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PHAR1001 Notes Lectures 1-7: The Nervous System (TGS) 1) The Nervous System (NS) and its subdivisions are as follows: - The NS is split into the CNS (Brain + Spinal Cord) and the PNS - The PNS is split into the afferent (sensory) and efferent (motor) Nervous Systems - The afferent NS is split into t...

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PHAR1001 Notes Lectures 1-7: The Nervous System (TGS)

1) The Nervous System (NS) and its subdivisions are as follows: - The NS is split into the CNS (Brain + Spinal Cord) and the PNS - The PNS is split into the afferent (sensory) and efferent (motor) Nervous Systems - The afferent NS is split into the somatosensory, Viscerosensory and special sensory divisions - The efferent NS is split into the somatomotor and autonomic Nervous Systems - Finally, the autonomic NS is split into the Sympathetic, Parasympathetic and Enteric Nervous Systems. 2) The cells of the nervous system can ultimately be classified as either neurones or glial cells. Neurones can be classified as either sensory, motor or intermediate. They are outnumbered by as much as 4:1 by glial cells, which work to support the neurones, one of the most important being Schwann cells in the PNS, or oligodendrocytes in the CNS, which myelinate neurones, enabling them to conduct action potentials at a much faster rate. Other glial cells in the CNS include astroglia (from the blood-brain barrier) and microglia (phagocytes to protect against infection). 3) Nerve fibres are bundles of neurones. They are classified based on whether or not they are myelinated. Nerves that are myelinated have a lipoprotein covering called a myelin sheath, with each neurone in the fibre associated with a myelinating Schwann cell (PNS) or oligodendrocyte (CNS). Nerves that are unmyelinated lack the myelin sheath, and a number of neurones are loosely associated with a non-myelinating Schwann cell/oligodendrocyte. Nerve fibres can also be defined in terms of their function e.g. DRG vs VRG, Sympathetic vs Parasympathetic, as well as by their diameter/electrical resistance/capacitance. Myelination refers to the coating of a neurone by a Schwann cell/oligodendrocyte. The purpose of this is to increase the rate of action potential transmission, as Saltatory Conduction can be achieved in addition to the local circuit effect, with depolarisation occurring only at Nodes of Ranvier. Myelination allows for conduction at 120 m/s, compared to a max of 2.5 m/s in unmyelinated fibres. 4) The Membrane Potential is the voltage that exists across the plasma membrane of a cell when it is not conducting action potentials, i.e. it is at rest (quiescent); normally about -70 millivolts, though this varies depending on the excitability of a given cell.

The Membrane Potential is generated & maintained by the active electrogenic Na+-K+ ATPase primarily (works to achieve a Na+ electrochemical gradient into the cell), but also by leaky Na+ and K+ ion channels. PK is 10-100 times greater than PNa, hence the low PNa ensures that the work of the pump is supported as Na cannot easily leak back into the cell. The value of EK and ENa can be calculated using the Nernst equation. The value of EK often closely matches the membrane potential, since K+ is fairly close to equilibrium across the plasma membrane – some K+ diffuses back into the exoplasm down their concentration gradient, though this effect is minimised by an influx of K+ down the ion’s electrical gradient, such that the two gradients are of equal size. The existence of the hydrophobic core of the phospholipid bilayer that forms the basis of the membrane is also vitally important as this ensures that Na/K can only diffuse across the membrane via ion channels once pumped by Na/K ATPases. 5) Voltage-gated ion channels will open as a result of a change in the voltage across the plasma membrane. For instance, voltage-gated K+ channels open once the action potential of +40 mV is achieved, permitting K+ efflux. In contrast, ligand-gated ion channels will open as a result of the binding of a specific ligand to its complementary binding site to form a complex. This often leads to a conformational change in the binding domain (e.g. a receptor), hence permitting influx of a molecule or ion. This is seen at the neuromuscular junction, where the binding of ACh to its receptor on the sarcolemma (postsynaptic membrane) induces a conformational change that allows Na+ influx and K+ efflux via a non-selective cation channel. GABA-A Cl- channels are another example, permitting hyperpolarisation. 6) The Action Potential is the fleeting reversal of the membrane potential. It is usually very close to the value of the sodium equilibrium potential, E Na. This is because, when VGSCs open, Na influx occurs down a steep electrochemical gradient, until the point that there is no net gradient across the plasma membrane i.e. [Na] is equal on both sides, and the electrical gradient is directed outwards into the exoplasm. The AP is generated as a result of the influx of a small number of Na+ ions (Generator Potential) that can be understood as a superthreshold stimulus, i.e. the GP depolarises the plasma membrane such that TP is exceeded. The subsequent stages of depolarisation, repolarisation and afterhyperpolarisation result from influx and efflux via voltage-gated Na+ and K+ ion channels respectively, with the pump coming into action in the final stage before the cycle completes. There are drugs associated with manipulating action potentials to treat disease. For instance, Multiple Sclerosis (MS) can be treated by giving a patient tetraethylammonium or 4-aminopyridine (4AP). These drugs block VG K+ channels, thus synaptic potentials are prolonged in the muscle effectors, allowing for longer periods of contraction, helping to mitigate symptoms such as vision problems. MS arises when parts of the myelin sheath of many motor neurones are lost, thus saltatory conduction fails and, because myelinated neurons are much thinner, electrical resistance is far greater, so conduction velocity is incredibly slow or fails altogether. Pain can be treated by prescribing Tetrodotoxin (TTX), which blocks VG Na+ channels, thus no depolarisation can occur, thus no APs generated, so the brain is oblivious to the pain. 7) Synaptic Transmission is a function of action potential transmission. The ‘wave of depolarisation’ (i.e. GP of Na+ diffusing down inside of axon membrane down an electrochemical gradient) reaches an axon terminal (aka synaptic knob/bouton), causing VG Ca2+ channels to open, triggering Ca2+ influx. These ions stimulate synaptic vesicles carrying neurotransmitters to migrate along the cytoskeleton to the presynaptic membrane, at which they exocytose their contents into the synaptic

cleft. The neurotransmitters diffuse across the cleft (10-20 nm) down their concentration gradient, binding to complementary postsynaptic receptors, inducing a conformational change that opens ligand-gated ion channels, permitting Na+ influx into the postsynaptic neurone, thus depolarisation. An AP will be generated if GP > TP. Summation (amplification of low-level stimuli) can occur at the presynaptic membrane to achieve this. Summation may be either temporal (repeated APs cause further NT release hence further receptor activation for additional Na influx) or spatial (balance of depolarising and hyperpolarising inputs e.g. Na influx vs Cl influx). Important neurotransmitters include: Acetylcholine (ACh – important in parasympathetic NS (receptors vary at different synapses e.g. nAChRs at preganglionic (as seen also in Symp NS), mAChRs at postganglionic) and in somatic NS – both nAChRs and mAChRs), Noradrenaline (important in sympathetic NS at postganglionic synapses), Glutamate (excitatory), GABA and glycine (inhibitory), Dopamine (reward, addiction) and Serotonin (euphoria, empathy). Glutamate, GABA, Dopamine and Serotonin (aka 5-hydroxytryptamine or 5-HT) are only found in the CNS. Transmission is terminated by the hydrolysis of ACh by ACh Esterase on the postsynaptic membrane, forming Choline and Acetate. Choline is reclaimed by means of the choline uptake carrier (aka choline transporter, ChT) making use of the Na+ gradient to facilitate co-transport. The acetate dissolves in the tissue fluid that bathes the neurones as it is a hydrophilic species. ChT is blocked by hemicholinium, whilst coluracetam is an enhancer of the carrier. One final point to consider is how the choline that is reclaimed is used to reproduce ACh presynaptically. This occurs by the action of the choline acetyltransferase (ChAT) enzyme, which transfers the acetate from Acetyl-CoA to choline to form ACh (Ch + Acetyl-CoA -> ACh + CoA). The Acetyl-CoA forms as the final product of the link reaction in mitochondria at the axon terminal concerned. ACh is then packaged into synaptic vesicles (as many as 10 000 ACh per vesicle). This synthetic pathway can be interfered with by Triethylcholine (TEC), which diffuses into the presynaptic neuron via ChT and can also bind to the active site of ChAT hence a false neurotransmitter is produced called acetyltriethylcholine (ATEC), which cannot activate postsynaptic receptors hence cannot facilitate e/c coupling. This knowledge is applied to treat the disease Myasthenia Gravis (translates from Latin ‘serious muscle weakness’). This is an autoimmune disease, wherein the body’s own immune system attacks and destroys many nAChRs on the sarcolemma, thus very few functional nAChRs remain, so the EPP that can be produced is much lower from a given ACh release, thus contraction is very weak, hence muscle control is poor. This can be treated by prescribing a drug that blocks ACh Esterase, such that [ACh] in the synaptic cleft increases greatly, hence the sarcolemma is stimulated for much longer and a greater EPP is generated as there is greater re-binding of ACh to its complementary nAChRs, giving greater contractile force and thus greater muscle control. These drugs include edrophonium, neostigmine and physostigmine. 8) Main differences between APs and SPs: - SPs amplitude is proportional to stimulus (able to summate); APs amplitude is all or nothing + limited by ENa / EK; APs are related to stimulus via their frequency. - SPs can be depolarising or hyperpolarising; APs only depolarising. - SP ion channels are ligand-gated (or others); APs are always voltage-gated. - SPs have no associated refractory period; APs have both absolute and relative refractory periods.

- SP amplitude is decremental (i.e. it decreases as the wave moves towards the axon hillock from the dendrites); AP amplitude is non-decremental (amplitude does not change with transmission). Interesting + Useful Point A good way of understanding the refractory period is to give it its logical name – Na+ channel inactivation – since the bottom gate closes during the absolute refractory period, thus no Na+ can enter (even if the stimulus is enormous). The bottom gate opens again during the relative refractory period; the top gate is closed though can be forced open if a superthreshold stimulus arises that can manage to successfully depolarise the neurone from its hyperpolarised state (requires a lot of work considering the membrane potential can be as polarised as -100 mV, TP being -55 mV). 9) Local Anaesthetics (LAs) are a class of drugs that share a common 3-part structure: Aromatic side chain + Ester OR Amide linkage + 2o/3o amine side chain. -

Mechanistically, all LAs work in the same way – they block VG Na+ channels. Therefore, their main use is to eliminate pain e.g. in dental procedures like putting in a filling. They work in a given region of the body where they are administered (hence ‘local’ rather than general anaesthetic). They all end in the -caine suffix, e.g. lignocaine, cocaine, procaine, etc.

(Cocaine) -

The amine side chain also tends to exist as a quaternary amine in (aq), due to the fact that the N atom has a lone pair of electrons that it will donate to a proton, giving N + and four groups bound to it.

Mechanism of Action – how do LAs actually block VG Na + ion channels? LAs can block their target channel by either the hydrophilic or hydrophobic pathway. In the hydrophilic pathway, the lipid-soluble (deprotonated) form of the drug diffuses across the phospholipid bilayer into the cell. The N atom of the amine of the LA then forms a quaternary amine (LA + H+  LAH+). This charged molecule thus diffuses into the hydrophilic interior of a VG Na+ channel, thus blocking it. This is also how the LA penetrates into neural tissue (route of administration) across the connective tissue sheath and axolemma. In the hydrophobic pathway, the lipid-soluble form of the LA diffuses into the VG Na+ channel directly via the phospholipid bilayer, entering through small pores in the walls of the VGSC.

Finally, how are LAs administered? There are four ways in which LAs can be administered to a patient: A) Topical – where the anaesthetic is applied on the surface of a tissue, e.g. on the skin or eyes. B) Infiltration – injections around nerve endings, such as in intradermal injections. Often take about 10 minutes to kick in due to Le Chatelier’s Principle (in terms of the equilibrium LA + H  LAH+, starting from the left with high [LA]). The charged product thus forms intracellularly, hence facilitating its action by the hydrophilic pathway (can also operate via hydrophobic pathway by diffusing into VGSCs via pores in channel in phospholipid bilayer). Often used in concert with vasoconstrictors (e.g. adrenaline) so as to reduce blood flow to the nerve endings, thus prolonging the duration of anaesthesia by slowing the rate of absorption of the LA. C) Peripheral Nerve Block – Where a LA is injected close to a major sensory nerve trunk, so as to reduce or stop all action potential transmission from one region of the body to the brain, thus no pain is registered. This is typically a subcutaneous injection. D) Central Nerve Block – This can be subdivided into intrathecal and epidural injections. In intrathecal injections, a LA is injected into the subarachnoid space, normally in the lumbar region (around L2-L3) of the spinal cord, since the thickness of the cord is much lower here, thus the risk of the needle breaking a spinal nerve (axotomy) and causing paralysis is minimised. The purpose of an intrathecal injection is for the LA to be taken up into the cerebrospinal fluid (CSF), thus it has a more general anaesthetic effect than other methods of administration. In epidural injections, a LA is injected into the epidural space (the outermost layer of the spinal cord, aka the layer above the dura mater), so as to anaesthetise specific spinal nerves here, a more local anaesthetic effect. Remember: the three layers of tissue in the spinal cord (from outermost -> innermost): are dura mater, arachnoid mater, pia mater (acronym: look at my DAP). Thus we can now classify LAs based on the ways in which they are administered. Local Anaesthetic

Ester (E) or Amide (A)?

Cocaine E Procaine E Amethocaine E Bupivacaine A Lignocaine A Prilocaine A *due to high addiction potential.

Route(s) of Administration Not used medically* B-D A C-D A-D A-D

Duration of action Short ( k+1, hence association is favoured, whereas a negative value tells us k-1 < k+1 hence dissociation is favoured. The relationship is linear thus y = mx + c. Other methods of antagonism (other than reversible competitive antagonism) 1. Chemical antagonism – where the antagonist directly binds to its agonist counterpart to reduce its action e.g. EDTA to treat lead poisoning, acting as a chelating agent (multidentate ligand). No receptor is involved. EDTA is ethylenediaminetetraacetic acid. 2. Physiological antagonism – where the antagonist is an agonist that has the opposite biological effect of another agonist e.g. adrenaline stimulates bronchodilation, countering the bronchoconstriction brought about by histamines. 3. Pharmacokinetic antagonism – where the antagonist reduces [agonist] indirectly at its site of action e.g. phenobarbitone increases the activity of hepatic enzymes that inactivate warfarin in the blood, preventing anticoagulation (dangerous thinning of the blood). 4. Indirect antagonism – where an antagonist acts at a second ‘downstream’ receptor which links the action of the agonist to the desired response. For instance, β-blockers such as propranolol bind to β-adrenoceptors on myocardium, preventing noradrenaline from binding

so as to decrease heart rate; noradrenaline itself being secreted from noradrenergic nerve endings, stimulated by the tyramine agonist. However, some pharmacologists argue this is simply a variation of physiological antagonism, since the β-adrenoceptor blocker’s role in decreasing heart rate is a genuine biological function.

Lecture 13: Complementary Medicine (AS) There are three ‘theories of medicine’: -

-

Evidence-based: i.e. clinical trials; have to ensure these are randomised and double-blind (i.e. both patient and doctor don’t know whether they are getting/giving placebo or actual drug), and registered with a local registry to prevent publication bias (i.e. only publishing positive results to make the efficacy of the drug erroneously appear better than it actually is). Science-based: a hypothesis is formulated and experiments conducted to gather evidence that either proves or disproves this hypothesis. Alternative/Complementary: not based on scientific theory; may have support from clinical trials for its efficacy (how effective it is).

Complementary/Alternative Medicine (CAM) entails treatments that are not taught at medical schools or practiced in established institutions, since they are neither evidence nor science-based. They are not based on the biological sciences. Examples include: Aromatherapy, Hypnotherapy, Acupuncture, Chiropractic and Osteopathy. Less well known examples include craniosacral therapy, tai chi, massage and traditional Chinese medicine. One of the most remarkable forms of CAM is iridology, whose proponents argue that close examination of the eyes of a patient can reveal any problems with their health. Possible hints are said to be revealed in eye colour, pupil dilation, and different retinal patterns. For instance, the ‘arc of senility’ between 11 and 1 o’clock on the eye is said to suggest cerebral hypoxia. Why do patients use CAM rather than orthodox medicine?        

Reduced side-effects from treatment Mostly focused on musculoskeletal conditions Holistic approach (consider the whole e.g. mental/social health in addition to physical health) To treat conditions where orthodox medicine has failed/been inadequate Often cheaper and safer than orthodox treatments Feel like they are in greater control of their treatment Feel listened to and respected (most CAM practitioners are in private sector) Greater participation in therapy

However, a House of Lords committee found in 2000 that there was very little evidence to support the efficacy of CAM – some had no evidence (e.g. aromatherapy), others were regarded as ‘impossible’ as therapies e.g. homeopathy – an interesting CAM wherein a minute dose of a natural substance is administered that in larger doses would produce symptoms of the condition being treated.

Lecture 14: Selective Drugs Against Malaria & Aids (DW)

Chemotherapy 1. To understand the basic concept underlying the use of chemotherapy to treat diseases. Chemotherapy involves identifying a chemical that selectively destroys parasitic cells (or prevents their replication), but not host cells. In nature, a parasite normally refers to helminths (worms) and protozoa; a microbe to viruses, bacteria or fungi. However, when an entity from either group infects the body, it is termed a parasite. Cancer cells also come under this heading as they are not under the control of host regulatory mechanisms so cannot be defined as host cells. The idea of chemotherapy came from Paul Ehrlich, who was a Nobel Laureate in 1908 for developing the idea of the ‘magic bullet’ – a substance that could bind with specific affinity to parasitic cells to destroy them yet have no binding affinity nor an effect on host cells. Chemotherapy has three components to consider: 1. The host 2. The parasite 3. The drug To develop an efficacious chemotherapeutic drug, one first has to identify a clear biochemical difference between the host and the parasite. Ideally, this should be qualitative (e.g. presence or absence of an enzyme or pathway), though can also...