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Principles > Pharmacology > Flashcards

Pharmacology Flashcards

1
Q

What is the ENS?

A

All the neurones (cell bodies) embedded in the wall of the GI tract

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2
Q

What is an efferent nerve?

A

Motor nerve

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3
Q

What is an afferent nerve?

A

Sensory nerve

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4
Q

Which ANS reflexes can we exert some conciuos influence on with training?

A

Micturition, Deffication and accommodation in the eye

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5
Q

What is a ganglion?

A

A group of nerve cell bodies outside the CNS

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6
Q

What is a nucleus?

A

A group of nerve cell bodies inside the CNS

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7
Q

Where is the sympathetic outflow?

A

Thoracolumbar outflow T1-L2

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8
Q

In sympathetic neurones what is the neurotransmitter released by the preganglionic neurone?

A

ACh

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9
Q

In sympathetic neurones what is the neurotransmitter released by the postganglionic neurone?

A

Normally NA

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10
Q

In parasympathetic neurones what is the neurotransmitter released by the preganglionic neurone?

A

ACh

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11
Q

In parasympathetic neurones what is the neurotransmitter released by the postganglionic neurone?

A

ACh

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12
Q

Where is the parasympathetic outflow?

A

Cranialsacral outflow CN 3, 7, 9 and 10 and S2-S4

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13
Q

What receptors are used for the neurotransmitter ACh in the autonomic ganglia?

A

Nicotinic cholinoreceptors

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14
Q

What receptors are used for the neurotrasmitter ACh at effector cells/organs?

A

Muscarinic Cholinergic receptors

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15
Q

What receptors are used for the neurotransmitter NA at effector cells/organs?

A

Adrenoceptors

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16
Q

Where do sympathetic neurones synapse?

A

Within the sympathetic chain- paravertebral ganglia

Outside of the sympathetic chain- prevertebral ganglia

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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

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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

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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

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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

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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

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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)

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23
Q

Where are preganglionic fibre cell bodies located in the spinal cord?

A

Lateral horn

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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

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25
Q

What are chromaffin cells?

A

Modified post ganglionic neurones which secrete adrenaline (80%) and noradrenaline (20%) into the capillary circulation as hormones

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26
Q

What type of neurotransmitter is released by post ganglionic sympathetic neurones which innervate the thermoregulatory (eccrine) sweat glands and a few blood vessels?

A

ACh and they act on muscarinic cholinergic receptors

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27
Q

What are the neurotransmitters, other than NA is often used by the sympathetic nerves?

A

ATP and neuropeptide Y (NPY)

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28
Q

Where are parasympathetic ganglia usually located?

A

In the walls of target organs

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29
Q

Where are parasympathetic fibre cell bodies located?

A

Brainstem (mid brain, pons, medulla oblongata)

Sacral segment of the spinal cord

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30
Q

Where is the origin, ganglion and effector target for CN III (oculomotor)?

A 
Origin = Midbrain
Ganglion = Ciliary 
Target = Eye pupillary constrictor
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31
Q

Where is the origin, ganglion and effector target for CN VII (facial)?

A 
Origin = Pons 
Ganglion = Pterygopalatine and Submandibular
Target = Lacriminal glands (nasal cavity) and submandibular and sublingal glands.
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32
Q

Where is the origin, ganglion and effector target for CN IX (glossopharngeal)?

A 
Origin = Medulla oblongata
Ganglion = Otic 
Target = Parotid Gland
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33
Q

Where is the origin, ganglion and effector target for CN X (vagus)?

A 
Origin = Medulla Oblongata
Ganglion = Many
Target = Lots
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34
Q

What are the neurotransmitters, other than ACh is often used by the parasympathetic nerves?

A

NO nitric oxide

vasoactive intestinal peptide VIP

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35
Q

Release of what ion triggers action potentials to travel along and between neurones?

A

Ca++

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36
Q

What is a NANC?

A

Non adrenergic, non cholinergic transmission.

Where the post ganglionic neurone does not release NA or ACh

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37
Q

Which NANC neurone transmitters can be released and for what seed of response?

A 
Parasympathetic = VIP (slow response) and NO (intermediate response)
Sympathetic = ATP (fast respose) NPY (slow response)
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38
Q

What are nicotinic ACh receptors of the ganglia?

A

Ligand gated ion channels activated by nicotine

NB: structurally and pharmacologically different from nicotinic receptors at neuromuscular junctions or in CNS

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39
Q

What are muscarinic ACh receptors of effector cells?

A

G protein coupled receptors activated by muscarine

5 subtypes M1-M5 which are differentially expressed across organs

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40
Q

What are adrenoreceptors?

A

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)

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41
Q

What are the activators of alpha 1 adrenoreceptors?

A

NA > A > Isoprenalinie

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42
Q

What are the activators of alpha 2 adrenoreceptors?

A

Isoprenaline > A > NA

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43
Q

Micturation reflex: What happens during bladder filling?

A

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

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44
Q

Micturation reflex: What happens during bladder vioding?

A

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)

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45
Q

Micturation reflex: How do we voluntarily control the external urethral sphincter?

A

Somatic efferents (motor) and the release of ACh on cholinergic receptors

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46
Q

What is the bladder detrusor?

A

Smooth muscle wall

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47
Q

What is the Bladder trigone?

A

Smooth muscle triangular region formed by the 2 uteric orifices (from kidney) and the internal urethral orifice (sphincre)

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48
Q

Sympathetic//which receptors where?

Heart

A

Beta 1 adrenoceptors

Increase HR and force of contraction

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49
Q

Sympathetic//which receptors where?

Lungs

A

Beta 2 adrenoceptors

Relax bronchi, decrease mucus production

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50
Q

Sympathetic//which receptors where?

GI tract?

A

Alpha 1, 2 and beta 2 receptors

Decrease GI motility and constrict sphincters

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51
Q

Sympathetic//which receptors where?

Adrenal gland

A

Nicotinic ACh receptor

Release of adrenaline

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52
Q

Sympathetic//which receptors where?

Bladder

A

Beta 2 and 3 adrenoceptors
Relax detrusor
Alpha 1 adrenoceptors
Constricts the internal urethral sphincre

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53
Q

Sympathetic//which receptors where?

Penis

A

Alpha 1 adrenoceptor

Ejaculation

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54
Q

Sympathetic//which receptors where?

Vasculature?

A

alpha 1 adrenoceptors (most locations)
Constricts vasculature
Beta 2 adrenoceptors (skeletal muscle)
Relaxes vasculature

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55
Q

Parasympathetic// which receptor where?

Heart

A

M2

Decrease heart rate and force of contrition (atria only)

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56
Q

Parasympathetic// which receptor where?

Lungs

A

M3

Constrict bronchi and stimulate mucus production

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57
Q

Parasympathetic// which receptor where?

GI tract?

A

M3

Increases intestinal motility and relaxes sphincters

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58
Q

Parasympathetic// which receptor where?

Adrenal gland

A

No effect

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59
Q

Parasympathetic// which receptor where?

Bladder

A

M3
Contract detrusor
NO
Relaxes internal urethral sphincter

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60
Q

Parasympathetic// which receptor where?

Penis

A

M3 and NO

Penile erection

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61
Q

Parasympathetic// which receptor where?

Vasculature?

A

Largely no effect

except, penis, salivary glands, pancreas where it relaxes

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62
Q

Explain cholinergic synaptic transmission?

A

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

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63
Q

How is ACh synthesised in the cell?

A

Acetyl coenzyme A + choline –> Acetylcholine

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64
Q

What is the structure of nicotinic ACh receptors?

A

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.

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65
Q

What is the structure of nicotinic ACh receptors found in skeletal muscle?

A

2(alpha1), beta, gamma, epsilon

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66
Q

What is the structure of nicotinic ACh receptors found in ganglia?

A

2(alpha3), 3(beta4)

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67
Q

What is the structure of nicotinic ACh receptors found in CNS?

A 
5(alpha7)
or 2(alpha4), 3(beta2)
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68
Q

What is an epsp?

A

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

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69
Q

To stimulate and AP the epsp must reach what?

A

Threshold
Either by multiple preganglionic fibres synapsing at one post ganglionic fibre or repeated stimulation of one preganglionic fibre

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70
Q

Which G protein is activated by M1 receptors and what is the effect?

A

Gq => stimulation of phospholipase C => increase secretions

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71
Q

Which G protein is activated by M2 receptors and what is the effect?

A

Gi => inhibition of adenylyl cyclase and opening of K+ channels => decreased heart rate

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72
Q

Which G protein is activated by M3 receptors and what is the effect?

A

Gq => stimulation of phospholipase C => increase secretions/ contraction of visceral smooth muscle

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73
Q

Which G protein is activated by beta 1 adrenoceptors and what is the effect?

A

Gs => Stimultion of adenylyl cyclase => increased heart rate and force

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74
Q

Which G protein is activated by beta 2 adrenoceptors and what is the effect?

A

Gs => stimulation of aadenlyly cyclase => Relaxation of bronchial and vascular smooth muscle

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75
Q

Which G protein is activated by beta 3 adrenoceptors and what is the effect?

A

Gs => stimulation of adenylyl cyclase => Relaxation of bladder detrusor

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76
Q

Which G protein is activated by alpha 1 adrenoceptors and what is the effect?

A

Gq => Stimulation of phospholipase C => contraction of vascular smooth muscle

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77
Q

Which G protein is activated by alpha 2 adrenoceptors and what is the effect?

A

Gi => inhibition of adenylyl cyclase => Inhibition of NA release

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78
Q

There are receptors on both pre and post synaptic neurones at synapses. What are the receptors on presynaptic neurones called?

A

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

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79
Q

What is pharmokinetics?

A

What the body does to a drug

Absorptions, distribution, metabolism and excretion of drugs and metabolites

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80
Q

What is pharmodynamics?

A

What a drug does to the body

Biological effect and mechanisms of action

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81
Q

Metabolism + excretion = ?

A

Elimination

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82
Q

What is a drug?

A

Any singel synthetic or natural substance of fnown structure used in the prevention, treatment or diagnosis of a disease

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83
Q

What is a medicine?

A

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

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84
Q

Drugs bind to target molecules. How are they selective?

A

Chemical structure of the drug (binding site specificity

Target recognizing ligands of a precise structure (ligand specificity)

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85
Q

Most drugs bind to regulatory proteins. What are these?

What are the none protein targets?

A

Enzymes, carrier molecules, ion channels, receptors

DNA (anti cancer drugs) and RNA (antibiotics can bind to prokaryotic RNA)

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86
Q

What is an agonist?

A

A drug that binds to a receptor to produce a cellular response

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87
Q

What is an antagonist?

A

A drug that blocks the actions of an agonist by binding to the same receptor

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88
Q

What is affinity?

A

Strength of association between ligand and receptor

89
Q

What is efficacy?

A

The ability of an agonist to evoke a cellular response

90
Q

How is affinity determined?

A

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
Q

Do agonists possess affinity and efficacy?

A

Yes
Affinity is binding and has 2 rate constants (association and dissociation)
Efficacy is activation and has 2 rate constants (activation and deactivation)

92
Q

What determines efficacy?

A

The activation rate as the deactivation rate is similar for all drugs

93
Q

Do antagonists possess affinity and efficacy?

A

No just affinity as they do not produce a conformational change- just block the site

94
Q

Do drugs demonstrate michaelis menton kinetics?

A

Yes

95
Q

What is a full agonist?

A

A drug which can produce a 100% response

96
Q

Why would you plot concentration against response on a logarithmic axis rather than a linnear axis?

A

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
Q

What is potency?

A

Concentration range over which a drug is effective

98
Q

What is the MEC and MTC?

A

Minimal effective concentration

Maximal tolerated concentration

99
Q

What is the therapeutic index?

A

MTC/MEC

100
Q

What is the therapeutic window?

A

The range of plasma concentrations we want the drug to be within

101
Q

What is first order kinetics?

A

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
Q

What is the half life?

A

The time taken for the plasma concentration to fall by 50%

103
Q

What is the equation for half life?

A

t 1/2 = 0.69/Kel

Where Kel is the elimination rate constant

104
Q

Is the half life constant for a drug with first order kinetics?

A

Yes

105
Q

What is clearance?

A

The volume of plasma cleared of a drug per unit time

only for drugs with first order kinetics

106
Q

What is the equation for calculating the elimination rate constant?

A

Kel = Cl x Cp

Where Cl= clearance and Cp = plasma concentration

107
Q

What determines the maintenance dose rate?

A

Clearance

108
Q

What is the point of stready state?

A

Where rate of drug elimination = rate of drug administration

109
Q

What is the calculation for the rate of administration (IV) at steady sate?

A

Cl x (Cp at ss)

110
Q

How long does it take to reach steady state plasma concentration after administration?

A

5 half lives

111
Q

What is oral bioavailability?

A

The fraction of the drug administered that enters the systemic circulation

112
Q

What is a loading dose?

A

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
Q

Why is a loading dose used?

A

To decrease the time to steady state for drugs with a long half life

114
Q

What is the calculation for a loading dose when giving IV?

A

LD= Vd x target Cp

Where Vd = volume of distribution

115
Q

What is the volume of distribution?

A

The volume in which a drug appears to be distributed with a concentration equal to that of plasma

116
Q

What is zero order kinetics?

A

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
Q

Why must you be careful with drugs with zero order kinetics?

A

Plasma steady state concentration is not linnearly related to dose. Hard to stay within the therapeutic window

118
Q

What is depolarisation?

A

The membrane potential becomes less negative.

referring to the excess of charge on the inside of a cell

119
Q

What is hyperpolarisation?

A

The membrane potential becomes more negative. referring to the excess of charge on the inside of a cell

120
Q

WHat drives the passive movement of ions?

A

electrochemical gradient for the ion

121
Q

Why does Na+ normally move into the cell?

A

Concentration gradient is inward and the electrical gradient is inward

122
Q

When the driving force for Na+ influx is negative, what happens to Na+?

A

Moves INTO the cell

Vm - ENa+ = -80 - 60 = -140mV

123
Q

Why does K+ normally move out of the cell?

A

The concentration gradient is outward and has an energy which EXCEEDS that of the electrical gradient which is inwards

124
Q

When the driving force for K+ is positive, what happens to K+?

A

Moves OUT of the cell

Vm - EK+ = -80 - -100 = +20mV

125
Q

What happens to the membrane potential when:

a) Na+ channels open
b) K+ channels open

A

a) The membrane potential is driven towards ENa+ (+60mV)

b) The membrane potential is driven towards EK+ (-100mV)

126
Q

What is ENa+ and EK+?

A

The equilibrium potential for Na+/K+

127
Q

What is the threshold potential?

A

The potential which must be exceeded to generate an action potential (-60mV)

128
Q

What is the resting potential?

A

Unexcited state of the membrane (-80mv)

129
Q

What is the upstroke?

A

Depolarisation of the membrane

130
Q

What is the Downstroke?

A

Hyperpolarisation/repolarisation

131
Q

What is an action potential?

A

A brief electrical signal in which the polarity of the nerve cell membrane is momentarily reversed (2 milliseconds)

132
Q

Do action potentials have a constant magnitude and velocity?

A

Yes- its axon dependent

133
Q

What activates voltage gated Na+ and K+ channels?

A

Membrane depolarisation
Na+ immediately
K+ after a delay

134
Q

Does activation of Na+ channels follow positive or negative feedback? Explain.

A

Positive feedback. Depolarisation => Increasing Na+ conductance => greater inward Na+ current => Greater depolarisation

135
Q

Does activation of K+ channels follow positive or negative feedback? Explain.

A

Negative feedback.
Depolarisation => Increased K+ conductance => Outward K+ current => repolarisation.
Repolarisation turns the signal for channel opening off

136
Q

There are two gates within the voltage activated sodium channel. What are these?

A

Activation gate and the inactivation gate

137
Q

Following depolarisation what state is the Na+ channel in?

A

Open conducting state

Both activation gate and inactivation gate are open

138
Q

Following maintained depolarisation what state is the Na+ channel in?

A

Inactivated non-conducting state

Inactivation gate is closed but the activation gate is open

139
Q

Following repolarisation what state is the Na+ channel in?

A

Closed non conducting state

Activation gate is closed but the inactivation gate is open

140
Q

What does the inactivation state of the Na+ channel allow?

A

Repolarisation phase and is responsible for the absolute refractory period

141
Q

How can the inactivation gate of a Na+ channel be opened?

A

Repolarisation of the membrane

142
Q

What is the absolute refractory period?

A

Where no stimulus, however strong can elicit a second action potential (all Na+ channels are inactivated)

143
Q

What is the relative refractory period?

A

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
Q

Why is propagation of a action potential unidirectional?

A

Refractory period and Na+ channels are inactivated

145
Q

Why does an action potential decay?

A

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
Q

What is cable therory?

A

Where current leaks back into the extracellular space across the membrane resistance generating a potential change.

147
Q

What will increase the leakage of current across the membrane?

A

Decreasing the membrane resistance and increasing the axon resistance

148
Q

What is saltatory conduction?

A

Propagation of action potentials along myelinated neurones from one node of ranvier to the next increasing the AP velocity

149
Q

What are some demyelinating disorders?

A

MS (CNS)
Guillian Barre syndrome (PNS) (Reversible)
Both cause slowing/ceasing of nerve conduction

150
Q

Is axial resistance smaller in wide or narrow APs?

A

Wide and therefore conduction is faster

151
Q

Which cells produce myelin in the PNS and CNS?

A 
PNS = schwann cells
CNS = Oligodendrocytes
152
Q

How many schwann cells are needed for each axon of the PNS?

A

many

153
Q

How many oligodendrocytes are needed for each axon in the CNS?

A

One oligodendrocyte can insulate many axons in the CNS

154
Q

What is absorption?

A

The process by which a drug enters the body from its site of administration and enters the general circulation

155
Q

What is distribution?

A

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
Q

What is metabolism?

A

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
Q

What is excretion?

A

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
Q

What characteristics of a drug can affect its absorption?

A

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
Q

Which drugs can enter the vascular compartment?

A

Hydrophilic drugs

160
Q

Why are some drugs ineffective orally?

A

Digested in gut or destroyed by stomach acid

161
Q

Give an example of a drug destroyed by stomach acid and must be given IV?

A

Benzylpenicillin

162
Q

Give an example of a drug digested by enzymes and must be given IM?

A

Insulin

163
Q

In IBS treatment the drug is inactive in the small intestine but active in the colon. How is this?

A

Drug is modified by the GI tract. Bacteria in the colon activate the drug.

164
Q

What is the lipid to water partition coefficient?

A

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
Q

What is the ionised form of an acid and a base?

A

Acid A-

Base BH+

166
Q

WHat is the unionised form of an acid and a base?

A

Acid HA

Base B

167
Q

Onle ionised/unionised forms of a drug will diffuse across a biilayer?

A

Unionised

168
Q

What does the degree of ionisation depend on?

A

pKa of the drug and the pH of the environment

169
Q

When does pH = pKa?

A

At equilibrium, when half the drug is ionised and half the drug is not?

170
Q

Give an example of an acidic drug?

A

Asprin pKa = 3.4

171
Q

What equations can be used to calculate the proportions of drugs ionised?

A

Henderson hasselback equestions

See workshop sheets

172
Q

An acidic drug will ionise more/less in an acidic pH but will ionise less/more in a basic pH.

A

Less in acid

More in base

173
Q

An basic drug will ionise more/less in an acidic pH but will ionise less/more in a basic pH.

A

more in acid

Less in base

174
Q

Where are acidic and basic drugs absorbed?

A

Acidic = stomach
Basic = small intestine
NB: most absorption, even of weak acids occurs in the intestine

175
Q

Weak acids and bases are better absorbed than strong acids and bases. T or F?

A

True

176
Q

What GI factors can affect absorption?

A

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
Q

What is oral availability?

A

The fraction of the drug that reaches the systemic circulation after oral ingestion
Oral availability = amount in systemic circulation / amount administered

178
Q

What is systemic availability?

A

The amount of a drug that reaches the systemic circulation after absorption
Systemic availability = amount in systemic circulation / amount absorbed

179
Q

Why do IV drugs have a 100% systemic availability?

A

Bypass liver/ first pass metabolism

180
Q

What is first pass metabolism/presystemic metabolism?

A

The modification/destruction of someoral drugs by the liver and gut wall enzymes

181
Q

What is an entral route?

A

A drug which is swallowed and enters the GI tract

182
Q

Give 3 entral routes of drug administration?

A

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
Q

What is the paraentral route?

A

Not via the GI tract

184
Q

Give 6 examples of paraentral route administration?

A

IV, IM, SC, INH, TOP, Transdermal

185
Q

What are the advantages and disadvantages of IV administration?

A 
\+ 100% systemic availability
\+ Rapid onset
\+ Continuous infusion
- Embolism
- Sterile site/infection
- High drug levels at heart
186
Q

What are the advantages and disadvantages of IM administration?

A

+ depo injection for slow release
+ Rapid onset of lipid soluble drugs
- Absorption dependent onmuscular perfusion
- Painful tissue damage

187
Q

What are the advantages and disadvantages of transdermal administration?

A

+ slow absorption across skin

- Local irritation possible

188
Q

What are the 5 fluid compartments of the body?

A

Plasma water, interstitial water, intracellular water, transcellular water (CSF, synovial fluid), Fat

189
Q

Only free/bound drugs can move between compartments?

A

Free

190
Q

Where can both ionised and unionised drugs move by diffusion?

A

From plasma water to interstitial water only. To get further only unionised drugs move by diffusion

191
Q

Are drugs evenly distributed in the body?

A

No

192
Q

What is the calculation for Vd?

A

Vd = amount of drug in body / plasma concentration

193
Q

What does a Vd imply?

a) <10L
b) 10-30L
c) >30L

A

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
Q

To perfuse the CNS what must a drug be?

A

highly lipid soluble

195
Q

What is autocrine signaling?

A

Signaling molecules released by signaling cell bind to receptors on signaling cell to generate a response

196
Q

What is paracrine signaling?

A

Signaling molecules released by signaling cell bind to receptors on nearby or adjacent target cells = response

197
Q

What is endocrine signaling?

A

Signaling molecules released by signaling centre enter circulation and travel to another body region to target cells => response

198
Q

What type of signaling is neuronal communication?

A

Specialist form of paracrine signaling

199
Q

What are the 4 major classes of receptor?

A

1) Ligand gated ion channels (ionotraphic)
2) GPCR (metabotrophic)
3) Kinase linked (linked to the addition of phosphate)
4) Nuclear

200
Q

Where are nuclear receptors located?

A

Plasma membrane, intracellular membrane (ER), cytoplasm or nucleus (hydrophobic molecules)

201
Q

What molecules target kinase linked receptors?

A

Hydrophilic mediators eg insulin and growth factors

202
Q

What forms ion channels?

A

Transmembrane pore formed by gylcoproteins which span the membrane

203
Q

How are ion channels gated?

A

CHemical signals = ligand gated ion channels
Transmembrane voltage = voltage gated
Physical and mechanical stimuli = thermal and mechanical energy

204
Q

What are the 3 categories of ligand gated ion channel based on protein sub unit assembly?

A

Trimeric (3 subunits, 2 membrane spans)
Tetrameric (4 subunits, 3 membrane spans)
Pentameric (5 subunits, 4 membrane spans)

205
Q

How many binding sites on a nicotinic receptor?

A

2 and both must be filled for the ion channel to open effectively

206
Q

What is a second messenger?

A

Water soluble signaling molocule which moves from the periphery to the centre of a cell to intracellular targets

207
Q

What is the structure of a GPCR?

A

SIngle polypeptide with intracellular NH2 and intracellular COOH termini.
7 transmembrane spans with 3 intra and 3 extracellular loops

208
Q

What is the structure of a G protein?

A

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
Q

Where is the guarnine nucleotide binding site in the G protein?

A

Alpha sub unit which holds GTP or GDP

210
Q

How are G proteins activated?

A

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

211
Q

How is the G protein signal switched off?

A

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

212
Q

How do Gs and Gi proteins work?

A

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

213
Q

How does Gq protein work?

A

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

214
Q

How does insulin signal?

A

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

215
Q

How does nuclear signaling work?

A

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

216
Q

What is a nuclear receptor?

A

Ligand gated transcriptional factor

217
Q

Where are steroid and thyroid hormone receptors found?

A 
Steroid = cytoplasm
Thyroid = nucleus
218
Q

What is the slowest and fastest form of signaling?

A

Nuclear receptors slowest

Ligand gated ion channels fastest

Principles (12 decks)

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