Complete Pharm Notes PDF

MODULE 1: PHARMACODYNAMICS Pharmacodynamics What do drugs do in the body What is a drug The pharmacological principles that describe drug effects on “a chemical substance of known structure, other than a nutrient or an the body, explaining both...

MODULE 1: PHARMACODYNAMICS Pharmacodynamics What do drugs do in the body What is a drug The pharmacological principles that describe drug effects on “a chemical substance of known structure, other than a nutrient or an the body, explaining both mechanism of action and dose– essential dietary ingredient*, which, when administered to a living response relationship organism, produces a biological effect” Drug origins Synthetic à Aspirin Genetically engineered à parathyroid Phytochemical à morphine from opium hormone poppy Anti-inflammatory Used to treat hypoparathyroidism Poppies are picked to make alkaloids Was originally found in animal kingdom but made where there is lack of parathyroid Also used to make medicine to treat synthetically now for time/cost efficiency hormone causing hypercalcemia opioid addiction Drug interaction with molecular targets Receptors - biological macromolecules that recognises and responds to endogenous chemical signals or exogenous drugs o Agonist à ligand activates receptor o Antagonist àligand binds but doesn’t activate Ligand gated - Tube -like macromolecule with protein subunits that pass through plasma membrane ion channels - Ligand binds to extracellular or in channel or intracellular à ionotropic - Binding alters conductance of ions through channel - E.g. nicotinic acetylcholine transporter o Acetylcholine binds to α subunits ➔ Na+ channel opens ➔ Na+ entry ➔ ap G-protein - Mostly on plasma membrane coupled - Has 7 transmembrane regions à - Extracellular region = ligand binding metabotropic - G-protein = α and βγ subunits à not covalently linked - Effector = enzymes, ion channels, transporters or gene transport regulators - E.g. muscarinic acetylcholine receptors Kinase linked - Transmembrane receptors with enzymatic cytosolic domains - Tyrosine-kinase is largest - Usually large dimeric peptides - E.g. targets for growth factors, cytokines and hormones like insulin - Ligand indued activation à dimerization of receptors à transphosphorylation of tyrosine residues Nuclear - Monomeric proteins - Normally expressed in nucleus but can also be in cytosol - E.g. steroid hormone receptors - Ligand binding à conformation change of receptors à nucleus à receptor-ligand dimer binds to DNA à alters transcription rate à modulates protein expression Ion channels - Allow passage of particular ions Ligand gated - Also a type of receptor Voltage gated E.g. Nifedipine à L-type Voltage operated calcium channel (VOCC) blocker - Ca+ channels important for contraction of smooth muscle cells and blood vessels - Increased Ca+ influx causes more Ca+ release from SERCA pumps Nifedipine àBlocks calcium channels = prevents release of Calcium = reduces blood pressure  Enzymes - Also blocked when treating hypertension - E.g. RAS blocker o ANG-2 = vasoconstriction = increases blood pressure o Enalapril = prevents conversion of ANG1 to ANG2 by blocking angiotensin converting enzyme in lungs Transporters - Allows passage of some ions and small molecules - Has recognition sites - E.g. selective serotonin reuptake inhibitors à fluoxetine, sertraline, citalopram o Used to treat depression and anxiety o Patients have less serotonin = re-uptake inhibitors block re-uptake = serotonin stays in synapse longer and prolong its effect Drug selectivity factors - Rarely tissue/target selective à many tissue/receptor targets - Usefulness of drug directly proportional to binding site selectivity à less selective = more adverse - Lack of selectivity à increase risk of adverse effects Adverse effects from poor selectivity Relative selectivity inducing Dose-control adverse effects - Some drugs selective at low dose = but still chance of adverse effect - Indicates dose is high for specific patient and concentration in circulation is causing adverse effects Drug affinity to two targets Use/develop selective drugs àDrug with only one target Drug is tissue non-selective Change administration - Drugs used to target lungs may effect heart when taken orally à use inhalation Drug binding - Factors that increase binding o Increase drug concentration o Increase receptor concentration - What determines binding o Receptor concentration [R]total o R total = R + LR o Equilibrium direction depends on: § K1 = association complex § K-1 = disassociation complex Affinity - Measure of attraction of ligand for biological target à strength of binding - KD is ligand concentration = where half of receptors is occupied o High KD = low affinity à needs lots of drug to reach KD - High affinity ligand o Rapid binding for long time o Results in à many bound targets at lower concentration compared to others with low affinity Efficacy - Ability of ligand to initiate cellular effect once bound to target Agonist Partial Agonist Antagonist Full activation Submaximal (partial) activation No activation Affinity + + + Efficacy ++ + -  Drugs that target β1-adrenoceptors - β1-adrenoceptors found in sympathetic nervous system, heart (SA/AV node, ventricles) - When adrenaline/noradrenaline bind à increases heart rate and blood pressure Isoprenaline à Agonist Pindolol à Partial agonist Metoprolol à Antagonist Non-selective β1-adrenoceptor agonist Is an agonist but decreased blood Beta-blocker Binds to multiple receptors including β2- pressure as well Selective to β1-adrenoceptors adrenoceptors It outcompetes noradrenaline to Inhibits ability for noradrenaline to bind to Has similar effect as noradrenaline = increase HR and activate fully by partially activating receptors so heart rate doesn’t increase contractions receptors Used for anti-hypertension Used for patients with heart block or arrythmia Not used in Australia anymore Drug dose relationship - Very high dose = makes drugs non-selective = effects receptors it’s not supposed to - Curves o X-axis = ligand concentration o Y-axis = effect as % of maximum effect it can produce Emax Maximum effect of drug in given system Same ligand can have different effect on different systems Potency Drug concentration needed to produce intended effect Usually measured at 50% of maximum effect EC50 Potency of drug at 50% of maximum effect High EC50 = low potency = more drug needed Agonist vs Partial Agonist - Agonists have higher efficacy than partial agonists - Because agonists can occupy less that 50% of receptors illicit maximum response - But partial agonist needs to occupy more than 50% or all receptors to illicit same response o EC50 ≥ KD → no spare receptors Benefits of partial agonist Salbutamol à β2-adrenoceptor agonists = Sumatriptan à 5-HT1A receptors - Used to dilate airways in asthma - Used for migraine - Preferred over full agonist because it can cause desensitization of receptors - It constricts blood vessels associated with migraines by overstimulating and fewer receptors will be left without constricting blood vessels in the heart which - So partial agonists can be used for long term treatment prevents heart attachs Antagonists - interferes with interactions of agonist and receptor proteins or molecules Types of antagonists Receptor Agonist Reversible Competitive Naloxone à Agonist + competitive antagonist binding site - reversible binding that competitive opioid = ↓potency of agonist without doesn’t stabilise the receptor affecting efficacy conformation - used for opioid Concentration of agonist required - of the receptor à receptor overdose to produce 50% response will be stays in inactive - outcompetes increased conformation blocks opioid ligands But if enough agonist is added, agonist from binding can still reach Emax - doesn’t effect number of receptor à binds/unbinds Irreversible Non-competitive Omeprazole à proton Binding to agonist site: - can’t be outcompeted pump inhibitor - Agonist + competitive - binds irreversibly to agonist Used for heart burn to antagonist: ↓potency of binding site covalently or decrease acid agonist & ↓ efficacy with high affinity concentration - More agonist needed  Binds to proton pumps and makes them internalised. Receptor is recycled and new one will come up so doesn’t have permanent effect Allosteric Reversible Non-competitive allosteric Binding allosteric site site binds reversibly and irreversibly - Agonist + competitive Irreversible to allosteric site antagonist: ↓potency of agonist (not necessarily) & ↓ efficacy - Potency can be same - Efficacy can decrease Non- Chemical Inactivates agonist by modification or Protamine à for heparin receptor sequestering before agonist can bind to - Heparin given as anti-coagulant receptor - Thins blood Non-competitive antagonist Protamine breaks it down Functional AKA physiological antagonist Omeprazole à against histamine Causes response that is opposite to agonist - Used for heart burn without targeting the same receptors - Histamine is à expressed in parietal cells of stomach lining that binds to receptor to Non-competitive increase acid secretion - Omeprazole will bind with proton pump and reduce its actions so histamine will still function but acid production reduces elsewhere Partial agonist - partial agonist can function as an antagonist in the presence of a full agonist - binds to same site as agonist so it outcompetes full activation of agonist receptors à competitive antagonism - Agonist + partial agonist: ↓potency of agonist without affecting efficacy - If you treat patient with partial agonist in absence of full agonist = functions as normal agonist - E.g. Pindolol à β2-adrenoceptor partial agonist MODULE 2: PHARMACOLOGY ANS Targeting ANS Pro Cons Wide therapeutic opportunity Potential for adverse effects Neuron - Dendrites = receive synaptic input - Soma = housekeeping à protein synthesis and processing - Axon = action potential conductance - Pre-synaptic terminal = converts electrical signal (AP) into chemical (neurotransmitters) Processing CNS Peripheral 1. CNS receives and integrates information - Brainà Anything external to from internal/external environment via meninges dura mater afferent sensory neurons - Spinal cord - Cranial nerves à 2. CNS integrates information and à cervical, most responds to maintain homeostasis via thoracic, - Spinal nerves à all efferent motor sensory neurons and PNS lumbar, sacral - Peripheral ganglia - Sensory receptors 3. Tissue respond to feedback loop by CNS  ANS vs Somatic Autonomic à Neuroeffector junction à neuron to non-neuron Somatic à Neuromuscular junction = neuron to muscle Involuntary control of visceral organs Voluntary control of muscles Maintains homeostasis Single neuron system Two neuron systemà pre/post ganglionic Neurons that control skeletal muscles have their cell body in the CNS and axons project directly onto skeletal muscle fibre ANS Sympathetic à Nerves from thoracic-lumber region - Increases heart rate and contractility fight or flight Lies in the sympathetic chain which runs on both sides of the vertebrae - In the adrenal medulla à releases Very close to spinal cord so pre-ganglionic neuron is short and post catecholamines ganglionic is long Parasympathetic Nerves from craniosacral region - Decreases heart rate, contractility à rest and digest Lies in ganglia close to/on the target organ/tissue - Airway constriction Long pre-ganglionic and short post ganglionic Enteric Outside PNS Regulates intestinal smooth muscle and epithelial cells Modulated by parasympathetic and sympathetic Chemical transmission at junction via action potential 1. Action potential 2. Causes membrane depolarisation 3. Leads to opening of voltage gated calcium channels 4. Increase of Ca inside àHigh Ca concentration outside the nerve terminal so it moves inside 5. Influx of Ca helps the binding/fusion of synaptic vesicles to the membrane 6. Release of the neurotransmitters into the synapse/junction 7. Neurotransmitters bind to the receptors on the post-synaptic junction 8. Produce a cellular response Neurotransmitters and Receptors Division/Process Primary neurotransmitter Receptor class Somatic Acetylcholine Cholinoceptors Parasympathetic Acetylcholine Cholinoceptors Sympathetic Noradrenaline Adrenoceptors Except ACh at sweat glands/adrenals Except cholinoceptors at sweat glands/adrenals Ganglionic transmission Acetylcholine Cholinoceptors Different types of receptors Cholinoceptors Adrenoceptors Nicotinic Muscarinic α-, β-adrenoceptors Type Ligand-gated ion channel G protein-coupled receptor G protein-coupled receptors Response time Fast Intermediate Intermediate Function Ganglionic transmission & skeletal Post-ganglionic parasympathetic responses Post-ganglionic sympathetic muscle responses (and some sympathetic!) responses Neurotransmitter pathways Somatic ACh (from CNS) à nAChR à target tissue/organ ANS Parasympathetic ACh (from CNS)à nAChR à ACh (pre-ganglionic) à mAChR à target tissue Sympathetic Normal ACh (from CNS) à nAChR (in sympathetic chain) à NA à a-b adrenoreceptor à target tissue Sweat glands ACh (from CNS) à nAChR (in sympathetic chain) à ACh à mAChR à sweat glands Adrenaline ACh (from CNS) à nAChR (in adrenal gland/Chromaffin cells) à Adrenaline à circulation à a-b adrenoreceptor on target tissue  Peripheral nervous system - Agonist à mimic activity of nerve interactions and block exogenous NA or - Antagonist à block nerve mediated response - Illicit response by stopping o Reuptake of neurotransmitters to nerve terminal o Degrade/metabolise neurotransmitters Co-Transmission - Multiple neurotransmitters released from single nerve terminal - Enables local fine-tuning responses o Different ligand-receptor interaction can lead to differences in magnitude, type, temporal o Pre- and post-junctional neuromodulation Adrenergic mediators Noradrenaline Adrenaline Neurotransmitter and hormone Hormone From sympathetic nerve terminal, adrenal gland, post ganglionic neurons From adrenal gland à Chromaffin cells Catecholamine synthesis In nerve terminal à Noradrenaline In adrenal medulla à Adrenaline - L-tyrosine à transported inside via - Same steps as NA tyrosine hydroxylase (rate-limiting) synthesis à NA à converted to L-DOPA à converted into converted to dopamine à adrenaline by PNMT transported into vesicle via à taken into granules vesicular monoamine transporter à released by binding àconverted into NA of ACh Inactivation of sympathetic neurotransmission via re-uptake Primary Process Secondary Process Neuronal uptake via high-affinity norepinephrine (NE) transporter (NET) Extra-neuronal uptake via low affinity organic cation Taken back to nerve terminal and recycled and re-released by VMAT or transporter (OCT3) metabolised by MAO Can be metabolised by COMT Drugs used in adrenergic pathways L-DOPA/Carbidopa - L-DOPA can cross blood-brain barrier to increase dopamine and NA synthesis. Parkinson’s Disease - Adverse effects if it enters PNS - Carbidopa can’t cross blood/brain barrier - Is inhibitor for L-DOPA and binds to any that enters PNS L-DOPs - Pro-drug directly converts into noradrenaline à skips dopamine - Used for hypertension to increase BPà decreased NA synthesis VMAT inhibitor Targets neurotransmitter storage - NA in cytoplasm is degraded my monoamine oxidase (MAO) - Inhibits monoamine transport into vesicle - Was used to treat hypertension but poor absorption and adverse effects N-Type VGCC Targets neurotransmitter release inhibitors - Periphery nerve terminals and CNS have N-type voltage gated calcium channels that allow influx of calcium needed for fusion of vesicle to cell W-conotoxin membrane Ziconotide - Inhibits channel = no influx = no fusion = no neurotransmitter release Cocaine Uptake inhibitors - Inhibits NETà no neuronal re-uptake of NA - Greater concentration and prolonged effect of NA in synapse MAO inhibitors Uptake inhibitors - Prevents breakdown of NA in cytoplasm - More NA taken into vesicles so more released during vesicular exocytosis - NA can leak into junction Indirectly Acting Sympathomimetics (IAS) - Indirectly acting = doesn’t directly bind to and stimulate adrenoreceptors - Sympathomimetics = mimics effect of endogenous agonists of sympathetic nervous system - Mechanism 1. Structurally similar to NA so transported by NET into nerve terminal (can limit neuronal re-uptake) 2. Transported into vesicles by VMAT and exchanged for NA à NA displaced in cytosol 3. Displaced cytosolic NA enters junction via NET 4. Increases NA in junction à activation of post junctional adrenoreceptors 5. Can be metabolised by MAO o Will decrease concentration if IAS, but will decrease metabolism of actual NA à increased NA concentration - Example à Pseudoephedrine o Nasal decongestant à constricts arteries in nasal mucosa with limited central effects Tyramine - Is a dietary product - Don’t get any adverse effects because gut has natural MAO that helps breakdown à won’t reach periphery - Effects o Bronchodilation o Peripheral vasoconstriction o Increased heart rate and contractile force o Inhibition of gut motility Drugs targeting post-junctional adrenoreceptors - Blood vessels o Measured parameter: vasoconstriction PE > NA ≥ ADR >> ISO - Heart o Measured parameters: contractile rate & force ISO > ADR ≥ NA >> PE - Drugs o Endogenous adrenoreceptors § NA = noradrenaline § ADR = adrenaline  o Synthetic drugs § Based on the structure of endogenous adrenoreceptors § PE = phenylephrine § ISO = isoprenaline - Potency o > = more potent o >> = a lot more potent o ≥ = more or equally potent Classification of adrenoreceptors and effects - All adrenoreceptors are G-protein coupled receptors B1,2 - Linked to Gas protein à activation = activated of adenylate cyclase (AC) à generates cAMP à activates PKA à activates smooth and cardiac muscle Smooth - Relaxation in airway, blood vessels, GI tract Cardiac Increases muscle contractile force A1 - Activates GAq protein à activates PLC à leads to PIP2 (à DAG) and IP3 à IP3 increases Ca+ à smooth muscle contraction A2 Modulates auto-inhibitory feedback - NA binds to auto-inhibitory receptor à activates Gai protein à inhibits release of more neurotransmitters Sympathetic nerve mediated response TISSUE/ORGAN RESPONSE RECEPTOR Heart Increase rate & force of contraction β1 Blood vessels (most) Constriction α1 Blood vessels (skeletal muscle) Dilation β predominates 2 Bronchi Dilation β2 Gastrointestinal (tract) Relaxation α β 1 2 Gastrointestinal (sphincters) Contraction α1 Radial dilator muscle (pupil) Contraction (pupil dilates) α1 Kidney Renin secretion β1 Liver, skeletal muscle Glycogenolysis α β 1 2 Adrenoreceptor Signalling Summary Receptor subtype α1 α2 β1 β2 G-protein α subunit Gαq Gαi Gαs Gαs Effector Stimulates phospholipase Inhibits adenylate Stimulates adenylate Stimulates adenylate What is activated/inhibited C (PLC) cyclase (AC) cyclase (AC) cyclase (AC) Second messengers Increased IP3 + DAG Decreased cAMP Increased cAMP Increased cAMP Decrease Increased contractile Smooth muscle Response (some) neurotransmitter rate/force (heart), renin Smooth muscle relaxation contraction release release (kidney)  Tissue/Organ Response Somatic Skeletal muscle Contraction Parasympathetic Ganglia Transmission Heart Decrease rate of contraction (bradycardia) Airway Bronchoconstriction GI tract Increase rate of constriction Sphincter muscle (pupil size) Contraction (pupil constriction; miosis) Glands Secretion Sympathetic Ganglia Transmission Sweat glands Sweating/perspiration Adrenal gland Adrenaline secretion Receptor subtype β1 β2 β1 + β2 Smooth muscle (bronchi, vascular, GI Localisation Heart, kidney (juxtaglomerular cells) tract, bladder etc) Dobutamine Agonists Salbutamol (asthma) Isoprenaline (acute heart failure, cardiogenic shock) Propranolol (anti- Antagonists Atenolol (anti-hypertensive) X hypertensive) Receptor subtype α1 α2 α1 + α2 Pre-junctional (esp. sympathetic nerve Localisation Vascular smooth muscle, radial dilator muscle terminals) Clonidine (anti-hypertensive but mostly Agonists Phenylephrine (nasal decongestant) X through CNS actions) Antagonists Prazosin (anti-hypertensive) Yohimbine Phentolamine Acetylcholine Synthesis and Storage - Choline à transported inside via high-affinity choline transporter(RLS) à choline acetyltransferase transfers acetyl from Acetyl Coenzyme A into choline à vesicular acetylcholine transport transports ACh inside vesicle Ca2+ dependent vesicular exocytosis 1. Vesicle with membrane protein synaptobrevin docks at active zone of pre-synaptic membrane 2. Synaptobrevin forms SNARE complex with Syntaxin and SNAP-25 (plasma membrane proteins). 3. Ca2+ enters nerve terminal and binds to synaptotagmin found on the vesicle membrane. - Synaptotagmin has calcium detection - Binds calcium - Changes conformation - Un-locks complex - Get fusion of synaptic vesicles 4. Ca2+-bound synaptotagmin triggers membrane fusion leading to neurotransmitter release Botulinum Toxin - Mechanism 1. Heavy chain binds with high-affinity to specific receptors on membrane of terminal containing ACh à won’t effect sympathetic nerve terminal 2. Botulinium toxin is endocytosed 3. Light chain detaches from heavy chain, enters cytosol and cleaves SNARE protein 4. SNARE complex doesn’t form 5. Vesicle and plasma membranes don’t fuse = neurotransmitter release is inhibited - Poisoning à C. Botulinum (anaerobic bacteria)  Progressive motor paralysis (varying degree of muscle weakness) Inhibition of parasympathetic-mediated effect Difficulty swallowing Dry mouth Facial weakness à (droopy eyelids, hanging jaw) Dry eyes Trouble talking Urinary retention Limb paralysis Constipation May progress to respiratory paralysis - Botulinum Toxin à Poison to Medicine Cosmetic Use Paralyses superficial muscles that pucker the skin (local injection) à botox Clinical Use - Unwanted movement disorders (blepharospasm, torsion dystonia) - Urinary incontinence associated with bladder overactivity - Hyperhidrosis (excessive sweating) Medical use - Uncontrolled contraction of muscles responsible for eyelid closure – excessive blinking or full closure - Local administration of botulinum toxin A decreases ACh release from nerves innervating muscles – inhibits muscle contraction Drugs effecting cholinergic neurotransmitters Hemicholinium Targets ACh synthesis Experimental drug (not tissue selective) High affinity for choline transporter Depletes ACh concentration inside nerve terminal because transporter is RLS Vesamicol Targets ACh synthesis Inhibits vesicular ACh transporter Anti- - Acetylcholinesterase used to breakdown ACh into Acetyl CoA - inhibitor of acetylcholinesterase Acetylcholinesterase and choline - used as pesticide - Anti-Acetylcholinesterase prevents breakdown of ACh - used as neurotoxic nerve agent - neostigmine Organophosphate - Irreversible anticholinesterase - Binds and covalently modifies enzyme to AChE is not active - Use mAChR antagonist to alleviate muscarinic mediated symptom Physostigmine - Medium duration reversible cholinesterase inhibitor Glaucoma à eye disease caused by high - Selective parasympathetic junction intraocular pressure due to blockage of - Activates M3 receptors on ciliary smooth muscle causing eye drainage system contraction facilitated by accumulated fluid Neostigmine - Medium duration reversible cholinesterase inhibitor Myasthenia Gravis à body develops auto- - Selective for neuromuscular junction antibodies for nAChR that targets it for - Reversible competitive block for Myasthenia Gravis degradation d-Tubocurarine Blocks cholinergic receptors - Is a neuromuscular blocking drug for - Competitive reversible antagonist surgical paralysis à obsolete - At neuromuscular junction but also autonomic ganglia at - Hypotension due to ganglion-block higher concentration - Replaced with drugs that are less - A nicotinic cholinoceptor antagonist (a component of a native effective at autonomic ganglia South American arrow poison) used as a skeletal muscle relaxant. - Competitively prevents activation of the nicotinic ACh receptor. Hexamethonium Blocks cholinergic receptors - First effective anti-hypertensive à - Reversible cholinesterase inhibitor obsolete - Indiscriminate block of sympathetic and parasympathetic ganglia Atropine - Muscarinic cholinoreceptor antagonist - Anticholinesterase poisoning - Reduces secretions during anaesthesia Myasthenia Gravis Normal NMJ Myasthenia Gravis Myasthenia Gravis with Neostigmine - Arrival of signal nerve impulses releases - Body develops auto-antibodies - Neostigmine prevents ACh metabolism package of ACh for nAChR that targets it for - Enables lateral diffusion ACh to bind unaffected - Some ACh is hydrolysed by AChE degradation nAChRs and rebinding of ACh to multiple - Some ACh binds and activates nAChRs - Prevents ACh from binding and nAChRs to elicit an end-plate potential activating nAChRs. Most - Restores cholinergic transmission in NMJ leading - ACh molecules bound to nAChR degrade rapidly before to symptomatic improvement dissociates and are rapidly hydrolysed sufficient receptors are - End plate potential restored by AChE activated - Can be used to treat myasthenia gravis but have - Neurotransmitter inactivation = end of - Generates weak end plate to have enough nicotinic receptors left on tissue response potential skeletal muscles - Leads to muscle weakness Post junctional acetylcholine receptors - DUMBELS à defecation, urination, miosis, bronchoconstriction, emesis, lacrimation, salivation Nicotinic acetylcholine Ligand gated ion channels receptor (nAChR) Two subtypes - N1 à neuromuscular junction - N2 à autonomic ganglia Many functional receptor isoformsà differences in subunit composition leads to differences in: - Ligand specificity - Cation permeability - Physiological function Muscarinic M2 Acetylcholine Receptor - Receptor in heart G-protein - Linked to GAi - Inhibits activity of adenylate cyclase - Required for production of cAMP and PKA - Lack of AC leads to decreased contractility à decreases heart rate M3 - Receptor location à smooth muscles (GIT, airways, bladder, eye), glands - Linked to GAq à same as A1 adrenoreceptor - Binds to PCL and leads to increased GIT contraction Cholinoceptors agonist AGONIST NICOTINIC ACTIVITY MUSCARINIC ACTIVITY HYDROLYSIS BY AChE Acetylcholine +++ +++ +++ Carbachol +++ ++ - Methacholine + +++ ++ Bethanechol - +++ - Pilocarpine - ++ - Muscarine - +++ - Nicotine +++ - - Receptor subtype Nicotinic Muscarinic Tissues with parasympathetic innervation + Localisation Autonomic ganglia & skeletal muscle sweat glands Agonists ACh, nicotine ACh, muscarine Antagonists Hexamethonium (ganglia) D-tubocurarine (NMJ) Atropine MODULE 3: DRUG DISCOVERY à THEN Observations and Experience - Cannabis o Analgesic and anti-emetic o Accidental discovery à >500 chemical constituents o Multiple pharmacologically active compounds at unknown quantities and varying proportions Discovery of Penicillin - Very potent à even when diluted by 100 times o Crude extract was non-toxic to humans but could work on bacteria Observation & Experience - In the laboratory o Sulphonamide (anti-bacterial drug) used in 1942 by an infectious disease physician to treat patients o Appeared to lower blood glucose à Informed a physiologist àLed to the development of orally- acting hypoglycaemic drugs for non-insulin dependent diabetes o A side-effect that was exploited for therapeutic gain Screening - Discovery of tetracyclines o Following success of penicillin, Pfizer began search for other antibiotics o Collected 135 000 soil samples o Grew organisms o Screened millions of fermentation samples for antibiotic activity § Isolated oxytetracycline Approach 3 - Synthetic chemistry - The story of aspirin o Sold for the treatment of pain, fever and inflammation in 1899 (mechanism of action was unknown until 1971). o Enabled oral administration without accompanying nausea Natural versus synthetic method - Sometimes its easier to just use the natural product rather than synthesising it - E.g morphine hasn’t been viable cost/resource wise to be made synthetically, so its easier to just source it from the plants Drug Discovery Then - A reflection of limited techniques, knowledge, infrastructure and resources - Working with smaller knowledge base - Less known about human physiology and pathophysiology - Sharing of information, especially between disciplines was limited - Limited computational power – impacts data generation, analysis and knowledge transfer  - Obtaining extracts, screening extracts for activity, isolation and purification of natural products was time consuming - Fewer available compounds for exploratory biological screening Drug Discovery Now - Rationale drug design. Uses information about: - Structure of receptors and ligands and ligand-receptor interactions - Disease mechanisms - Can target specific steps in the disease mechanism to treat people - Mechanism of action of drug - Biochemical pathways MODULE 4: PHARMACOKINETICS/PHARMACOGENOMIC Pharmakinetics: - Study of how body disposes drugs - Aà Absorption - D à Distribution - M à Metabolism - E àExcretion Routes of Drug Administration - Drug administration route is determined by: o Properties of the drug § e.g. solubility, ionization, dosage form, etc o Therapeutic objectives § e.g. need for a rapid onset of action, longer duration of action, restriction to a local site etc. First pass hepatic metabolism - Drug is absorbed by GI tract and passes liver before going into circulation to - Liver metabolises drug into inactive form - Can reduce efficacy of the drug Effect of food on absorption - Retardation of absorption o Antibiotics like tetracycline à decreases with calcium or ion - Increases absorption o Fatty food à Griseofulvin Local Systemic Effect on or near site of administration Enters bloodstream and accesses tissue Skinà topical Enteric à linked to GI tract Lung à inhalation - Oral àThough mouth Application on epithelial surface - Sublingual à under tongue - Cornea (Ophthalmic) à eye drop - Buccal à between gum - Nasal mucosa à nasal drop - Rectal àinto rectum - Vagina (pessaries) Parenteral (next to intestine) - Rectal - Intravenous - Intramuscular - Subcutaneous Route Mechanism Advantage Disadvantage Oral Most common Non-invasive Slower action No special training Irregular absorption of drug Safer à dose control First hepatic pass Convenient Can be effected by food Inactivation of drug by gastric juice Not suitable for unconscious/vomiting Possible overdose Sublingual/ Drug diffuse into blood Rapid onset Only few drugs adequately absorbed Buccal vessels (capillaries) under Avoids first hepatic pass Drug shouldn’t be swallowed tongue or in cheek Swallowing not required Compliance difficult Can be used for unconscious patients Rectal Drug inserted to rectum Less first pass metabolism than oral Irregular absorption of solid drugs Both local/systemic effect - 50% of drug absorbed from Not well accepted Inferior & middle rectal rectum will bypass liver Hard administration veins drain into vena cava For pt can’t take oral meds Can cause irritation to rectal mucosa Good for children Parenteral Rapid onset Pain at injection site Good for drugs that are poorly Not suitable for self-medication absorbed from GI tract or unstable Asepsis must be maintained from gastric juice (insulin) Expensive For unconscious pt May be toxic because of rapid response Intravenous (IV) Can be given at once Good for emergency Can’t give drugs with oily covering or drugs (bolus) or over time No first pass that cause hemolysis (infusion) Easy to give drugs that may cause Can’t have solid suspensions as it can block irritation blood vessels Intra- muscular Injection into skeletal Faster than oral Rate of absorption depends on (IM) muscle Can self-administer à insulin - Site of injection Drugs can be: - Type of preparation - Aqueous solution à - Physiological factors àblood flow to fast absorption area - Specialised depot preparation à slow absorption Subcutaneous Injected into subcutaneous For poorly soluble suspensions Only for non-irritant drugs tissue à between muscle Less common method Not suitable for large volume of suspension and skin Intraarterial Directly into arteries Localise to specific organ When drug is highly bound - E.g. treatment of liver tumour or to plasma protein head/neck cancer Intrathecal Into subarachnoid space in For drugs that can’t cross blood brain Needs expert administration spinal cord and brain barrier Blood brain barrier and Blood cerebrospinal fluid barrier prevents drug going into CNS Inhalation Used for local effect on Rapid delivery à fast as IV respiratory tract or for No first pass system action Local à asthma puffer Systemicàgas anaesthetic Transport across membrane - Drugs need to be partially lipid soluble to pass through lipid bilayer  - Exceptions if administered intravenously or local administration Passive diffusion Movement down concentration gradient Lipid soluble drugs readily move through membranes Water soluble drugs can penetrate through aqueous channels Active transport Movement against concentration gradient Requires ATP Endocytosis Cell membrane creates bulge and makes vesicle - Phagocytosis àsolids engulfed - Pinocytosis à external fluids engulfed Bioavailability (BA) - Fraction/proportion of unchanged drug that reaches systemic circulation after administration - Is the: o Rate à how fast o Extent à how much of total administered drug reaches circulation - Is important to understand how much of the drug reaches plasma - Depends on: o Route of administration o pH of site o chemical properties of the drug Route of IM and SC absorption can be modified by: administration - Increasing absorption o Massaging area o Heating o Exercise - Decrease absorption o Adding vasoconstrictor o Slow release à depot pH of area Nonionised drugs readily pass lipid membranes pH different in gut - A weakly acidic drug in the Stomach (pH 1-3): In an acidic environment a weakly acid drug will remain in its nonionised form and therefore be better absorbed from the stomach as it is more lipid soluble, and can pass the lipid membrane. - A weakly basic drug in the in the Duodenum (pH: 5) or Stomach (pH:1-3): The duodenum and stomach both have acidic environments, therefore a weakly basic drug will be ionised (through interaction with the acid to form a salt). The now ionised basic drug is less lipid soluble and will not be absorbed from the duodenum or stomach. - A weakly basic drug in the Lower small intestine (pH: 5-7) A weakly basic drug would remain in its non ionised from in this basic environment, therefore it would be lipid soluble and better absorbed in the lower part of the small intestine. Physiological - Blood flow to area à blood flow greater in intestine than stomach so greater absorption factors - SA à small intestine has greater surface area that stomach due to villi - Contact time at absorption site à if drugs moves through GI tract quickly it won’t be absorbed Chemical - Molecular weight/size à smaller = absorb properties of - Solubility à hydrophilic = poorly absorbed drug - Dosage form - Chemical instability - Peptide unstable in gastric pH - pKa à rate of ionisation Route Bioavailability (%) Characteristics Intravenous (IV) 100 Most rapid onset  Intramuscular (IM) 75 to ≤ 100 Large volumes often feasible; may be painful Subcutaneous (SC) 75 to ≤ 100 Smaller volume than IM, may be painful Oral (PO) 5 to ≤ 100 Most convenient, first-pass effect may be significant for certain drug Rectal (PR) 30 to ≤ 100 Less first pass effect than oral Inhalation 5 to ≤ 100 Often very rapid onset Transdermal 80 to ≤ 100 Usually very slow absorption; used for lack of first-pass effect, prolonged duration of action Distribution - Reversible transfer of drugs to and from site of action - Drugs are being distributed and eliminated at same time à but distribution is faster - Steps o Bind to plasma protein à all drugs o More to extracellular fluid à small and non-protein bound o Bind to tissue à lipid solubility Factors that determine distribution - Cardiac output o Well perfused organ à high cardiac output à receive lots of blood § E.g. liver (31%), kidney, brain have access to drugs faster o Less perfused organs § Muscles, skin, fast, viscera = receive drug slowly - Plasma protein binding - Molecular size of drug - Lipid solubility Binding to plasma protein - Two major plasma proteins o Albumin à binds acidic drugs = warfarin, NSAIDs o α1-acid glycoprotein/β-globulin à bind basic drugs = quinine, propranolol - Binding is non-selective o Drug with better affinity or high in concentration preferentially bound o Competitive for binding site increases free concentration o Leads to toxicity Volume of distribution à Vd - Apparent volume of fluid that is needed to hold the total amount of drug in the body at the same concentration as in the plasma - Vd = Total amount of drug in the body (Q)/ plasma concentration in blood/plasma (Cp) - Tells us how much drug is needed to get a particular concentration of the drug in the plasma Vd determined by: Drug highly bound to plasma Greater concentration in blood (0.08L/kg) or plasma (0.05L/kg) = smaller Vd protein, hydrophilic or high - Heparin à 0.05-0.1 L/kg molecular weight - Warfarin à 0.1-0.2 L/kg Drug distributed to extracellular Can escape vasculature à small size fluid (0.2L/kg) But can’t permeate membranes à polar or not lipophilic E.g. mannitol à monoclonal antibody Drug can distribute throughout Readily crosses plasma membrane à lipid soluble water body (0.6L/kg) - Ethanol à 0.53 L/kg à close to total amount of body water Binds to tissues or fat Very lipophilic Vd can be greater than total body water volume - Morphine à 3L/kg - Digoxin à 7L/kg - Fluoxetine à 35L/kg - Can act as drug reservoir and can prolong drug action Renal excretion Glomerular filtration Small drugs à high doses for euphoria or self management of opioid withdrawal > some cases of misuse leading to cardiac failure and respiratory depression > death Anti-spasmodics (spasmolytics) Example - Hyoscine BUTYLbromide “Buscopan” - Also known as scopolamine butylbromide - Anti-cholinergic – muscarinic receptor antagonist (high affinity) Mechanism - Does not cross Blood brain barrier – acts peripherally - Smooth muscle relaxant, reduces GI motility and spasm - Used for symptomatic relief in pathological conditions in which there is gastrointestinal spasm - Oral, IV/IM administration - Well tolerated Inflammatory bowel disease - For ulcerative colitis and Crohn disease Corticosteroids - ie prednisolone or budesonide - anti-inflammatory and immunosuppressive 5-aminosalicylates (5- - the “salazines”àmesalazine ASA) - reduce cytokine production - inhibit prostaglandin production TNF-alpha - ie adalimumab and infliximab (monoclonal antibodies) antagonists - inhibit cytokine TNF alpha - blocks TNF mediated inflammation - thus anti-inflammatory MODULE 9: DRUGS TO TREAT ASTHMA Asthma Host factors Environmental factors - 1/9 Australia had asthma - Genetic - Indoor allergen - Heterogenous disease of chronic airway inflammation - Gender - Outdoor allergen - Obesity - Chemical irritant - Tobacco smoke Allergic (TH2-type) Asthma Pathogenesis - Air pollution - Epithelium lines airway - Respiratory infections o Forms barrier between external and internal environment - Goblet cells o Specialied cells that secrete mucus à protect epithelium - Mechanism o Allergens is identified by antigen presenting cells and undergo endocytosis o Naïve T cells initiates sensitization o T cells are activated and differentiated into TH2 cells o TH2 cells may be cytokines including: IL-4 - Which stimulates the B-lymphocytes which secretes IgE - IgE has high affinity for receptors on mast cells à makes them sensitive to subsequent exposure to same IgE IL-3 - Important for survival and activity of mast cells IL-5 - Drives recruitment and activation of eosinophils which are important for allergen type asthma o In subsequent exposure to allergens § IgE primed masted cells rapidly degranulate o Causes airway obstruction by: § Smooth muscle contraction à bronchoconstriction § Narrowing of airway lumen leading to swelling § Increased microvascular leakage in airways à leads to oedema § Hypersecretion of mucous from goblet cells - Obstruction leads to o Wheezing o Chest tightness o Coughing breathlessness  Characteristics of allergic (TH2-type) asthma - Airway obstruction - Increased airway hyper responsiveness - Chronic eosinophilic airway inflammation Airway Hyper Responsiveness - FEV = forced expiratory volume Inflammation - Anti-histamines aren’t effective for treating asthma because histamine is one mediator causing bronchoconstriction but there are still many other contributors that effect asthma response Allergic (TH2-type) asthma pathogenesis - Induction phase à poorly understood, related to how allergy was established - Smooth muscle shortening (bronchoconstriction) à understood, important chemical mediators have been identified (histamine, PGD2, Cys-LTs) - Inflammation à poorly understood, some key chemical mediators known - Airway hyperresponsiveness is poorly understood Strategies to target asthma Prevent development of allergy Very heart Prevent or reverses airway B-agonist à safe and effective obstruction Relivers à used to relieve asthma short term Preventers à long lasting bronchodilation to prevent bronchoconstriction Airway smooth muscle contraction Easy to treat the smooth muscle constriction Prevents or reverses airway Chronic inflammation & structural changes sensitive to glucocorticoid à main preventers for asthma inflammation Cytokine targets being evaluated Drug delivery to lungs - Most asthma drugs delivered through inhalation - Inhalation preferred for: o Faster response o Higher bioavailability o More targeted à direct effect on lungs Airway smooth muscles (ASM) - Balance of relaxation and constriction - Example of functional antagonist Mechanism of β2-agonists in airway smooth muscle - When B2 agonist or circulating adrenaline binds to receptor à adenylate cyclase activity increases à increases cAMP à increases activity of PKA à decrease in intracellular calcium - Decrease in calcium important because all mediators all increase intracellular calcium levels that leads to airway smooth muscle constriction Short Acting β2-adrenoreceptor Agonist (SABA) à Reliver Long Acting β2-adrenoreceptor Agonist (LABA) à Preventors Acute symptom relief or exercise induced bronchoconstriction Prophylaxis Must be inhaled corticosteroids - Reduces flareups Frequent use associated with poor outcomes - Always combined with ICS (glucocorticoids) in single - β2-adrenoreceptor downregulation à ↓ bronchodilator response, ↑ actuator allergic response E.g. - Rapid onset à 2-5 mins - Salmeterol à slow onset à 12 hour duration Duration à 2-4 hours à diffusion not metabolism - Formoterol à rapid onset à 12 hour duration E.g. Salbutamol, terbutaline β2-adrenoreceptor Agonists Adverse effects & Precautions - Adverse effects o Selectivity for the β2-adrenoceptor is very important! - Precautions o Cardiovascular disorders o Diabetes (high doses) o Sympathomimetic amines Glucocorticoid à Prevent/Reverse Inflammation Mechanism - Needs to be lipid soluble à needs to cross lipid cell membrane to bind to glucocorticoid receptor - When it binds to receptor and activates it: o The receptors dimerise and translocate into the nucleus o In nucleus the receptor-agonist complex changes protein synthesis of proteins involved in inflammation by: § Direct interaction with DNA § Or independent of direct interaction Effects Increase anti-inflammatory gene expression à Annexin-1, B2-adrenoreceptors Decreases inflammatory proteins à COX2, PLA2 Adverse Inhaledà corticosteroid Effects - Well tolerated - Hoarseness & weakness of voice (dysphonia) – atrophy of vocal cords Oral thrush (oropharyngeal candidiasis) § Treated by using mouthwash reduces local absorption - Levels are controlled in body Systemic (oral) - Suppression of the hypothalamic-pituitary-adrenal axis (after chronic use taper dose) - Mood changes, weight gain, diabetes, osteoporosis Mechanism of cysteinyl-leukotriene receptor antagonists (Preventer) - Effects o Has anti-inflammatory and bronchodilation effect o Not as effective as inhaled glucocorticoid or β2-adrenoreceptor agonist - Leukotriene o Are synthesized in the arachidonic acid pathway due to actions of 5’-lipoxygenase enzyme o Leukotrienes are synthesized and released by mast cells o Effects § Acts on blood vessels to cause oedema § Increases mucous secretion § Causes bronchoconstriction of cells § Leads to recruitment of eosinophil that increases inflammatory response o E.g. Antagonist à Montelukasts à block actions of leukotrienes at receptors - Are orally active à increases compliance - Modest bronchodilation o Used in adults as add on to asthma medication o Used as alternative for children instead of glucocorticoid - Aspirin-induced asthma (overproduction of LTs?) o Polymorphism that leads to overproduction of leukotrienes in response to asthma o Aspirin blocks cyclo-oxygenase o More arachidonic acid metabolised  o More leukotrienes à more bronchoconstriction o Leukatriene-1 receptor antagonist can be used to prevent aspirin induced asthma - Exercise-induced bronchoconstriction - Rare adverse effects: o Mood and behavioural changes à Increased in children Using monoclonal anti-bodies (biological) to treat allergic asthma - Targets specific steps in the pathway à Mast cells, IgE, IL-5, IL-4, IL-3 - Reserved for specific patients who aren’t responsive to conventional asthma treatment MODULE 10: DRUGS IN CARDIOVASCULAR SYSTEM Function of the cardiovascular system - Distribution of essential substances (tissue function, growth and repair) - Removal of metabolism by-products - Circulation of hormones & neurotransmitters (enable chemical signalling) - Heat distribution (temperature regulation) - Mediation of inflammatory and host defence responses Heart Pump System - Pressure drives blood flow - Right atrium and ventricle pumps deoxygenated blood to lungs for O2/CO2 exchange (pulmonary circulation - Left atrium and ventricle pumps blood to tissues of the body (systemic circulation) Blood Vessels Distributing tubes: Arteries/arterioles High pressure system (supply). 20% blood volume. Exchange tubes: Capillaries Extensive network. Thin-walled vessels facilitate rapid exchange of materials between vasculature and tissues. Collecting tubes: Veins/venules Low pressure system (reservoir). Compliant. 65% blood volume. Blood Flow - Blood flow requires a driving force (blood pressure) - P1 à High pressure point à Near heart (e.g. Aorta ) - Larger the pressure gradient = higher the flow - The greater the resistance = the slower the flow - Arteries and arterioles are a great site of resistance o Because it contains autonomic nervous system (sympathetic), contains local factors of vascular system, oxygenating system Blood Pressure Total Peripheral Sum of all vascular resistance in systemic circulation Heart Rate Resistance (TPR) Change in resistance in circuit determines relative - Diastole à heart filling blood flow - Systole à heart emptying Mean Arterial Average arterial pressure during a single cardiac cycle - Heart has pace-maker cells in SA Pressure (mmHg) MAP = DP + 1/3PP & DP +1/3 (SP-DP) node Is kept constant to ensure adequate perfusion of o Different ions can depolarise organs spontaneously to generate Blood Pressure (BP) TPR x CO action potential Cardiac Output SV (per beat) x HR (beat per min) o Have B1 receptors on SA (CO) node  - Contractility (chronotropic) o NA from sympathetic nerve or adrenaline from adrenal gland à binds to cardiac myocyte à increase contractility o Enhance contractility = increases stroke volume = increase cardiac output - Sympathetic and parasympathetic systems tonically active so need to modulate both systems to alter HR o To decrease heart rate = increase parasympathetic and decrease sympathetic Sympathetic Innervation (positive ionotropic) Parasympathetic innervation (negative ionotropic) - Increased sympathetic activity à more release of NA à binds to B1 receptors à - Release ACh à binds to M2 receptors on SA increases HR node à decreases HR - Increased sympathetic activity à adrenaline released from adrenal gland à activates B1 receptors à increases HR Regulation Short Term Long Term Mechanism Via neural reflexes detected via Body has set blood BP increases = Increased passive stretch= activation of mechanoreceptors baroreceptors in the walls of carotid pressure = activation of baroreceptors = increased firing of afferent sensory = arteries and aortic arch Involves extracellular transfer information to cardiovascular control centre = sends out Moment to moment regulation fluid and blood volume information via efferent nerves to lower blood pressure via organs such as Effectors: heart, vessels, adrenal Targets: blood vessels heart and adrenal medulla medulla and kidney BP decreases = less activation of baroreceptors = sends info to cardiovascular control centre = increases Preload After load - Stretch of cardiac muscle fibres before contraction - Resistance to outflow from left ventricle - Depends on ventricular filling/venous return - If there is increase in TPR arterial circulation, will impede - Increased venous flow = Increased ventricular filling = Increased cardiac stroke volume à decrease cardiac output muscle fibre length = Greater force generation Increased venous return can be from - Redistribution of blood from arterial to venous - Increase in total volume of blood Total volume of blood dependent on Na+/H2O retention - Influenced by renin-angiotensin system - Increased sympathetic activity à B1 receptor activation à renin release à aldosterone à increases sodium retention à increases blood volume à increases ventricular filling à increases preload à increases stroke volume Why should we treat HYPERTENSION? - Elevated BP causes pathological changes in vasculature & hypertrophy of left ventricle - Leading cause of stroke, coronary artery disease, MI & sudden death, heart failure, renal insufficiency... - Treatment to decrease blood pressure AND prevent these lethal & disabling cardiovascular sequelae Hypertension Causes Primary/essential hypertension (≈90-95%), no apparent cause Secondary essential hypertension (5-10%), identifiable cause - typically occurs in patients > 40 years - Renal disease (augmented renin-angiotensin system) - genetic predisposition to hypertension and/or other cardiovascular - endocrine disorders (e.g. pheochromocytoma – adrenal disease medulla tumour leads to excessive secretion of - diet (high Na+ diet, recommended consumption is less than 2 g/day) adrenaline) - obesity, high alcohol consumption, physical inactivity - preeclampsia in pregnancy - personal, psychosocial and environmental factors  Hypertension Treatment First choice therapy – lifestyle modifications Drugs (long-term) and all have some adverse effects Manage/monitor > Decrease Drug choice depends on patient profile Increase exercise - associated risk factors & concomitant disease - Moderate-to-high level of aerobic exercise (but dependent on - age age, disease severity, fitness level). - side effects How to lower TPR - By decreasing heart rate and contractility - By decreasing blood volume and therefore preload β-adrenoceptor antagonists: mechanism of action - Aka β-blockers – aka the ‘olols’ - Bind but do not activate β-adrenoceptors. - Thus inhibit activation of cardiac β1-adrenoceptors by noradrenaline and circulating adrenaline. o decrease HR à decrease contractility à SV à decrease CO à BP - Bind to and inhibit activation of kidney β1-adrenoceptors o decreases renin secretion and aldosterone mediated Na+/H2O retention o decreases blood volumeà preload à SV à decrease CO and BP β-adrenoceptor antagonists: adverse effects - Minimise with β1-selective antagonists (cardioselective) that are more hydrophilic Adverse effect Details and mechanism of adverse effect Decreased exercise capacity Decreased cardiac output Muscle fatigue Cold extremities Inhibition of β2-adrenoceptor-mediated dilatation of skeletal muscle blood vessels Bronchoconstriction Reflex vasoconstriction due to fall in BP. Inhibition of β2-adrenoceptor- mediated dilatation of cutaneous (contraindicated in asthmatics) blood vessels. Dreams & insomnia Inhibition of β2-adrenoceptor-mediated relaxation of airway smooth muscle \ inhibits bronchodilation. Vascular Resistance Artery Arteriole - Poiseuille’s Law r @ rest = 1 mm R r @ rest = 0.05 mm 4 4 - Resistance determined by: = 1/(1 ) = 1 R = 1/(0.05 )= 160 000 o Vessel length (L) – constant r under active r under active tension = tension = 0.9 mm 0.045 mm o Blood viscosity (η) – relatively constant 4 4 o Vessel diameter (or radius, r) – can be easily changed! R = 1/(0.9 ) = R = 1/(0.045 ) = 1.524 243,865 - Resistance is inversely proportional to the fourth power of the ∆0.524 ∆83,865 vessel radius o even small changes in internal radius can markedly change resistance Determinants - R∝ 1/r4 o R is resistance o r is internal radius - Smaller arteries and arterioles have a greater capacity to affect TPR than larger arteries - Arterioles have higher resistance Arterial Tone Regulator - Balance between constrictors and dilators Passive Active - Pressure à intravascular pressure, extravascular pressure (tissue ) - Sympathetic nerveà vascular smooth structure - Architecture/structure of vessels - Circulating factors - Local vasoactive factors à layer that lines inside of cell  Hypertension = Elevated TPR - TPR elevated due to functional imbalance between constriction and relaxation, and structural changes - Excessive sympathetic activation o Can lead to structural changes o Augmented vasoconstriction can lead to remodelling of blood vessels - As blood pressure rises, blood vessels undergo structural changes (remodelling) - Increased pressure = increased stress Inward eutrophic Inward hypertrophic - Rearrangement of smooth muscle cells around a smaller lumen - Inward hypertrophy of medial layer - Thicker media, narrower lumen encroaches lumen - Greater wall thickness: lumen ratio - Thicker media, narrower lumen - Internal and out thickness has changed - Greater wall thickness: lumen ratio Consequences of vascular remodelling - Structural changes serve to decrease wall stress in the face of increased pressure but there are pathological consequences - Rest à resting vascular resistance is raised - @ 20% decrease in r à For a given constrictor stimulus, there is a greater increase in R and thus BP - Smaller radius = increased resistance = increase BP Lowering TPR - By inhibiting sympathetic activation of blood vessels - By inhibiting the renin-angiotensin system - By inhibiting signalling pathways involved in smooth muscle contraction Sympathetic Nerves - NA release on two pathways 1. Activates vascular a1 adrenoreceptor o Constriction of vascular smooth muscle = narrowing of lumen = increase TPR 2. Activates B1 receptors on kidney o Increases synthesis and release of renin = ANG2 production (potent constrictor) = binds to vascular AT1 receptors = causes vascular constriction = increases TPR α1-Adrenoceptor antagonists: Mechanism of action - Bind to and inhibit vascular α1-adrenoceptors à Inhibit endogenous noradrenaline- mediated vasoconstriction (inhibit sympathetic vascular tone) à Decrease TPR à Decrease BP - Class: α1-adrenoceptor antagonists - Exemplar: Prazosin (α1-selective antagonist) α1-adrenoceptor antagonists: side effects 1st dose hypotension Excessive fall in BP within 90 min of 1st dose. Approx 50% patients. Nasal congestion Inhibits α1-adrenoceptor-mediated constriction of arteries in nasal mucosa. Subsequent dilatation leads to nasal congestion. Postural hypotension Fall in BP upon standing. Particularly problematic in elderly due to age-related blunting of baroreceptor reflex. Initial reflex tachycardia Baroreceptor reflex  Postural hypotension - Unable to restore MAP – can lead to dizziness and fainting due to lack of cerebral perfusion Renin-Angiotensin-Aldosterone system àANG2 effects Vasoconstriction via vascular AT1 receptor Aldosterone secretion by binding to AT1 Increases reabsorption of water à increase blood receptors in adrenal cortex volume à increase BP Cardiovascular remodelling à long term Changes in levels of Renin or ACE can effect blood effects in heart and blood vessels pressure Renin secretion increased by - Sympathetic activation of B1 adrenoreceptors on granular cells - fall in blood pressure sensed by afferent arteriole Fall in sodium detected in the macula densa ACE inhibitors: mechanism ACE Bradykinin - Less angiotensin II formation - Inhibit the breakdown of Bradykinin into - Is sensory o Less AT1-R mediated inactive metabolites by inhibiting Kininase II nerve vasoconstriction thus lower (same as ACE) peptide TPR - So accumulation of Bradykinin leads to dry - Can cause cough vasodilation o Less AT1-R mediated - So patients that are on ACE inhibitors can have à decreases aldosterone secretion thus decreased BP because of accumulation of TPR à less NA+/H2O retention. Bradykinin decreases BP Lower preload Dihydropyridines and thus CO leads to e.g. nifedipine more effect on vascular, less effect on cardiac Benzothiazepines e.g. diltiazem equal effect on vascular and cardiac Phenylalkylamines e.g. verapamil more effect on cardiac, less effect on vascular lower BP - Inhibit bradykinin breakdown thus more vasodilatation, lower TPR and BP. - Long-term mechanism o May inhibit or decrease morbid influences of angiotensin II on cardiovascular structure, independently of blood pressure lowering effects o Prevent angiotensin II stimulation of vascular remodelling RAAS inhibitors: Adverse effects Adverse effect Details or mechanism of adverse effect 1st dose hypotension Excessive fall in BP within 90 min of 1st dose. Approx 50% patients. Hyperkalaemia Aldosterone excretes K+ into urine. If there is decreased AT1R activation, aldosterone secretion is decreased, (increase in K+) leading to K+ retention. Problematic for patients on K+-sparing diuretics or with renal impairment. Acute renal failure In patients with renal artery stenosis where renal function dependent on angiotensin II to maintain GFR. (reversible) Dry cough Due to increase in bradykinin. Thus, only observed with ACE inhibitors RAAS inhibitors: Advantages - Less effect on cardiovascular reflexes - Safe in asthmatics - Beneficial effects on cardiovascular remodelling  - Have advantages over other therapies: Calcium channel antagonists (calcium channel blockers) - Differences in gating, ion conductance, pharmacology and tissue distribution - Many different types of VOCC (L-, T-, P-, Q-, R-) - Ca2+ influx through L-type VOCC important determinant of vascular and cardiac contractility Calcium channel blockers: effects in other tissues Vascular smooth muscle contraction is dependent on free [Ca2+]intracellular à Inhibit L-type VOCC (prevents channel opening) à decrease Ca2+ entry in vascular smooth muscle so lower [Ca2+]intracellular à decrease vascular contractile tone à decrease TPR due to arteriolar (resistance vessel) dilatation à decrease BP Cardiac tissue - VOCC in plasma membrane important for controlling cardiac rate and rhythm - Ca2+ channel antagonists lower heart rate (and force of contraction) Veins - Minimal effect on veins - Does not affect preload à don’t effect venous tone Skeletal muscle Minimal effect on skeletal muscle (sarcoplasmic reticulum pools) Ca2+ channel antagonists: 3 classes - Different site specificities but all relax arterial smooth muscle to lower TPR Arterial smooth muscle: Nifedipine >> Verapamil > Diltiazem - Myocardium and nodal/conducting tissue: Verapamil > Diltiazem >> Nifedipine Calcium channel blockers: mechanism of action Initial reflex Fall in TPR and BP activates baroreceptor reflex tachycardia mostly with vascular-selective calcium channel blockers Flushing Dilatation of blood vessels in the face Dilatation of blood vessels in the meninges Headache Dilatation of blood vessels in the meninges MODULE 11: DRUGS TO TREAT OBESITY Medical complications of obesity Factors influencing development of obesity Classification BMI (kg/m2) Overall health risk Excess body fat leads to - Genetic factors Underweight 30 greater increase in - Non-alcohol fatty liver - Socioeconomic status health risk disease - Environmental factors Morbid >40 severe increase in - Osteoarthritis obese health risk Control of Appetite Short Term Long Term - Vagal afferents Peripheral  - Circulating factors that monitor injection and digestion and absorption to medulla Give info of how much fat is in body - Which then transfers information to hypothalamus which regulates hunger and food intake Include insulin and leptin - Hypothalamus regulates body weight by internal and external stimulus Leptin - Leptin secreted by white adipose tissues and circulates at levels in proportion to fat stores in body - Binds to hypothalamus and regulates synthesis of peptides that increase/decrease appetite and/or energy expenditure. - If leptin level is low= appetite stimulated, energy expenditure conserved - Allows body weight to be modulated and regulate energy balance - Inhibits food intake via CNS mechanism - Where there is high circulating leptin which leads to disruption in cellular signalling o Could be due to resistance of CNS access of leptin due to transporters o Could be due to leptin receptor signalling Peptides increase feeding (Orexigenic) Peptides decrease feeding (Anorexigenic) Peptides regulating food intake Brain - Body is redundant Neuropeptide Y a-melanocyte stimulating hormone - If we take medication to reduce Melanin concentrating hormone Urocortin Agouti-related peptide Corticotrophin releasing hormone actions of certain Orexin A and B Serotonin hormones/peptides, another Endocannabinoids Noradrenaline hormone/peptide will adapt and Peripheral compensate Ghrelin Leptin - So a single peptide drug can’t Insulin Cholecystokinin prevent/reduce obesity Gluc