Psychological medicine week 2 Flashcards

Question

Treating phobias ?

Answer 1

To be effective a punishment must 1) link response to consequences (no time delay): eg 5 year old Sarah breaks a plate and then later tells mother what happened. Her mother scolds Sarah, but this will tend to be associated with telling about the accident (reduced in future) not breaking the plate. Or paradox of person who continues to drink despite repeated warnings about cirrhosis of the liver (immediate pleasure of brandy outweighs distant worry of liver failure) AND 2) be consistently applied (reinforced) eg criminal behaviour is reinforced through its success and the threat of possibly being caught in the future is a weak deterrant. Hence criminals will say “there is nothing wrong with robbing banks: its getting caught I don’t like”.

Answer 2

Physical or emotional harm or injury eg smacking Paradoxical attention: can act as +ve reinforcer of negative behaviour (any attention better than none) Teaches aggression as model to solve difficulties No alternative behaviour provided (reward = “repeat this”, punishment = “stop it”) Leads to fear/dislike of person (parent, teacher, employer) and situation (home, school, office) = classical conditioning These cautions do not mean that punishment should never be used. It can effectively stop an undesirable response if it is consistent, delivered immediately and if an alternative response is rewarded.

Answer 3

Extinction can occur in both classical and operant conditioning: In classical conditioning, no longer pairing the CS with UCS results in CR disappearing In operant conditioning, passive process eg Cancel TV viewing for a child who misbehaves (unlike punishment which reduces behaviour with an aversive stimulus).

Answer 4

Screening for depression (PHQ-2): in primary care & general hospital, screen patients with previous depression or current significant physical illness. Using these 2 questions can detect up to 95% cases: 1) During the last month, have you often been bothered by feeling down, depressed or hopeless? 2) During the last month, have you often been bothered by having little interest or pleasure in doing things?

Answer 5

- Long pre-ganglionic neurons from the brainstem (CNIII, VII, IX and X). - Oculomotor, facial, glossopharyngeal and vagus - The long preganglionic sacral nerves are (S2,3 and 4) - The preganglionic neuron synapses with the postganglionic neuron close to, on, or in its effector tissue.

Answer 6

The sympathetic nervous system ganglia (cell bodies) are found in the paravertebral (sympathetic chain) and precerterbral

Answer 7

Now what are the neurotransmitters associated with this system? The parasympathetic system is associated with acetylcholine transmission in both pre and post ganglionic connections. In contrast the sympathetic system is associated with acetylcholine preganglionic nerves connected to either noradrenalin nerves which connect to the muscle, such as the smooth muscle within the cardiovascular system, or to the adrenal glands, to induce the production of noradrenaline to act as a hormone within the body. Now if we look at how acetylcholine can transmit its signal it is via two types of receptor, the muscarinic and nicotinic receptors. Here we have a slide looking at the muscarinic receptors. There are 5 muscarinic receptors, M1-M5, and there have different locations within the body as shown here. The M1 receptors are associated with the autonomic ganglia, and glands such as the salivary glands. The M2 receptors are associated with the heart and Central Nervous System, the M3 receptors are associated with exocrine glands in the gastric system and the smooth muscle, and the M4 and M5 receptors are located in the Central Nervous System. All the muscarinic receptors are seven transmembrane G protein coupled receptors, and as we went through in the Basic Biochemistry lecture have two mechanisms by which they work. The M1, M3 and M5 link onto the Gq pathway, which causes an elevation of Phospholipase C activity, the production of inositol triphosphate (IP3) and then the release of Calcium to drive downstream signalling. Alternatively, the M2, and M4 receptors link through Gi to a reduction in the activity of adenylyl cyclase (AC), of which there are different types, and a decrease in the concentration of cAMP, an important secondary signalling agent. This reduction in cAMP will then link into the activity of Protein Kinase A, reducing it. The functional response induced by the receptors is linked to their location with M1 receptors for instance linked to Central Nervous System excitation and gastric secretion whilst M2 receptors are linked to changes in cardiac function, and neural inhibition.

Answer 8

Alongside the muscarinic receptors Acetylcholine can also bind to nicotinic receptors. Nicotinic receptors are ion channels, pentameric ion channels that in a resting state are closed. Upon binding of acetylcholine to the nicotinic receptor it undergoes a conformational change causing it to open and for ions to flow through the channel across the cell membrane. There are multiple different types of nicotinic receptors, with 4 different types, and further subtypes. Each of these receptors is made up of different combinations of  or  subunits to make up the pentameric structure of the nicotinic receptor as we will see in a later slide.

Answer 9

As we have just stated the nicotinic receptor exists normally in a closed state but upon binding of acetylcholine will open and allow the flow of ions across the cell membrane. However, it is important to realise that if there are repeated doses of acetylcholine or excessive amounts the receptor can have a desensitised state. In this state the receptors will not allow the flow of ion across the membrane and need to become resensitised in order to become active again.

Answer 10

Just as with the muscarinic receptors the nicotinic receptors have different locations. There are types associated with the muscle, Ganglion and the Central Nervous System. If we look at the main molecular form associated with these locations, it has two subunits of the 3 protein, and 3 of the 2 protein. The location of this type is mainly postsynaptic within the muscle and ganglion but can also be presynaptic in the Central Nervous System. Finally, the other major molecular form is made up of 5 subunits of the 7 subunit, which is found both pre and post synaptically in many brain regions. Although these are the major molecular groups, there are other types present within your body. The membrane response is as you would expect for an ion channel, increased cation permeability, mainly to Na+ and K+ ions, which induces an excitatory response.

Answer 11

Now when we think about where you can target the Acetylcholine system clinically there are multiple different potential target areas. It is possible to target presynaptically. The Acetylcholine transport into the vesicle can be targeted, the uptake from the synaptic cleft can be targeted, and the release of acetylcholine into the synaptic cleft can be inhibited. Alternatively, once the acetylcholine has been released into the synaptic cleft its action can be changed by altering its metabolism through changing the action of Acetylcholinesterase, or by using non-depolarising or depolarising agents to prevent acetylcholine from binding to its receptor. We will go through each of these different mechanisms and identify potential drugs which disrupt them.

Answer 12

The first possible mechanism is through disrupting the uptake of acetylcholine into vesicles, a process that is driven by proton exchange via ATP driven pumps. A compound called Vesamicol has been shown to be effective in inhibiting this process by binding the acetylcholine transporter. This compound is not at present used clinically. However, this shows that this mechanism could be a useful target in the control of acetylcholine neurotransmission. The next mechanism is via the inhibition of the reuptake of acetylcholine from the synaptic cleft. This can be completed with the use of Hemicholinium which blocks reuptake of Acetylcholine into the presynaptic cell. The Reuptake of acetylcholine is the rate limiting step in Acetylcholine production and therefore reduces Acetylcholine concentration within the presynaptic cell. Finally, there is the inhibition of the release of acetylcholine vesicles into the synaptic cleft. An example here is Botulinium. This has been heavily used by the beauty industry to block muscle movement as it helps to remove wrinkles.

Answer 13

The next potential mechanism is through the inhibition or modification of acetylcholinesterase. Once the acetylcholine is released into the synaptic cleft it will then be metabolised by the presence of the enzyme acetylcholinesterase. The reaction is shown here. Acetylcholinesterase causes the metabolism of acetylcholine into choline and acetic acid, stopping its action within the synaptic cleft. This also then releases choline ready for it to be reuptaken into the presynaptic cell. As this acetylcholinesterase is an enzyme this means that it is possible to target it effectively with the use of drugs to disrupt its function. There are two different types of inhibitor that it is possible to use. One type are reversible inhibitors, which will bind the enzyme active site, and block it. But the inhibitor over time will be released and therefore allow the enzyme to work again. An example here is Neostigmine. The second class are irreversible inhibitors which will bind the enzyme and will no longer come off, and prevent the binding of the substrate permanently, meaning the enzyme will no longer work. The binding here is either covalent between the inhibitor and the enzyme or the on/off rate is so slow that the inhibitor does not come off. An example here is organophosphates

Answer 14

The next potential mechanism is through the inhibition or modification of acetylcholinesterase. Once the acetylcholine is released into the synaptic cleft it will then be metabolised by the presence of the enzyme acetylcholinesterase. The reaction is shown here. Acetylcholinesterase causes the metabolism of acetylcholine into choline and acetic acid, stopping its action within the synaptic cleft. This also then releases choline ready for it to be reuptaken into the presynaptic cell. As this acetylcholinesterase is an enzyme this means that it is possible to target it effectively with the use of drugs to disrupt its function. There are two different types of inhibitor that it is possible to use. One type are reversible inhibitors, which will bind the enzyme active site, and block it. But the inhibitor over time will be released and therefore allow the enzyme to work again. An example here is Neostigmine. The second class are irreversible inhibitors which will bind the enzyme and will no longer come off, and prevent the binding of the substrate permanently, meaning the enzyme will no longer work. The binding here is either covalent between the inhibitor and the enzyme or the on/off rate is so slow that the inhibitor does not come off. An example here is organophosphates

Answer 15

As we said on the previous slide organophosphates (found in pesticides for example) are an example of an irreversible inhibitor of Acetylcholinesterase. The process that occurs is that the organophosphate will cause a bond to form between itself and a serine within the active site of the Acetylcholinesterase enzyme. This bond initially is not covalent, but a process called aging which is the addition of water, leads to the removal of the R2 group. This causes the bond between the organophosphate to strengthen and therefore become irreversible. This aging process can occur between minutes or hours dependent on the organophosphate present.

Answer 16

However, it is possible if you can treat the patient quickly enough to reverse this process. The use of a compound called PAM (Pralidoxime) can reverse this process as PAM attacks the bond between the organophosphate and the serine within the Acetylcholinesterase enzyme, causing the bond to be weakened. This can then cause the release of the Pam-organophosphate complex from the enzyme. This leads to the regeneration of the enzyme and therefore allows it to function again.

Answer 17

Now we will talk about the compounds that can target the receptors on the post synaptic cell. These are your non-depolarising and depolarising agents which can target the muscarinic or nicotinic receptors. Firstly, we will look at the non-depolarising agents which target the nicotinic receptors. These agents act as competitive antagonists. Therefore, they inhibit the receptors, but can be overcome by increased concentrations of acetylcholine. The antagonists bind the receptors but do not produce an action potential. Due to their binding they can cause muscle relaxation + paralysis. Examples of these agents are Mivacurium, Atracurium and Pancuronium, which have different lengths of time associated with their effect as a muscle relaxant. The second type is the Depolarizing Agents. These bind to Acetylcholine receptors but still generate an action potential. They are not metabolised by acetylcholinesterase, therefore by binding to the receptor they cause persistent depolarisation of muscle fibres which causes full paralysis of the muscle itself. An example here is suxamethonium, which is the only one available clinically at present. It is very quick acting, obtaining a maximum block within a minute or so but is also rapidly metabolised by cholinesterase resulting in a duration of action of around 5-10 minutes. One of the issues however is that certain number of patients do not have effective levels of cholinesterase and therefore cannot process suxamethonium effectively. Therefore the effect of suxamethonium is far longer lasting in these patients, and they need to be kept on ventilation until the muscle paralysis is alleviated.

Answer 18

It is also possible to target the muscarinic receptors with either antagonists or agonists. Antagonists targeted to the muscarinic receptors are for example atropine which can be used to reverse effects of organophosphate poisoning. Alongside this you have Scopolamine which can have dose dependent effects but has been approved for nausea and vomiting associated with motion sickness and surgical procedures. Alternatively, an example of an agonist used to target the muscarinic receptor is Pilocarpine, which is used to reduce the pressure in the eye and therefore is used to treat glaucoma.

Answer 19

Therefore overall there are multiple different ways by which you can target the acetylcholine pathway. Within the presynaptic cell you have your uptake inhibitors, you have your vesicle release inhibitors, and potentially you have your transport of your choline into the vesicles. Within the synaptic cleft you can modulate the action of the acetylcholinesterase which will then affect how long the acetylcholine will be present in the synaptic cleft. Then finally you have your non-depolarising and depolarising agents, which can modulate the effect of the receptors on the post synaptic cell.

Answer 20

We will now change direction and look at Noradrenaline. Noradrenaline is one of the catecholamines. Within this group of compounds you will find, Noradrenaline, Adrenaline, Dopamine, and Isoprenaline. Therefore, as a recap from the previous two lectures Noradrenaline is produced downstream of dopamine. They come originally from Phenylalanine, which is turned into tyrosine, which can be changed into L-Dopa, Dopamine, Noradrenaline and finally Adrenaline. This metabolic pathway is driven by enzymatic reactions which make small changes to the side chains of these compounds so that each compound can be used in a distinctive manner within the body.

Answer 21

Now where is noradrenaline used within the Central Nervous System? It is used within the sympathetic division, and connects to the smooth muscle tissue, such as the smooth muscle associated with the cardiovascular system. In addition, you need to remember that Noradrenaline can also be secreted by the adrenal gland. You will find out about this in more detail Gastrointestinal Pathophysiology at the end of year 2 so there is not a great need to go into too much detail here. However, preganglionic fibres from the thoracic spinal cord pass to adrenal glands via splanchnic nerves. They synapse with chromaffin cells which then release Adrenaline (Ad) & Noradrenaline (NA) into the bloodstream to act as hormones.

Answer 22

Once Noradrenaline is released into the synaptic cleft it will bind to the adrenergic receptors in the post synaptic cell. There are two main groups of receptors, the alpha adrenergic, and the beta adrenergic receptors. The alpha adrenergic receptors are split into two groups, the 1, and 2 receptor types. These two types of alpha adrenergic receptors are again split down into further subgroups. The  adrenergic receptors are split into 3 groups, the 1, the  and the 3 receptors. As you have multiple different types of adrenergic receptor it is then possible to produce inhibitors to try to target a specific receptor or to target multiple receptors, such as the whole class of adrenergic receptors or just to target the beta adrenergic receptors for example. There are three key agonists for the adrenergic receptors, and these are adrenaline, noradrenaline and isoprenaline and the different receptors will bind these agonists with different potency. If we look at some of the conditions which these receptors are associated with, they are associated with issues around the cardiac tissue, or asthma and respiratory issues.

Answer 23

If we now look at the different types of receptor subtypes we see that they use different signalling systems. The 1 adrenergic receptors use Phospholipase C activation, IP3 production and an increase in Calcium concentration. In contrast the 2 adrenergic receptors cause a decrease in cAMP concentration. Finally the  adrenergic receptors use an elevation in the concentration of cAMP leading to downstream signalling changes. We can also see that when we look at the binding of agonists to these receptors, we see that noradrenaline, adrenaline and finally isoprenaline can bind with different potency to each type of adrenergic receptor. There are a series of different antagonists and agonists that can be targeted to these receptors. For example 2 agonists such as salbutamol are targeted for treatment of asthma, whilst 1 antagonists such as atenolol, are used to target high blood pressure and arrythmia.

Answer 24

Now when we think about how noradrenaline works as a neurotransmitter there are multiple different points at which it can be targeted. Therefore, let’s just quickly recap how it works. Noradrenaline is made from Dopamine. It is then transported into vesicles by a transport mechanism, and these vesicles are then stored. Upon activation of the presynaptic cell, the vesicles fuse to the cell membrane and release noradrenaline into the synaptic cleft. The noradrenaline can then bind the receptors on the post synaptic cell. However, to stop the signal noradrenaline is metabolised by 2 different enzymes, Monoamine Oxidase or catechol O methyltransferase (COMT) Alternatively it is reuptaken into the presynaptic cell by transport systems. This metabolism or reuptake removes the noradrenaline from the cleft and then stops the signal and its ability to bind its receptors.

Answer 25

Therefore, a key potential target are the transport systems that can move noradrenaline. There are three main types. The first system is the neuronal transport system. This is present in the neuronal membrane, and will preferentially move Noradrenaline, and then move adrenaline and finally isoprenaline. Importantly it also has other substrates it can transport such as tyramine and amphetamines, which we will go through in a bit. However, these transport systems can be targeted by substances such as cocaine or the Tricyclic antidepressants. The second transport system is the extraneuronal transport system which is present in the non neuronal cell membrane. It will also move adrenaline, noradrenaline and isoprenaline, and also move other substrates such as dopamine and histamine. Finally, we have the vesicular transport system. This is present in the vesicles within the neuronal cell that hold the noradrenaline. Again, it can transport multiple different catecholamines. Again, it can be targeted with drugs such as reserpine and its action blocked.

Answer 26

Lets look at presynaptic inhibitors first. These are either targeted to inhibit synthesis of noradrenaline, or inhibit the transport systems linked to Noradrenaline reuptake from the synaptic cleft. If we look at the inhibition of noradrenaline synthesis, first this will reduce the amount of noradrenaline present in the presynaptic cell. This in turn will lessen the effect that noradrenaline can cause due to the reduce amount of noradrenaline present. Addition of substances such as methyltyrosine can then help to prevent the production of noradrenaline. Alternatively, there are also Noradrenaline reuptake blockers. Here we have examples such as cocaine, or the TCA antidepressants. By blocking the reuptake of noradrenaline these inhibitors prolong the action of the neurotransmitter within the synaptic cleft.

Answer 27

There are also substances that can act as sympathomimetics. An example is Tyramine. Tyramine is a substance found within the diet in foods such as marmite, red wine and cheese. Normally it is brokendown in the liver. However, in some cases it can be present and be exchanged for noradrenaline by the action of the NET transport system. This then allows the noradrenaline to come out of the neuronal cell and move into the synaptic cleft in exchange for tyramine. As noradrenaline is in the synaptic cleft it can then act as a neurotransmitter without the presence of a signal from the presynaptic cell. If a patient is on a MAO inhibitor this can then lead to hypertensive crisis, as the noradrenaline released cannot be metabolised as the MAO is inhibited and therefore leaves the noradrenaline to act within the synaptic cleft.

Answer 28

The next potential mechanism for therapy is the targeting of noradrenaline metabolism in the synaptic cleft. As we have previously identified MAO, metabolises noradrenaline alongside COMT as shown here on this slide. If therefore MAO is then targeted this will then cause the reduction in this metabolic processing of noradrenaline and therefore elongate the action of noradrenaline in the synaptic cleft.

Answer 29

It is important to remember that there are different types of MAO within the body, MAO A and MAO B. Due to this there are there are multiple different types of MAO inhibitor that are present in the clinic. You can have MAO inhibitors that target MAO non specifically (ie target both types of the enzyme). Examples here are Phenelezine. Alternatively, you can have isotype specific inhibitors, which will target either MAO-A or MAO-B isotypes. Importantly within the MAO-A class of inhibitors, you have reversible or irreversible inhibitors.

Answer 30

It is important to remember that there are different types of MAO within the body, MAO A and MAO B. Due to this there are there are multiple different types of MAO inhibitor that are present in the clinic. You can have MAO inhibitors that target MAO non specifically (ie target both types of the enzyme). Examples here are Phenelezine. Alternatively, you can have isotype specific inhibitors, which will target either MAO-A or MAO-B isotypes. Importantly within the MAO-A class of inhibitors, you have reversible or irreversible inhibitors.

Answer 31

Now finally it is possible to target the  and  adrenergic receptors in the post synaptic cell. We have already identified that adrenaline, noradrenaline and isoprenaline are agonists for these receptors, but that there are a significant range of other agonists and antagonists, which we will go through in a bit more detail in the next few slides. However, what are the effects of activation of these receptors on the pressure within the blood system for example. IV infusions of Noradrenaline will cause an increase in both systolic and diastolic pressure, and it acts in a mainly  adrenergic manner. Isoprenaline will decrease blood pressure as it is a vasodilator and acts mainly in a  adrenergic manner. Adrenaline on the other hand combines both actions.

Answer 32

Here we have some examples of  adrenergic receptor antagonists. Phenoxybenzamine is a nonselective irreversible inhibitor, which is used to treat Phaeochromocytoma, whilst Prazosin for example is an 1 selective antagonist. Therefore, within this class of drugs you have drugs which are targeted to one particular receptor such as prazosin, or those which are targeting multiple adrenergic receptors. As hopefully you can see many of these drugs, even if they are more selective, have similar side-effects such as Tachycardia, postural hypotension, and impotence.

Answer 33

Here are some  adrenergic antagonists. Examples here are propranolol, which is nonselective, or the more selective metoprolol. These are used to treat angina, and hypertension for example, but have significant side effects such as bronchoconstriction (though metoprolol shows a reduced risk in regards bronchoconstriction). Importantly, some of these drugs have poor bioavailability due to their rapid first pass metabolism

Answer 34

Finally we have some antagonists, which act on both the alpha and beta receptors. This maybe less selective, and so has the potential to have more non-specific effects, rather than being selective in the targeting of the drug, but these drugs can have clinical benefit. Examples here are Labetalol which is used to treat hypertension in pregnancy. Therefore, in conclusion Noradrenaline is a key neurotransmitter within the sympathetic division of the Autonomic Nervous System. It is one of the catecholamines and is therefore produced from tyrosine. Its action within the synaptic cleft is via the adrenergic receptors, and its metabolism is controlled through the action of MAO. There are multiple points which noradrenaline action can be targeted, presynaptically (by uptake blockers), within the synaptic cleft (with MAO inhibitors) and finally post synaptically by targeting the adrenergic receptors

Answer 35

Definition: An acquired, chronic and progressive cognitive impairment, sufficient to impair activities of daily living Dementia is not a specific disease but is rather a general term for the impaired ability to remember, think, or make decisions that interferes with doing everyday activities. Alzheimer's disease is the most common type of dementia. Though dementia mostly affects older adults, it is not a part of normal aging.

Answer 36

The risk of dementia increases with age 5% over the age of 65 years 20% over the age of 80 years - The biggest risk factor of dementia is AGE

Answer 37

- Alzheimer's dementia - Vascular dementia - Lewy Body dementia - Frontotemporal dementia -

Answer 38

Abnormal deposits of proteins from amyloid plaques and tau tangles through the brain Acetylcholinesterase inhibitors (AChEIs) – Donepezil, Rivastigmine, Galantamine NMDA antagonist - Memantine IT’S NORMAL FOR THE BRAIN TO SHRINK WITH AGE! Weight of the brain < with age! 5% reduction aged 30 – 70 years By 90 reduced by 20% weight INCREASE in ventricular size IN ALZHERIMER’S: Generalised atrophy (more marked cf normal) With Alzheimer’s, the areas of loss are fairly predictable – CT report “Medial-temporal lobe atrophy” is classic

Answer 39

Abnormal deposits of the alpha-synuclein protein (Lewy-bodies) affect the brain’s chemical messengers Drug responses can be extreme – susceptibility to side effects (mostly concerning psychotropic medications)

Answer 40

Personality, behaviour and language more affected initially then memory Frontal – impulse and behavior control loss Says unexpected, rude, mean, odd things to others Disinhibited – food, drink, sex, emotions, actions Temporal – language loss Can’t speak or get words out Can’t understand what is said, sound fluent – nonsense words