MGEM2016

Question 1

What are molecular target of Tubocurarine, Atracurium & Pancuronium? (these drugs aka?)

target of pyridostigmine & neostigmine?

target receptors/ion channels/enzymes/transporters?

Answer 1

CUR: reversible competitive antagonist of nicotinic acetylchocline receptor (=ligand-gated ion channels) aka non-depolarizing neuromuscular blocking agent

STIG: reversible acetylcholinesterase inhibitor

Question 2

Identify cellular mechanisms of action including excitation, contraction and secretion?

Describe how these actions translate into responses at the tissue and organ level?

Question 3

Explain the mechanism of action of nicotinic receptor antagonists?

Answer 3

reversible competitor to ACh, prevent ACh from binding to receptors by blocking ACh binding site on receptor

Question 4

Explain how acetylcholinesterase (AChE) inhibitors can be used as medicines and as poisons?

Answer 4

Medicine: AChE inhibitor
prevent ACh being broken down to acetate + choline
thus ACh conc increases in synaptic cleft, eventually outcompete nicotinic antagonists so pyridostigmine/neostigmine used as antidote for curare poisoning

pyridostigmine/neostigmine relieve myasthenia gravis, an Autoimmune condition where some nicotinic receptor inactivated causing reduced muscle control, by overstimulating nicotinic receptor

Poison: Sarin/Soman/Novichok gas
irreversible binding to AChE, ACh not broken down so conc increases, results in overstimulation of nicotinic ACh receptor, leading to depolarising blockade, thus muscle weakness & eventually paralysis. Death commonly by respiratory muscle paralysis especially diaphragm causing respiratory failure.
(Overstimulate muscarinic Ach receptor cause bronchoconstriction & excess mucus production, CNS also suppress respiration due to overstimulate both nico & musca)

Answer 5

acetylcholinesterase inhibitor
 acetate + choline
This terminates the action of acetylcholine
Choline is transported back into the presynaptic terminal
Choline is combined with acetyl-CoA to form acetylcholine again.

Question 6

Explain why anticholinesterases can be used to reverse competitive neuromuscular blockade (e.g. with pancuronium or tubocurarine)

Answer 6

In competitive neuromuscular blockade, antagonists such as pancuronium & tubocurarine occupy nicotinic ACh receptor and prevent ACh from binding and activating the receptor. Therefore release of ACh from the nerve doesn’t cause muscle to contract

When anticholinesterase is present, AChE is inhibited & can’t break down ACh. ACh conc increases in synapse, so more receptors are activated (receptor binding & activation is conc-dependent), thus more muscle contraction.

Question 7

what would happen if a patient with myasthenia gravis took too high a dose of pyridostigmine?

Answer 7

Pyridostigmine is AChE inhibitor.

At neuromuscular junction, ACh is released and acts on nicotinic ACh receptors to cause muscle contraction.

If pyridostigmine is present, ACh is not broken down in synapse, so ACh conc builds up. A higher conc of ACh in synapse means that the nicotinic ACh receptors are activated more and eventually they get desensitised. meaning that they no longer respond to ACh, thus losing muscle control

Question 8

Explain why pyridostigmine is used but Sarin is not even though both are acetylcholinesterase inhibitors

Answer 8

Sarin not used as it irreversibly bind to AChE prevent ACh being broken down, ACh conc increases, receptors activated more eventually desensitised, so permanently lost muscle control?

whereas pyridostigmine & neostigmine are slowly reversible

Question 9

data interpretation tutorial Qs

Question 10

Compare & contrast nicotinic & muscarinic receptors

Answer 10

nicotinic: Ligand gated ion channel receptor; Activation results in contraction of skeletal muscle; Activated by nicotine; Blocked by tubocurarine

muscarinic: G protein coupled receptor; Activation results in contraction of smooth muscle; Activated by muscarine and pilocarpine; Blocked by atropine

both: activated by ACh

Question 11

A farmer is exposed to an organophosphate sheep-dip which contains an anticholinesterase. What symptoms might you expect? Why?

Answer 11

Anticholinesterases inhibit acetylcholinesterase which is the enzyme responsible for breaking down acetylcholine in the synapse.
If acetylcholinesterase is inhibited, then conc of ACh builds up in the synapse, results in overactivation/overstimulation of ACh receptors.

There are ACh receptors in many places in the body:
* Nicotinic ACh receptors in skeletal muscle – overactivation here means ultimately paralysis as the nicotinic ACh receptors get desensitised.
.
* Muscarinic ACh receptors in smooth muscle – results in contraction
* * of gut means more peristalsis and so diarrhoea;
* * of bladder means more contraction- micturition
* * Of bronchi means more bronchoconstriction and so breathlessness
.
* Muscarinic ACh receptor in glands – results in secretions
* * Of bronchi means more mucus secretion
* * Of stomach means more acid secretion
* * Of salivary gland means more salivation

Question 12

muscarinic ACh receptor agonists? antagonists?

which muscarinic antagonist is fast-acting but short duration?

Answer 12

Agonist: ACh, muscarine (not used), pilocarpine
.
Antagonist: atropine, ipratropium, tiotropium

ipratropium fast-acting, short duration
tiotropium slow-acting, long duration

Question 13

• Explain how drugs that activate muscarinic ACh receptors can be used therapeutically & Explain their mechanism of action
• Explain how muscarinic ACh receptors antagonist can be used therapeutically

Answer 13

muscarinic agonist like pilocarpine induce PNS effects like reducing heart rate, salivation, bronchoconstriction, increasing GI motility & micturition. Thus can treat tachycardia, dry mouth, constipation & urine retention

Muscarinic agonists are ACh analogue, they mimic ACh by binding to muscarinic (Gq protein-coupled) receptor, initiate intracellular signalling, PIP2 is hydrolysed to IP3 & DAG by phospholipase C (PLC). IP3 trigger calcium release from sarcoplasmic reticulum, calcium activate myosin light chain kinase (MLCK) which phosphorylate MLC, trigger muscle contraction

muscarinic antagonists like ipratropium & tiotropium inhibit parasympathetic effects so can treat bronchoconstriction, over-reactive bladder, irritable bowel

Question 14

A woman has had surgery and is left with xerostomia (dry mouth). What class of drug could be used to treat this and what possible unwanted effects might be observed?

Answer 14

She needs to increase salivation so this would mean a muscarinic agonist would be useful – e.g. is pilocarpine.
Pilocarpine would also activate muscarinic receptors elsewhere in the body leading possibly to e.g. bronchoconstriction, sweating, increased peristalsis (and so diarrhoea), micturition.

Question 15

A group of teenagers visiting the Chelsea Physic garden in London decided to sample the berries of Atropa belladonna (contains atropine). Describe the effects this could have on them.

Answer 15

Atropine is an antagonist at muscarinic receptors so this will prevent all the effects of the parasympathetic nervous system:
increased heart rate (since the slowing effect of ACh is prevented)
less gut movement – possibly constipation
Dry mouth

Atropine crosses the blood brain barrier and can cause hallucinations and sedation.

Question 16

Which of the following could theoretically be used for overactive bladder?

Muscarinic agonist,
muscarinic antagonist
Nicotinic agonist,
nicotinic antagonist

Answer 16

muscarinic antagonist
.
We tend not to use nicotinic agonists and antagonists for their effects in the autonomic nervous system because they affect both sympathetic and parasympathetic pathways and so can have complex effects.

Question 17

Why does atropine cause central nervous system side effects but ipratropium does not?

Answer 17

Ipratropium has a positive charge so it does not cross cell membranes easily whereas atropine is relatively lipid soluble so it cross membrane easily.

There are muscarinic receptors in the brain and atropine can cross blood brain barrier, cause confusion & hallucinations.

Question 18

Why is ipratropium given by inhaler?

What would you expect if it was given by tablet?

Answer 18

Because ipratropium/tiotropium are charged so don’t cross membranes very easily and it acts at the smooth muscle in the airways so direct administration will improve delivery to the site of action and reduce unwanted effects.

if given by tablet, more widespread side effects eg reduced GI motility, difficulty of micturition (=urine retention)

Question 19

A patient is found after suspected poisoning and has excessive saliva, bronchoconstriction and slow heart rate. What is the poison?

Answer 19

This all points to excessive activation of the parasympathetic nervous system. It is therefore likely to be a muscarinic agonist.
An anticholinesterase is a potential candidate but there is no sign of skeletal muscle weakness so this would rule this out.

Question 20

A patient with myasthenia gravis is given pyridostigmine but is experiencing abdominal cramps, diarrhoea, excessive tearing and hypersalivation. What drug could you give to reduce these unwanted effects without affecting their skeletal muscle strength?

Answer 20

A muscarinic antagonist such as atropine

Nicotinic antagonists like atracurium & pancuronium can prevent parasympathetic postganglionic neurons from being activated, so can reduce these side effects but may affect skeletal muscle as nicotinic receptors are also in skeletal muscles

Question 21

Explain the assessment of receptor selectivity

Question 22

Predict & explain unwanted effects of drugs acting in the parasympathetic nervous system, namely muscarinic ACh receptor antagonist?

Answer 22

can include:
* increased heart rate (since the slowing effect of ACh is prevented)

• less gut movement – possibly constipation
• Dry mouth (reduced salivation)
• bronchodilation & reduced mucus secretion
• urine retention
• Atropine crosses blood brain barrier, so can cause hallucinations & sedation. Atropine can also cause Dilation of pupils(=Mydriasis) & blurring of near vision

wanted effect= bronchodilation & reduced mucus secretion in case of asthma

Question 23

Which receptors are present at the synapse between the pre-ganglionic and post-ganglionic neurons of the parasympathetic nervous system?

Answer 23

neuronal nicotinic ACh receptor

Question 24

What effect will atracurium have on heart rate?

Answer 24

No effect

atracurium bind to nicotinic recetor but heart smooth muscles have muscarinic receptor???

Question 25

Which of the following results from the action of atropine?

a.increased bronchial secretions

b.
decreased heart rate

c.
dry mouth

d.
increased micturition

e.
increased gut motility

Answer 25

dry mouth

Question 26

In bronchial smooth muscle, activation of muscarinic acetylcholine receptors results in activation of which protein next in the sequence?

Gi G protein

b.
Gs G protein

c.
calcium channels

d.
sodium channels

e.
Gq G protein

Answer 26

Gq G protein

Question 27

What effect will neostigmine have on salivary glands?

Answer 27

increase salivation

Question 28

What substance is released from the vagus nerve and slows heart rate?

neurotransmitter

Answer 28

ACh

Question 29

Pilocarpine will have what effect on gut motility?

Answer 29

increase

is a muscarinic agonist

Question 30

cellular mechanisms of action of noradrenaline/adrenaline in increasing heart rate & contraction force?

Answer 30

NA/adrenaline bind to β1-adrenergic Gs protein coupled-receptor in heart, upregulates adenylyl cyclase which converts ATP to cAMP. cAMP increase Na+ influx, increasing heart rate.
cAMP stimulate protein kinase A (PKA) to phosphorylate calcium pumps, increasing cellular calcium influx, so increasing contraction force

Question 31

Explain the assessment of receptor selectivity

Question 32

β2 agonist for bronchodilation?
.
Predict & explain unwanted effects of them?

Answer 32

salbutamol, salmeterol

unwanted effect: increased hear rate, decreased GI motility, decreased stomach secretion & urine retention

Question 33

A child has taken an overdose of a nasaldecongestant containinganα1-adrenergic agonist.What symptoms might you observe? Why?

Answer 33

Activation of alpha1 adrenergic receptors causes vasocontriction – in this case in the blood vessels in the nose as the drug is administered usually by nasal spray. At higher doses, there is more general vasoconstriction so an increase in blood pressure could be expected.

Question 34

Adrenaline and salbutamol both activateβ2-adrenergic receptors to cause bronchodilation. Whydon’t we use adrenaline?

• Would it help to use both?

Answer 34

Adrenaline has a very short duration of action and it affects other adrenergic receptors and so has a lot of unwanted effects. In contrast salbutamol is longer acting [up to 6 h as more resistant to metabolism by monoamine oxidase (MAO) & by Catechol-O-methyltransferase (COMT)] and is selective for β2-adrenergic receptors.
.
Using both wouldn’t help because they would both compete for beta2 receptors which are the target for bronchodilation and adrenaline would also cause lots of unwanted effects through acting on other adrenergic receptors.

Question 35

sympathetic tutorial graph Qs

Question 36

cellular mechanisms of action of adrenaline in bronchodilation?

Answer 36

Adrenaline bind to β2-adrenergic Gs protein coupled-receptor in lungs, upregulates adenylyl cyclase which converts ATP to cAMP. cAMP stimulate protein kinase A (PKA) to phosphorylate myosin light chain kinase (MLCK), cause relaxation of smooth muscle

Question 37

Compare & contrast synapses with acetylcholine acting on muscarinic receptors and noradrenaline acting on β1-adrenoreceptors

Answer 37

muscarinic: =endogenous agonist is ACh
=Coupled to Gq G-protein, so increase in intracellular calcium [phospholipase C (PLC) hydrolyse PIP2 to IP3 & DAG, IP3 trigger calcium release from sarcoplasmic reticulum to cause muscle contraction]
=Also coupled to Gi G-protein and so decrease in cAMP
=antagonists: atropine, ipratropium, tiotropium
.
both: G-protein-coupled-receptor
.
beta-1 adrenoreceptor: =endogenous agonist is noradrenaline
=Coupled to Gs G-protein, so increase in cAMP (Gs=stimulatory G protein)
=Antagonist e.g. propranolol (both beta1 & beta2), atenolol (just beta1)

Question 38

What are effects of amphetamine in the sympathetic nervous system?

including unwanted effects as NA build up in synapse

Answer 38

=tachycardia, increased heart contraction force
=vasoconstriction,
=increased fluid volume so increased blood pressure via renin-angiotensin-aldosterone system (renin released from granular cells of renal juxtaglomerular apparatus under sympathetic β1 stimulation)
.
=difficulty urinating

excessive strain on Cardiovascular system, may cause heart attack

amphetamine & cocaine inhibit NA reuptake transporter recycle NA back into presynaptic neuron, so NA remain in synapse, continuously activating adrenoreceptors, so greater activation of sympathetic NS

angiotensin vasoconstrict & stimulate aldosterone release, aldosterone cause kidneys retain water & salt to increase body water volume

Question 39

Cocaine inhibit which protein in the sympathetic nervous system?

Answer 39

noradrenaline reuptake transporter

Question 40

Which receptor responds to noradrenaline in the airways, in heart, in gut & in blood vessels?
.
Adrenaline is more potent than NA at what types of adrenergic receptor?

Answer 40

airways/lungs: β2 adrenergic

gut: α1 & β1 adrenoreceptors

vessel: α1 & β2 adrenoreceptors

heart: β1

Adrenaline is more potent than NA at α1-, α2-, β2-adrenergic
.
they have same potency at β1-adrenergic

Question 41

Which neurotransmitter is released from sympathetic neurons forming synapses with heart tissue?

Answer 41

Noradrenaline

Question 42

Which are actions that occur after activation of the sympathetic nervous system?

Answer 42

Sweating, (ACh at synapse)

Urinary retention,

Bronchodilation, reduced mucus secretion

reduced salivation,

increased heart rate,

decreased GI motility,

adrenal medulla secrete adrenaline & noradrenaline (ACh at synapse)

Question 43

• Identify molecular targets for drug action in the treatment of asthma and COPD (Chronic Obstructive Pulmonary Disease)
  .
• Identify cellular mechanisms of action and describe how these actions translate into responses at the tissue and organ level

Question 44

State the major classes of drugs used in the management of respiratory disease?
.
Describe their pharmacological mechanism of action
Explain their major adverse effects

Answer 44

β2-agonists (salbutamol): activate β2-adrenoreceptor in bronchial smooth muscle, activate sympathetic system cause bronchodilation & muscle relaxed. also Stabilise mast cells & inhibit inflammatory mediator release. May induce skeletal muscle tremor (may due to hypokalaemia as interstitial K+ enter muscle), tachycardia/arrhythmia (some β2 receptor in heart&drug not 100% β2-selective)
.
muscarinic ACh receptor antagonists (ipra/tiotropium): prevent ACh inducing parasympathetic NS effect of bronchoconstrict & increased muscus secretion. May cause dry mouth, urine retention, blurred vision (due to drug non-specificity/mydriasis effect of drug).
.
Methylxanthines (theophylline): Inhibit phosphodiesterase (so cAMP not broken down, cAMP build up to prolong bronchial smooth muscle relaxation by β2 activation. also block adenosine receptors. May cause CNS stimulation (As theophylline same class as caffeine) & GI disturbances

.
Corticosteroids (Beclomethasone, fluticasone): Diffuse into cytoplasm, bind to cytoplasmic receptor then translocate to nucleus to modify transcription, increase anti-inflammatory mediator, decrease pro-inflammatory. Inhibit Th2 cytokine-induced IgE antibodies production & eosinophil & mast cell activation. prolonged high dose cause Adrenal suppression, Osteoporosis, immunosuppression (prone to infection)
.
Cys-leukotriene receptor antagonists (Montelukast/Zafirlukast): inhibit bronchoconstriciton, plasma exudation, eosinophil recruitment & mucus secretion. May cause headaches, abdominal pain

Question 45

Describe different routes of respiratory drug administration
.
explain main advantages & disadvantages of each

Answer 45

topical (skin) application of corticosteroids: fewer systemic adverse effect & avoid 1st pass metabolism but can cause skin irritation & epidermis enzymes may denature drug
.
inhalation (with spacer/mouth wash): fewer adverse effect as little systemic absorption, direct delivery to affected area but not guaranteed to reach affected area & drug retention can happen
.
oral: convenient, safe, but more systemic adverse effect & unpredictable GI absorption
.
Intravenous: Bioavailability=100%., drug action rapid, but more systemic adverse effect & need asceptic condition

Question 46

Predict and explain unwanted effects of drugs used in the treatment of asthma and COPD

Answer 46

COPD: muscarinic antagonists & β2-agonists used so reversal of parasympathetic effect (dry mouth, urine retention) & skeletal muscle tremor, tachycardia
.
asthma: β2 agonists with anti-inflammatory e.g. inhaled corticosteroid so skeletal muscle tremor, tachycardia & (due to prolonged high dose corticosteroid) adrenal suppression, osteoporosis

Question 47

An asthmatic student has an asthma attack during an exam. They try to use their blue asthma inhaler but get no effect. They are given oxygen and a nebuliser with salbutamol in the ambulance on the way to hospital and begin to feel better.
When asked later in A&E whether they had taken any other drugs they said that a friend had given them something called propranolol because they had been very anxious and it helped calm them down.
.
1.Why didn’t their asthma inhaler work?
2.What other questions should you ask them?

Answer 47

1.Propranolol is a beta adrenergic antagonist and so it would have prevented the salbutamol from being able to bind to its receptor and cause the bronchodilation. It is also possible that their airways were so constricted that they weren’t able to get the salbutamol down into the bronchi and enough salbutamol was delivered via the nebuliser to overcome this.
.
2.What other questions should you ask them?
You should ask them whether they have been using their inhaler a lot over the last few weeks (i.e. more than 3x per week). In this case they need to start taking a corticosteroid (e.g. beclomethasone or fluticasone) to reduce the inflammation.

Question 48

Explain why constipation and a dry mouth are common side effects of ipratropium.

Answer 48

Ipratropium is a muscarinic antagonist. It is normally given as an inhaled so quite targeted to the airways for COPD but sometimes some can be swallowed or be absorbed into the salivary glands. Muscarinic ACh receptors in salivary glands cause salivation when activated by ACh so an antagonist will prevent that and cause a dry mouth.
ACh action in the gut is to increase smooth muscle contraction so blocking this will lead to less motility and therefore constipation.

Question 49

A patient has been taking their blue asthma inhaler twice a day for the last few weeks and find that it is no longer working so well.
.
1.What other class of drugs should they be given?
2.What would you need to explain to them regarding onset of action of the drug?
3.Why is this class of drug given as an inhaler rather than a tablet?

Answer 49

1.Corticosteroid such as beclomethasone or fluticasone. This is to reduce the inflammation so they don’t need to take the beta2 agonist as often.
.
2.Corticosteroids can take several days to start to work. (This is because they alter gene transcription of endogenous inflammatory mediators – they increase anti-inflammatory mediators and decrease pro-inflammatory mediators.
.
3.To reduce the likelihood of systemic adverse effects. Corticosteroids have effects on a lot of tissues and can cause unwanted effects such as muscle wasting, thinning skin, decreased infection response etc.

Question 50

Compare and contrast acetylcholine and adrenaline

what structures they are produced in,
how/if they are stored and released
where in the body to exert their effects.
how their action is terminated

Answer 50

ACh: stored in vesicles, released as neuronal membrane depolarised by action potential; nicotinic ACh receptors in skeletal muscle, between pre- & post-ganglionic neurons; muscarinic ACh receptor in smooth muscle & glands; action terminated by AChE breaking ACh down to choline & acetate
.
Adrenaline: released by adrenal medulla in response to stress; produced in the final step of conversion of tyrosine, which is gradually converted by various enzymes into L-Dopa, then dopamine, then noradrenaline, then adrenaline; adrenergic receptor in heart, lungs, gut, blood vessels; action terminated by metabolic breakdown by catechol-O-methyltransferase (COMT) or monoamine oxidase (MAO), by reuptake into nerve endings (when as neurotransmitter in CNS) & by diffusion from active sites

Question 51

Compare & contrast thromboxane & adrenaline

what structures they are produced in,
how/if they are stored and released
where in the body to exert their effects.
how their action is terminated

Answer 51

Adrenaline: released by adrenal medulla in response to stress; produced in the final step of conversion of tyrosine, which is gradually converted by various enzymes into L-Dopa, then dopamine, then noradrenaline, then adrenaline; adrenergic receptor in heart, lungs, gut, blood vessels; action terminated by metabolic breakdown by catechol-O-methyltransferase (COMT) or monoamine oxidase (MAO), by reuptake into nerve endings (when as neurotransmitter in CNS) & by diffusion from active sites
.
thromboxane: arachidonic acid converted by cyclo-oxygenase (COX) to cyclic endoperoxides, converted to thromboxane A2 (TxA2) by thromboxane synthase; released to plasma by platelets; bind to TP receptor (G Protein-Coupled) expressed in platelets, smooth muscle, endothelial cells, lungs, kidneys, heart, thymus & spleen, to stimulate vasoconstriction & platelet aggregation. TxA2 is hydrolyzed to TxB2 (inactive metabolite) prior to enzymatic degradation

Question 52

State the following drugs’ target, effect on target tissue & what they’re used for:
.
Adrenaline/Salbutamol/Salmeterol
Theophylline
Beclomethasone
Fluticasone
Montelukast

Question 53

absorption

Describe the mechanisms underlying passive diffusion & active transport of drugs

Answer 53

active: drug is a substrate for transporter/carrier driven by ATP
.
passive: faster if smaller molecule & more permeable memb. Drugs need to be sufficiently Hydrophobic to pass bilayer but not too hydrophobic otherwise tablets cant dissolve in bodily fluids

Question 54

absorption

Describe the relationship between pH, pKa & degree of ionisation of acidic and basic drugs
.
use this relationship to predict movements of drugs across membranes at various sites of the body

Answer 54

weak acid (high pKa): in stomach has lower pH, higher [H+], so equi shift to uncharged HA (=more weak acid in unionised form), so lots absorbed passively in stomach
.
weak base (low pKa): in intestine & kidney have higher pH, lower [H+], so equi shift to B, uncharged (=more weak base in unionised form) so lots absorbed in intestine & lots reabsorbed in kidneys

A- + H+ <-> HA (uncharged so cross memb more easily =more absorbed)
B (uncharged) + H+ <-> BH+

Question 55

pharmacokinetics

List and describe factors that can affect the absorption of a drug

absorption= rate of drug absorption into systemic circulation

Answer 55

1. site/route of administration –affect rate of plasma conc increase, so affect how fast plasma conc enter therapeutic window & for how long plasma conc stay within it
   .
2. drug formulation

Question 56

absorption

Define the term bioavailability (F)
.
Define the term ‘first-pass effect’ and understand its relationship to organ extraction

Answer 56

F= Quantity of drug reaching systemic circulation as intact drug divided by the dose (=drug quantity administered)
.
1st pass effect: drugs metabolised by enzymes in gut wall/liver, cause activation/inactivation of drug
.
organ extraction ratio close to 1 indicates that most of drug is metabolised during a single pass through the organ.

low extraction ratio < 0.3
high extraction ratio > 0.7

Question 57

absorption

Indicate the advantages and problems associated with drug administration via the common routes (oral, i.v., i.m.)
.
Give examples of drugs administered by other routes, and the reasons for choice of such routes

Answer 57

Intramuscular depot injection, eg contraceptives: Gradual release so prolonged drug action & rapid onset of action but muscle size, vascularity affect absorption & difficult to self-administer
.
oral: convenient, safe, but more systemic adverse effect & unpredictable GI absorption
.
intravenous: Bioavailability=100%, drug action rapid, but more systemic side effect & need asceptic condition
.
Sub-lingual, eg, glyceryl trinitrate 4 angina, bypass 1st pass metabolism
.
Topical, eg, Corticosteroids, avoid systemic side effects of long term use
.
Inhalation, eg, asthma COPD drugs
Direct to target, minimise side effects

Question 58

pharmacokinetics

Describe factors that favour/limit absorption of drugs from the mouth, stomach, small intestine and rectum

Answer 58

from gut/stomach/mouth: solubility, molecular weight/size, binding to calcium (eg in milk) or fat in food, 1st pass Metabolism (by enzyme in intestinal wall & in liver), pH of drug & if ionised/charged or not

from rectum: solubility, degree of ionization, partition coefficient & particle size

Question 59

pharmacokinetics

Describe, with examples, the role of gastric emptying, gastric and intestinal juices, and pharmaceutical factors in modifying drug absorption from the small intestine

Answer 59

Gastric emptying, eg absorption take longer after big meal
.
gastric juice lower pH favour weak acid absorption, intestinal juice higher pH favour weak base absorption
.
=Extended-release formulation: keep plasma conc within therapeutic window for longer =prolonged drug action
=Enteric coatings prevent gastric acid from dissolving or stomach enzymes degrading drugs

Question 60

pharmacokinetics

List & describe factors that can affect the distribution of a drug.

Answer 60

bound to plasma protein
.
bound in tissues, eg, bones & fat
.
conc of drug transporters in blood, pH, perfusion, body water & fat composition
.
disease conditions (e.g., volume depletion, burns, third spacing (=too much fluid moves from blood vessels into interstitial space), abnormal physiology cause protein binding changes, fluid shifts, pH changes & vascular organ (eg heart, kidneys) perfusion changes

Question 61

Define the term volume of distribution’ (Vd)
.
Predict Vd from a plot of log (plasma level) versus time

Answer 61

Vd= volume of plasma that would contain the total body content of the drug at a conc equal to that in plasma

For a drug restricted to the plasma (large hydrophilic, hard to exit blood), Vd~3.5L
.
Plasma + extracellular(interstitial fluid): Vd~14L / 70kg (small hydrophilic, hard to enter cell)
.
total body water (moderately lipid-soluble): Vd~ 40L/70Kg
.
Concentrated in tissues/fat (very lipid soluble): Vd >40 L / 70 kg

Question 62

Predict concentration of a drug immediately after i.v. administration, given an apparent volume of distribution in litres from a text

Answer 62

𝑐𝑜𝑛𝑐 = mass/Vd

Eg, For a drug restricted to the plasma and interstitial fluid, Vd ~ 14 L
If a dose of 50 mg is given,
What is the plasma concentration (before there is appreciable elimination)?
.
A: 𝑐𝑜𝑛𝑐= 𝑚𝑎𝑠𝑠/𝑣𝑜𝑙𝑢𝑚𝑒=(50 𝑚𝑔)/(14 𝐿)=3.6 𝑚𝑔/𝐿

Question 63

A novel drug has been discovered for the treatment of epilepsy in adults. The volume of distribution, Vd, is 12L. Will it be useful for epilepsy? (ignoring transporters take drug into brain) Yes/no & why?

Answer 63

No, Vd of 12L suggest drug is too hydrophilic, suggest drug is restricted to plasma & interstitial fluid so hasn’t gone into cells (plasma+extracellular: Vd~14L). To treat epilepsy drug need to go into brain so drug required to be lipid soluble, lipophilic drugs more likely to have Vd~40L

Question 64

Heparin is generally restricted to plasma because of its size. The desired plasma conc of heparin is approximately 1.5mg/L. What dose would be required to achieve this conc in plasma? Assume a 70 kg adult.
(hint: conc = amount / volume)

Answer 64

3.5L x 1.5mg/L ~5mg

For a drug restricted to the plasma (large hydrophilic, hard to exit blood), Vd~3.5L

Question 65

elimination

List & describe factors that can affect the metabolism & excretion of a drug.

Answer 65

Affecting excretion:
Extensive binding of drug to plasma protein can slow down its elimination(=metabolism+excretion), eg, slow down kidney excretion when Blood is filtered at the glomerulus
.
=lipid soluble drugs can diffuse back into blood
=Some drugs can be actively excreted from blood to urine, if 2 drugs compete 4 same transporter, can lead to drug-drug interactions
.
Dose, frequency, route of administration, tissue distribution
.
Affect metabolism:
=Presence of inhibitors
=Induction of enzymes
=Presence of isoforms/polymorphisms of enzymes or transporters
=Blood flow to liver
=Liver disease
=If 2 drugs are given together & are metabolised by same enzyme (eg CYP450), one may inhibit metabolism of the other
=if CYP450 enzymes inhibitors & inducers taken together with drug

Elimination (removal of original drug from bloodstream):
Either by metabolism to a different chemical structure (not original drug anymore)
Or by excretion in kidney, breath, skin & hepatobiliary system

Question 66

Define the terms ‘clearance’ (CL) & half-life’ (t½)

Answer 66

Clearance= the efficiency of elimination, i.e. rate of elimination divided by plasma conc
.
half-life= time taken for (plasma) concentration to decrease by half

renal/hepatic clearance= rate of eliminiation into urine/via liver divided by plasma conc
.
𝑟𝑎𝑡𝑒 𝑜𝑓 𝑒𝑙𝑖𝑚ination=𝑣𝑜𝑙𝑢𝑚𝑒×𝑐𝑜𝑛𝑐(𝑢𝑟𝑖𝑛𝑒) divided by time, unit = mg/h

Question 67

Explain that the total plasma clearance is the sum of renal & hepatic clearances
.
predict the consequence of change in any of these clearances on plasma drug concentrations

Answer 67

𝑡𝑜𝑡𝑎𝑙 𝑝𝑙𝑎𝑠𝑚𝑎 𝐶𝐿=𝑟𝑒𝑛𝑎𝑙 𝐶𝐿+ℎ𝑒𝑝𝑎𝑡𝑖𝑐 𝐶𝐿
.
if clearance is lower, then plasma drug conc decrease slower as slower elimination?

Question 68

Outline, with examples, the principal routes by which drugs may be metabolised
.
Describe the physico-chemical consequences of drug metabolism

Answer 68

Phase 1: reactions often catalysed by cytochrome P450 enzymes (CYP) to Make drug good substrate for phase 2. Important for non-polar drugs
Eg: oxidation, hydrolysis, hydroxylation
.
Phase 2: Increases solubility in water for excretion in kidneys (Some drug can go straight into Phase 2 without Phase 1)
Eg: conjugation (increase molecular size)

Question 69

Describe the pharmacological consequences of drug metabolism

Answer 69

In most cases, when a drug is metabolized it becomes inactivated. However, metabolites of some drugs are pharmacologically active and exert an effect on body. In fact, the active metabolite of some medications is responsible for the principal action of drug (then drug formulation =prodrug)

Question 70

List, with examples, the factors that may modify the level of metabolism of a drug

Answer 70

CYP450 enzymes inhibitors (eg, grapefruit juice, cimetidine, oral contraceptives)
.
CYP450 inducers (eg, St John’s Wort, cigarette smoke, Brussels sprouts)

inhibitors cause reduced metabolism, so slower elimination of drug from body
.
inducers can induce CYP450 enzymes – meaning amount of enzyme increases – in turn increasing metabolism of a drug, so faster elimination from body

Question 71

Identify factors that affect the shape of a graph of plasma concentration with time after an I.V. infusion?

Answer 71

CYP450 enzymes inhibitors (eg, grapefruit juice, cimetidine, oral contraceptives)
.
CYP450 inducers (eg, St John’s Wort, cigarette smoke, Brussels sprouts) make decreasing curve steeper
(with st john’s wort, plasma conc of drug decrease more after same amount of time)
.
if Half life of drug not constant (=conc decrease rate not directly proportional to conc) because:
* =drug is redistributed into fat/tissues (steeper decreasing curve, slower elimination)
* =elimination mechanism becomes saturated

Question 72

Describe mechanism of action of the main drugs/classes of drugs used in the management of inflammation

Answer 72

Cromoglicate stabilise mast cells so inhibit degranulation
.
Histamine H1 receptor antagonist (fexofenadine, cetirizine, loratadine) Reduce blood flow, epithelial & vascular permeability & secretions, stop runny nose, wheezing, flare and wheal.
.
COX inhibitor (NSAIDs) reduce PG production:
aspirin irreversibly inhibit COX1&2
ibuprofen inhibit COX1&2
etoricoxib selectively inhibit COX2
.
Cys-leukotriene receptor antagonist (Montelukast, Zafirlukast) reduce Bronchoconstriction, chemoattractanst for neutrophil, mucus secretion & vascular permeability for asthma
Zileuton inhibit lipoxygenase required in leukotriene synthesis
.
glucocorticoids (beclomethasone)Reduce gene expression of pro-inflammatory mediator, increase gene expression of anti-inflammatory mediators.
* stimulate synthesis of lipocortin which inhibits phospholipase A2 (PLA2) so inhibit arachidonate release from membrane phospholipids so inhibit PG/leukotriene production
* suppress genes for PLA2, COX-2 & IL-2 receptor

Question 73

Discuss the main side effects for anti-inflammatory drugs with reference to their mechanism of action.

Answer 73

glucocorticoids (beclomethasone): more susceptible to infection, osteoporosis, adrenal suppression, muscle wasting (protein catabolism increased)
.
histamine H1 receptor antagonist (cetirizine, loratadine): Headache. Tiredness. cough, Sore throat
.
COX inhibitor (NSAIDs): increased stomach acid secretion, nephrotoxicity, skin rash. selective COX-2 inhibitors increase risk of myocardial infarction (=heart attack)
.
cys-leukotriene antagonist: diarrhoea, high temperature, headache, stomach ache

Question 74

Explain why inhibition of cyclooxygenase is a good strategy in the treatment of inflammation?

Answer 74

Cyclooxygenase is an enzyme that is involved in synthesising a number of inflammatory mediators including PGD2, PGE2, PGF2a, PGI2, TxA2 so inhibiting its activity will reduce the levels of these mediators

Question 75

What advantage does etoricoxib have over ibuprofen for treatment of inflammation and pain in arthritis?

Answer 75

Etoricoxib is a COX2 selective inhibitor whereas ibuprofen is nonselective between COX1 and COX2.
COX2 is induced in inflammation whereas COX1 is responsible for a lot of normal functions of prostaglandins such as stomach mucus and bicarbonate secretion and contraction of uterine smooth muscle. Inhibiting COX1 leads to a number of unwanted effects, in particular, removing the protective effect of mucus and bicarbonate on the stomach. COX2 inhibitors have much less unwanted effect on the stomach compared to ibuprofen.

Question 76

Explain why a low dose of aspirin can be used to reduce thrombus formation through inhibiting platelet aggregation but ibuprofen does not

Answer 76

Aspirin is a nonselective COX1 and COX2 inhibitor. It acts irreversibly which means that once the enzyme is inhibited, new enzyme needs to be synthesised to recover activity.
.
PGI2 and TxA2 have opposing actions on platelet aggregation and vasoconstriction:
PGI2 is synthesised in endothelial cells (express COX2) and inhibits platelet aggregation and causes vasodilation
TxA2 is synthesised in platelets (express COX1) and causes platelet aggregation and vasoconstriction.
.
Since platelets have no nuclei, they are not able to synthesise more COX1 once it has been irreversibly inactivated by aspirin whereas endothelial cells do have nuclei to synthesise new COX2 so they are less susceptible to lower dose (70-100mg) of aspirin =PGI2 effect of inhibit platelet aggregation not affected
.
ibuprofen reversibly inhibit both COX 1 & 2, platelet not permanently inhibited, so no net increase in inhibitory effect of platelet to produce TxA2 ???

Question 77

Explain why cetirizine and loratadine are the drugs of choice for mild hayfever and allergic responses. How do they work and what advantage do they have over chlorpheniramine?

Answer 77

Chlorpheniramine, cetirizine and loratadine are histamine H1 receptor antagonists and so they block the inflammatory response mediated by histamine. Chlorpheniramine is able to cross into the brain whereas the other two are not so chlorpheniramine causes sedation and the other two don’t.

Question 78

What are prostaglandins (PG)? Outline how they are produced in the body & how they exert their action.
.
What class of drugs are important to reduce prostaglandin production?

Answer 78

1.PG are eicosanoic acids= fatty acids with 20 carbons
synthesis: Arachidonate is released from memb phospholipids by phospholipase A2, then undergo cyclo-oxygenase (COX) pathway to make PG (COX2 in inflammation)
.
PGs bind to their own receptors (G protein-coupled) eg PGE2
bind to EP receptor
.
2.NSAIDs

Question 79

Which of the following drugs is most appropriate in this case?
Aspirin, ibuprofen, etoricoxib, paracetamol
.
A 40 year old man visits his GP having sprained his ankle two weeks ago playing tennis. Swelling around the ankle has still not resolved.

Answer 79

Paracetamol is not anti-inflammatory so will not reduce the swelling. Etoricoxib and ibuprofen would be best at treating the inflammation. Further assessment would need to be done to choose between them since ibuprofen would be contraindicated in people with gastric reflux or dyspepsia whereas etoricoxib has the small risk of myocardial infarction in people with atherosclerosis so a full cardiovascular risk profile would need to be done

Question 80

A 10 year old boy visited his GP with his mother in the spring. His current symptoms of rhinorrhoea, nasal congestion, sneezing and itching eyes were interfering with his schoolwork. He had no history of asthma; his mother had allergic rhinitis; they had two cats. He was otherwise fit.
1. What might be causing his symptoms?

2.What pharmacological treatments might be offered?

Answer 80

1.It could be hayfever as it’s spring but he could be allergic to the cats.
.
2.Possibly histamine H1 antagonists such as loratadine however given that it’s mainly his eyes and nose that are affected he might be better off with cromoglycate eye drops to treat the itching eyes and a corticosteroid nasal spray to treat the rhinorrhea and nasal congestion.

Question 81

State / Explain the WHO analgesic ladder

Answer 81

Move up a step if persistent pain, move down a step/reduce dose to reduce toxicity
.
Step 1 Non-opioid + optional adjuvant analgesics for mild pain;
.
Step 2 Weak opioid + non-opioid + adjuvant analgesics for mild to moderate pain;
.
Step 3 Strong opioid + non-opioid + adjuvant analgesics for moderate to severe pain.

adjuvant analgesics (co-analgesics) = medications whose primary indication is the management of a medical condition with secondary effects of analgesia.

Question 82

Describe mechanisms of action of the main drugs/classes of drugs used in management of pain - NSAIDs / coxibs, paracetamol, opioids (weak & strong) & local anaesthetics

Answer 82

NSAIDs: inhibit COX so Decrease production of prostaglandins – mainly PGE2 which sensitise nociceptors to inflammatory mediator (in end organ). May also have CNS/spinal cord effect. Likely to be COX-2 mediated
.
paracetamol: inhibit COX likely in CNS (mechanism unclear)
.
opioid: act on µ opioid receptor (=Gi protein-coupled receptor) in spinal cord & end organ. decrease cAMP, open K+ channel to cause hyperpolarisation, so less likely nerve ending become depolarised to send pain signal to brain (=reduced neurotransmitter release)
.
weak opioid codeine can be metabolised (phase 1) into morphine (a strong opioid) - morphine’s metabolite (morphine-6-glucuronide) is active at µ opioid receptor
.
weak opioid tramadol has 2 actions:
* Opioid receptor agonist
* Noradrenaline & 5-HT/serotonin reuptake inhibition
=Only partially reversed by naloxone (opioid antagonist)
=Metabolised in liver, Active metabolite (O-desmethyl-tramadol) more potent than tramadol

weak opioid: codeine, tramadol, dihydrocodeine
strong opioid: morphine, oxycodone, buprenorphine, fentanyl

Question 83

Discuss the main side effects for NSAIDs/coxib, paracetamol & opioids with reference to their mechanism of action.

Answer 83

NSAID: increased stomach acid secretion, skin rash, inhibit (thromboxane-induced) platelet aggregation so harder to stop bleeding, (COX-2 selective) increased risk of myocardial infarction
.
paracetamol: few gastric/platelet side effects at therapeutic doses
.
opioid: Nausea/vomit, Sedation, Constipation, Increased intracranial tension

Question 84

State the principles of drug therapy in the management of pain

fist choice route of administration?
which route if vomiting/dysphagia(difficult/painful to swallow)?
analgesics dose?
what to do if analgesic medication for a patient change?

Answer 84

=Continuous pain requires continuous relief
=Use oral route where possible
=Parenteral route if vomiting, dysphagia - ensure equivalent analgesic dose
=Dose for each patient is individually determined
=Reassess pain at each change of analgesia
=Explain each change of medication and reassure patient
=Follow analgesic ladder but look out for updates

Question 85

list the drug classes used in the treatment of hypertension & give examples
.
Explain the mechanism of these drugs?

Answer 85

ACE inhibitor, eg, ramipril, lisinopril inhibit angiotensin converting enzyme on endothelial cells to convert angiotensin I to angiotensin II, so inhibit increasing BP by vasoconstrict & salt retention to increase blood volume
.
Angiotensin AT1 receptor antagonists, eg, candesartan, losartan, valsartan, inhibit angiotensin II activate AT1 receptor on vascular smooth muscle to trigger Gq-protein coupled signalling to cause contraction [Phospholipase C (PLC) hydrolyse PIP2 to DAG & IP3, IP3 trigger Ca2+ release from sarcoplasmic reticulum]
.
Ca channel antagonist, eg, amlodipine, nifedipine, selectively inhibit Ca influx in vascular smooth muscle to cause contraction, so inhibit vasoconstriciton =vasodilate to decrease arterial resistance, BP & total peripheral resistance (TPR=cardiac afterload???)
.
beta blockers, eg, propranalol, atenolol (β1 selective), reduce coronary and skeletal blood flow, reduce vasoconstriction, reduce heart rate & contractility, reduce renin release
affects renin-angiotensin-aldosterone system (RAAS)
.
α1-adrenoreceptor antagonist, eg, doxazosin, prazosin, block NA/adrenaline activation of α1-adrenergic receptor (Gq-coupled), [Phospholipase C (PLC) hydrolyse PIP2 to DAG & IP3, IP3 trigger Ca2+ release from sarcoplasmic reticulum]. so cause vasodilation, Decrease peripheral resistance & BP.
.
K+ channel opener, eg, minoxidil
Activate ATP-dependent K+ channels, induce Hyperpolarisation, Closes Ca2+ channel, Less calcium influx =Less contraction=vasodilate
.
diuretics
* (Loop diuretics) furosemide/frusemide Block Na/K/Cl transporter in ascending loop of Henle, reduce ion & water reabsorption in nephron so greater urine volume= reduced blood volume, strong diuretic effect
* .
* bendroflumethiazide (thiazide) Blocks Na/Cl transporter in distal convoluted tubule, reduce ion & water reabsorption in nephron so greater urine volume= reduced blood volume, mild diuretic effect
* .
* (potassium-sparing) amiloride Inhibit ENaC/Epithelial sodium channel in collecting duct,
* .
* (potassium-sparing) spironolactone =aldosterone antagonists in collecting duct, block mineralocorticoid receptor, inhibit increased expression of ENaC & Na/K ATPase pump via altering gene transcription

Question 86

Explain the mechanism underlying key side effects & contraindications of hypertension drugs?

Answer 86

ACE inhibitor, eg, ramipril, lisinopril inhibit angiotensin converting enzyme on endothelial cells to convert angiotensin I to angiotensin II, so inhibit increasing BP by vasoconstrict & salt retention to increase blood volume. Side effect hypotension, Reversible renal impairment as it vasodilate kidney efferent arteriole causing decrease in renal perfusion pressure & subsequent decrease in glomerular filtration, Hyperkalaemia as inhibiting angiotensin II prevents downstream secretion of aldosterone so K+ not secreted to urine
.
Angiotensin AT1 receptor antagonists, eg, candesartan, losartan, valsartan, inhibit angiotensin II activate AT1 receptor on vascular smooth muscle to trigger Gq-protein coupled signalling to cause contraction [Phospholipase C (PLC) hydrolyse PIP2 to DAG & IP3, IP3 trigger Ca2+ release from sarcoplasmic reticulum]. Side effect hypotension, Reversible renal impairment as it vasodilate kidney efferent arteriole causing decrease in renal perfusion pressure & subsequent decrease in glomerular filtration, Hyperkalaemia as inhibiting angiotensin II prevents downstream secretion of aldosterone so K+ not secreted to urine.
.
beta-blockers, eg, propranalol, atenolol (β1 selective) inhibit sympathetic effect so side effects, eg, Bronchoconstriction (β2), Impaired glycogenolysis/gluconeogenesis
(β2), cardiac depression/bradycardia(β1), fatigue
.
Ca channel antagonist, eg, amlodipine, nifedipine, selectively inhibit Ca influx in vascular smooth muscle to cause contraction, so inhibit vasoconstriciton. headache as it cause vasodilation, peripheral oedema as it decrease arteriolar resistance but not equal decrease in venous resistance. This disproportionate resistance change increases hydrostatic pressures in precapillary circulation & allow fluid shifts into interstitial space. increased risk of gastro-oesophageal reflux as it significantly reduce the tone of Lower Esophageal Sphincter, increase esophageal exposure to gastric acid & reduce amplitude & duration of esophageal peristalsis. so contraindication: gastro-esophageal reflux disease (GERD)
.
α1-adrenoreceptor antagonist, eg, doxazosin, prazosin, block NA/adrenaline activation of α1-adrenergic receptor (Gq-coupled), [Phospholipase C (PLC) hydrolyse PIP2 to DAG & IP3, IP3 trigger Ca2+ release from sarcoplasmic reticulum]. so cause vasodilation, Decrease peripheral resistance & BP. 1st dose adverse effect: postural hypotension & syncope(=faint).
if drug not 100% α1-selective so also affect α2 receptor, cause reflex tachycardia
.
K+ channel opener, eg, minoxidil
Activate ATP-dependent K+ channels, induce Hyperpolarisation, Closes Ca2+ channel, Less calcium influx =Less contraction=vasodilate. tachycardia, increased heart contractility due to Baroreceptor-mediated activation of sympathetic NS due to BP decrease. fluid & salt retention as Activation of K+ channel in thick ascending limb of Loop of Henle increase Na+/2Cl-/K+ co-transporter activity, so increase Na & Cl reabsorption. hypertrichosis=excessive hair growth as they possibly stimulate ATP-sensitive K+ channel in hair follicles to increase hair growth
.
diuretics
* (Loop diuretics) furosemide/frusemide Block Na/K/Cl transporter in ascending loop of Henle, reduce K+/Ca reabsorption so hypokalaemia/hypocalcaemia. compete with uric acid 4 transporter so reduced loss of uric acid, causing gout (N from protein metabolism excreted as uric acid). stronger side effect than thiazide
* .
* bendroflumethiazide (thiazide) Blocks Na/Cl transporter in distal convoluted tubule, reduce K+ reabsorption so hypokalaemia. compete with uric acid 4 transporter so reduced loss of uric acid, cause gout. reduce blood flow to penis, cause erectile dysfunction
* .
* amiloride Inhibit ENaC/Epithelial Na+ channel in collecting duct but potassium-sparing, so hyperkalaemia. GI irritation
* .
* spironolactone=aldosterone antagonists in collecting duct, block mineralocorticoid receptor, inhibit increased expression of ENaC & Na/K ATPase pump via altering gene transcription. potassium-sparing, so hyperkalaemia, has steroidal structure so can act on progesterone/androgen receptor outside kidney so menstrual disorder/testicular atrophy

Question 87

Angina

Describe autonomic, hormonal & metabolic substances mediating the control of tissue perfusion?

Answer 87

Nitric Oxide (NO, cause vasodilation) is produced locally in response to
* Shear stress: increased perfusion pressure leads to flow-mediated NO formation.
* Bradykinin & ACh activate their respective receptors to induce NO formation
.

organic nitrates, eg, glyceryl trinitrate, isosorbide mononitrate
Produce nitric oxide (NO) in endothelial cells, NO diffuses into smooth muscle cell & activate guanylyl cyclase (GC), produces cGMP from GTP, relax smooth muscle (vascular, biliary & oesophageal) =increased perfusion
.
Adverse Effects Headache, Postural hypotension
.
β-blockers – reduce oxygen demand (decrease rate & force)
.
Ca2+ channel blockers vasodilate
.
Ivabradine – slows heart rate by direct action on the pacemaker in SinoAtrial node (SAN).
.
Nicorandil – K+ channel opener & NO donor

Glyceryl trinitrate
first pass metabolism
 given sub-lingual spray or transdermal
30 min duration of action
.
Isosorbide mononitrate
Oral, Longer duration of action
 Twice daily for prophylaxis

Question 88

Describe the major mechanisms of drug action in Central Nervous System?

Answer 88

glutamate,
(ligand-gated ion channel) NMDA receptor agonist, eg, glutamate, aspartate, NMDA =Slow excitatory transmission, Synaptic plasticity, Excitotoxicity
.
(ligand-gated ion channel) AMPA receptor agonist, eg, glutamate, AMPA= Fast excitatory transmission
.
(ligand-gated ion channel) Kainate/kainic acid receptors agonist, eg, kainate, glutamate, domoate= Fast excitatory transmission
.
metabotropic glutamate receptor:
* group 1=post-synaptic, Gq protein-coupled & Ca2+ signalling =excitatory
* group 2&3=pre-synaptic, Gi/o protein-coupled, regulate glutamate release

.
GABA, type A receptors= ligand-gated ion channel receptors, Cl- channel cause hyperpolarisation =inhibitory effect
type B= GPCR, generally inhibitory
.
Benzodiazepines =positive allosteric modulators on GABA type A receptor (induces conformational change in GABA-A receptor allow GABA to bind & conformation change in chloride channel that cause hyperpolarization) only has effect if GABA present
* Barbiturates (e.g. phenobarbital) = Allosteric modulator & directly activate GABA receptor at higher doses
* Steroid anaesthetics (e.g. alphaxalone)

.
tiagabine (anti-epilepsy) inhibit GAT (GABA Transporter) reuptake GABA from synapse into neurons (GAT1) & astrocytes (GAT3) so prolong inhibitory transmission
.
vigabatrin (anti-epilepsy) inhibit GABA transaminase in astrocytes to break it down so prolong inhibitory transmission
.
dopamine: GPCR receptor
D2 receptor Antagonists = anti-psychotics
D2 Agonists for Parkinson’s Disease, hyperprolactinemia
D3 Agonists for Parkinson’s
D4 Agonists for ADHD
.
serotonin: GPCR receptor except 5HT3 =ion channel
* 5HT1A receptor agonist =anxiolytic (relieve anxiety) & antidepressant
* 1B/1D agonist ‘triptans’ eg, sumatriptan =anti-migraine
* 5HT2 Antagonists for migraine prophylaxis, Antidepressants, antipsychotics
* 5HT2 Agonist = hallucinogenics
* 5HT3 Antagonists for nausea and vomiting

NMDA=N-methyl-D-aspartate
AMPA=α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid

Question 89

Understand the specificity & selectivity of drugs in the CNS
.
Explain the rationale for the use of drugs that affect specific neurotransmitter systems

Answer 89

The expression of specific enzymes determines which transmitter the neurone can synthesise

Question 90

Understand the “plasticity” of synaptic transmission and how it can affect drug treatment

Answer 90

Mechanisms of Long-Term Potentiation (LTP)
A: Infrequent synaptic activity
 just AMPA receptors activated.
B: After conditioning train of stimuli
mGluR activated, NMDA channels unblocked
↑Ca signalling
  ultimately results in changes in gene expression

Question 91

Identify the major neurotransmitters in the CNS
.
Understand the importance, synthesis, action & limitation of action of the major neurotransmitters in CNS and related with pharmacology?

Answer 91

glutamate: exitatory transmission, Glutamate is synthesized de novo from α-ketoglutarate via tricarboxylic acid (TCA) cycle in astrocyte. In glutamate-glutamine cycle, glutamate is converted to glutamine by glutamine synthetase in astrocyte, then transported into neuron by glutamine transporter. Neuronal glutaminase catalyzes conversion from glutamine to glutamate, which is released as neurotransmitter from presynaptic terminal & is rapidly recycled by EAAT (Excitatory Amino Acid Transporter) back into astrocytes.
metabotropic glutamate receptor group 2&3 =pre-synaptic, Gi/o protein-coupled, regulate glutamate release limit its action
.
GABA: inhibitory transmission, Glutamate to GABA via glutamic acid decarboxylase in neuron, Arousal, attention, Memory formation, Anxiety, Sleep, Muscle tone. Receptor abundant in cortex & limbic system

.
NA: tyrosine to DOPA via tyrosine hydroxylase
2: DOPA to dopamine via DOPA decarboxylase
3: UPTAKE into vesicles via vesicular transporter
4: dopamine to NA via dopamine-β-hydrolase
pain, sedation, mood, arousal, blood pressure

.
dopamine: tyrosine to DOPA via tyrosine hydroxylase. DOPA to dopamine via DOPA decarboxylase. motor control, behaviour, endocrine control - D1 & D2 antagonists cause catalepsy, increase prolactin secretion & breast development. behavioural effects – amphetamine (competitively inhibits dopamine reuptake at dopamine transporters and increases dopamine transporter–mediated reverse transport of dopamine from the cytoplasm into the synaptic cleft) & cocaine (inhibit dopamine transporter so inhibit dopamine reuptake) cause euphoria
.
serotonin (5-HT): tryptophan to 5-Hydroxytryptophan via Tryptophan hydroxylase, then to serotonin via decarboxylase. hallucinations, behaviour, sleep, mood, feeding, sensory transmission (especially pain)

Question 92

Glutamatergic and GABAergic transmission in the CNS
.
Dopaminergic, noradrenergic and serotonergic transmission in the CNS

Question 93

Describe the structure & function of the blood brain barrier (BBB)

Answer 93

Brain & spinal cord - capillary endothelial cells joined by tight junctions of high electrical resistance providing an effective barrier, ONLY water & gases can cross. endothelial cells sit on thick basal lamina (=basement memb) with pericyte under basal lamina which is surrounded by astrocytic endfoot with perivascular macrophage in betwn. Pia mater present under basal lamina in larger vessels ONLY
(Periphery - endothelium have gaps, through which water, ions & molecules up to the size of large proteins can easily diffuse)
.
functions:
maintains brain homeostasis & optimal conditions for neuronal function
.
protects brain against surging fluctuations in plasma ion conc
.
restrict entry of potentially harmful macromolecules e.g. albumin, prothrombin, plasminogen & neurotoxic substances from diet/environment
.
allows selective transport of essential nutrients into brain

Question 94

factors affecting whether or not compounds pass through blood brain barrier into brain?

Answer 94

Tight junctions prevent paracellular transport of water soluble molecules.
.
Transporters regulate nutrients (e.g. glucose) & ion transport.
.
Gases diffuse readily
.
Water transported by aquaporin (AQP4)
.
Passive diffusion
.
Substrate for transporter(s): Allow in/Push out
.
Metabolism
.
Transcytosis

Question 95

Give examples of:
* physiological implications​
​ * the impact of the BBB on drug delivery to the brain​

Answer 95

physiological: Central chemoreceptors do not directly detect arterial CO2 tension, they detect changes in CSF pH
Arterial CO2 diffuses through BBB into CSF, Carbonic anhydrase converts CO2 to carbonic acid, decreases CSF pH
.
impact on drug delivery to brain:
Small, uncharged and lipid-soluble molecules cross readily
E.g. ethanol, caffeine, nicotine, heroin, and methadone
hydrophilic compounds are almost universally excluded from the brain e.g. gentamicin
.
enzymes: Central capillaries express enzymes that degrade certain chemicals
E.g. peptidases, acid hydrolases, monoamine oxidase
 break down enkephalins, noradrenaline, dopamine
.
transporters & pump: Transporter proteins used for amino acids, glucose etc.
Solute carrier superfamily (SLC) – don’t directly use ATP or couple to electron transport  facilitated diffusion
E.g. transporters for glutamate, glucose, nucleosides, ions, exchangers
ATP-binding cassette transporters (ABC) = active transport
E.g. P-glycoproteins, multi-drug resistance proteins (MDRs) – have broad specificity
.
Some drugs use these transporters to get in
E.g. System L (heterodimer of SLC7A8 and SLC3A2)
Transports:
L-DOPA (Parkinson’s disease)
Baclofen (for spasticity)
Gabapentin (for chronic pain and epilepsy)
.
efflux pump: Some drugs are extruded from the brain by efflux pumps = members of ABC (ATP-binding cassette) transporter superfamily e.g. P-glycoprotein, Multi Drug Resistant Proteins, Breast Cancer Resistance Protein
actively transport range of lipid-soluble compounds out of brain
role is to remove potentially neurotoxic endogenous or exogenous molecules
vital neuroprotective and detoxifying function
.
clinical consequences = minimal effectiveness of some drugs in some patients e.g. HIV drugs in AIDS dementia, anti-bacterials in CNS infections, anticonvulsants in epilepsy, chemotherapy on brain tumours
.
P-glycoprotein
loperamide (antidiarrhoeal agent, potent opioid)
domperidone vs haloperidol
HIV protease inhibitors e.g. tenofovir, ritonavir, atazanavir
.
Multidrug resistance (MDR) associated protein
first non-P-glycoprotein MDR conferring transporter identified
transports wide range of compounds e.g. many chemotherapy & anti-HIV agents out of brain

Question 96

Examples of potential future approaches to drug delivery to the brain​

Example of the relationship between disease & the BBB

Answer 96

Inflammation: can drastically increase access of drugs to the brain
Bacterial protein lipopolysaccharide can increase permeability of BBB
Plasma and cerebrospinal fluid concentrations of an antibiotic (thienamycin) following an intravenous dose
.
stroke: cerebral ischaemia following e.g. stroke; cardiac/respiratory arrest; carbon monoxide poisoning involves loss of blood flow plus depletion of oxygen & essential nutrients

in vitro models of BBB indicate that hypoxia & hypoxia/reoxygenation lead to increased permeability and/or disruption of BBB tight junctions

hypoxic stress may also increase permeability via transcellular route

probably involved in progression of ischaemic brain injury
.
trauma: Bradykinin is produced
 stimulates production and release of IL-6
 opening of BBB
.
future drug delivery method: development of novel & specific inhibitors of efflux pumps - CAUTION!!
* design of **drugs with reduced affinity for efflux transporters, e.g. ceftriaxone & imipenem **
* design drugs that are recognised by endogenous BBB transport systems ‘’Trojan horses’’ to ‘’smuggle’’ drug cargo across
using exosomes - tiny lipid bilayer-bound bubbles produced in cells - body’s own transport vehicles

Question 97

What characteristics of a drug means it can get into the brain more easily?
What are the key structural features of the blood brain barrier?
Where are the weak points in the BBB and why do they occur?
For brain tumours and viral infections in the brain it is essential to get drugs across the blood brain barrier. What processes stop these drugs from accessing their site of action?
Why do we need a blood brain barrier?
Show on the diagram:
Transporters
Post-synaptic receptors
Enzymes that breakdown neurotransmitters.
Indicate where the neurotransmitter is synthesised and stored in the presynaptic neuron.
What three processes reduce the concentration of neurotransmitters in the synapse after the receptors have been activated?
Name three excitatory neurotransmitters
How does receptor activation lead to excitation (i.e. depolarisation of neurons)?
Name two inhibitory neurotransmitters
How does receptor activation lead to inhibition (i.e. hyperpolarisation of neurons)?
Name two neuromodulating neurotransmitters
Name three amino acid neurotransmitters
Name three amine neurotransmitters
Name three peptide neurotransmitters
What is the main mechanism for reducing the concentration of glutamate in the synapse?
Why are astrocytes important for glutamate neurotransmission?
What is the differences between ionotropic and metabotropic glutamate receptors?
Some anti-epileptic drugs work by increasing the activity of GABA in CNS synapses, increasing the degree of inhibition overall and thus reducing seizures.
Given your knowledge of how synapses work, what are three possible mechanisms that drugs could increase GABA activity.
Benzodiazepine drugs such as diazepam (a.k.a. Valium) are important as anti-anxiety, anticonvulsant and sleep-inducing drugs. Where do benzodiazepines bind and how do they increase the activity of GABA synapses?
amine neurotransmitterHow can activity at serotonergic synapses be enhanced?
What does activation of dopaminergic signalling do – what overall effects are seen?

Question 98

• Explain the rationale for the use of drugs that target monoaminergic transmission in Parkinson’s disease?

Question 99

Describe the rationale for the use of drugs that target GABAergic, glutamatergic, monoaminergic and other transmitters in anxiety, schizophrenia and affective disorders?