Pharmacology Flashcards
1
Q
What is the ENS?
A
All the neurones (cell bodies) embedded in the wall of the GI tract
2
Q
What is an efferent nerve?
A
Motor nerve
3
Q
What is an afferent nerve?
A
Sensory nerve
4
Q
Which ANS reflexes can we exert some conciuos influence on with training?
A
Micturition, Deffication and accommodation in the eye
5
Q
What is a ganglion?
A
A group of nerve cell bodies outside the CNS
6
Q
What is a nucleus?
A
A group of nerve cell bodies inside the CNS
7
Q
Where is the sympathetic outflow?
A
Thoracolumbar outflow T1-L2
8
Q
In sympathetic neurones what is the neurotransmitter released by the preganglionic neurone?
A
ACh
9
Q
In sympathetic neurones what is the neurotransmitter released by the postganglionic neurone?
A
Normally NA
10
Q
In parasympathetic neurones what is the neurotransmitter released by the preganglionic neurone?
A
ACh
11
Q
In parasympathetic neurones what is the neurotransmitter released by the postganglionic neurone?
A
ACh
12
Q
Where is the parasympathetic outflow?
A
Cranialsacral outflow CN 3, 7, 9 and 10 and S2-S4
13
Q
What receptors are used for the neurotransmitter ACh in the autonomic ganglia?
A
Nicotinic cholinoreceptors
14
Q
What receptors are used for the neurotrasmitter ACh at effector cells/organs?
A
Muscarinic Cholinergic receptors
15
Q
What receptors are used for the neurotransmitter NA at effector cells/organs?
A
Adrenoceptors
16
Q
Where do sympathetic neurones synapse?
A
Within the sympathetic chain- paravertebral ganglia
Outside of the sympathetic chain- prevertebral ganglia
17
Q
Sympathetic preganglionic neurones are typically:
a) long/short?
b) myelinated/ unmyelinated
c) motor B/motor C fibres
A
a) short
b) myelinated (white)
c) Motor B fibres
18
Q
Sympathetic post ganglionic neurones are typically:
a) long/short?
b) myelinated/ unmyelinated
c) motor B/motor C fibres
A
a) long
b) unmyelinated (grey)
c) motor C fibres
19
Q
Paraympathetic preganglionic neurones are typically:
a) long/short?
b) myelinated/ unmyelinated
c) motor B/motor C fibres
A
a) long
b) myelinated (white)
c) motor B fibres
20
Q
Paraympathetic post ganglionic neurones are typically:
a) long/short?
b) myelinated/ unmyelinated
c) motor B/motor C fibres
A
a) short
b) unmyelinated (grey)
c) motor C fibres
21
Q
What is the sympathetic innervation to the adrenal medulla (chromaffin cells)?
A
Preganglionic neurones via splanchnic nerves and the the neurotransmitter is ACh
22
Q
What are 4 important abdominal pre vertebral ganglia in the sympathetic system?
A
Coeliac (liver, stomch and pancreas)
Aortocorticorenal (adrenal gland and kidneys)
Superior mesenertic (accending colon, illeum)
Inferior mesenteric (descending colon, rectum, anus and genitalia)
23
Q
Where are preganglionic fibre cell bodies located in the spinal cord?
A
Lateral horn
24
Q
How do sympathetics get from the lateral horn to the organs?
A
Anterior rootlets, anterior roots, spinal nerve, (anterior) rami, synapse at
a) paravertebral ganglia and post synaptic nerves join peripheral nerves (grey rami communicants) to organs
b) pre vertebral ganglia ad post synaptic neurones travel in splanchnic nerves to organs
25
What are chromaffin cells?
Modified post ganglionic neurones which secrete adrenaline (80%) and noradrenaline (20%) into the capillary circulation as hormones
26
What type of neurotransmitter is released by post ganglionic sympathetic neurones which innervate the thermoregulatory (eccrine) sweat glands and a few blood vessels?
ACh and they act on muscarinic cholinergic receptors
27
What are the neurotransmitters, other than NA is often used by the sympathetic nerves?
ATP and neuropeptide Y (NPY)
28
Where are parasympathetic ganglia usually located?
In the walls of target organs
29
Where are parasympathetic fibre cell bodies located?
Brainstem (mid brain, pons, medulla oblongata)
| Sacral segment of the spinal cord
30
Where is the origin, ganglion and effector target for CN III (oculomotor)?
```
Origin = Midbrain
Ganglion = Ciliary
Target = Eye pupillary constrictor
```
31
Where is the origin, ganglion and effector target for CN VII (facial)?
```
Origin = Pons
Ganglion = Pterygopalatine and Submandibular
Target = Lacriminal glands (nasal cavity) and submandibular and sublingal glands.
```
32
Where is the origin, ganglion and effector target for CN IX (glossopharngeal)?
```
Origin = Medulla oblongata
Ganglion = Otic
Target = Parotid Gland
```
33
Where is the origin, ganglion and effector target for CN X (vagus)?
```
Origin = Medulla Oblongata
Ganglion = Many
Target = Lots
```
34
What are the neurotransmitters, other than ACh is often used by the parasympathetic nerves?
NO nitric oxide
| vasoactive intestinal peptide VIP
35
Release of what ion triggers action potentials to travel along and between neurones?
Ca++
36
What is a NANC?
Non adrenergic, non cholinergic transmission.
| Where the post ganglionic neurone does not release NA or ACh
37
Which NANC neurone transmitters can be released and for what seed of response?
```
Parasympathetic = VIP (slow response) and NO (intermediate response)
Sympathetic = ATP (fast respose) NPY (slow response)
```
38
What are nicotinic ACh receptors of the ganglia?
Ligand gated ion channels activated by nicotine
| NB: structurally and pharmacologically different from nicotinic receptors at neuromuscular junctions or in CNS
39
What are muscarinic ACh receptors of effector cells?
G protein coupled receptors activated by muscarine
| 5 subtypes M1-M5 which are differentially expressed across organs
40
What are adrenoreceptors?
G protein coupled receptors.
Alpha 1 + 2, Beta 1, 2 and 3.
Alpha 1 and 2 are divided into 1(A, B and D) and 2(A, B and C)
41
What are the activators of alpha 1 adrenoreceptors?
NA > A > Isoprenalinie
42
What are the activators of alpha 2 adrenoreceptors?
Isoprenaline > A > NA
43
Micturation reflex: What happens during bladder filling?
Sympathetic activity predominates
Detrusor is relaxed by NA acting on beta 2 and 3 adrenoceptors
Internal urethral sphincre is constricted by NA acting on alpha 1 receptors
44
Micturation reflex: What happens during bladder vioding?
Parasympathetic activity predominates
Detrusor is contracted by ACh acting on M3 receptors
Internal urinary sphincter is relaxed by NO release that stimulates the production of cGMP (relaxant)
45
Micturation reflex: How do we voluntarily control the external urethral sphincter?
Somatic efferents (motor) and the release of ACh on cholinergic receptors
46
What is the bladder detrusor?
Smooth muscle wall
47
What is the Bladder trigone?
Smooth muscle triangular region formed by the 2 uteric orifices (from kidney) and the internal urethral orifice (sphincre)
48
Sympathetic//which receptors where?
| Heart
Beta 1 adrenoceptors
| Increase HR and force of contraction
49
Sympathetic//which receptors where?
| Lungs
Beta 2 adrenoceptors
| Relax bronchi, decrease mucus production
50
Sympathetic//which receptors where?
| GI tract?
Alpha 1, 2 and beta 2 receptors
| Decrease GI motility and constrict sphincters
51
Sympathetic//which receptors where?
| Adrenal gland
Nicotinic ACh receptor
| Release of adrenaline
52
Sympathetic//which receptors where?
| Bladder
Beta 2 and 3 adrenoceptors
Relax detrusor
Alpha 1 adrenoceptors
Constricts the internal urethral sphincre
53
Sympathetic//which receptors where?
| Penis
Alpha 1 adrenoceptor
| Ejaculation
54
Sympathetic//which receptors where?
| Vasculature?
alpha 1 adrenoceptors (most locations)
Constricts vasculature
Beta 2 adrenoceptors (skeletal muscle)
Relaxes vasculature
55
Parasympathetic// which receptor where?
| Heart
M2
| Decrease heart rate and force of contrition (atria only)
56
Parasympathetic// which receptor where?
| Lungs
M3
| Constrict bronchi and stimulate mucus production
57
Parasympathetic// which receptor where?
| GI tract?
M3
| Increases intestinal motility and relaxes sphincters
58
Parasympathetic// which receptor where?
| Adrenal gland
No effect
59
Parasympathetic// which receptor where?
| Bladder
M3
Contract detrusor
NO
Relaxes internal urethral sphincter
60
Parasympathetic// which receptor where?
| Penis
M3 and NO
| Penile erection
61
Parasympathetic// which receptor where?
| Vasculature?
Largely no effect
| except, penis, salivary glands, pancreas where it relaxes
62
Explain cholinergic synaptic transmission?
1) Uptake of choline into the cell via choline transporters (rate limiting in ACh synthesis)
2) Synthesis of ACh by choline acetyltransferase (ChAT)
3) Storage of ACh within vesicle via transporter VChAT (ATP and other anions are co stored)
4) Depolarisation of terminal by AP
5) Ca++ influx by voltage activated Ca++ channels
6) Ca++ induced release of ACh into synaptic cleft
7) Activation of ACh receptors causing cellular response
8) Degradation of ACh to choline and acetate by acetylcholinesterase AChE which terminates transmission
9) Uptake and reuse of choline and acetate diffuses out of the synaptic cleft
63
How is ACh synthesised in the cell?
Acetyl coenzyme A + choline --> Acetylcholine
64
What is the structure of nicotinic ACh receptors?
5 protein subunits that form a central cation conducting channel
Assembled from a diverse range of subunits. Alpha 1-10, beta 1-4 gamma, delta and epsilon.
65
What is the structure of nicotinic ACh receptors found in skeletal muscle?
2(alpha1), beta, gamma, epsilon
66
What is the structure of nicotinic ACh receptors found in ganglia?
2(alpha3), 3(beta4)
67
What is the structure of nicotinic ACh receptors found in CNS?
```
5(alpha7)
or 2(alpha4), 3(beta2)
```
68
What is an epsp?
Excitatory post synaptic potential
A graded depolarisation generated by the infux of Na+ in a post synaptic neurone - amplitude is based on number of ACh receptors
69
To stimulate and AP the epsp must reach what?
Threshold
Either by multiple preganglionic fibres synapsing at one post ganglionic fibre or repeated stimulation of one preganglionic fibre
70
Which G protein is activated by M1 receptors and what is the effect?
Gq => stimulation of phospholipase C => increase secretions
71
Which G protein is activated by M2 receptors and what is the effect?
Gi => inhibition of adenylyl cyclase and opening of K+ channels => decreased heart rate
72
Which G protein is activated by M3 receptors and what is the effect?
Gq => stimulation of phospholipase C => increase secretions/ contraction of visceral smooth muscle
73
Which G protein is activated by beta 1 adrenoceptors and what is the effect?
Gs => Stimultion of adenylyl cyclase => increased heart rate and force
74
Which G protein is activated by beta 2 adrenoceptors and what is the effect?
Gs => stimulation of aadenlyly cyclase => Relaxation of bronchial and vascular smooth muscle
75
Which G protein is activated by beta 3 adrenoceptors and what is the effect?
Gs => stimulation of adenylyl cyclase => Relaxation of bladder detrusor
76
Which G protein is activated by alpha 1 adrenoceptors and what is the effect?
Gq => Stimulation of phospholipase C => contraction of vascular smooth muscle
77
Which G protein is activated by alpha 2 adrenoceptors and what is the effect?
Gi => inhibition of adenylyl cyclase => Inhibition of NA release
78
There are receptors on both pre and post synaptic neurones at synapses. What are the receptors on presynaptic neurones called?
Autoreceptors
M2 or Alpha 2 receptors
Mediate negative feedback inhibition of neurotransmitter by inhibiting Ca++ entery and opening K+ channel.
If the receptors are stimulated by neurotransmitters than they will decrease further release
79
What is pharmokinetics?
What the body does to a drug
| Absorptions, distribution, metabolism and excretion of drugs and metabolites
80
What is pharmodynamics?
What a drug does to the body
| Biological effect and mechanisms of action
81
Metabolism + excretion = ?
Elimination
82
What is a drug?
Any singel synthetic or natural substance of fnown structure used in the prevention, treatment or diagnosis of a disease
83
What is a medicine?
A chemical preparation containing one or more drugs with the intention of causing a therapeutic effect. Usually contain agents in addition to the active drug eg stabalisers
84
Drugs bind to target molecules. How are they selective?
Chemical structure of the drug (binding site specificity
| Target recognizing ligands of a precise structure (ligand specificity)
85
Most drugs bind to regulatory proteins. What are these?
| What are the none protein targets?
Enzymes, carrier molecules, ion channels, receptors
| DNA (anti cancer drugs) and RNA (antibiotics can bind to prokaryotic RNA)
86
What is an agonist?
A drug that binds to a receptor to produce a cellular response
87
What is an antagonist?
A drug that blocks the actions of an agonist by binding to the same receptor
88
What is affinity?
Strength of association between ligand and receptor
89
What is efficacy?
The ability of an agonist to evoke a cellular response
90
How is affinity determined?
The the dissociation rate as the rate of binding is almost constant.
By the number or type of chemical bonds a agonist makes with a receptor
91
Do agonists possess affinity and efficacy?
Yes
Affinity is binding and has 2 rate constants (association and dissociation)
Efficacy is activation and has 2 rate constants (activation and deactivation)
92
What determines efficacy?
The activation rate as the deactivation rate is similar for all drugs
93
Do antagonists possess affinity and efficacy?
No just affinity as they do not produce a conformational change- just block the site
94
Do drugs demonstrate michaelis menton kinetics?
Yes
95
What is a full agonist?
A drug which can produce a 100% response
96
Why would you plot concentration against response on a logarithmic axis rather than a linnear axis?
Easier to get an accurate value or EC50 or Km
| Compresses the range of concentrations at the upper end and expands them at the low end
97
What is potency?
Concentration range over which a drug is effective
98
What is the MEC and MTC?
Minimal effective concentration
| Maximal tolerated concentration
99
What is the therapeutic index?
MTC/MEC
100
What is the therapeutic window?
The range of plasma concentrations we want the drug to be within
101
What is first order kinetics?
The rate of elimination is directly proportional to drug concentration. => Drug concentration falls exponentially initially and then the rate of drug leaving the body falls as plasma concentration falls
102
What is the half life?
The time taken for the plasma concentration to fall by 50%
103
What is the equation for half life?
t 1/2 = 0.69/Kel
| Where Kel is the elimination rate constant
104
Is the half life constant for a drug with first order kinetics?
Yes
105
What is clearance?
The volume of plasma cleared of a drug per unit time
| only for drugs with first order kinetics
106
What is the equation for calculating the elimination rate constant?
Kel = Cl x Cp
| Where Cl= clearance and Cp = plasma concentration
107
What determines the maintenance dose rate?
Clearance
108
What is the point of stready state?
Where rate of drug elimination = rate of drug administration
109
What is the calculation for the rate of administration (IV) at steady sate?
Cl x (Cp at ss)
110
How long does it take to reach steady state plasma concentration after administration?
5 half lives
111
What is oral bioavailability?
The fraction of the drug administered that enters the systemic circulation
112
What is a loading dose?
AN initial higher concentration of a drug given at the beginning of a course of treatment before stepping down to a lower maintenance dose
113
Why is a loading dose used?
To decrease the time to steady state for drugs with a long half life
114
What is the calculation for a loading dose when giving IV?
LD= Vd x target Cp
| Where Vd = volume of distribution
115
What is the volume of distribution?
The volume in which a drug appears to be distributed with a concentration equal to that of plasma
116
What is zero order kinetics?
Saturation kinetics where the drug is initially eliminated at a constant rate because the plasma concentration is greater than the rate of metabolism of the enzyme which metabolises it
eg alcohol
117
Why must you be careful with drugs with zero order kinetics?
Plasma steady state concentration is not linnearly related to dose. Hard to stay within the therapeutic window
118
What is depolarisation?
The membrane potential becomes less negative.
| referring to the excess of charge on the inside of a cell
119
What is hyperpolarisation?
The membrane potential becomes more negative. referring to the excess of charge on the inside of a cell
120
WHat drives the passive movement of ions?
electrochemical gradient for the ion
121
Why does Na+ normally move into the cell?
Concentration gradient is inward and the electrical gradient is inward
122
When the driving force for Na+ influx is negative, what happens to Na+?
Moves INTO the cell
| Vm - ENa+ = -80 - 60 = -140mV
123
Why does K+ normally move out of the cell?
The concentration gradient is outward and has an energy which EXCEEDS that of the electrical gradient which is inwards
124
When the driving force for K+ is positive, what happens to K+?
Moves OUT of the cell
| Vm - EK+ = -80 - -100 = +20mV
125
What happens to the membrane potential when:
a) Na+ channels open
b) K+ channels open
a) The membrane potential is driven towards ENa+ (+60mV)
| b) The membrane potential is driven towards EK+ (-100mV)
126
What is ENa+ and EK+?
The equilibrium potential for Na+/K+
127
What is the threshold potential?
The potential which must be exceeded to generate an action potential (-60mV)
128
What is the resting potential?
Unexcited state of the membrane (-80mv)
129
What is the upstroke?
Depolarisation of the membrane
130
What is the Downstroke?
Hyperpolarisation/repolarisation
131
What is an action potential?
A brief electrical signal in which the polarity of the nerve cell membrane is momentarily reversed (2 milliseconds)
132
Do action potentials have a constant magnitude and velocity?
Yes- its axon dependent
133
What activates voltage gated Na+ and K+ channels?
Membrane depolarisation
Na+ immediately
K+ after a delay
134
Does activation of Na+ channels follow positive or negative feedback? Explain.
Positive feedback. Depolarisation => Increasing Na+ conductance => greater inward Na+ current => Greater depolarisation
135
Does activation of K+ channels follow positive or negative feedback? Explain.
Negative feedback.
Depolarisation => Increased K+ conductance => Outward K+ current => repolarisation.
Repolarisation turns the signal for channel opening off
136
There are two gates within the voltage activated sodium channel. What are these?
Activation gate and the inactivation gate
137
Following depolarisation what state is the Na+ channel in?
Open conducting state
| Both activation gate and inactivation gate are open
138
Following maintained depolarisation what state is the Na+ channel in?
Inactivated non-conducting state
| Inactivation gate is closed but the activation gate is open
139
Following repolarisation what state is the Na+ channel in?
Closed non conducting state
| Activation gate is closed but the inactivation gate is open
140
What does the inactivation state of the Na+ channel allow?
Repolarisation phase and is responsible for the absolute refractory period
141
How can the inactivation gate of a Na+ channel be opened?
Repolarisation of the membrane
142
What is the absolute refractory period?
Where no stimulus, however strong can elicit a second action potential (all Na+ channels are inactivated)
143
What is the relative refractory period?
Where a stronger than normal stimuli may elicit a second action potential (mixed population of inactivated and closed Na+ channels). The membrane is hyperpolarised so a large depolarisation is required to reach threshold
144
Why is propagation of a action potential unidirectional?
Refractory period and Na+ channels are inactivated
145
Why does an action potential decay?
The nerve cell membrane is leaky and not a perfect insulator so passive signals do not spread far from their site of origin due to current loss across the membrane
146
What is cable therory?
Where current leaks back into the extracellular space across the membrane resistance generating a potential change.
147
What will increase the leakage of current across the membrane?
Decreasing the membrane resistance and increasing the axon resistance
148
What is saltatory conduction?
Propagation of action potentials along myelinated neurones from one node of ranvier to the next increasing the AP velocity
149
What are some demyelinating disorders?
MS (CNS)
Guillian Barre syndrome (PNS) (Reversible)
Both cause slowing/ceasing of nerve conduction
150
Is axial resistance smaller in wide or narrow APs?
Wide and therefore conduction is faster
151
Which cells produce myelin in the PNS and CNS?
```
PNS = schwann cells
CNS = Oligodendrocytes
```
152
How many schwann cells are needed for each axon of the PNS?
many
153
How many oligodendrocytes are needed for each axon in the CNS?
One oligodendrocyte can insulate many axons in the CNS
154
What is absorption?
The process by which a drug enters the body from its site of administration and enters the general circulation
155
What is distribution?
Transport of a drug by general circulation. Drugs often leave the blood and enter perfused tissue (extracellular fluid, intracellular fluid) Further reversible distribution dictated by a concentration gradient may occur by diffusion or carrier mediated transport
156
What is metabolism?
The process by which tissue enzymes (mostly liver hepatic metabolism) catalyse the chemical conversion of a lipid soluble drug into a less active and more polar form that is more readily excreted from the body
157
What is excretion?
Processes that remove the drug or its metabolites from the body. This occurs mostly in the kidneys but can occur through bile (enters GI tract), lactate of females, lungs (ethanol)
158
What characteristics of a drug can affect its absorption?
1) Solubility- the drug must dissolve in an aqueous solution
2) Chemical stability- not be destroyed by stomach acid or digested by enzymes
3) Lipid to water partition coefficient
4) Degree of ionisation
159
Which drugs can enter the vascular compartment?
Hydrophilic drugs
160
Why are some drugs ineffective orally?
Digested in gut or destroyed by stomach acid
161
Give an example of a drug destroyed by stomach acid and must be given IV?
Benzylpenicillin
162
Give an example of a drug digested by enzymes and must be given IM?
Insulin
163
In IBS treatment the drug is inactive in the small intestine but active in the colon. How is this?
Drug is modified by the GI tract. Bacteria in the colon activate the drug.
164
What is the lipid to water partition coefficient?
The ratio of the drug concentration is the membrane and concentration in water a equilibrium.
Eg a partition coefficient of 4 means the drug is 4 times more concentrated in the membrane than water. Good for diffusion across the lipid membrane
165
What is the ionised form of an acid and a base?
Acid A-
| Base BH+
166
WHat is the unionised form of an acid and a base?
Acid HA
| Base B
167
Onle ionised/unionised forms of a drug will diffuse across a biilayer?
Unionised
168
What does the degree of ionisation depend on?
pKa of the drug and the pH of the environment
169
When does pH = pKa?
At equilibrium, when half the drug is ionised and half the drug is not?
170
Give an example of an acidic drug?
Asprin pKa = 3.4
171
What equations can be used to calculate the proportions of drugs ionised?
Henderson hasselback equestions
| See workshop sheets
172
An acidic drug will ionise more/less in an acidic pH but will ionise less/more in a basic pH.
Less in acid
| More in base
173
An basic drug will ionise more/less in an acidic pH but will ionise less/more in a basic pH.
more in acid
| Less in base
174
Where are acidic and basic drugs absorbed?
Acidic = stomach
Basic = small intestine
NB: most absorption, even of weak acids occurs in the intestine
175
Weak acids and bases are better absorbed than strong acids and bases. T or F?
True
176
What GI factors can affect absorption?
1) GI motility- rate of stomach emptying (increases with food)
2) pH at absorption site
3) Blood flow to stomch and intestine
4) Physiochemical interactions- rate of some drug absorption is altered by Ca++ rich foods
5) Transporters (in epithilial membranes that facilitate drug absorption
6) Tablet manufacture- release drugs at different sites/rates
177
What is oral availability?
The fraction of the drug that reaches the systemic circulation after oral ingestion
Oral availability = amount in systemic circulation / amount administered
178
What is systemic availability?
The amount of a drug that reaches the systemic circulation after absorption
Systemic availability = amount in systemic circulation / amount absorbed
179
Why do IV drugs have a 100% systemic availability?
Bypass liver/ first pass metabolism
180
What is first pass metabolism/presystemic metabolism?
The modification/destruction of someoral drugs by the liver and gut wall enzymes
181
What is an entral route?
A drug which is swallowed and enters the GI tract
182
Give 3 entral routes of drug administration?
PO- oral
SL- buccal or sublingual = Drug is absorbed into the blood
PR- Rectal = aviods some first pass metabolism and good for slow release is vomiting/fitting
183
What is the paraentral route?
Not via the GI tract
184
Give 6 examples of paraentral route administration?
IV, IM, SC, INH, TOP, Transdermal
185
What are the advantages and disadvantages of IV administration?
```
+ 100% systemic availability
+ Rapid onset
+ Continuous infusion
- Embolism
- Sterile site/infection
- High drug levels at heart
```
186
What are the advantages and disadvantages of IM administration?
+ depo injection for slow release
+ Rapid onset of lipid soluble drugs
- Absorption dependent onmuscular perfusion
- Painful tissue damage
187
What are the advantages and disadvantages of transdermal administration?
+ slow absorption across skin
| - Local irritation possible
188
What are the 5 fluid compartments of the body?
Plasma water, interstitial water, intracellular water, transcellular water (CSF, synovial fluid), Fat
189
Only free/bound drugs can move between compartments?
Free
190
Where can both ionised and unionised drugs move by diffusion?
From plasma water to interstitial water only. To get further only unionised drugs move by diffusion
191
Are drugs evenly distributed in the body?
No
192
What is the calculation for Vd?
Vd = amount of drug in body / plasma concentration
193
What does a Vd imply?
a) <10L
b) 10-30L
c) >30L
a) Drug is largely retained in vascular compartment (too large or bound to plasma proteins)
b) Drug largely restricted to extracellular fluid (low lipid solubility)
c) Distribution throughout body water, accumulation in cirtain tissues or bound to tissue proteins
194
To perfuse the CNS what must a drug be?
highly lipid soluble
195
What is autocrine signaling?
Signaling molecules released by signaling cell bind to receptors on signaling cell to generate a response
196
What is paracrine signaling?
Signaling molecules released by signaling cell bind to receptors on nearby or adjacent target cells = response
197
What is endocrine signaling?
Signaling molecules released by signaling centre enter circulation and travel to another body region to target cells => response
198
What type of signaling is neuronal communication?
Specialist form of paracrine signaling
199
What are the 4 major classes of receptor?
1) Ligand gated ion channels (ionotraphic)
2) GPCR (metabotrophic)
3) Kinase linked (linked to the addition of phosphate)
4) Nuclear
200
Where are nuclear receptors located?
Plasma membrane, intracellular membrane (ER), cytoplasm or nucleus (hydrophobic molecules)
201
What molecules target kinase linked receptors?
Hydrophilic mediators eg insulin and growth factors
202
What forms ion channels?
Transmembrane pore formed by gylcoproteins which span the membrane
203
How are ion channels gated?
CHemical signals = ligand gated ion channels
Transmembrane voltage = voltage gated
Physical and mechanical stimuli = thermal and mechanical energy
204
What are the 3 categories of ligand gated ion channel based on protein sub unit assembly?
Trimeric (3 subunits, 2 membrane spans)
Tetrameric (4 subunits, 3 membrane spans)
Pentameric (5 subunits, 4 membrane spans)
205
How many binding sites on a nicotinic receptor?
2 and both must be filled for the ion channel to open effectively
206
What is a second messenger?
Water soluble signaling molocule which moves from the periphery to the centre of a cell to intracellular targets
207
What is the structure of a GPCR?
SIngle polypeptide with intracellular NH2 and intracellular COOH termini.
7 transmembrane spans with 3 intra and 3 extracellular loops
208
What is the structure of a G protein?
Guarrine nucleotide binding protein
Peripheral membrane protein with 3 polypeptide subunits (alpha, beta and gamma)
Exist in 3 types named according to alpha subunit
209
Where is the guarnine nucleotide binding site in the G protein?
Alpha sub unit which holds GTP or GDP
210
How are G proteins activated?
1) agonist binds to GPCR
2) In inactive state, beta and gamma paired to form a sub unit, GDP in alpha subunit, both attached covelently to the membrane
3) Alpha subunit contains GTPase domain with Ras and AH sub domains. Ras is the GTPase and AH clamps the nucleotide in place
4) GPCR undergoes a conformational change and G protein can bind causing a chage in alpha subunits
5) GDP is releases and GTP binds (guarnine nucleotide exchange)
6) Alpha subunit separates from receptor and beta/gamma dimer subunit dissociation
7) Generates a free GTP bound alpha subunit and a beta/gamma dimer that can signal
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How is the G protein signal switched off?
NB: the agonist may dissociate from the GPCR but the signal can continue
1) alpha subunit enzyme GTPase hydrolyses GTP and the signal is turned off
2) G protein alpha sub unit recombines with beta/gamma subunit completing the G protein cycle
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How do Gs and Gi proteins work?
Gs stimulates and Gi inhibits adenylyl cyclase.
Andenylyl cyclase converts ATP to cAMP which is a second messenger activating Protein kinase A in the cytoplasm which can phosphorylate other proteins for a cellular effect
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How does Gq protein work?
Gq activates phospholipase C
Phospholipase C converts PIP2 to IP3 and DAG (second messengers)
IP3 diffuses into the cytoplasm and binds to a receptor on the ER or SR => muscle contraction
DAG activates Protein kinase C => Phosphorylation of Ser/Thr residues and cellular effects
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How does insulin signal?
Receptor kinase unbound = 2 alpha and 2 beta subunits held by disulphide bonds
Binding of insulin causes autophosphorylation of intracellular tyrosine residues
=> Recruitment of multiple adapter proteins that are tyrosine phosphorylated
=> cellular effects- incorporation of glucose transporterd in the membrane to allow glucose absorption into the cell
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How does nuclear signaling work?
1) Steroid hormones enter cell by diffusion
2) Bind to an intracellular receptor producing dissociation of inhibitory HSP proteins
3) Receptor steriod complex moves into the nucleus and forms a dimer than binds to hormone response elements in DNA
4) Transcription of specific genes is transactivated or transrepressed to alter mRNA levels in the cell
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What is a nuclear receptor?
Ligand gated transcriptional factor
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Where are steroid and thyroid hormone receptors found?
```
Steroid = cytoplasm
Thyroid = nucleus
```
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What is the slowest and fastest form of signaling?
Nuclear receptors slowest
| Ligand gated ion channels fastest
