for ?
mild analgesic
| use with aspirin and paracetamol
151
What is dyhydrocodeiene ?
similar to codeine but more side effects
152
What is tolerance ?
subjects reduced reaction to a drug following repeated use
semsitivity can return after withdrawal
might need to increase dose to have therapeutc effect
153
What is dependence ?
following abrupt withdrawal after chronic treatment
| abstinence syndrome after acute treatment
154
What do anaesthetics do ?
prevent pain for a limited period of time for surgical procedures
155
What are local anaesthetics ?
prevent localieed pain and prevent tactile sensation
156
What are general anaesthetics ?
induce loss of consciousness and prevent pain
157
What are the 2 classes of general anaesthetics ?
inhaled
| intravenous
158
What are examples of inhaled GA ?
halothane
| nitrous oxide
159
What are examples of IV GA ?
thiopental
| etmodiate
160
What are the 2 theories of GA action ?
ion channel theory
| lipid theory
161
What is the lipid theory ?
strong relationship between the potency of the A and t the lipid solubility
A interact with the lipid bilayer leading to membrane expansion and inability of the membrane to signal
162
What is the ion channel theory of GA ?
anaesthetics have different affinities for different types of receptors
163
Which receptors do GA have an affinity for ?
GABAa receptors- these are inibitory receptors that GA act as agonists for
affinity for the excitatory receptors as anatgonists
164
How is the depth of anaesthesia determined ?
concentration in the bran and spinal chord
165
What is the blood/gas coefficient ?
measure of blood solubility
low- rapid induction and recovery
high- slow induction and recovery
166
What is the oil/gas coefficient ?
measure of lipid solubility
determines the potency as the brain has a high lipophilicity
lower solubility less potent
167
How does vascularisation effect anaesthetics ?
determines the level of A in the tissue
brain has high vascularisation so high levels of anaesthetic
body fat- low vascularisation means A doesnt accumulate in fat- problems with obesity and A
168
How does ventilation rate effect A ?
effects removal
| some A can cause respiratory depression
169
Are inhaled A metabolised ?
not entirely
| metabolism can lead to hepatotoxicity and nephrotoxicity
170
What are the side effects of inhaled A ?
```
malignant hyperthermia
cardiovascular
decreased respiration
hepatotoxicity
nephrotoxicity
```
171
What are IV Anaesthetics ?
thiopental
etmomidate
ketamine
propofol
172
How do thiopental and etomidate work ?
acts on the GABAa receptor
inihibitory NT released- hyperpolarisation
reduced excitabilty
173
What are the benefits of etomidate ?
wider TI between anaesthesia and respiratory depression
rapidly metabolised
quick recovery
174
How does Propofol work ?
acts on GABAa receptor
an agonist
rapidly metabolised by plasma esterase
daycare
175
How does ketamine work ?
on the NMDA receptor - excitatory
as an antagonist
rarely used due to hallucination and psychosis
176
How can neurones alter their membrane potential ?
voltage gated sodium channels
| crucial for initiation and propagation of APs
177
What is the structure of a voltage gated sodium channel ?
3 subunits
hydrophobic sensors
change orientation when voltage varies
orientation controls opening and closing of pore
178
How does LA interact with the voltage gated sodium channel ?
interact with the alpha subunit - plug the transmembrane pore and block sodium from entering
179
Where does LA bind to in the sodium channel ?
area located in the inner end of the channel
| need intracellular access
180
In which form can LA only bind to the binding area ?
ionised and hydrophobic form
181
Why is their problem with LA entry ?
needs to be unionised to pass lipid bilayer
| needs to be ionsied to bind to area
182
How is the LA entry problem overcome ?
most anaesthetics are weak bases
pH outside is 7.4- unionised can enter the neurone
inside the pH drops and LA now ionised and can bind to area
183
What is the general structure of LA ?
aromatic group
ester/amide
amine
184
What is the function of the LA aromatic group ?
lipid solubility
185
What is the function of the LA ester/amide group ?
duration of action is limited by hydrolysis of this drug
186
What is the function of the amine group ?
basic- allowing ionisation
187
How are esters metabolised ?
by plasma esteraes
| LA with ester groups have short half life
188
How are amdies metabolised ?
in the liver
CYP
leading to longer half life
dont use amides in liver failure patients
189
How is LA adminstered ?
weak base
injected as hypochlorite solution in salt
dissolves in solution quicker
190
How can we manipulate LA ?
restrict site of action with adrenaline- alpha 1 receptors leading to local vasoconstriction
accelerate the speed of onset using an alkaline solution - assists with absorption into nerve tissue
191
Which type of axon does LA work most effectively in ?
small
192
What is the order of axon LA sensitivity ?
small myelinated > non myelinated > large myelinated
193
What size are nociceptive and motor fibres and what is the significance of this ?
nociceptive- small- sensitive
| motor- large- less sensitive
194
What are the side effects of LA due to ?
escape into systemic circulation
inhibition of sympathetic activity
inhibition of sodium conductance in cardiac tissue
195
Why is LA not effective in inflamed tissue ?
ionised straight away due to acidic environment
196
What is chemotherapy ?
elimination of invading cells and microorganisms
197
What are chemotherapic targets ?
mechanisms associated with invading species
198
What are effective chemotherapic agents ?
are toxic to invading cells and non toxic to host cells
199
What is selective toxicity ?
exploiting differneces between species to use therapeutically
Distributonal toxcity - drug accumulates in certain areas can be difficult to control if systemic
200
What are examples of invading cells that can be selectively targeted ?
neoplastic cells
bacteria
fungi
viruses
201
What are the 2 reasons for antibiotic use ?
treatment and prophylaxis
202
What is antibiotic prophylaxis ?
prevent infection following surgery
| antibiotics given beforehand to high risk patients
203
Which 2 amino acids does transpeptidase join ?
glysine and lysine
204
What are the subunits of prokaryotic ribosomes ?
50s and 30s
205
What are the subunits of eukaroyte ribosomes ?
60s and 40s
206
What is the mode of action of tetracycline ?
stops tRNA binding to the smaller 30s sub unit
| this prevents elongtion
207
What is the mode of action of erythromycin ?
binds to 50s subunit and prevent translocation- movement of the mRNA along the ribosome
208
What type of antibiotic are tetracycline and erythromycin ?
macrolides
209
What is the mode of action of fluoroquinolones ?
target topoisomerase II
| DNA gyrase
210
What are other ways to target bacterial nucleic acid synthesis ?
inhibit synthesis of nucleotides
alter base pairing of DNA template
inhibit DNA/RNA polymerase
inhibit DNA
211
What are some examples of herpes virsues ?
herpes simplex
varicella zoster
epstein barr- glandular fever
212
What is the mode of action of herpes virus ?
re stimulated in sensory ganglia by external stimuli and replicate- often around the mouth
213
What is an antiviral agent that shows selective toxiciyt ?
aciclovir
214
What is the structure of aciclovir ?
synthetic guanosine analogue - nucloetide structure
215
What does aciclovir have a high specificity for ?
herpes simplex
216
What are the properties of aciclovir ?
high therapeutic index
| prodrug- needs to be activated via intracellular phosphorylation to become active
217
Describe the metabolic activation of aciclovir ?
aiclovir enters HSC infected cell
phosphorylated once- monophosphate aciclovir bia Herpes simplex thmidine kinase
cellular kinase adds more phosphates
218
Which form of aciclovir shows antiviral function ?
triphosphate aciclovir
219
What is the mode of action of aciclovir triphosphate ?
DNA chain terminator
| inhibitor of viral DNA polymerase
220
What are fungal infections ?
superficial- candidosis, dermatomycoses
| systemic- systemic candidiasis in immunocompromised patients
221
Why has there been an increase in fungal infections recently ?
widespread antibiotic use
| increase in immunocompromised individuals
222
What do fungal cell membranes contain ?
ergesterol
223
What are the 3 classes of anti fungal agents ?
azoles
polyenes
mitotic inhibitors
224
What is the mode of action of azoles ?
affect membrane lipid synthesis
blocks 14 alpha demethylase
needed in synthesis of ergesterol
225
What does a decrease in ergesterol lead to ?
inhibition of replication
effects membrane functions
increased permeability
226
What are the subclasses of the azoles ?
imidazoles- ketocozanole, miconazole
| triazoles- flucozanoles
227
What is ketocozanole ?
given orally
inhibits reactions catalysed by cytochrome p450- leads to drug-drug interactions
can cause hepatotoxicity so use safer alternative
228
What is miconazole ?
used topically/orally/IV
| can also inhbit drug metabolism
229
What is fluconazole ?
a triazole- nitrogen containing
given orally
well distributed across the BBB- into CSF- use in gungal meningitis
230
What are polyenes ?
form pores in the membrane
bind to sterols in the membrane and form an ion channel
leads to leakage of intracellular ions
231
How are polyenes selective ?
Higher affinity for ergesterol rather than cholesterol
232
Why are polyenes poorly absorbed ?
protein bound
233
How can we administer polyenes ?
liposome on outside
234
What are mitotic inhibitors ?
inhibits cell division by interfering with spindle formation
selectively uptaken by cells that synthesis keratin- dermatomycoses
235
What are anxiolytic drugs ?
alleviate fear and anxiety
236
What are sedatives ?
alleviate fer and anxiety and produce amnesia and analgesia
237
What are hypnotic drugs ?
induce sleep
238
What are signs of anxiety ?
```
uneasiness
apprehension
tension
headache
palpitation
flushing
```
239
What odes conscious sedation do ?
helps you to relax as a sedative and anaesthetic to block pain - allows verbal contact and protective reflexes to be intact
240
What is deep sedation ?
general anaesthesia
241
What is an inhalation sedation drug used in dentistry ?
nitrous oxide- entonox
242
What is an oral sedative ?
benzodiazepines- also use IV
243
Does sedation control pain effectively ?
no use LA as well
244
What are the characteristics of NO as a sedative ?
light ad rapid absorption
50% NO in oxygen recovery in 4 minutes
mild nausea and vomiting as sie effects
245
What are the limitation so NO as an inhalation sedative ?
expensive
limited patient use- cant use in high risk patient
prolonged exposure can change bone marrow and lead to teratogenic risk
246
What are the dose dependent effects of sedatives ?
relief of anxiety
sedation
hypnosis
GA
247
What are barbiturates ?
positive allosteric modulator of GABAa receptor
248
What are the actions of barbiturates ?
block AMPA receptor and stop glutamate release- an excitatory NT
bind to GABAa chloride channel complex and encourage GABA to bind
249
How do barbiturates produce their pharacological effects ?
increasing duration of chloride channel opening
250
What are BDZs used to treat ?
panic disorders
general anxiety disorders
phobia
251
How do BDZS work ?
increase frequency of chloride channel opening
252
What should be given to patients with autonomic symptoms ?
b adrenorecpetor antagonist- propanolol
253
What is the structure of BDZs ?
7 membered ring fused to an aromatic ring with 4 main substituent groups - can be modified
254
What is the variety of the BDZs ?
there are 20 varieties of each compound
255
What are the main pharmacological effects of the BDZs ?
```
sedation
reduction of anxiety and aggression
muscle relaxation
anti convulsant
amnesia
```
256
How exactly to BDZ affect sleep ?
decrease time taken to get to sleep
increase duration of sleep
reduce dreaming and decease deep sleep
257
What is the mode of action of the BDZs ?
BDZ act on specific regulatory site of the GABA/chloride channel receptor
enhance GABA binding - incrrease GABA affinity
dont open the chloride channel themselves
increase frequency
258
Where does GABA bind on the GABAa receptor ?
A and B subunits
259
Where does BDZ bind on the GABAa receptor ?
Alpha and gamma subunits
260
Which 4 things can bind to the GABAa receptor ?
GA
BDZ
Barbiturates
GABA
261
When are BDZ well abosrbed ?
when given orally
262
How do we get BDZ into systemic circulation ?
bound strongly to plasma proteins- give a different form to get into systemic circulation
263
What does BDZ high lipid solubiltiy mean ?
accumulation on body fat
264
How are BDZ excreted ?
inactivated by metbaolism and excreted as glucoronides in urine
265
What are the 2 forms of acting BDZs ?
short acting
| long acting
266
What are short acting BDZs?
they are metabolised to inactive compounds
| short half life
267
What are the long acting BDZs ?
metabolised to pharmacologically active metabolites
long half lives
diazepam-nordiazepam
268
What are the unwanted effects of BDZs ?
interaction with alcohol leads to further CNS depression
long lasting hangover
development of dependence- higher dose to get same efffects
sexual fantasies
269
What are b adrenoreceptor antagonists ?
propanolol
anxiolytic but not sedative
inhibit autonomic responses due to less NA transmission
bradycardia
270
What is the 5 HT agonist ?
```
agonist of inhibitory autoreceptro- serotonin
anxiolytic not sedative
takes long time to develop anti anxiety
less withdrawal effects
buspirone
```
271
What are depression and schizophrenia thought to be caused by ?
dysregulation in monoamine oxidase NT function
272
What are the monoamine NTs ?
5 HT
dopamine
serotonin
273
/What are the steps in 5 HT biosynthesis
tryptophan taken into neurone by amino acid transporter
converted to 5HTP via trytophan hydroxylase
5HT via decarboxylase AADC
stored in vesicles
released in response to APs
act on 5HT receptors
termiantion via reuptake and metabolism
274
What are the steps in DA biosynthesis ?
```
Tyrosine taken up
convered to LDOPA by tyrosine hydroxylase
LDOPA to DA via DOPA decarboxylase
stored in vesicles
released onto receptors when AP
reuptake and recycle
```
275
What is the DA theory of schizophrenia ?
schizophrenia is assocaited with increased DA fucntion
276
What are the 3 DA pathways in the brain ?
nigrostriatal
mesocortical
tuberoinfindubular
277
What is the nigrostriatal pathway ?
DA neurones extend from the substantianigra to the dorsal striatum
controls fine movement
problems lead to Parkinsons
278
What is the mesolimbic pathway ?
DA neurones from the ventral tegmental area to the cortex and ventral striatum
cortex controls modd
ventral striatum controls reward/addiction
279
What is the tuberoinfindubular pathway ?
DA from the hypothalamus to the pituitary stalk
| results in tonic inhibition of prolactin secretion
280
What is the prolactin pathway ?
```
suckling
hypohalamic nuclei
anterior pituitary
mammary tissue
milk production
```
281
What do hypothalamic nuclei release when suckling ?
release prolactin releasing factor
282
What does DA act as in the proloactin pathway ?
prolactin release inhibiting factor
283
What can we use to target schizophrenia ?
D2 antagonists
284
How are d2 receptor antagonists effective as being antipsychotics ?
they are potent- have a high affinity at low doses
285
What does D2 antagonism in the nigrostriatal pathway lead to ?
extrapyrimidal side effects - movement disorders
286
What are the movement disorders that are EPS ?
parkinsons disease
| tardive dyskinesia
287
What are the symptoms of parkinsons disease ?
tremor
muscle rigidity
loss of facial expression
288
What are the symptoms of tardive dyskinesia ?
repetitive rhythmical involuntary movements
289
What does D2 antagonism in the tuberoinfindubular pathway lead to ?
galactorrhoea- spontanaeous milk flow in females
| gynaecomastea - man boobs
290
Why do antipsychotics have affinity for other receptors besides DA ones ?
tricyclic structure
affintity for histamine receptors
M1 receptors
adrenergic receptors
291
What are the H1 mediated side effects of antipsychotics ?
sedation and weight gain
292
What are the M1 mediated side effects of antipsychotics ?
sry mouth
blurred vision
constipation
293
What are the alpha 1 mediated side effects of antipsychotics ?
postural hyptension
294
What is the classification of antipsychotics ?
```
phenothiazenes- class I,II,III
thioxanthenes
butyrophenes - no tricyclic structure so selective for D2- no sedatio as o muscarninic or histamine activity
```
295
What are the limitations of the classical antipsychotics ?
not all schizophrenic patients will respond
limited efficacy against negative symptom s
side effects and compliance issue
296
What are the ideal characteristics for antipsychotics ?
lower EPS
| effective against negative and positive symptoms
297
What are positive symptoms of schizophrenia ?
disorganised behaviour
hallucinations
paranoia
298
What are the negative symptoms of schixphrenia ?
blunted emotions
social withdrawal
loss of energy
299
What are the characteristics of the atypical antipsychotic drugs ?
better EPS profile
high metabolic effects though- weight gain
lower affinity fro the D2 receptor
300
How are atypical antipsychotics effective if they have alowe D2 affinity ?
they have a faster dissociation rate from the D2 receptor - loose binding
301
What are the 2 types of DA release ?
phasic- high bursts then low- nigro
| tonic- constant- meso
302
What does phasic DA transmission do ?
drugs displaced by phasic bursts of DA transmission
| less distortion of DA signalling
303
What are the 3 types of antidepressant drugs ?
TCAs- tricyclic antidepressants
selective serotonin reuptake inhibitor- SSRIs
Monoamine oxidase inhibitors
304
What is the role of TCAs ?
inhibit 5 HT and NA uptake
affinity for other receptors- side effects
often feel worse before better
imipramine
305
What are the SSRIs ?
include SNRIs and NARIs
selective for 5HT and NA transporter - dont have postsynaptic receptor affinity
better side effect profile than TCAs
306
What are the 2 forms of MAO ?
MAOa- breakdown 5HT and NA
| MAOB- breakdown DA
307
What do old MAOIs do ?
irreversibly bind to both isoforms leading to stimulant effects
308
What do new MAOISs do ?
block MAOa only and reversible - safer in overdose
309
What has to be done when taking MAOIs ?
avoid food rich in amine (cheese and marmite) as the dietary amines can trigger NA release - normally MAOa would get rid of- but inhibited
hypertensive crisis
310
What is a hormone ?
a hormone is a chemical substance synthesised by cells and secreted into blood where it is carried to non adjacent sites in the body where it exerts its action
311
What is a nerotransmitter ?
chemical substance synthesised by a neurone and secreted directly onto adjacent neurones where it exerts its action
312
What is the HPA axis ?
hypothalamus- CRH
anterior pituitary- ACTH
adrenal gland - cortisol
313
What is the negative feedback of cortisol ?
cortisol acts on the anterior pituitary and the hypothalamus
314
What activates the HPA axis ?
physical and mental stress
315
What is the role of cortisol ?
increase and maintains normal blood glucose
increases gluconeogeneis
decrease muscle and adipose glucose uptake
decrease in protein synthesis- use the amino acids for glucoeogenesis
316
What are the causes of cushings syndrome ?
iatrogenic glucocorticoid therapy
| adrenal tumour
317
What are the side effects of cushings syndrome ?
```
loss of protein synthesis- skin thinning
immunosupression
high lipid redistribution
muscle wasting
buffalo hump
```
318
What is the treatment of cushings syndrome ?
remove tumour
| inhibit synthesis of cortisol using mettyropone
319
What is the synthesis of cortisol ?
11 beta deoxycortisol to cortisol
| via 11 beta dehydroxylating enzyme
320
How does metyrapone work ?
block 11 beta dehydroxylating enzyme
| less cortisol for secretion
321
How can cortisol be used therapeutically ?
as an immunosupressor and for its anti inflammatory effects
322
Why is the insulin glucose axis
high blood glucose leads to insulin release from the pancreas
insulin acts on receptors in the liver and muscle
323
Where is insulin synthesised and secreted from ?
beta islets of langerhans
| stored in insulin granules
324
What is the effect of insulin ?
conversion of glucose into glycogen
| inhibition of fat breakdown
325
How is insulin released from the islets of langerhans ?
cells take up glucose and convert to ATP in glycolysis
ATP binds to potassium ion channel
leads to depolarisation and opening of calcium channels
exocytotic release of insulin
326
What is type I diabetes ?
insulin dependent
insulin hyposecretion due to lack of beta cells-autoimmune
treat with insulin substitutions
327
What type of insulin is best for the background ?
intermediate acting insulin
328
What is the best insulin for after a meal ?
short term
| fast acting
329
What is type 2 diabetes ?
non insulin dependent
functioning beta cell
receptor insensitivity
not enough glucose to meet with metabolic demands of obesity
330
How do we treat type 2 diabetes ?
with sulphonylureas
331
What are the 3 types of insulin preparation ?
short term acting
intermediate
long term
332
What is the short term acting insulin ?
soluble
rapid onset
subcutaneous (normally) and IV (emergen
333
What is intermediate acting insulin ?
insulin complexed with zinc or protamine
| slowly released from particles
334
What is long term acting insulin ?
insulin complexed with larger molecules like zinc
very slowly released
known as glargin/determir
335
How do sulphonylureas work ?
block ATP sensitive K channels in the beta cells
cause depolarisation
increase in insulin secretion
336
What is an example of a sulphonylureas ?
glibencalmide
337
What is the HPO axis ?
Hypothalamus- GRH
Pituitary- LH and FSH
Ovaries- Oestrogen and progesterone
338
What are the effects of oestrogen ?
responsible for uterus development
makes LH cells in the pituitary more sensitive
allows proliferation of the endometrium
inhibits FSH - regulate the cycle
339
What are the effects of progesterone ?
renders endometrium suitable for implanting a fertilised ovum
inhibit further FSH LH and GRH
340
What is progesterone secreted by ?
corpus leteum
341
What happens when there is no fertilisation ?
corpus luteum regresses
progesterone levels drop
endometrium levels cant be maintaned so menstruaion
clamp on FSH LH and GRH is released so a follicle can develop again
342
What happens if the ovum is fertilised ?
ovum secretes human chorionic gonadotrophin
stimulates corpus luteum to keep secreting progesterone
maintains the endometrium for the ovum
inhibits further secretion of GRH FSH and LH
prevents further follicles developing
343
What are the action of oral contraceptives ?
they target negative feedback of progesterone
mimic pregnant state
2 types - combined and progesterone only
344
What is the action of the combined pill ?
oestrogen inhbits FSH via negative feedback - stop follicle development
progesterone inhibits LH secretion
progesterone makes cervical mucus to stop sperm passage
345
What is the action of the progesterone only pill ?
main effect is cervical mucus
doesnt stop ovulation
irregular periods
less reliable
346
Why is is not recomended to take amoxicillin with a contraceptive pill ?
drug is glucoronidated by liver to excrete into bile by the duodenum
normal flora cleave the glucoronide with glucoronidase - drug can be reabsorbed again in the gut and create a reservoir
normal flora removed by antibiotic- reserovoir taken away-
347
Which 2 processes do anti coagulant drugs target ?
blood coagulation
| platelet adhesion
348
Which state are patients in who take anti coagulant drugs ?
on the edge of haemorrhagic state
349
What is haemostasis ?
spontaenous arrest of blood loss from a damaged vessel
| required subendothelial exposure
350
What are the 3 processes in haemostasis ?
vasconstriction
platelet adhesion and aggregation
conversion of fibrinogen to fibrin in the clot
351
What is thrombosis ?
unwanted formation of haemostatic plug - thrombus
| within a blood vessel or the heart
352
Why can thrombosis occur >
vascular disease
prosthetic heart valves
atrial fibrilation
353
What are the consequences of thrombosis ?
deep vein thrombosis
pulmonary embolism
myocardial infarction
354
Where does the blood clot form ?
in vitro- outside
355
What is the structure of a blood clot ?
amorphous
356
Where does the thrombus form ?
in vivo
357
What is the structure of the thrombus ?
white head and red tail
arterial- large head of platelets
venous- large tail that breaks off to form emboli
358
What are active blood clotting factors made from ?
zymogen precursors
359
What is required for the instrinsic pathway ?
collagen exposure
| subendothelial damage
360
What happens in the intrinsic pathway ?
factor XII is activated
factor 11
factor 9
factor 10
361
What is needed for the extrinsic pathway ?
damaged tissue which exposes factor III
362
What happens in the extrinsic pathway ?
factor 3 exposed
factor 7 activated
activates factor 10
363
What happens in the common pathway ?
factor 10 converts prothrombin to thrombin
thrombin converts fibronogen to fibrin
thrombin activates factor 13
factor 13 cross links the clot
364
What is the structure of heparin ?
sulphated mucopolysaccharides
365
Where are heparins found ?
mast cells
| same as histamine
366
What do the sulphate groups on heparins allow ?
binding to ATIII
367
What does heparin binding to ATIII allow ?
interact with other clotting factors
| inactivate 9 10 11 12
368
What are LMWHs ?
consistent activity
only bind to ATIII
longer action but not as broad
369
How is heparin adminstered ?
not orally- has to be given by IV or SC
370
How can we treat heparin overdose ?
give protamine- strongly basic protein
protamine will bind to heparin and sequester it
stop heparin binding to other clot factors
371
What is an example of an oral anticoagulant ?
warfarin
372
What is the action of warfarin ?
inhbits the sythesis of vit K dependent clotting factors
373
What are the vit K dependent clotting factors ?
2
7
9
10
374
How does warfarin act ?
it doesnt act immediately
has a lag time
takes 1-2 days to see the effects
375
How can we treat warfarin overdose ?
vitamin K
| frozen plasma
376
Which enxyme is needed to activate the Vit K dependent clotting factors ?
glutamic acid to carboxyglutamic acid
| via gamma carboxyglutamate
377
What does the activation of vit K dependent clotting factors require ?
oxidation of vit K
| hydroquinone to epoxide
378
What has to happen to allow the activation of Vit k dependent clotting factors to activate again ?
vit K has to be reduced back to the reduced form via Vit K reductase
379
How does warfarin effect the vit K process ?
inhibit vit K reductase
| stops activating clotting factors
380
How is warfarin administered ?
orally
381
What is the Vd of warfarin ?
small
| highly plasma protein bound
382
What is the absorption of warfarin like ?
easily absorbed
383
How do we start anti coagulation therapy ?
combination of warfarin and heparin
heparin is fast acting- initial effects
warfarin has lag time
once warfarin starts working the heparin is withdrawn
384
How do we measure the clotting ability of warfarin ?
INR
385
How do we measure the clotting ability of heparin ?
partial thromboplastin time
386
How do we calculate INRs ?
PT (patient)/ PT (ref)
| should be 2-4
387
What are the new direct oral anticoagulants ?
factor 10 inhibitors- Rivaroxabin and Apixaban
| Factor 11 inhibitors- dabigatran
388
How do the new direct oral anticoagulants work ?
interact with clotting factors directly
| dont require anti thrombin - bind to thrombin directly to stop fibrin production
389
Which drugs potentiate the effects of anti coagulants ?
drugs which decrease platelet aggregation- aspirin
inhibit cytochrome p450S- Co- trioxazole
inhibit vit K reductase- antibiotics
390
Which drugs decrease the effect of anti coagulants ?
induce cytochrome p450s
| reduce absorption
391
What does aspirin do to inhibit platelet aggregation ?
aspirin inhibits eicosamoid production and hence inhbits platelet aggregation
392
What are the 2 eicosanoids that can effect platelet aggregation ?
PGI2- endothelium derived
| TXA2- promotes aggregation
393
What does aspirin do to the eicosanoids ?
stops cox mediated synthesis of both
394
What is the effect of aspirin on the eicosanoids ?
reduced both
but TXA2 cant regenerate quickly
net effect is increase in PGI2- platelet inhibition
395
What is aspirin useful in ?
arterial thrombosis
396
What are the implications of anticoagulation therapies on dental patients ?
patients are on edge of haemorrhagic state
local haemostatic measures- sutures, pressure packs and vit k packs
antibiotics enhance anti coagulation effect
increased risk of bleeding with aspirin
397
What is the primary target for sulphonamide antibacterials ?
folic acid synthesos
398
What is the target process for TCAs in the treatment of anti depression ?
reuptake
399
The volume of distribution of Paroxetine is 300L . The fraction unbound in the plasma is 0.06. The plasma concentration when 30 mg of the drug id given would therefore be ?
Vd- dose/plasma conc at 0
plasma= dose/Vd
30/300
0.1
400
What could be a potential side effect of giving polyene type anti fungals ?
hypokalaemia
| induced by increased cell permeability
401
What is a barrier to glomerular filtration but not active tubular secretion ?
plasma protein binding
402
Serum levels of warfarin can be increased using which drug ?
ibuprofen
403
Local anaesthetics with an amide bonde have a longer duration of action than an ester bond ?
true
404
Steroidal anti inflammatories induce lipocortin which inhibits the activity of phospholipase A2 ?
true
405
The higher the blood/gas coefficient of a an Inhalation GA the more rapid the induction and recovery ?
false
406
The volume of distribution of a drug is 300L, the amount in the body when the plasma concentration is 0.2 is ?
Vd= dose/plasma conc
dose= Vd x plasma conc
300 x 0.2= 60
407
if youa administer codeine and the patient returns with shortness of breath and increased tiredness what is the likely cause ?
reduced adenylate cyclase activity following K receptor binding
408
What is the order of gram measurements ?
mg ug ng
| x 1000 to get smaller
