Pharmacology Notes PDF - Module 1, 2, 3, 4
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These notes cover four modules of pharmacology, including historical drug discovery, various drug targets, and therapeutic uses of different drugs.
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CONTENTS (Lectures Organised by Week) MODULE 1: Pharmacological principles L 1.1 HISTORY OF PHARMACOLOGY pg 2 L 1.2 DRUG DISCOVERY (THEN) pg 2 L 1.3 DRUG TARGETS...
CONTENTS (Lectures Organised by Week) MODULE 1: Pharmacological principles L 1.1 HISTORY OF PHARMACOLOGY pg 2 L 1.2 DRUG DISCOVERY (THEN) pg 2 L 1.3 DRUG TARGETS pg 5 L 2.1 AGONISTS pg 8 L 2.2 ANTAGONISTS pg 10 L 2.3 INTRODUCTION TO THE AUTONOMIC NERVOUS SYSTEM pg 11 L 3.1 ADRENERGIC PHARMACOLOGY pg 13 L 3.2 CHOLINERGIC PHARMACOLOGY pg 17 L 3.3 HOW DRUGS GET INTO THE BODY pg 22 L 4.1 HOW DRUGS GET OUT OF THE BODY pg 25 MODULE 2: Therapeutic uses of drugs L 4.2 PHARMACOGENOMICS & PRECISION MEDICINE pg 27 L 4.3 EICOSANOIDS pg 29 L 5.1 IMMUNOPHARMACOLOGY pg 33 L 5.2 DRUGS TO TREAT ASTHMA pg 36 L 5.3 DRUGS IN SPORT pg 40 L 6.1 DRUGS TO TREAT GI DISORDERS pg 44 L 6.3 DRUGS IN THE CARDIOVASCULAR SYSTEM I pg 49 L 7.1 DRUGS IN THE CARDIOVASCULAR SYSTEM II pg 53 L 7.3 DRUGS TO TREAT DIABETES pg 58 L 8.1 DRUGS TO TREAT OBESITY pg 63 MODULE 3: Pharmacology of the CNS L 8.2 INTRODUCTION TO CNS PHARMACOLOGY pg 66 L 8.3A PARKINSON’S DISEASE (PD) pg 69 L 8.3B ALZHEIMER’S DISEASE (AD) pg 71 L 9.2 DRUGS TO TREAT DEPRESSION pg 72 L 9.3 DRUGS FOR PAIN pg 75 L 10.1 DRUGS OF DEPENDENCE pg 79 MODULE 4: Medicines from nature & harnessing toxicity L 10.2 MEDICINAL CANNABIS pg 83 L 10.3 INDIGENOUS MEDICINES pg 85 L 11.1 VENOMS AND TOXINS pg 87 L 11.2 TOXICOLOGY pg 89 L 11.3 ANTIMICROBIAL DRUGS pg 91 L 12.1 ANTICANCER DRUGS pg 94 L 12.3 DRUG DISCOVERY NOW pg 96 Examinable Content from Practical 1 pg 99 Note: L6.2, L7.2, L9.1 and L12.2 did not contain content. 1 L1.1: History of Pharmacology Hippocrates Medicine = to not do harm or injustice Drugs might benefit patients OR cause harm Paracelsus Everything is poison, only dose permits something not to be poisonous Dosage of drugs will determine their effects Ehrlich Substances do not act unless they are bound Drugs MUST be able to bind to their targets Safe and Effective drugs: 1) Can bind to a target Are at an effective concentration, bind with good affinity, have an effect + are selective (which reduces chance of adverse effects) 2) Are able to get there Can be absorbed, distributed + reach target at an effective concentration 3) Are able to get out Can be metabolised and excreted Pharmacodynamics: How drugs bind to and cause effect on their targets Pharmacokinetics: How drugs reach their target + are metabolised after Drug Naming: - Trade name (what companies use; can change) e.g. nurofen, ventolin - Generic name (universal) e.g. ibuprofen, salbutamol - Drug class (mechanism of action) e.g. NSAID, β-2 adrenergic agonist L1.2: Drug Discovery (Then) Approach 1: Observation & Experience Example 1: Cannabis used as an analgesic and antiemetic by many ancient civilisations BUT it contains >500 chemical constituents; difficult to analyse which compounds are producing the desired effect + what doses are being administered Example 2: morphine (+ codeine and thebaine) from opium poppies Opium poppy first used by Sumerians in 3400 BC Morphine isolated as the 1o ingredient in 1805 Morphine commercially manufactured & distributed in 1827 Led to an era of natural product chemistry (using natural products as therapeutics -> this has had a resurgence since 2021!) 2 Example 3: penicillin 1926 Discovered by Fleming but only in its crude form (which is unstable!) Was a potent antibacterial but with selective toxicity (non-toxic to WBCs) 1938 Florey + Chain (the Oxford team) isolated + concentrated penicillin 1940 Florey + Chain mice experiments (showed in vivo efficacy without toxicity; but only experimented on 8 mice!) 1941 First administration to a human (for a staph infection) Was somewhat successful; patient died after supply exhausted! 1941 Collaboration Between scientists (w/ fermentation researches to increase yield) With industry (collab with US pharmaceutical companies) for infrastructure, manpower + financial support 1942 Extensive trials in humans (successful treatments) 1943 Mass production of penicillin by Pfizer 1943-4 Used to treat infections in WWII 1945 Available for public use Noble Prize awarded! Dangers of using penicillin after limited animal trials: 1) Structure of the drug was unknown 2) Mechanism of action was also unknown 3) Toxicity was not well characterised Accelerated development of COVID-19 Vaccines - Due to lots of financial investment, large volumes of patients (so more options for clinical trials) and parallel clinical trials (didn’t have to wait for outcomes) -> a lot faster!! Example 4: sulphonamide (drug repurposing) Used as an antibacterial drug but found to lower blood glucose Led to the development of orally-acting hypoglycaemic drugs for non-insulin dependent diabetes Approach 2: Screening Example 5: tetracyclines Pfizer searched for other antibiotics after penicillin by screening fermentation samples of multiple organisms in 135 000 soil samples for antibiotic activity; eventually isolated oxytetracycline 3 Approach 3: Synthetic Chemistry Example 6: aspirin Based on salicin from willow tree which contains salicylic acid Salicylic acid treats pain, fever + inflammation BUT has GIT complications So is modified into aspirin Example 6: morphine Could be chemically synthesised but we found it’s easier and cheaper to cultivate + isolate its natural source (opium poppies) Full Process of Drug Discovery: 1. Observe medicinal properties of natural sources 2. Obtain organisms 3. Obtain crude extracts + assess bioactivity 4. Obtain fractions + assess bioactivity 5. Isolate compounds and characterise in bioassays + in vivo Note: often there is low bioavailability in the organisms and crude extracts, hence fractions are needed to increase concentration. Drug discovery then vs now - Smaller knowledge base + limited sharing between disciplines - Limited computational power (e.g. data generation/analysis/knowledge transfer) - Fewer available compounds for screening Now - Rational drug design -> uses info on structures of receptors/ligands + interactions between them, disease mechanisms, mechanisms of action of drugs + biochemical pathways (e.g. does metabolism increase/decrease potency or can we synthesise a prodrug instead?) Steps in Drug Discovery Now 1. Choose a disease 2. Identify a therapeutic target 3. Search database for new lead compounds 4. Optimise leads 5. Toxicology assessment and preclinical development 6. Clinical trials 4 L1.3: Drug Targets Drug: A chemical substance of known structure, other than a nutrient or essential dietary ingredient*, which, when administered to a living organism, produces a biological effect *Exception: some essential dietary constituents used in drugs e.g. iron/vitamins Origin of Drugs 1. Synthetic e.g. aspirin 2. Genetically engineered e.g. parathyroid hormone 3. Phytochemicals (plant obtained) e.g. morphine Drugs need a drug target (Ehrlich)* *Exception: osmotic diuretics or antacids don’t target tissue constituents! Drug target: A drug binding site which, upon association with a drug, leads to a change in a physiological response - Normally proteins - Exceptions: antimicrobial + antitumor drugs bind to DNA Bisphosphonates (for osteoporosis) bind to calcium salts Types of Drug Targets 1) Receptors: Biological macromolecules which recognise + respond to endogenous chemical signals OR exogenous drugs Endogenous chemical signals: Are made in the body Exogenous drugs: Are administered Ligands bind to receptors via binding sites Agonist = ligand which activates a receptor Antagonist = ligand which binds to receptor without activity Types of receptors (from fastest to slowest) - Ligand-gated ion channels (ionotropic receptors) - G-protein coupled receptors (metabotropic receptors) - Kinase-linked receptors - Nuclear receptors Ligand-gated Ion Channels - Tube passing through plasma membrane - Ligand-binding domain can be extracellular, in channel or intracellular - Ligand binding = altered conductance of selective ions through the channel 5 Example: nicotinic acetylcholine receptor - 5x subunits (2x alpha + beta + gamma + epsilon) - Acetylcholine binds = Na+ channel opens (= action potential) NOTE: These also have a refractory period meaning after activation they cannot be activated for a period of time regardless of if there’s more ligand attempting to bind G-protein Coupled Receptors (e.g. muscarinic acetylcholine receptor) - Extracellular region = usually the ligand-binding domain - Inside = G-protein (has alpha and beta-gamma subunits) - The alpha-GTP binds to an effector - Effector: enzyme, ion channel, transporter or gene transcription regulator Process: 1. Agonist binds causing GDP to be exchanged for GTP activating G protein 2. α-GTP subunit diffuses to the effector + activates it 3. Heterotrimer (alpha + beta + gamma subunits) reconstituted 4. GTP is hydrolysed back into GDP by GTPase in the α-subunit 5. Agonist unbinds Kinase-Linked Receptors - Single-membrane spanning proteins with enzymatic cytosolic domains - 5 main types - Tyrosine kinase - Tyrosine phosphatase - Non-receptor tyrosine kinase - Serine/threonine kinase - Guanylyl cyclase - Modify proteins either via phosphorylation or dephosphorylation Nuclear Receptors - Type i Inside cytoplasm - Type ii Inside nucleus Nuclear receptors are targets for lipophilic drugs (which can diffuse through the membrane) + act on intracellular proteins (e.g. enzymes or transcription regulatory factors) Example: estrogen receptors - Ligand diffuses through membrane + binds to cytosolic hormone receptor - This causes conformational change to receptor so it can enter nucleus - Inside nucleus the receptor-ligand dimer binds to DNA - Alters transcription therefore modulates protein expression 6 2) Ion Channels - Are ion selective (only allow passage of particular ions) - Two main types: - Ligand-gated channels in response to ligand binding (type of receptor) - Voltage-gated channels in response to changes in transmembrane potentials - Normally have multiple drug targets (e.g. that block, inactivate or alter gating) 3) Enzymes - Normally targeted by drugs acting as competitive inhibitors - So the drugs are endogenous substrate analogues Example: enalapril = competitive inhibitor against Angiotensin I for ACE (angiotensin converting enzyme from lungs) 4) Transporters Gateways in cell membranes for passage of polar small molecules + ions Example: selective serotonin reuptake inhibitors (fluoxetine, sertraline or citalopram) - To treat anxiety caused by decreased serotonin in the synapse or problems with serotonin release - Increases levels of serotonin = increased chance of binding Drug Selectivity - More selective = more useful Less risk of adverse effects Examples of non-selective drugs: tricyclic antidepressants or aspirin We have some ways to overcome issues of poor selectivity: Issue Solution Relatively selective drug induces Dose control adverse effects Drug has similar affinity for different Use or develop selective drugs targets Drug is tissue non-selective Change the route of administration 7 L2.1: Agonists Pharmacodynamics The pharmacological principles that describe drug effects on the body, explaining both mechanism of action and dose-response relationship Activation of a receptor involves: 1. Binding of the ligand 2. Creation of a stimulus (there must be signal transduction following the initial binding) 3. Response Binding of ligands - Normally temporary (ligands tend to bind and then unbind quickly) - Dependent on receptor concentration [R] and ligand concentration [L] Affinity The likelihood/tendency of a ligand to bind to receptor This governs the occupation of a receptor Efficacy The likelihood/tendency of a bound ligand to initiate a cellular effect This governs the activation of a receptor 𝑘−1 Affinity can be quantified the equilibrium dissociation constant KD = 𝑘+1 KD is proportional to 1/affinity It is the ligand concentration at which half the receptors are occupied High affinity = many bound targets at lower concentrations Agonists vs Partial Agonist vs Antagonist - Agonist = high affinity + high efficacy - Partial agonist = high affinity + low efficacy - Antagonist = high affinity + no efficacy 8 Example: β1-adrenoceptors (endogenous agonist = noradrenaline) Agonist Partial Agonist Antagonist Drug Name Isoprenaline Pindolol Metoprolol Treatment for Bradycardia (slow Hypertension Severe heart rate) hypertension Explanation Increases heart Outcompetes Decreases heart rate noradrenaline to rate decrease heart rate Pharmacodynamics are dependent on the system! Dose-Response Curve For agonists in vivo Concentration-Response Curve For agonists in vitro Note: These curves only exist for agonists since they involve a response Emax = Maximal response capable of being produced in a given system - This can indicate the efficacy of a drug EC50 = The drug concentration that elicits 50% of the maximal effect - This can indicate the potency of a drug Partial Agonists Why do they differ in response to full agonists? - The mechanism which links receptor binding & response has a reserve capacity (ie there are spare receptors) - The receptor pool is therefore larger than what is needed for a full response 9 Why are they used? - No desensitisation of receptors - E.g. salbutamol binds to β2-adrenoceptors but doesn’t make them desensitised so they stop responding to endogenous agonists - Less activation of non-target receptors - E.g. Sumatriptan to treat migraines via vasoconstriction; won’t cause vasoconstriction of coronary arteries and cause heart attacks - Less addictive effects - E.g. buprenorphine binding to opioid receptors L2.2: Antagonists Antagonist A molecule that interferes with the interaction of an agonist and a receptor protein or a molecule that blocks the constitutive elevated basal response of a physiological system Types of Antagonists: - Receptor - Competitive (bind to orthosteric site) - Reversible or Irreversible - Non-Competitive (bind to allosteric site) - Reversible or Irreversible - Non-Receptor Antagonists - Chemical Antagonist - Physiological Antagonist - Pharmacokinetic Antagonist (we don’t learn) Competitive Antagonists - Usually reversible (dissociate + rebind continuously) - Reduces agonist occupancy - Does not stabilise the conformation of receptors - So receptor is in inactive conformation - BUT number of available receptors unaffected Effects: - Decreases potency EC50 increases - Does not affect efficacy Emax the same Irreversible Competitive Antagonists - Dissociate very slowly or not at all from agonist binding site - So they affect the number of available receptors at a given time point - Cannot be outcompeted even at high concentration - Very rare in clinical use 10 Effects (varies a lot) - Decrease potency (not necessarily…) - Decrease efficacy (not necessarily…) Partial Agonists - Will behave similar to competitive antagonists (since they also compete with the agonist) Allosteric Modulation - Binds to an allosteric site (not an orthosteric site) - Upon binding, influences receptor function by changing conformation of the receptor - Increases or decreases affinity of agonist to orthosteric site - Increases or decreases efficacy of agonist - NOTE: could increase affinity of one ligand while decreases efficacy of another or vice versa! Chemical Antagonists - Chemically deplete agonist by scavenging the compound - So the agonist can no longer bind to its target Physiological Antagonist - Have the opposite biological actions to an agonist by acting at a different receptor L2.3: Introduction to the Autonomic Nervous System Importance of Autonomic Nervous System: Innervates many visceral organs to maintain parameters (for homeostasis) Importance of Somatic Nervous System: Voluntary control of skeletal muscle Targeting the ANS: Pharmacologically alters variety of tissue/organ functions Pro: Has wide therapeutic opportunity Con: Has great potential for adverse effects Overview of ANS + CNS - Stimuli - Visceral stimuli = from inside (e.g. stretch or internal temperature) - Sensory stimuli = from external environment - Afferent (sensory) neurons - CNS (determines if there’s been a deviation to the norm) 11 - Efferent neurons: - SNS = Motor neurons (act on skeletal muscles) - ANS = sympathetic + parasympathetic neurons (act on effector tissues/organs) - Also interacts with enteric neurons (act on GIT) - Tissue response Divisions of the ANS: - Sympathetic Division - From thoracic + lumbar spinal segments - Parasympathetic Division - From cranial-sacral origin - Enteric Division - Entirely within PNS, modulated by sympathetic/parasympathetic divisions Effector Sympathetic Parasympathetic Eyes Pupils dilate Pupils constrict Salivary Glands Mucus + enzyme secretion Water secretion Heart Increases heart rate + Decreases heart rate contractility Lungs Relaxes airways Constricts airways GIT Inhibits digestion, Increases bile secretion, decreases enzymes + stomach and intestine motility insulin + secretion, pancreatic enzyme + insulin release Kidneys Increased renin secretion N/A Adrenal Glands Adrenal medulla secretion N/A of catecholamines Urinary Bladder Relaxes bladder (= no pee) Release of urine Penis Induces ejaculation Induces erection Uterus Stimulates contraction Engorgement + secretions Neuromuscular junction Neuron + skeletal muscle cell Neuroeffector junction Neuron + non-neuronal cell Ganglia Collection of nerve cell bodies (for amplification) Somatic NS Single neuron system Autonomic NS Two neuron system 12 Sympathetic Chain/ Paravertebral ganglia Ganglia in sympathetic ANS Chromaffin cells Exception to 2 neuron system in parasympathetic NS; directly innervated by only 1 neuron to release adrenaline into circulation PNS Chemical Codes Somatic NS Mimicked by Acetylcholine Parasympathetic NS Acetylcholine Sympathetic NS Noradrenaline (EXCEPT ACh in sweat + adrenal glands) Ganglionic Transmission Acetylcholine Cholinergic Receptors (cholinoceptors) respond to acetylcholine Nicotinic (nAChR) Ligand-gated ion channel; very fast Ganglionic transmission + skeletal muscle + Chromaffin cells Muscarinic (mAChR) G protein-coupled receptor; intermediate speed Postganglionic parasympathetic responses + Sweat Glands Adrenergic Receptors (adrenoceptors) respond to noradrenaline α-, β-adrenoceptors G protein-coupled receptors; intermediate speed Postganglionic sympathetic responses Co-Transmission How the same nerve can release multiple neurotransmitters (so different ligand-receptor interactions can lead to differences in magnitude, type + temporal) Pharmacology of the PNS: Agonists Mimic nerve activation (e.g. exogenous NA or ACh) Antagonists Block nerve-mediated responses (from endogenous NA/ACh) Also block responses to exogenous ACh or NA L3.1: Adrenergic Pharmacology Catecholamines = Catechol group (benzene + 2x OH) + NH2 group There are 2 main types: Noradrenaline - Catechol + amine - Neurotransmitter + hormone (since it can be released into bloodstream) - Source = sympathetic nerve terminals + adrenal glands (but not much) Adrenaline - Catechol + amine + extra methyl group - Hormone - Source = adrenal glands 13 Noradrenaline Adrenaline Structure Catechol + amine Catechol + amine + methyl Function Neurotransmitter Hormone Hormone (since can be released into bloodstream) Source Sympathetic nerve terminals Adrenal glands Adrenal glands (some…) Noradrenaline Synthesis in Nerve Terminals 1. L-tyrosine transported into the cell by a tyrosine transporter 2. L-tyrosine converted into L-DOPA by Tyrosine hydroxylase (rate limiting step!) 3. L-DOPA converted into Dopamine (DA) by DOPA decarboxylase 4. Dopamine transported into vesicles by VMAT (vesicular monoamine transporter) 5. Dopamine converted into Noradrenaline by dopamine β hydroxylase (DβH) inside the vesicle Adrenaline Synthesis in Chromaffin Cells (in adrenal medulla) 6. Noradrenaline leaves vesicle + is converted into adrenaline by PNMT 7. Adrenaline is packaged into a neurosecretory granule Treating Parkinson’s Uses L-DOPA + Carbidopa - L-DOPA can cross the blood-brain barrier - Increases substrate availability and therefore increases dopamine synthesis (and NA synthesis) in the CNS - Can also add a VMAT inhibitor (e.g. reserpine) to prevent dopamine from being synthesised + released - Carbidopa is a DOPA decarboxylase inhibitor - It cannot cross the blood-brain barrier - So it prevents dopamine synthesis in the periphery! - This also stops the decarboxylation of L-DOPA in the periphery which can cause adverse effects in the GIT 🙂 14 Drugs targeting Neurotransmitter Inactivation Neurotransmitter Reuptake - 1o process = neuronal uptake (back into neurons) via high affinity NET (norepinephrine transporter) - Most is transported into vesicles by VMAT for re-release - Excess can be converted to other metabolites by MAO (monoamine oxidase) in the neuron o - 2 process = extraneuronal uptake (into other cells) via low-affinity OCT3 (organic cation transporter) - Can be converted into other metabolites by COMT (catechol-O-methyltransferase) - Lower affinity so less likely to happen; neuronal uptake is preferred anyway since it allows neurotransmitters to be reused Tricyclic Antidepressants (TCAs) e.g. cocaine - TCAs inhibit NET (preventing neuronal reuptake of NA) - Leads to increased [NA] and longer presence in junction - So more NA can bind + activate post-junctional adrenoceptors MAO Inhibitors - Prevent NA breakdown into metabolites in the cytoplasm - So more NA is taken up into vesicles -> & more released via exocytosis - ALSO sometimes so much NA in the cell that it can leak into junction Indirectly acting sympathomimetics (IAS) e.g. ephedrine or tyramine (vegemite) - Indirect = doesn’t directly bind + stimulate adrenoceptors BUT triggers NA (or adrenaline) release - Sympathomimetics = mimics effects of endogenous agonists of sympathetic NS How they work: - Have similar structure to NA so are transported into cells by NET and into vesicles by VMAT in exchange for NA - Basically displaces the NA - Displaced NA enters junction via NET 15 Adrenoceptor Types Subtype Alpha1 (stimulates) Alpha2 (inhibits) Beta1 (stimulates) Beta2 (inhibits) G-protein α Gαq Gαi Gαs Gαs subunit (i = inhibitory) (s = stimulatory) (s = stimulatory) Effector Stimulates PLC Inhibits AC Stimulates AC Stimulates AC (phospholipase (adenylate (adenylate (adenylate C) cyclase) cyclase) cyclase) Second Increased IP3 + Decreased cAMP Increased Increased messenger DAG cAMP cAMP Leads to increased (cAMP stimulates PKA) [Ca2+]i Responses Smooth muscle Decreased Heart = Smooth contraction neurotransmitter Increased muscle release contractile relaxation rate/force, Kidney = renin release Responds to NA > A NA > A NA = A A > > NA Receptor most present in tissue types: - Alpha1 for smooth muscle contraction e.g. blood vessel constriction, GI sphincters, pupil dilation - Alpha2 is basically never present Mainly for nerves - Beta1 for heart + kidney - Beta 2 for relaxation e.g. blood vessel relaxation, bronchi + GIT relaxation - Glycogenolysis (in liver + skeletal muscle) = alpha1 AND beta2 Drugs acting on specific receptors: Both α receptors are targeted by phentolamine (antagonist; manages hypertension) Both β receptors are targeted by isoprenaline (agonist) and propranolol (anti-hypertensive, non-selective antagonist ) 16 Specific examples: (need to memorise) Receptor Alpha1 Alpha2 Beta1 Beta2 Agonist Phenylephrine Clonidine (anti- Dobutamine Salbutamol (nasal hypertension) (acute heart (asthma) decongestant) failure) Antagonist Prazosin (anti- Yohimbine Atenolol (anti- hypertensive) hypertensive) L3.2: Cholinergic Pharmacology Receptor distributions: Note that in the ANS some of the pre-ganglionic neurons are shorter -> this means they are further away from the effector so the responses can be spread more Cholinergic Responses in Peripheral Tissues (DUMBELS mnemonic) Defecation (pooping) Urination (peeing) Miosis (pupil constriction! Note: not the same as meiosis!) Bronchoconstriction (airway constriction) Emesis (vomiting) Lacrimation (crying) Salivation (producing saliva) 17 Acetylcholine Synthesis & Storage 1. Choline enters via high-affinity choline transporter (rate limiting step) 2. Choline added to acetyl group from acetyl coenzyme A by choline acetyltransferase to make ACh (acetylcholine) (+ CoA byproduct produced) 3. ACh packaged into vesicles by vesicular acetylcholine transporter (an antiporter -> so higher concentrations can enter) 4. ACh released + binds to post-junctional nAChR OR mAChR (depending on tissue types) Hemicholinium = experimental drug only - Inhibits the high-affinity choline transporter Vesamicol = experimental drug only - Inhibits vesicular acetylcholine transporter Ca2+-dependent vesicular exocytosis 1. Vesicles contain synaptobrevin in their membranes 2. Ca2+ enters and binds to synaptotagmin on the vesicle membrane. This causes a conformational change in synaptotagmin. 3. The conformational change in synaptotagmin prompts binding of synaptobrevin to the membrane via a complex with syntaxin and SNAP-25 (plasma membrane proteins). 4. The bound vesicle can release neurotransmitters into the synapse. Botulinum toxin - Has heavy and light chain - Heavy chain binds to receptors on cells containing ACh. Brings in the whole toxin via receptor-mediated endocytosis - Light chain detaches + leaves vesicle. Enters cytosol and cleaves SNARE proteins (preventing vesicular exocytosis) Symptoms of botulinum poisoning: - Progressive motor paralysis - Difficulty swallowing, facial weakness, trouble talking, limb paralysis, eventually respiratory paralysis - Inhibition of parasympathetic-mediated effects - Dry mouth, dry eyes, urinary retention + constipation Cosmetic uses (botox injections) - Paralyses superficial muscles which pucker the skin (causing wrinkles) Clinical uses - Unwanted movement disorders - Urinary incontinence due to bladder overactivity - Hyperhidrosis (excessive sweating) - Blepharospasm (uncontrolled blinking) 18 Acetylcholinesterase (AChE): hydrolyses ACh into acetyl groups + choline Anticholinesterases = AChE inhibitors E.g. organophosphates (irreversible anticholinesterases; bind + covalently modify AChE so that it’s no longer active) To treat against organophosphate poisoning can use muscarinic antagonists (e.g. atropine) Muscarinic Effects (SLUDGE + DUMBBELLS) Salivation Lacrimation Urination Diarrhoea GIT upset Emesis (vomiting) Diarrhoea + diaphoresis (excessive sweating) Urination Miosis (pupil contraction; NOT meiosis cell division) Bradycardia (slow heart rate) Bronchospasm Emesis + excitation (vomiting) Lacrimation Lethargy (feeling tired) Salivation Physostigmine (medium-duration reversible anticholinesterase) - Selective for parasympathetic junctions - Used to treat glaucoma (eye disease) - Glaucoma caused by blockage of eye drainage system - Need to drain fluid from the eye to treat - Activates M3 receptors (muscarinic) on ciliary smooth muscles to cause contraction (so accumulated fluid is removed) Neostigmine (medium-duration reversible anticholinesterase) - Hydrolysed by AChE, but hydrolysis is slower compared to ACh - Selective for neuromuscular junctions (lipid insoluble so can’t cross BBB) - Used to treat symptoms of Myasthenia Gravis (weakened muscles) - Caused by auto-antibodies binding to nAChR (targeting them for degradation) so it’s harder for enough ACh to bind and activate sufficient receptors before the ACh is degraded; only generates a weak EPP (end-plate potential) - Neostigmine = ACh remains in synapse; can bind to unaffected nAChRs 19 Muscarinic Acetylcholine Receptors (mAChR) - Type of GPCR - 5 subtypes (M1-5) but we need to know M2 (cardiac) & M3 (glandular, smooth muscle) - Effects are listed on previous page (salivation, lacrimation, urination, defecation, sweating, decreased heart rate (bradycardia) + bronchoconstriction) M2 Receptors in heart - GPCR contains Gαi which inhibits adenylate cyclase - Causes decrease in cAMP - Decreases contractile rate M3 Receptors in smooth muscle (GIT, airways, bladder, eye) + glands (including sweat glands) - GPCR contains Gαq which activates PLC (phospholipase C) - PLC causes hydrolysis of PIP2 into DAG + IP3 - IP3 causes increase in [Ca2+]i - DAG (and increased [Ca2+]i) activates PKC (protein kinase C) - Increased [Ca2+]i and activated PKC cause contraction of smooth muscles + increased secretion from glands Nicotinic Acetylcholine Receptors (nAChR) - Ligand-gated ion channels (are ionotropic) - N1 = neuromuscular junction - N2 = autonomic ganglia - Have differences in subunit composition causing changes to ligand specificity, cation permeability + physiological function Nicotine - Activates nicotinic receptors Muscarine - Activates muscarinic receptors Muscarinic Antagonists - Anti-DUMBBELLS - Tachycardia (increased heart rate) - CNS effects restlessness, disorientation + coma Atropine - Muscarinic antagonist - Reduces secretions during anaesthesia - Causes anticholinesterase poisoning 20 Nicotinic Antagonists d-Tubocurarine - Competitive reversible antagonist - Selective for neuromuscular junctions (but also binds to autonomic ganglia when at high concentrations) - Used for surgical paralysis (not used anymore) - Adverse effects: Hypotension due to ganglion-block Hexamethonium - Indiscriminate block of sympathetic + parasympathetic ganglia - Used to be used for anti-hypertension - Had complex adverse effects so not used anymore Responses of different receptors in the body to SYMPATHETIC activation: Tissue/Organ Response Primary Receptor(s) Heart Increased rate + force of Beta 1 contraction Blood vessels (most) Constriction Alpha 1 Blood vessels (skeletal Dilation Beta 2 muscle) Bronchi Dilation Beta 2 Gastrointestinal Tract Relaxation Alpha 1 + Beta 2 Gastrointestinal Contraction Alpha 1 Sphincters Radial dilator muscles (of Contraction (= pupil Alpha 1 the pupil) dilation) Kidney Renin secretion Beta 1 Liver + Skeletal Muscle Glycogenolysis Alpha 1 + Beta 2 21 L3.3: How Drugs Get Into the Body A drug with good pharmacodynamic properties must: - Be absorbed across physiological membranes - Distributed to reach its intended target organ after crossing the membrane - Reach the target organ at sufficient concentration to be therapeutically effective Drug plasma concentration depends on: - Absorption - Distribution - Metabolism - Elimination (to not build up toxicity) Movement of drugs can be via: - Bulk Flow (through the cardiovascular system) - Diffusion (through membranes) Movement across membranes can be via: - Small hydrophobic molecules diffusing directly through lipids - Solute carrier or other glycoproteins - NOTE: polymorphisms can affect the types available! - Diffusing through aqueous pores - Pinocytosis P = permeability coefficient = number of molecules able to cross through the membrane per unit membrane area Dependent on: - Partition coefficient (solubility of molecule in the membrane) - Diffusion coefficient (diffusivity) Effect of pH - Can cause ionisation of weak acids and bases - Note the effects of different compartments (e.g. stomach, small intestine) on pH and thus on the drugs - Normally only unionised drugs can effectively penetrate membranes - Example: in stomach, pH = 1 so a weak acidic drug will be better absorbed than bases - Low pH: acid is non-ionized HA, base is ionised BH+ - High pH: Acid is ionised A-, base is non-ionized B Cell-mediated Transportation (very susceptible to polymorphisms!) - SLC transporters (Solute carrier transporters) e.g. OCT or OAT - Facilitate passive movement of solutes down electrochemical gradients - ABC transporters (ATP-binding cassette transporters) - Active pumps which utilise ATP to transport solutes 22 Drug absorption = passage of a drug from its site of administration to the plasma - NOTE: This means an intravenously administered drug has no absorption! - Fastest for intramuscular, then subcutaneous, then oral (note intravenous is fastest but doesn’t count as absorption) Drug Bioavailability: the fraction (f) of administered dose of drug which makes it to systemic circulation in an active form - Often drugs need to avoid first-pass metabolism (metabolism by gut + liver enzymes) - Calculated by comparing plasma concentration of the drug over time - Cmax = maximum [drug] in the plasma - f = AUCoral/AUCIV - AUC = area under the curve (where the curve is the drug concentration) - AUCIV shows the maximum plasma drug concentration at each time point (since drug being administered directly into plasma) - AUCoral shows the plasma drug concentration after the drug has been taken up Routes of Administration - Enteral = via GIT - Oral, rectal, buccal, sublingual - Parenteral = bypasses the GIT - Intravenous, intramuscular, subcutaneous, intrathecal, intravitreal - Other epithelial surfaces - Topical (skin), transdermal, inhalation, nasal mucosa, conjunctiva, vaginal Oral Administration - Slower, about 1-3 hours for an effect (for 75% of orally administered drugs) - Due to limited absorption until the drug reaches small intestines - Drugs need to be stable to travel to the GIT for absorption (e.g. can’t be a peptide or protein cause they’ll just be digested) - Rate dependent on many factors (e.g. gut content, other foods, gastrointestinal motility (like if you’re constipated it’ll take longer), drug formulations, drug-drug interactions, genetics, splanchnic circulation) Oromucosal Administration (buccal + sublingual) - Absorption from the mouth meaning it can enter circulation directly (avoids first-pass metabolism and changes from gastric pH) - But often bad tasting 🙁 23 Rectal Administration - Can be used for drugs which are required to produce either local (e.g. intestinal) or systemic effects - Less capillary drainage from the rectum passes through the portal vein - So it’s less prone to first-pass metabolism🙂 - Can be taken by those who can’t take using mouth or are vomiting - BUT absorption can be irregular and administration uncomfortable 🙁 Topical + Transdermal Administration - Useful when local effects on skin is required (BUT most drugs poorly absorbed by intact skin) - Have to be moderately lipophilic to be absorbed through skin - Sometimes cause irritation + systemic effects 🙁 Inhalation Administration - Rapidly absorbed - Normally have partial systemic absorption though (and this can cause systemic adverse effects) 🙁 - BUT we can stop it crossing the lung membrane by making the drug larger or more hydrophilic 🙁 - Can also have irritation of the respiratory tract Parenteral Administration - Intravenous = fastest route of administration - Bolus injection = all the drug at once; has high Cmax + short Tmax - Intravenous infusion = drug infused over time; low Cmax + longer Tmax - Subcutaneous + intramuscular administration is dependent on site of administration (and the local blood flow at that site) - But we do things to increase duration (e.g. adrenaline for local anaesthetics, more poorly soluble salts of insulin) Drug Distribution - H2O = 75% of body weight found in 4 main compartments: - Plasma (blood) - Interstitial fluid (fluid outside cells) - Intracellular fluid (cytoplasmic) - Transcellular fluid (inside epithelial compartments; e.g. CSF, synovial fluid, foetal fluids, peritoneal) - Movement between compartments depends on: - Permeability across tissue barriers - Protein binding (normally only free drugs can move between compartments since if bound to proteins, it’s unlikely the protein moves between compartments) - pH partition (e.g. might become ionised or non-ionised in a compartment) - Fat:water partition 24 Volume of Distribution (Vd) NOTE: it’s theoretical; could exceed total body volume! - Vd = Q/Cp (I guess if rearranged makes sense since Cp = Q/Vd) - Q = Total amount of absorbed drug in the body - Cp = plasma concentration - Vd = Theoretical volume required for Q to be same concentration as Cp Low Vd similar to plasma volume = drug distribution is restricted to plasma - I guess like the completely absorbed form is in the plasma Vd equal to body water = drug is distributed to intracellular fluids as well High Vd indicates drug has been distributed to other compartments (interstitial + intracellular) L4.1: How Drugs Get Out of the Body Drug elimination = metabolism + excretion Metabolism = inactivation and detoxification of drugs + xenobiotics by metabolising enzymes - Produces metabolites (which are normally inactive; have no apparent pharmacological activity) Metabolism includes: - Phase 1: catabolic reactions to unmask a chemical group needed for phase 2 reactions (e.g. oxidation, hydroxylation, dealkylation, deamination, hydrolysis) - Often involve adding a reactive group where conjugates can be added - Often occurs in liver (often CYP450); crosses membrane to enter liver - Phase 2: inactivation of drug via conjugation (adding group = anabolic) - Normally makes inactive products - Occurs mainly in the liver - Normally makes metabolite hydrophilic so it can be excreted in urine Cytochrome P450 (CYP450): family of enzymes + oxidising agents - 18x CYP families with haem proteins (as Fe3+ can be reduced!) - CYP1, CYP2 and CYP3 are responsible for 70-80% of drug metabolism! - Oxidation uses the enzyme NADPH-P450 reductase - Mainly in liver, but some in plasma, lungs & gut - Very susceptible to genetic polymorphisms - Grapefruit juice causes inhibition of some CYPs -> less metabolism - St John’s wort causes induction of some CYPs -> increases metabolism (so reduces [drug]) 25 Prodrugs = inactive compounds when administered which are biotransformed into active drugs in the body - E.g. aspirin is hydrolysed into salicylic acid; giving it anti-inflammatory effects Drug Excretion - Most is via urine or bile - Can also be via sweat, saliva, tears, breast milk, faeces + exhaled air Renal Drug Excretion - Renal blood flow = 25% of total systemic blood flow (basically everything will come here!) - Can be via: 1. Glomerular filtration Normally for smaller, unbound drugs 2. Active tubular secretion Weak acids + bases secreted via OAT and OCT Drugs must be unbound 3. Passive tubular reabsorption Non-ionised drugs; highly affected by urine output changes + pH (which can change based on what foods we eat) Favours weak bases as the tubular fluid is acidic (so it will trap the weak bases!) Rate of drug elimination is increased by: - Increased blood flow - Increased glomerular filtration rate - Decreased plasma protein binding Renal Clearance (CLren) - Measured in mL/min - CLren = (Cu x Vu) / Cp Cu = drug urinary concentration Vu = rate of urine flow (velocity) Cp = drug plasma concentration Elimination half-life t1/2 = time required to reduce the plasma [drug] by 50% - Is constant and independent of administered dose - Used to determine how often a drug needs to be administered Higher Vd = less drug contained in plasma compartment = prolonged t1/2 26 L4.2: Pharmacogenomics & Precision Medicine Pharmacogenetics Study of variability in drug responses related to genetic differences Pharmacogenomics Utilisation of global genomic technology to serve pharmacogenetic aims Precision Medicine Personalised medicine (based on individuals’ genomes) Important as polymorphisms can lead to ADRs (adverse drug reactions) - These have costs to patient, costs to healthcare system, costs to pharma companies (e.g. pre- or post-marketing due to ADRs or lack of efficacy) - Also might miss out on drugs which are great therapies for some groups! Genetic differences are often due to mutations - Often SNPs (single nucleotide polymorphisms) - Can be germ line; inherited and in all cells - Can also be somatic; not inherited but applicable to cancer treatment especially Genomic Technologies: - $1000 genome can sequence 1x genome a day (or 4x exomes) - Multiplex detection of SNPs - Are microarray-based - Often use Genome-Wide Association Studies (GWAS) What do polymorphisms affect: - Often metabolism (due to polymorphisms in certain enzymes) -> affects pharmacokinetics - Example: drug metabolising enzymes - Can affect pharmacodynamics by affecting receptors + enzymes - Example: the Epidermal Growth Factor Receptor - Example: Vitamin K Reductase Metabolism example: Plasma cholinesterase metabolises (inactivates) suxamethonium (a skeletal muscle relaxant) - Different polymorphisms in the plasma cholinesterase cause huge variety of durations of muscle relaxation from suxamethonium doses Metabolism example: Thiopurine Methyltransferase (TPMT) metabolises and inactivates 6-mercaptopurine (a prodrug to treat leukemia) - NOTE: 6-mercaptopurine is a prodrug; but TPMT inactivates it (there’s a different enzyme, HPRT, which activates it) - The active drug however can lead to high levels of toxicity! So it’s dangerous to have mutations causing reduction in TMPT levels 27 Epidermal Growth Factor Receptor - Consider effects in germline and tumour genomes - If there are EGFR mutations in tumour = can use certain kinase inhibitors to treat lung cancers - So it’s beneficial! Warfarin - An oral anticoagulant - Inhibits the enzyme VKORC1 which reduces vitamin K so that it can be used in the carboxylation of clotting factors (this activates clotting factors) - But it has a very narrow therapeutic window! If polymorphisms cause the enzyme to be more susceptible to warfarin then blood won’t be able to clot 28 L4.3: Eicosanoids Agues = chills + fever which used to be treated using herbal remedies containing salicylate Salicylate: - Can be converted into acetylsalicylic acid (in aspirin) - This has less adverse effects in the stomach - Has antipyretic, analgesic and anti-inflammatory properties - These are similar properties to NSAIDs (non-steroidal anti-inflammatory drugs) Discovery of Eicosanoids - Realised there were bioactive compounds in semen - As they contraction of the uterus was observed during artificial insemination - Due to drugs termed prostaglandins (as we thought from prostate gland; but actually it’s the seminal vesicle…) - Eicosanoid = compounds containing 20x carbons - We realised that PGE1 structurally similar to arachidonic acid (an essential fatty acid) - Hence we hypothesised that arachidonic acids were eicosanoid precursors Discovered that arachidonic acids could lead to formation of bioactive compounds: - Prostaglandins - Thromboxanes (prostaglandins + thromboxanes = prostanoids) - Leukotrienes We also noted that most cells can produce prostaglandins but they are made on demand (not stored in cells; we know as there’s very very low intracellular concentrations) Arachidonic acids are often one of the fatty acids found in phospholipids - They are cleaved off (liberated) by Phospholipase A2 (PLA2) - PLA2 is activated by Ca2+ Arachidonic acids are converted into - Prostanoids by the enzyme cyclooxygenase (COX) - Leukotrienes by the enzyme lipoxygenase (LOX) COX 1 = a constitutively active COX enzyme in most cells COX 2 = an inducible COX enzyme induced by inflammatory stimuli 29 COX enzymes convert arachidonic acid to PGG2 (prostaglandin G2) - Other synthase or isomerase enzymes present in different cells will convert PGG2 to other prostaglandins - PGI2 (prostacyclin) in the endothelium - PGF2α in uterus - PGD2 in mast cells - PGE2 in most cells - TXA2 in platelets Leukotriene formation: - Arachidonic Acid converted in LTA4 by 5-Lipoxygenase (5-LO) - 5-LO predominately in inflammatory cells - LTA4 converted into LTB4 or LTC4 - LTC4 can be further converted to LTD4 and LTE4 - LTC, LTD + LTE = cysteinyl-leukotrienes and are targets for anti-asthma drugs (as they’re bronchoconstrictors) Eicosanoids effects - Eicosanoids act via selective receptors on GPCRs - They then generate second messengers Pharmacological actions of eicosanoids - Affect smooth muscle - Vascular: - PGE2 and PGI2 = vasodilators - TXA2 = vasoconstrictor - Bronchial - Cysteinyl-leukotrienes = constrictors - Uterine - PGE2 and PGF2α = contraction - Gastrointestinal - PGE2 and PGF2α = contraction - PGE2 and PGI2 = inhibit gastric acid secretion; enhance gastric mucous production - Blood - PGI2 = anti-aggregatory (for platelets) - TXA2 = proaggregatory (for platelets) - LTB4 = chemoattractant for leukocytes - Kidneys - PGE2 and PGI2 = increased renal blood flow + excretion of water and sodium 30 Inflammation Mediators - Histamine: lots of vascular permeability + a bit of dilation - Bradykinin: lots of dilation, some vascular permeability, lots of pain - Prostanoids: lots of dilation, some vascular permeability, chemotaxis, some pain (but they act synergistically to produce much greater effects!) - Leukotrienes: lots of vascular permeability, chemotaxis Pain - PGE2 and PGI2 are hyperalgesic - They increase sensitivity of receptors to painful stimuli - Note they have synergistic effects (are much more effective) together with bradykinin (BK) Fever - Inflammation and/or immune response = neutrophil activation - Neutrophils release cytokines which leads to production of PGE2 - PGE2 causes increase in body temperature set point in hypothalamus So we can see the pharmacological actions of eicosanoids in fever, pain + inflammation NSAIDs (non-steroidal anti-inflammatory drugs) = COX inhibitors - Anti-Inflammatory - Inhibit vascular dilation (by prostanoids) - Inhibit vascular leakiness (due to synergism of prostanoids with other mediators) - Analgesic - Inhibit synergistic effects of prostanoids with bradykinin - Often used for headaches, menstrual + musculoskeletal pain - Antipyretic - Since PGE2 responsible for body temperature set point - BUT we normally prefer to use paracetamol instead Classes of NSAIDs Salicylates (e.g. aspirin): used as analgesics, antipyretics + antithrombotics Propionic Acids (e..g ibuprofen): used as antiinflammatories, analgesics + antipyretics Acetic Acids (e.g. diclofenac): used for long term antiinflammatory treatment Adverse Effects of NSAIDs (only really occur at high doses for long periods) - Increase chance of GI ulceration + bleeding (since PGE2 and PGI2 help protect mucosal lining + reduce gastric acid secretion) - Increased bleeding time (due to anti-thrombotic effects) - Kidney damage + reduced renal blood flow - Pulmonary constriction (bronchospasm) 31 COX-selective Inhibitors - COX-1 is constitutively active in most cells - COX-2 is inducible by inflammation in inflammatory cells - So theoretically something which selectively inhibits COX-2 would have less adverse GIT affects - BUT it actually increases risk of cardiovascular death Link to COX-1 and COX-2 to Thrombosis - COX-1 = pro-thrombotic as it causes production of TXA2 in platelets - COX-2 = anti-thrombotic as it causes production of PGI2 in endothelial cells Paracetamol - Analgesic + antipyretic - BUT doesn’t inhibit peripheral COX and is not anti-inflammatory - So not really an NSAID - We think its mechanism of action involves a metabolite having activity at some ion channels + cannabinoid receptors? But we don’t really know… Liver Toxicity of Paracetamol in Overdose - Normally paracetamol is metabolised by glucuronidation or sulfation - If not it undergoes CYP-mediated N-Hydroxylation and rearrangement - The product is toxic BUT it normally undergoes GSH conjugation to make a non-toxic product - The toxic product will only build-up if all 3 pathways are saturated (due to paracetamol overdose) 32 L5.1: Immunopharmacology Types of immunomodulatory therapies: - Anti-Inflammatory therapies - Against acute inflammation - Use NSAIDs or glucocorticoids - Against allergic inflammation - Use antihistamines or anti-IgE therapy (e.g. omalizumab) - Against autoimmune or chronic inflammatory disease - Immunosuppressive therapies - Against of tissue transplant rejection - E.g. cyclosporin - Against autoimmune or chronic inflammatory disease - Use drugs which can modulate effects of cytokines E.g. anti-TNFα therapy - Immunostimulatory therapies - Boost immunity to infection or cancer - E.g. vaccines or antibody checkpoint inhibitors Mast Cells, Histamine & Allergic Disease - Hypersensitivity to an allergen causes IgE to be developed against it - The IgE binds to Mast Cells via a FcεRI - A high affinity receptor that binds the Fc portion of the ε region of the IgE heavy chain - Has very high affinity; so will bind strongly and for a long period of time - Mast cells degranulate (releasing contents of granules e.g. histamine) Treating Allergic Inflammation H1 Receptor Antagonists (a type of antihistamine) - Antagonist to histamine receptors - Treat: hayfever, urticaria, anaphylaxis & angioedema Anti-IgE Therapeutic Antibodies (e.g. omalizumab) - Chemical antagonists; bind to free IgE to prevent them engaging with their receptors - Treat: severe asthma + chronic idiopathic urticaria 33 Monoclonal Antibodies (using Hybridoma Technology) - Inject mouse with antigen + extract spleen B cells (as some will be producing antibodies to the antigen) - Fuse with mutant myeloma line (a blood cancer -> will be immortal) - Grow hybridomas (the fused cell) - Only these cells actually survive and grow since the myeloma is unable to survive in the selection medium and the B cells are mortal HAMA Response (Human Anti-Mouse Antibody) - If we use monoclonal antibodies for treating a chronic disease, eventually we’ll produce an antibody response against them (since they’re foreign particles!) Chimeric & Humanised Monoclonal Antibodies - How we make fully human antibodies to avoid HAMA response 1. Isolate RNA and make cDNA for the antigen-binding V regions (variable regions) of the mouse antibody 2. Splice the V regions into human antibody cDNA - So essentially we just introduce the gene from the monoclonal antibody into human antibody DNA Antibody Targets in Chronic Inflammatory Disease Rheumatoid Arthritis: - Can target TNFα (e.g. adalimumab using chemical antagonism) - Can target IL-6 Receptor (e.g. tocilizumab using receptor antagonism) Asthma: - Can target IL-4 Receptor (e.g. dupilumab using receptor antagonism) - Can target IL-5 (e.g. mepolizumab using chemical antagonism) Immunosuppressants - Normally to prevent transplant rejection - Have to be taken for life - So there must be a compelling reason! Since they’ll cause an increased risk of cancer and infection - Often target IL-2 (used for T-cell clonal expansion) Immunosuppressant Therapies: - Calcineurim inhibitors e.g. cyclosporin - Glucocorticoids - Anti-metabolites e.g. anti-cancer drugs too - Antibodies e.g. anti-IL2 receptor antibody 34 T-Cell Proliferation and IL-2 Synthesis - T-Cell activation by APCs: - Costimulation + binding of APC’s MHCII to the TCR = increased [Ca2+]i - This activates calcineurin - Calcineurin = a phosphatase which cleaves the phosphate group off of NFAT (nuclear factor of activated T-cells) - This allows NFAT to enter the nucleus + increase transcription of IL-2 - Allows IL-2 to be synthesised + IL-2 - IL-2 then binds on the T cell itself (autocrine signalling) + T cells nearby (paracrine) allowing them to proliferate Cyclosporin: a prototype drug in the class of calcineurin inhibitors; is orally active as it’s a cyclic polypeptide (so can survive proteases + low pH in the GIT) - Cyclosporin forms a complex with immunophilins (e.g. cyclophilins) in the cytoplasm - The complex inhibits calcineurin - So it won’t phosphatase NFAT so there’s no IL-2 release Antibodies for Cancer Therapy: Checkpoint Inhibitors (e.g. pembrolizumab) - Often in tumour sites there are suppressed T-cells - Suppression is occurring due to binding of the PD-1L (on tumour cells) to the PD-1 on T cells - PD-1 = programmed cell death 1 - Antibodies can block binding of the PD-1L by binding to PD-1 themselves (as antagonists) 35 L5.2: Drugs to Treat Asthma Factors influencing asthma development: - Host - Genetics (e.g. atopy (increased likelihood of developing immune diseases), airway hyperresponsiveness), gender + obesity - Environmental Factors - Allergens (indoor or outdoor), chemical irritants, tobacco smoke, air pollution, respiratory infections TH2-Type Asthma (allergic type) has 3 characteristics: 1. Airway obstruction 2. Increased Airway Hyperresponsiveness (AHR) 3. Chronic eosinophilic airway inflammation Pathogenesis of TH2-type Asthma: - Allergen crosses airway epithelium - APC digests allergen + presents antigen to native T-lymphocyte, leads to development of TH2 cells which release - IL-4 + IL-13 to stimulate B lymphocytes - These then secrete IgE antibodies to activate mast cells - IL-5 to stimulate eosinophils - Mast cells can also be directly stimulated by the allergen (without IgE) - Eosinophils + Mast Cells secrete their mediators leading to: - Bronchoconstriction - Mucous secretion (by Goblet cells in airway epithelium) - Vascular leak = increase edema - These factors all lead to obstruction of the airway! Airway Obstruction - Caused by narrowing of the airway lumen (could be a range of things from mucous hypersecretion, hyperplasia of goblet cells, hypertrophy of SMCs, thickening of basement membrane, increased blood vessel formation, etc.) - Causes a decrease in FEV (Forced Expiratory Volume) - FEV = volume of air which can be forcibly blown out after a full inspiration - This is used to diagnose asthma AHR (airway hyperresponsiveness) - When airway constricts too easily & by too much in response to: - Histamine = binds to H1 receptors to cause bronchoconstriction - Methacholine = muscarinic agonist (so causes parasympathetic activation of lungs = bronchoconstriction) 36 Asthma Treatment Options - Prevent development of asthma (very difficult) - Prevent/reverse airway construction (by relievers) - Prevent airway smooth muscle contraction (by preventers) - Prevent/reverse airway inflammation (by preventers) Drug Delivery to Lungs - Inhalation - Uses an MDI (metered-dose inhaler) - Goes straight to site of action + very little absorbed into systemic circulation; reducing side effects - Oral (drugs which are swallowed) - Has to enter GI tract + be absorbed by GI tract + make it past first-pass metabolism in the liver (where majority of drugs go after GIT absorption) to enter systemic circulation - After entering systemic circulation can target lungs; but may also have side effects Airway Smooth Muscle (ASM) - Bronchodilator response: - In response to adrenaline or β2-adrenoceptor agonists - Bronchoconstrictor response: - In response to histamine (on H1 receptors), leukotrienes (on LT1 receptors) or acetylcholine (on M3 receptors) Mechanism of β2-agonists - Is a GPCR; binding of agonist activates α subunit - α subunit activates adenylyl cyclase -> makes cAMP - cAMP activates PKA which has 3 effects: - Inhibits myosin light chain kinase - Activates myosin light chain phosphatase - Decreases cytoplasmic Ca2+ - This prevents contraction and inhibits myosin light chain kinase - Overall this prevents phosphorylation of myosin light chain (MLC) so it can’t grab onto actin; prevents cross bridge formation and therefore contraction Short-Acting β2 adrenoceptor agonists (SABA) e.g. salbutamol - Rapid onset 2-5 mins - Duration 2-4 hours (effects lost due to diffusion; not metabolism) - Used for acute symptom relief (e.g. exercise-induced bronchoconstriction) - Must also be used with an ICS (inhaled corticosteroid) - Frequent use is problematic as it causes: - Downregulation of β2 adrenoceptors - Decreased bronchodilator response 37 Long-Acting β2 adrenoceptor agonists (LABAs) e.g. preventers - Duration 12 hours; is a prophylaxis (prevents symptoms) - Onset Depends on drug - Allows for chronic bronchodilation - Must be combined with ICS (as it induces expression of β2 adrenoceptors) Adverse Effects of β2 agonists - Tremor - Due to binding to β2 in skeletal muscle - Headache - Heart palpitations + tachycardia - Binding of β2 receptors in blood vessels = vasodilation - This decreases blood pressure, so the reflex is to increase heart rate Precautions for administration of β2 agonists - Cardiovascular disorders (as they can cause palpitations and tachycardia) - Diabetes (as β2 agonists can cause increase in circulating blood glucose) - Sympathomimetic amines (as these already stimulate β2 adrenoceptors) Glucocorticoid Mechanism of Action for Asthma Treatment - Glucocorticoids are lipid soluble so pass through cell membrane - Bind to glucocorticoid receptors in cytoplasm - Complexes dimerise + translocate into nucleus to regulate transcription - Increased expression of anti-inflammatory genes - Annexin-1 - β2-adrenoceptors - Decreased expression of inflammatory genes - COX-2, PLA2 (inflammatory enzymes) - TNF-α (cytokine) - ICAM-1 (for adhesion) Glucocorticoids (as preventers) - Slow onset of action (hours to days) - Very slow maximum therapeutic effect (weeks to months) - Can be an inhaled corticosteroid (ICS) or systemic (taken orally via tablet or liquid) Adverse Effects of Glucocorticoids - ICS - Atrophy of vocal cords -> hoarseness + weakness of voice (dysphonia) - Oral thrush (oropharyngeal candidiasis) - Due to immunosuppressive effects - Effects can be decreased using mouthwash to reduce local absorption 38 - Oral - A lot (since it’s systemic)! So only used for severe asthma - Mood changes, weight gain, hyperglycaemia, osteoporosis, hypertension, immune suppression - Suppression of hypothalamic-pituitary-adrenal axis - Cortisol has a negative feedback loop, inhibiting CRH and ACTH - Very important that after chronic use, doses are tapered (since it’ll take a while for the body to start producing normal levels of endogenous cortisol) Cysteinyl-Leukotriene Receptor Antagonists (preventer) - Cysteinyl-leukotrienes bind to LT1 receptors leading to: - Increased exudate - Mucus secretion - Bronchoconstriction - Eosinophil recruitment - LT1 antagonists will stop binding of leukotrienes to LT1 receptors Use of Cysteinyl-Leukotriene Receptor Antagonists - Often used as an add-on therapy in very hard to treat asthma - Is orally active - Causes modest bronchodilation, helpful for treating aspirin-induced asthma - Aspirin-Induced Asthma = when COX are inhibited so arachidonic acids are redirected to LOX pathways causing increased levels of leukotrienes - Rare adverse effects: mood + behavioural changes Monoclonal Antibodies to treat allergic asthma - Can target: - IL-4 and IL-13 (to stop activation of B lymphocytes) - IgE (to decrease activation of mast cells) - IL-5 (to stop activation of eosinophils) - IL-5 receptors (on eosinophils to stop their activation) 39 L5.3: Drugs in Sport Advantages of drugs in sport: - Recovery/injury treatment/pain relief Sometimes prohibited (e.g. narcotics or opioids) - E.g. local anaesthetics (decrease sensation), analgesics (reduce pain without loss of sensation) or anti-inflammatory drugs (e.g. NSAIDs or glucocorticoids) - Performance enhancement Prohibited - Improved aesthetics Prohibited (e.g. anabolic steroids) - Therapeutic use Might be prohibited! - BUT urine concentration must fall within the expected therapeutic range, and masking agents must not be detected! Doping: Use of prohibited substances (or methods) with the deliberate intention or effect of enhancing performance - This is standardised by WADA (World Anti-Doping Agency) which makes The Code Prohibition of drugs requires 2/3 of the following criteria: - Drug has potential to enhance or enhances sport performance - Drug represents a potential or actual health risk to the athlete - Drug violates the spirit of sport - Spirit of sport includes the values of ethics, fairplay, honesty, health, fun, joy, teamwork, respect, etc. Levels of Prohibition - Prohibited at all times - Prohibited in-competition - Prohibited in particular sports Drugs which are prohibited at all times: - Non-approved substances (not yet under clinical use; are in development or are for veterinary use) - Anabolic agents - Peptide hormones, growth factors, related substances + mimetics - β2 agonists - Hormone + metabolic modulators - Diuretics and masking agents Anabolic Androgenic Steroids (AAS) - E.g. endogenous androgens or synthetic derivatives of testosterone 40 Anabolic Androgenic Steroid Mechanism of Action - Lipid soluble; diffuses into cell + binds to receptor (can be inside or outside nucleus) - Steroid-receptor complexes dimerise + bind to the steroid response element (SRE) on the DNA - This upregulates transcription Effects of binding to androgen receptors: Anabolic: Promotes increased muscle mass + strength Androgenic: Promotes development of male reproductive tract + 2o sex characteristics (e.g. acne, hirsutism (beard growth), in females: irregular menses + masculinisation) Behavioural + Psyche: Aggression, hostility + mood disorders Liver Toxicity by ROS overproduction Testosterone is converted to dihydrotestosterone by 5α-reductase - Dihydrotestosterone has much higher affinity to androgen receptors (AR) than testosterone - 5α-reductase is expressed in reproductive tissue, brain, adipose tissue + bone - NOT in skeletal muscle!! AAS can also be converted to oestradiol by aromatase (present in some tissues e.g. adipose) - Estradiol will bind to oestrogen receptors - Can cause enlargement of breast tissue in males Structural Modification of AAS (e.g. for nandrolone (NT)) - NT has higher affinity than T (testosterone) - BUT DHNT has lower affinity than DHT (and NT) - This means NT has good anabolic effects in skeletal muscles where it won’t be metabolised to DHNT (due to lack of 5α-reductase) - And will have fewer androgenic effects in other tissue where it’s converted to DHNT as DHNT has low affinity to AR receptors - NT is also poorly aromatized - This prevents it being converted to estradiol Erythropoiesis-Stimulating Agents (ESAs) - Erythropoietin (EPO) = a hormone which stimulates RBC production - EPO produced + released from kidney cells in response to low arterial O2 - Binds to EPOR to stimulate RBC production - Increased RBC = increased haemoglobin = increased O2 carrying capacity (leads to restoration of arterial O2) 41 - rHuEPO (recombinant human EPO) = an ESA to treat anaemia in patients with chronic kidney disease (athletes dope on it to increase aerobic capacity) - 1st generation rHuEPO: included multiple isoforms with different glycosylation patterns. Short half-life of 8-24 hours - 2nd generation rHuEPO: had more glycosylation sites and an increased potency and half-life (72 hours) - 3rd generation rHuEPO: Pegylated rHuEPO with very long half-life (130 horus) - So earlier generations were worse for patients BUT better for athletes since a short half life = shorter detection window Adverse Effects of rHuEPO - Due to negative feedback can cause depletion of endogenous EPO - Can cause increased blood viscosity (due to more RBCs) - Increased risk of hypertension + clotting - Chronic use can lead to cardiovascular complications Masking Agents - Diuretics - Increase urine volume; decreases [drug] in urine so they’re harder to detect - Renal Tube Secretion Inhibitors - Inhibits secretion of drugs into the urine Stimulants (stimulate CNS) - Are only prohibited during competition - Can cause excitement, euphoria + decrease fatigue - Might cause increase in muscle strength - Examples: ephedrine, amphetamine, cocaine Beta-Blockers - Only prohibited in some sports (e.g. diving or archery -> require high precision of movement) - Slow heart rate, lower blood pressure + decrease skeletal muscle tremors Prevention of Doping (2x strategies) 1. Education & awareness of effects of doping on health + legal/social ramifications 2. Ban use of drugs + test athletes for the presence of banned substances 42 Direct detection of drugs - Detecting of drugs or drug metabolites in urine or blood samples - Blood is required for protein detection - Might use techniques such as gas or liquid chromatography + mass spectrometry - Issues: - Urine samples don’t detect proteins (so we need blood samples…) - Recombinant proteins hard to detect as they’re similar or identical to endogenous compounds Indirect detection of drugs - Look at biomarkers of doping such as: - Urinary T/E (testosterone/epitestosterone) ratio - Blood markers to indicate altered erythropoiesis - Issues: - Natural fluctuations (due to ethnic/sex differences + individuals’ polymorphisms) can be outside the normal range expected for a population Athlete Biological Passport: - A record of various doping biomarkers for an athlete - This minimises issues with fluctuations outside the norm due to genetic differences - Three modules: - Haematological (EPO) - Steroidal (anabolic agents) - Endocrinological (Growth Hormone besides EPO) 43 L6.1: Drugs to treat GI Disorders Enteric Nervous System: NS of digestive tract - 100s of millions of neurons - Can mediate reflex activity independent of the CNS! (this is intrinsic control!) - Also has extrinsic control as it can be influenced by the ANS Autonomic Innervation of GI Tract - Stimulatory = parasympathetic (craniosacral) - By vagus nerve and pelvis nerves - Inhibitor = sympathetic (thoracolumbar) - By prevertebral ganglia Plexi of the GI Tract (networks of neurons; lots of ganglia here!) - Myenteric plexus: mainly to control motility - Is between circular + longitudinal muscle - Submucosal plexus: mainly to control fluid/ion transport + for sensing environment - Located in the submucosa Vomiting (Emesis): - Variety of causes - Strong emotions, abnormal motion, unpleasant smells/sights - Headaches + migraines, pain - Toxins, GIT irritation - Different causes = different reflexes; can involve several different neurotransmitters + receptors (which helps inform our choice of the anti-emetic) Control of Vomiting - Signals for vomiting are processed by the vomiting centre in the medulla oblongata. Receives signals from: - Vagal afferent neurons (sending signals from the GI tract) - Can also be stimulated by serotonin released by enterochromaffin cells in the gut when they detect toxic chemicals - Chemoreceptor Trigger Zone (CTZ) (outside BBB but near medulla oblongata; detects things in the bloodstream e.g. toxins or drugs) - Vestibular nuclei - Higher cortical centres (from cerebral cortex); for higher order info like pain, sight, smells and emotion 44 Signalling Molecules & Drug Targets in Emesis Zone Signalling Molecules Drug Targets CNS (Cerebral Cortex) Acetylcholine Vestibular System Acetylcholine M1 Receptor Antagonists Histamine Antihistamines CTZ 5-HT (Serotonin) 5HT3 Antagonist Dopamine Dopamine Antagonist GIT 5-HT (Serotonin) 5HT3 Antagonist Substance P Antagonist Vomiting Centre Acetylcholine M1 Receptor Antagonist 5-HT (Serotonin) 5HT3 Antagonist Histamine Antihistamines Dopamine Receptor Antagonists - Metoclopramide - Domperidone - Both of these are antagonists of dopamine D2 receptors at the CTZ - Side effects: Gastric emptying (due to increased GIT motility), restlessness, anxiety + drowsiness - Phenothiazines - Mainly D2 receptor antagonists BUT also antagonists for muscarinic and histamine (H1) receptors - Antagonist of dopamine at CTZ, but also ACh at vomiting centre (at high doses) - Often also used as antipsychotics - Side effects: - Extrapyramidal effects (e.g. muscle spasms, Parkinson's stuff) + anticholinergic effects (e.g. constipation, dry mouth, etc.) Anti-Histamines (H1 antagonists) - E.g. promethazine or meclizine - Antagonist at H1 histamine receptors - To treat motion sickness - Side effects: sedation + drowsiness (since brain uses histamine for wakefulness) Muscarinic Receptor Antagonists - E.g. hyoscine (“Kwells”); are competitive antagonists - To treat motion sickness - Side effects: anticholinergic effects (e.g. dry mouth, constipation, tachycardia) 45 5HT3 Receptor Antagonists - Anything ending in -setron (e.g. ondansetron or dolasetron) - Target activity at the CTZ, vomiting centre and GIT - Used for nausea + vomiting associated with chemotherapy + post operative management - Very few side effects (no sedation or extrapyramidal/anticholinergic effects) Cells of the Gastric Pit: Cell Type Substance Secreted Mucous Neck Cell Mucous (protect stomach lining) Bicarbonate (protects stomach lining?) Parietal Cells Gastric Acid (HCl) Intrinsic Factor (for Vitamin B12 absorption) Enterochromaffin-like (ECL) Histamine (stimulates acid production) Cells Chief Cells Pepsinogen Gastric Lipase D Cells Somatostatin (Inhibits stomach acid) G Cells Gastrin (Stimulates stomach acid) Parietal Cells - Express receptors on the basolateral surface (since it’ll be closest to blood!) - Receptors which stimulate HCl production: - H2 histamine receptors (histamine from ECL cell) - M3 muscarinic receptors (ACh from vagus nerve) - CCKB gastrin receptor (gastrin from G-Cell) - Receptors which inhibit HCl production: - SSTR2 somatostatin receptor (somatostatin from D-Cell) - EP3 prostaglandin receptor (PGE2) D-Cells - Inhibited by ACh from vagal nerve G Cells (make gastrin) - Stimulated by ACh from vagal nerve (parasympathetic NS) - Inhibited by somatostatin (from D-cells; binds to SSTR2 receptors) Enterochromaffin Like Cells (ECL cells) - Stimulated by gastrin (to CCKB receptors) and ACh (to M3 receptors) - Inhibited by somatostatin (SSTR2 receptors) and PGE2 (EP3 receptors) 46 Hydrochloric Acid (HCl) Production - H+/K+ ATPase proton pumps become activated when the resting parietal cell is stimulated - Exchanged H+ used to make hydrochloric acid Stomach Ulcer + Reflux Disease Potential Treatment Options: - Neutralise acid - Suppress acid secretion - Protect cells (cyto-protective agents) - Eradicate H. pylori (Helicobacter pylori) Antacids (neutralise acid) - Neutralise HCl, bind to bile acids + decrease pepsin activity - Provide symptomatic relief - Cause pH changes -> thus will have many drug interactions; impairing rate/extent of other drug absorption - Different salts used together e.g. - Aluminium (e.g. in AlOH) decreases bowel activity - Magnesium (e.g. in Mg(OH)2) increases bowel motility H2 histamine receptor antagonists - End in “-tidine” e.g. cimetidine, famotidine, ranitidine - Bind to H2 histamine receptors blocking binding of histamine to gastric parietal cells (thus reducing acid secretion) - Treats peptic ulcer disease, GORD + dyspepsia - BUT can inhibit p450 enzyme (SO lots of drug-drug interactions!) Proton Pump Inhibitors - End in “prazole” e.g. omeprazole - Are prodrugs activated by acidic environment (converting them to cations) - Irreversibly bind to parietal cell H+/K+ ATPase, blocking active transport of H+ - Treats ulcerative oesophagitis + unresponsive gastric ulcers - As it will always reduce acid secretion (independent of how secretions are stimulated) Cyto-Protective Drugs (rarely used…) - Prostaglandin Analogues - Treat ulcers, especially those caused by NSAID use - Will decrease acid secretion + increase mucous secretion - Sucralfate - Sulfated sucrose + aluminium hydroxide - Dissociate in presence of acid, act as a sticky adherent gel + neutralising agent 47 Drugs which can cause oesophagitis + dyspepsia: - NSAIDs - Bisphosphonates - Antibiotics - Iron Supplements H. Pylori (Helibacter pylori) - A gram negative, helix shaped bacteria which infects 30-50% of world population! - Causes chronic active gastritis + development of gastric/duodenal ulcers - Also a risk factor for gastric carcinoma development Treating H. pylori Ulcers - Eradicating H. pylori = 1st line treatment (but the monotherapy is ineffective) - Now we use triple therapies of proton pump inhibitors + 3x antibiotics (clarithromycin, amoxicillin, metronidazole) Drugs for the Lower GIT Constipation Treatments that change Stool Consistency (not really pharmacological) - Softeners (e.g. docusate) - Bulk forming agents (e.g. psyllium) - Stimulants (e.g. senna) (work by irritating lining of GIT) - Osmotics (e.g. lactulose) Motility Stimulant Drugs (prokinetics) - Dopamine Receptor (D2) Antagonists - E.g. Domperidone (motilium) + Metoclopramide (maxolon) - Since dopamine inhibits ACh needed for smooth muscle activity - They’re able to promote motility without purgation (diarrhoea) Diarrhoea - Antimotility drugs - Opioids (e.g. codeine, morphine) - Loperamide (imodium) is good since it doesn’t cross the BBB so won’t have CNS addictive effects - BUT some people still use high doses to self-manage opioid withdrawal (which can lead to cardiac failure) - They bind to μ-opioid receptors in the myenteric plexus, causing reduction in secretion + propulsive movements of smooth muscle - Means there’s more time for transit + H2O absorption - Administered orally 48 - Anti-Spasmodics (Spasmolytics) - Muscarinic receptor antagonist (very high affinity) and doesn’t cross BBB - Smooth muscle relaxant that reduces GI motility + spasm - Low bioavailability (but it’s ok since very high affinity) - Can give symptomatic relief in pathological conditions causing GI spasms - Can be administered orally or via IV or IM Inflammatory Bowel Disease (IBD) - Ulcerative colitis = often in rectum, might extend to involve the colon - Crohn disease = end of small intestine + start of colon; can affect other parts of the GIT in patches Treatment options: - Corticosteroids (anti-inflammatory + immunosuppresive) - 5-aminosalicylates (reduce cytokine + prostaglandin production) - TNF-α antagonists (inhibit TNF-α to block TNF mediated inflammation) L6.3: Drugs in the Cardiovascular System I Cardiovascular Disease - Leading cause of death globally Cardiovascular System - Distributing tubes = Arteries/Arterioles: 20% blood volume - Exchange tubes = Capillaries - Collecting tubes = Veins: 65% blood volume ∆𝑃 Blood flows from high to low pressure: 𝑄 = 𝑅 Q = flow rate, ∆𝑃 = difference in pressure, R = resistance Resistance increases when blood vessel diameter decreases, making it difficult to measure resistance in the body as a whole. Hence we have the calculation: Total Peripheral Resistance (TPR): Sum of vascular resistance in systemic circulation Pressure is also pulsatile as it increases when the heart is emptying (called systole), and decreases when the heart is filling (called diastole). Hence we calculate: Mean Arterial Pressure (MAP): DP (diastolic pressure) + ⅓ PP (pulse pressure) 49 (Pulse pressure = Systolic pressure - Diastolic pressure) Blood Pressure Regulation - Humoral mechanisms - Vasodilation, vasoconstriction, alteration of blood volume - Can be short, medium or long term - Local mechanisms - E.g. NO release - Neural mechanisms - Most short-term via neural reflexes (e.g. baroreceptors detect pressure via stretch) - Increase stretch = increase in firing frequency - Decrease stretch = decrease in firing frequency - Fire action potentials to the cardiovascular control centre in the medulla - Which then sends out info via efferent fibres of ANS to Peripheral Effector Tissues to lower blood pressure (mix of parasymp. + symp.) Blood Pressure = TPR (total peripheral resistance) X CO (Cardiac Output) Cardiac Output = Stroke Volume (L) x Heart Rate (bpm) - Intrinsic rate of SA node (regular heart rate) = 60-100 bpm - Heart rate stimulated by binding to β1 receptors (by NA OR Adrenaline from adrenal glands) - Sympathetic - Heart rate decreased by binding to M2 receptors (by ACh) - Parasympathetic Stroke Volume = Affected by Contractility and Preload - Stroke volume increased by increased contractility by binding of β1 receptors (called positive inotropy) - Contractility = how much can a heart contract; may be affected by factors such as [Ca2+]i - Preload = load placed on cardiac muscle prior to contraction (depends on ventricular filling, and thus the amount of venous inflow) - Increased venous flow = increased ventricular filling - Cardiac muscle fibre length increases with increased ventricular filling (meaning we have higher force of contraction when the ventricles are filled) - Called Frank-Starling relationship - We can increase preload by increasing blood volume (e.g. with more Na+/H2O retention) - Can do this with the Renin-angiotensin system (renin released when the β1-adrenoceptors are activated) - Leads to release of aldosterone which increases blood volume 50 Afterload = resistance to outflow from the left ventricle Hypertension = a global health crisis - A high systolic blood pressure = largest contributor to global burden of disease - It’s also the leading factor for cardiovascular disease Effects of elevated BP - Potential pathological changes in vasculature + hypertrophy of left ventricle; potential effections: - Endothelial dysfunction - Rather than dilating, endothelial cells cause constriction via increase in vasoconstrictor factors (+ a decrease in vasodilator factors) Blood Pressures (Systolic/Diastolic) Optimal 110 (Grade 3 hypertension) Causes of Hypertension - Primary (essential) hypertension (90-95% of cases) = no apparent cause - Often in patients >40 years - May have genetic predisposition to hypertension or cardiovascular diseases - High Na+ diet - Often associated with obesity, high alcohol consumption + physical inactivity - May also involve personal, psychosocial + environmental factors - Secondary essential hypertension (5-10% of cases) = identifiable cause - Renal disease (e.g. augmented renin-angiotensin system) - Endocrine disorders (e.g. pheochromocytoma -> excessive release of adrenaline due to tumour on adrenal medulla) - Preeclampsia (hypertension during pregnancy -> don’t know exact cause but may be combination of problems with placenta, endothelial dysfunction, etc.) 51 Treatment of Hypertension 1. Lifestyle modifications Decrease in alcohol, NaCl, smoking Increase exercise (moderate-to-high aerobic exercise) 2. Drugs (but often have adverse effects) Prescribed based on patient profile (e.g. age, concomitant diseases, other risk factors) Pharmacological modulations of blood pressure - Regulate TPR and/or CO via: - Decrease in heart rate + contractility - Decrease in blood volume -> and thus preload Use of β-blockers (e.g. anything ending in -olol) - Bind to β-adrenoceptors without activating them (so act as receptor antagonists) - Inhibit activation of cardiac β1-adrenoceptors to NA + adrenaline - Decreases heart rate - Decreases contractility = decrease in SV - Decreases cardiac output (thus decreases BP) - Inhibit activation of kidney β1-adrenoceptors - Decreases renin secretion - Thus decreases aldosterone mediated Na+/H2O retention - Decreases blood volume - Thus decreasing preload -> reduces SV -> reduces CO = Reduced BP Adverse Effects - Decreased exercise capacity - Due to decreased cardiac output - Muscle fatigue - Due to inhibition of β2 adrenoceptors in skeletal muscle blood vessels (which would normally cause dilation during exercise) - Cold extremities - Fall in blood pressure = reflex vasoconstriction - ALSO there’s inhibition of β2 adrenoceptors which mediate dilation of cutaneous blood vessels - Bronchoconstriction - Inhibits β2-mediated relaxation of airway smooth muscles - Thus inhibits bronchodilation - Dreams + insomnia - Effects in CNS (if there is lipid solubility*) 52 To minimise adverse effects, can use β1-selective antagonists (cardioselective; since this is where we find β1-adrenoceptors) which are more *hydrophilic L7.1: Drugs in the Cardiovascular System II Poiseuille’s Law: Resistance is proportional to 1/r4 - Where r = radius (affects vessel diameter) Resistance also affected by - Vessel length (but this is constant) - Blood viscosity (normally also constant) Note: smaller arterioles constricting will have a larger effect on TPR than larger arteries. Example: Decrease in internal radius by 10% Artery (1mm diameter)