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Unformatted text preview: LCRS Pharmacology & Therapeutics Alexandra Burke-‐Smith 1. Drug Receptor Interactions Dr M J C roucher Pharmacology: “the science of the properties of drugs and their side effects on the body” • Pharmacology can be divided into two main areas: pharmacokinetics + pharmacodynamics Pharmacokinetics: “the study of how drugs are handled within the body, including their absorption, distribution, metabolism + excretion” This is concerned with… • how drug concentration changes with time • how drugs pass across cell membranes • how often drugs should be given • what the effect of long-‐term administration may be • how drugs interact with each other (it also addresses how individual variations affect all these things) Pharmacodynamics: “the interactions of drugs with cells and their mechanism of action on the body” It includes factors such as… • How drugs bind to cells • Uptake of drugs into cells • Intracellular metabolism of drugs BASIC CONCEPTS + TERMINOLOGY Drug: “a chemical that affects physiological function in a specific way” • This rules out substances like water, which affects physiological function in a non-‐specific way Drug target sites: “protein complexes key to drug mechanism of action” When a drug is administered, it first must interact with 1 of 4 target sites: • Cell Receptors • Ion channels • Transport systems • Enzymes 1) Cell Receptors • Effectively proteins which usually sit within cell membranes therefore are exposing an active site waiting to be activated by neurotransmitters or hormones. o NB: steroid hormone receptors are intracellular • There are 4 main families of receptors; differentiated on the basis of the protein structure of the receptor + the biochemical/transduction system the receptor interacts with in the cell Type 1 Type 2 Type 3 Type 4 Ionotrophic Metabotrophic Kinase-‐linked Intracellular steroid type receptors receptors (G-‐
receptors receptors (ligand-‐gated protein channels) coupled) Location Membrane Membrane Membrane Intracellular Effector Channel Enzyme or Enzyme Gene transcription channel Coupling Direct G-‐protein Direct or Via DNA indirect Speed Milliseconds Seconds Minutes Hours Examples Nictonic Ach Muscarinic Ach Insulin Steroid/thyroid receptors receptor receptor receptor 1 LCRS Pharmacology & Therapeutics (nAChR) GABAA receptor (mAChR) β1-‐
adrenoceptors in the heart Alexandra Burke-‐Smith Growth factor + cytokine receptors ANF receptor Receptor structure • T1 receptors = 4-‐5 subunits with an external binding domain. Specific transmembrane segment forms the channel pore. • T2 receptors = no subunits, but 7 transmembrane segments. Binding domain sits within the transmembrane segments, thus giving a smaller external domain. G-‐protein coupling domain lies within cytoplasmic loops. • T3 receptors = single transmembrane segment with large external binding domain. Binding initiates signal to cytoplasmic catalytic domain à enzymatic response • T4 receptors = similar classic receptor structure, except all intracellular. DNA binding domain lies within zinc fingers (these wrap around the nuclear DNA + promote gene transcription) 2 LCRS Pharmacology & Therapeutics Alexandra Burke-‐Smith Receptors often initiate sequences involving different 2nd messenger molecules. You should be aware of these (do not need to learn diagram!!) Receptors are also defined by their specific agonists + antagonists Agonists: a drug or other substance that acts on the cell receptor to activate it, initiating a response. Examples include: • acetylcholine at acetylcholine receptors • nicotine the normal dose-‐response curve has a hyperbolic shape, whereas the log dose-‐response curve has a sigmoidal shape. Antagonists: a drug or other substance that binds to the cell receptor without activating it, thus blocking the receptor active site and inhibiting the normal response. NB: the term agonist + antagonist are specifically used for drugs acting on receptors (not enzymes, where they may act as enzyme activators or inhibitors) 2) Ion channels Selective pores in the lipid bilayer in the cell membrane, which can be opened to promote the movement of ions down their electrochemical gradient There are 2 main types of ion channels, differentiated by their mechanism of gates: • Voltage-‐sensitive: channel opens in response to a change in membrane potential, e.g. Ca2+ channels (VSCC) • Receptor-‐linked: channel opens in response to the activation of a receptor (for info about receptor activation, see above) e.g. acetyl choline activates nAChR, which in turn opens an ion channel 3 LCRS Pharmacology & Therapeutics Alexandra Burke-‐Smith Drugs may interact with one or both types of ion channels. Examples of drugs include… • Local anaesthetics – interact with/block v-‐sensitive Na+ channels on pain conduction neurones, thus reducing the perception of pain • Calcium channel blockers – e.g. Nitradipine; very useful in the treatment of CV disorders, for example as anti-‐hypertensives + anti-‐angina drugs 3) Transport systems Specific carrier molecules that transport substances against their concentration gradient These are energy dependent Examples include.. • Glucose transporter in hepatocytes • Neurotransmitter transport e.g. active reuptake of noradrenaline into nerve terminals in the sympathetic NS • Na+/K+ ATPase Drugs may interact with transport systems in order to mediate their action. Examples include: • TCAs (tricyclic anti-‐depressants) – in clinical depression, the Na5HT transporter in the brain is not fully functional. TCAs slows down the postsynaptic reuptake of NA into the nerve terminals thus prolonging the effect of NA • Cardiac glycosides – act to slow down the Na/K ATPase, leading to an increase in intracellular Na+. this is useful in cardiac failure, as the increase in intracellular Na+ leads to an increased force of contraction, e.g. Digoxin 4) Enzymes Catalytic proteins that increase the rate of reaction, without changing the reaction A number of drugs interact with enzymes in 3 ways: • Enzyme inhibitors – act to slow enzyme function, e.g. neostigmine: an anticholinesterase which slows down the rate of degradation of acetylcholine thus enhancing its action • False substrates – act to subvert normal pathways by introducing a new substrate, e.g. Methyldopa: antihypertensive drug which subverts the normal noradrenaline synthesis pathway by introducing a different precursor à local vasodilation • Prodrugs – essentially drugs which interact with an enzyme to form the active component which then has an effect on the body, e.g. chloral hydrate which is converted to the active trichloroethanol NB: unwanted (non-‐therapeutic) effects of drugs are also mediated by enzymes, e.g. Paracetamol overdose (10-‐15x normal dose) saturates the metabolism enzyme system in the liver, leading the alternative metabolic pathways which involve the formation of free radicals + generation of toxic metabolites which cause irreversible liver + kidney damage – there is a delay in the organ damage by ~24-‐48 hrs, therefore treatment for overdose needs to happen in the first 12 hours to prevent the irreversible damage. Non-‐specific drug action There are drugs whose action are mediated solely by their own physiochemical properties, and do not involve the 4 main drug-‐target sites. Examples of these include… • General anaesthetics – interact with synaptic transmission in the brain, but the specific interaction is unknown • Antacids – used in the treatment of indigestion, dyspepsia and the symptoms of ulceration (in conjunction with anti-‐ulceration drugs) o Antacids are bases, therefore have no specific action, but their effects result from the general equation acid + base à salt + water • Osmotic purgatives/laxatives – act to draw water into the large intestine causing softening/expansion of faeces and promotion of excretion 4 LCRS Pharmacology & Therapeutics Alexandra Burke-‐Smith NB: plasma protein binding: plasma protein binding sites e.g. albumin, act to allow storage of drugs in the body in a protein-‐bound form. This allows transport of the drug, but does not mediate any action of the drug. Not all drugs can/will exist in a pp bound form. DRUG-‐RECEPTOR INTERACTIONS Further terminology… • Affinity: the strength (Avidity) of drug binding to receptor • Efficacy/intrinsic activity: the ability of the drug to induce a response in the receptor post-‐
binding (i.e. through a conformational change in the receptor) • Potency: the powerfulness of a drug, depending on its affinity and efficacy • Full agonist: an agonist which has the ability to induce a max response in tissue post-‐
binding • Partial agonist: an agonist which can only produce a partial response in tissue, and in conjunction with a full agonist may act with antagonistic activity • Selectivity: the preference of a drug for a receptor (this is not specificity; specific suggests one drug one receptor. In fact the adverse effects of many drugs are caused by the binding to their non-‐preferred receptors) • Structure-‐activity relationship: referring to the fact that the activity of a drug is closely related to the structure of the drug, therefore small changes in the structure may produce large effects on its action o This is like the lock + key theory, and is useful in drug design; small changes to an agonist may in turn form an antoagonists, as well as altering the pharmokinetics of the drug • Receptor reserve refers to the fact that in many tissues, not all receptors need to be occupied in order to achieve the maximal tissue response o With regards to physiological tissue, this results in an increased sensitive + speed of response ANTAGONISTS Agonists show affinity + efficacy for receptors. However antagonists have no efficacy, therefore post receptor-‐binding they do not induce a response. In turn they prevent agonists from binding and inducing the normal response from the receptor. Competitive antagonists bind to the same site as the agonist, therefore reducing the number of agonist molecules which can bind to the receptor, therefore reducing the normal agonist response • They are surmountable; therefore by increasing the concentration of the agonist, you can overcome a competitive antagonist block • Dose-‐response curve shows parallel displacement to the RIGHT • E.g. 1) atropine = acetyl CoA muscarinic antagonist • E.g. 2) propranolol = non-‐selective β1/2 blocker Irreversible antagonists bind either tightly to the same site as the agonist (by covalent bonds as opposed to the normal hydrogen bonding/electrostatic forces), or at a different site to the agonist. • These are insurmountable, therefore the maximal normal response cannot be achieved regardless of whether the concentration of agonist is increased further. • Dose-‐response curve shows shift of curve to the right + decreased maximal tissue response • E.g. hexamethonium – nicotinic antagonist; binds to the ion channel + blocs the flow of Na+ 5 LCRS Pharmacology & Therapeutics Alexandra Burke-‐Smith 2. Introduction to the autonomic nervous system Dr C hristopher John There are 3 principle efferent outputs from the CNS: autonomic, somatic + neuroendocrine • Autonomic is responsible for involuntary control, and accounts for the innervation of exocrine glands, smooth muscle, cardiac muscle, as well as being involved in metabolism + host defence. • Somatic is the innnervation of the muscle, including the diaphragm and respiratory muscles. • Neuroendocrine system is responsible for growth, metabolism, reproduction, development, salt + water balance as well as host defence. The basic branches of the ANS are the sympathetic + parasympathetic • sympathetic = fight + flight • parasympathetic = rest + digest These states are either end of the spectrum, but generally speaking we exist somewhere in the middle of the spectrum with a balance between sympathetic and parasympathetic control, and these branches are usually found to antagonise one another. Within the different body tissues (i.e. targets of the ANS), the innervation of sympathetic + parasympathetic is rarely equal and there tends to be dominance of one branch of the ANS. Examples include: • Lung tissue – sympathetic NS in the lung causes dilation, whereas parasympathetic control causes constriction of the airways. Here the parasympathetic NS tends to dominate to maintain a partial constriction of the airways which allows for finer control. • The eye – sympathetic NS tends to dilate the pupil, whereas the parasympathetic NS tends pupil constriction. Again parasympathetic dominance occurs to maintain partial constriction. NB: innervations of smooth muscle tends to favour parasympathetic dominance to allow for finer control, i.e. if you have partial constriction you have the ability to constrict further but also dilate. • The heart (NB: cardiac tissue is different than smooth muscle) – the sympathetic NS tends heart rate increase, and the parasympathetic tends heart rate decrease. Again parasympathetic dominance allows for more control of the heart rate. • Blood vessels – the parasympathetic NS tends not to innervate blood vessels, therefore the sympathetic NS is completely dominant. However it needs to be able to both constrict + dilate the blood vessels. The balance of action on the blood vessels is thus dependent on the presence of receptors in the tissues, and varies depending on the location of blood vessels within the body. PRINCIPLE TARGETS + FUNCTIONS In most cases, the actions of the two branches of the ANS act to antagonise each other, but in some cases they have the same effect, e.g. in the salivary glands. However the difference here is that the two branches result in different types of secretions. ANATOMICAL STRUCTURE General features: • 2 neurone set up; pre=ganglionic + post-‐ganglionic fibres • Neurones innervate together in ganglion Parasympathetic features: • Cranial sacral outflow • Long pre-‐ganglionic fibre • Short post-‐ganglionic fibre • Ganglia tend to lie within the innervated tissue • Only neurotransmitter involved is Ach, therefore all cholinergic synapses 6 LCRS Pharmacology & Therapeutics Alexandra Burke-‐Smith Sympathetic features: • Thoracolumbar outflow • Short pre-‐ganglionic fibre • Long post-‐ganglionic fibre • Ganglia form just outside spinal cord in the paravertebral chains • Preganglionic fibres release Ach, but post-‐ganglionic fibres vary: o Postganglionic fibres to effector organs release noradrenaline o Some preganglionic fibres innervate the adrenal medulla, thus the glad acts as the ganglion releasing noradrenaline (+~20%NA + little dopamine) via the bloodstream to effector organs o Postganglionic innervation to sweat glands release Ach NB: the enteric nervous system is the local nervous system of the digestive tract, consisting of the submucosal and myenteric plexus. The somatic nervous system consists of 1 long motor neurone with Ach release to skeletal muscle. CHOLINOCEPTORS + ADRENOCEPTORS Acetylcholine is a neurotransmitter which requires receptor binding in order to produce an effect, and is then broken down within ms by acetyl cholinesterases. There are two types of Ach receptors: • Nictonic receptors – membrane bound receptors present at autonomic ganglia o These are Type 1 ionotrophic receptors, thus produce rapid responses via ion channel opening o Stimulated by nicotine + acetylcholine o Blocked by hexamethonium • Muscarinic receptors – tend to be found in the effector organs innervated by post-‐
ganglionic parasympathetic fibres, thus mediating effector responses: o These are type 2 G-‐protein coupled receptors, thus require the generation of 2nd messenger molecules à slower responses o Stimulated by muscarine + acetylcholine o Blocked by atropine There are 3 subtypes of muscarinic cholinoceptors: • M1 – found in neural tissues • M2 – found in cardiac tissues • M3 – found in exocrine + smooth muscle There are also many subtypes of adrenoceptors. These are found at all effector organs innertvated by post-‐ganglionic sympathetic fibres. These mediate the effects of NA on the sympathetic effector organs (+ circulating in the bloodstream) The subtypes include: • Alpha 1 • Alpha 2 • Beta 1 • Beta 2 Summary of receptor locations within the ANS: • Nictonic cholinoceptors are found at all pre-‐ganglionic nerve terminals • Muscarinic cholinoceptors are found at all parasympathetic post-‐ganglionic nerve terminals + sympathetic port-‐ganglionic fibres innverating sweat glands • Adrenoceptors are found at sympathetic post-‐ganglionic nerve terminals in their effector organs NB: Drugs may interact with nictonic, muscarinic or adrenergic receptors; resulting in different effects 7 LCRS Pharmacology & Therapeutics Alexandra Burke-‐Smith BIOSYNTHESIS + METABOLISM OF THE AMINE NEUROTRANSMITTERS All amine transmitter synthesis follows a similar set of stages: 1. Precursor is taken up into pre-‐synaptic nerve terminal 2. Precursor is enzymatically converted into the active transmitter, and then packaged into vesicles 3. Following pre-‐synaptic nerve terminal depolarisation (with associated increased intracellular Ca2+), the vesicles fuse and release the transmitter into the synapse 4. The transmitter then binds with the receptor on the effector cell, is broken down and its degradation products are taken back up into the nerve terminal. Acetyl choline synthesis follows this norm… • Precursor = acetyl CoA + choline • Enzymatic conversion = choline acetyl transferase • Enzymatic degradation = acetylcholine esterase (with choline + acetate released as the degradation products) Noradrenaline synthesis is slightly more complex… • Precursor is tyrosine • Tyrosine is then hydroxylased into DOPA by tyrosine hydroxylase • DOPA is then decarboxylated to form Dopamine, which is then packaged into vesicles • Within the vesicle, dopamine is hydroxylased to form noradrenaline by dopamine beta hydroxylase • NA is then released from the vesicle like normal... • There are 2 uptake systems for NA tissue reuptake: o Uptake 1 – neural reuptake + degradation by MAO-‐A (monoamine oxidase A) to form secondary metabolites o Uptake 2 – extraneural uptake and degradation via COMT NB: this is very important in pharmacodynamics Generally speaking, drug targets are proteins, thus when considering a specific biosynthesis/metabolism system, you can determine what the possible enzyme/receptors could be targeted. 8 LCRS Pharmacology & Therapeutics Alexandra Burke-‐Smith 3. Mechanism of Drug Action Dr M J C roucher DRUG ANTAGONISM There are 4 main types of drug antagonists… 1) Receptor blockade See notes from lecture 1 on competitive + irreversible antagonists NB: “use-‐dependency”: this refers to the fact that some irreversible antagonists act by blocking ion channels (e.g. hexamethonium – blocks v-‐gated Na+ channels on nictonic receptors), therefore the effect of the antagonist is seen more quickly on rapidly firing neurones. This provides a degree of variation between antagonist effect on different neurones; allows a degree of selectivity useful for local anaesthetic and the blocking of pain perception neurones. 2) Physiological antagonism Here, drugs may act on different receptors in the same tissue to induce the opposite effect E.g. noradrenaline acts to induce vascular constriction à BP increase, whereas histamine acts on different receptors to induce vascular dilatation and BP decrease 3) Chemical antagonism This is a relatively rare event, whereby two drugs interact in solution For example, chelating agents e.g. dimercaprol, form complexes with heavy metals, allowing them to be more easily in urine. This is very useful in treatment for heavy metal poisoning 4) Pharmacokinetic antagonism Here, the antagonists act to reduce the concentration of the active drug at the site of action. The ways in which pharmacokinetic antagonism occurs include: • Decrease absorption • Increase metabolism • Increase ex...
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