Pharmacology Flashcards
What is the general sayings about the Parasympathetic and Sympathetic Nervous Systems?
Parasympathetic = Rest and Digest Sympathetic = Fight and Flight
Describe the balance of ANS in the liver, explaining it
Sympathetic dominant - need glucose in case of a fight or flight situation and sympathetic increases glycogenolysis and gluconeogenesis
Describe the balance of ANS in the lungs, explaining why
Parasympathetic dominant - causes partial constriction so further constriction and dilation can occur
Describe the balance of ANS in the eyes, explaining why
- causes partial constriction so further constriction and dilation can occur
Describe baroreceptor action at rest
- Baroreceptors are stimulatory to the parasympathetic nerve - They are inhibitory to the sympathetic nerve - At rest, the baroreceptor firing causes activation of the parasympathetic limb and inhibition of the sympathetic limb - PARASYMPATHETIC DOMINATES THE HEART AT REST
In terms of complexity, compare the PNS and the SNS
SNS = co-ordinated and divergent (1:20 pre vs post) - must be for fight or flight response PNS = discrete and localised (1:1 pre vs post)
State the pathway of the PNS
long pre-ganglionic fibre -> ACh -> short post-ganglionic fibre -> ACh -> effector organ
State the pathways of the SNS
short pre-ganglionic fibre -> ACh -> long post-ganglionic fibre -> NA -> effector organ short pre-ganglionic fibre -> ACh -> adrenal medulla -> A (80%) or NA (20%) -> effector organ short pre-ganglionic fibre -> ACh -> long post-ganglionic fibre -> ACh -> effector organ e.g. sweat gland
Name the small nervous system located in the gut and give a nickname due to it characteristic
Enteric Nervous System - ‘little brain’ - can act on its own accord
Describe Nicotinic receptors
- found in all autonomic ganglia - are ion channel linked receptors (ionotropic type 1) therefore when ACh binds it opens and allows Na/Ca influx - very, very fast
Describe Muscarinic receptors
- found in any tissue innervated by post-ganglionic parasympathetic fibres and also sweat glands (sympathetic so odd) - are Type 2-G-protein coupled much slower than nicotinic
At rest, what would happen to the lungs if parasympathetic effects are lost?
Bronchodilation
At rest, what would happen to sweat glands if parasympathetic effects are lost?
Reduced sweat production - however at rest no sweat should be produced
At rest, what would happen to the bowel if parasympathetic effects are lost?
Constipation
At rest, what would happen to urine frequency if parasympathetic effects are lost?
Urine frequency would reduce
At rest, what would happen to your ability to focus your eyes if parasympathetic effects are lost?
You would become long-sighted and unable to focus on nearby objects
State the sub-types of muscarinic receptors.
M1 - neural (forebrain - learning and memory)
M2 - cardiac (brain - inhibitory autoreceptors)
M3 - exocrine and smooth muscle (hypothalamus - food intake)
M4 - periphery
M5 - striatal dopamine release
What adrenoreceptors do sympathetic nerves use to control vasculature
alpha 1 - constricts beta 2 - dilates
Blockade of which of the following receptor sub-types would induce both an increased heart rate and a reduction in sweat production during exercise?
a. Muscarinic receptors
b. α1 adrenoceptors
c. α2 adrenoceptors
d. β1 adrenoceptors
e. β2 adrenoceptors
a. Muscarinic receptors
Describe the actions that occur at a Muscarinic receptor
- Acetyl CoA + Choline -> ACh + CoA 2. An action potential causes Ca2+ influx which triggers the release of ACh 3. ACh diffuses across the synapse and binds to muscarinic receptor on post-synaptic ganglion triggering an action potential 4. Acetylcholin-esterase digests ACh into Choline and Acetate which is absorb back into pre-synaptic cleft
Describe the actions that occur at a Adrenoreceptor
- Tryosine is converted to DOPA by Tryosine hydroxylase and the onto Dopamine by DOPA decarboxylase 2. Dopamine is packaged into vesicles and then converted to NA by Dopamine Beta Hydroxylase 3. NA is then released when the action potential comes along and triggers calcium influx 4. NA is NOT broken down in the synapse, it is either removed by: o Uptake 1 - back into the neuronal tissue o Uptake 2 - into extra-neuronal tissue 5. Once it has been taken up (by Uptake 1 or 2) it is broken down by: o Monoamine Oxidase (MAO) - mainly in neuronal tissue o Catechol-O-Methyl Transferase (COMT) - mainly in extraneuronal tissue
Blockade of which of the following targets would cause the most significant rise in synaptic noradrenaline concentrations?
a. Tyrosine hydroxylase
b. DOPA decarboxylase
c. Uptake 1 transport protein
d. Monoamine oxidase
e. Cathecol-O-methyl transferase
c. Uptake 1 Transport Protein - a and b are involved in synthesis of NA so would reduce NA in synapse - d and e will cause build up of NA in neuronal and extra-neuronal tissue so the gradient will reduce
Name the 4 drug target sites
- Receptors 2. Ion Channels 3. Transports systems 4. Enzymes NOTE: these are all proteins
Define Drug
A chemical substance that interacts with a biological system to produce a physiological effect
For what target site are the terms ‘agonist’ and ‘antagonist’ used
Receptors
Give 2 examples of drugs that target receptors
Acetylcholine - non-selective agonist of ACh receptors Atrophine - muscarinic cholinoceptor antagonist used as anaesthetic premediacation to dry up secretions
Give 2 examples of drugs that target ion channels
Local Anaesthetic - work by blocking voltage-gated NA+ channels in sensory axons so less action potential are propagated along the axons so perception of pain is reduced - usually ends in -caine (lidocaine) Calcium Channel Blockers - block voltage-sensitive Ca2+ channels - commonly used in cardiology for treatment of arrhythmias - usually end in -dipine (amlodipine)
Give 2 examples of drugs that target transport systems
Tricyclic antidepressants (TCAs) - prolongs the effect or noradrenaline which is below normal levels during clinical depression Cardiac Glycosides - these are cardiac stimulant drugs (e.g. digoxin) that interact with the Na+/K+ pump - if you give digoxin to a patient with heart failure, it will slow down their Na+/K+ pump and that has a knock on effect that increases the intracellular calcium concentration, therefore increasing the force of contraction
State the 3 types of drugs that target enzymes, naming examples for each one
Enzymes Inhibitors - e.g. anticholinesterases - neostigmine - increases the concentration of acetylcholine in the synapse by decreasing the rate of breakdown of acetylcholine - used to treat Myasthenia Gravis False Substrates - e.g. methyldopa (antihypertensive) - works by subverting the normal pathway that produces NA by taking the place of DOPA leading to the production of methyl noradrenaline is worse at causing vasoconstriction than NA so you get reduced TPR and hence reduced blood pressure this is a FALSE TRANSMITTER Prodrugs - e.g. chloral hydrate - must go to the liver to be metabolised into trichloroethanol before it is effective - used to treat insomnia
Describe an example of unwanted effects caused by drugs targeting enzymes
Paracetamol - if someone overdoses they saturate the liver’s microsomal enzymes so another set of enzymes (P450) starts breaking down the paracetamol and produces metabolites that cause damage to the liver and kidneys. Symptoms may not appear until 24-48 hours after the overdose, however at this point damage is irreversible
Explain the exceptions to the 4 target rule
Non-specific drugs produce responses due to their physicochemical properties - General Anaesthetics - dampen synaptic transmission - Antacids - reduces the acidity of the stomach contents - Osmotic Purgatives - stimulate the voiding of gut contents
Define Agonist
A molecule that binds to a receptor and stimulates it to generate a response (e.g. nicotine)
Define Antagonist
Substances that interact and bind to receptors but do not produce a response - they just get in the way of the agonist (e.g. atropine)
Define potency
How powerful the drug is, is dependent of affinity and efficacy
Define Affinity
How willingly a drug binds to its receptor
Define Efficacy
The ability of a drug to generate a response once it has bound to it receptor
Define Full Agonist
An agonist that generates the maximal response
Define Partial Agonist
An agonist that generates a less than maximal response
Define Selectivity
To have a preference for interacting with a particular receptor type (receptors are rarely specific - normally interact with a few other receptors)
Which of the following statements is most accurate?
a. a partial agonist will always have a higher efficacy than a full agonist
b. agonists have higher affinities than antagonists
c. full agonists that are selective for a given receptor will have the same efficacy
d. antagonists possess better efficacy than their respective agonists
e. competitive antagonists will preferentially occupy the relevant receptor in the presence of agonists
c. full agonists that are selective for a given receptor will have the same efficacy
A drug acting as an inhibitor at a particular drug target site prevents the removal of neurotransmitter from the synapse. Which type of drug target is this drug acting on? a. receptor b. voltage-sensitive ion channel c. receptor-linked ion channel d. transport protein e. non-proteinaceous target
d. transport protein
Name the 4 types of drug antagonisms.
- Receptor Blockade 2. Physiological Antagonism 3. Chemical Antagonism 4. Pharmacokinetic Antagonism
Explain how receptor blockade antagonists work
By simply binding to the receptor and therefore blocking the agonist from binding
What does Use Dependency refer to
Ion channel blockers - it means the more the tissue on which the drug is acting is being used (the more active they are) the more effective this type of blocker will be
Give an example which explain use dependency
- normal neurones fire at a relatively low rate so if you put local anaesthetic on them, there’ll be relatively low blockage. - nociceptor neurones fire rapidly and because the action potentials are being generated rapidly so the ion channels are open more often - local anaesthetics work by binding to the inside of the ion channels after they open - if the channels are opening more often then there is more chance that they’ll be blocked by LAs - this gives local anaesthetics a selective action on nociceptor neurones
What does Physiological Antagonism refer to
Two drugs acting at different receptors causing opposite effects in the same tissue
Give an example of a physiological antagonism
- NA causes vasoconstriction of vasculature by binding to adrenoceptors - co-administering histamine acts on different receptor to cause vasodilation
Explain what is meant by Chemical Antagonism
Interactions between drugs in solution
Give examples and one relevant point about chemical antagonists
- dimercaprol is a chelating agent which forms heavy metal complexes -> more rapidly excreted by the kidneys so, is useful for things like lead poisoning. Is very uncommonly used in practice
Explain what is meant by Pharmacokinetic Antagonism
- when one drug reduces the concentration of the other drug at the site of its action (absorption, excretion etc)
State a complication that must be looked for when using pharmacokinetic antagonisms
- repeatedly administer barbiturates increases the production of microsomal enzymes so, if we administer another drug (e.g. warfarin) that is metabolised by the enzymes then it is going to be metabolised quicker and its effect will be reduced
Name the 5 main causes of drug tolerance.
- Pharmacokinetic Factors
- Loss of Receptors
- Change in Receptors
- Exhaustion of Mediator Stores
- Physiological Adaptation
Explain how pharmacokinetic factors can lead to drug tolerance, include to examples where this occurs
Metabolism of the drug increases when repeatable given - barbiturates and alcohol
Explain how the loss of receptors occurs and therefore how it leads to drug tolerance, giving a receptor that is susceptible to this
Cells repeatable stimulated by an agonist will endocytose some receptors leaving fewer on the cell surface - this is called down regulation - beta adrenoceptors
Give a time when cells up regulate receptors
Denervation supersensitivity
State how change in receptors can cause increased drug tolerance
A conformational change in the receptor occurs so that the drug can no longer bind
Using an example explain how the exhaustion of mediator stores leads to drug tolerance
Amphetamines - amphetamine is a CNS stimulant that causes the blood-brain barrier from the blood and acts on noradrenergic neurones in the brain where it binds to uptake 1 protein and is taken into the central NA synthesis system causing a big increase in NA production - if you take a second dose the response is far less severe because NA stores have been exhausted
How does physiological adaptation lead to drug tolerance
- sort of like a homeostatic response -> the body is attempting the maintain a stable environment
What are the initial side effects of physiological adaptation causing drug tolerance
- tiredness and nausea
Describe Ionotropic Receptors (Type 1)
- are ion channels so are VERY, VERY FAST - 4 or 5 subunits including a transmembrane alpha helices section e.g. nicotinic acetylcholine receptor and GABA
Describe G-protein Coupled (Metabotropic) Receptors (Type 2)
- must link to G protein so a MUCH SLOWER than Type 1 - 1 subunit and 7 transmembrane domains (alpha helices) e.g. beta-1 adrenoceptors in the heart
Describe (Tryosine) Kinase-linked Receptors (Type 3)
- results in the phosphorylation of intracellular proteins so SLOWER than both Type 1 and 2 (usually minutes) - single protein with 1 transmembrane domain and 1 intracellular domain e.g. insulin receptor and growth factor receptors
Describe Intracellular Steroid Type Receptors (Type 4)
- activated by steroid and thyroid hormones so is the SLOWEST (can take hours) of all 4 receptors - drug must pass through the cell membrane (these receptors regulate DNA transcription via zinc fingers
A 4 year old girl is bitten by a Tiger Snake whilst holidaying in Australia. An anti-venom (harvested antibodies) is administered. Which form of antagonism is utilised by anti-venom? a. competitive receptor blockade b. physiological antagonism c. chemical antagonism d. pharmacokinetic antagonism e. irreversible receptor blockade
c. chemical antagonism
Tolerance to the euphoric effects of drugs of abuse (heroin or cocaine etc) can occur after repeated use. Which form of tolerance would not involve any change in the cells that mediate the euphoric effect? a. receptor desensitisation b. receptor down-regulation c. exhaustion of mediator stores d. receptor up-regulation e. increased metabolic degradation
e. increased metabolic degradation
Describe the journey of a drug through the body.
- administration
- Absorption
- Distribution
- Metabolism
- Excretion
- voided
REMEMBER: ADME
Name 7 types of drug administration
- intravenous 2. intraperitoneal 3. intramuscular 4. dermal 5. subcutaneous 6. inhalation 7. ingestion
State 2 approaches of drug administration, in terms of how much of the body is affected, that are used
- systemic (entire organism exposed to the drug) - local (restricted to one area)
What is the difference between enteral and parenteral administration routes?
- enteral = via the GI tract (usually orally)
- parenteral = avoids the GI tract (IV)
What are the two ways in which drug molecules move around the body?
- bulk flow transfer -> in the bloodstream in bulk to tissue - diffusion transfer -> molecule by molecule over short distances
Which drug transport mechanism occurs with IV and oral administration
- IV = bulk flow - oral = diffusion
Name some methods that drug use to cross barriers
- lipid soluble (non-polar solvents) - diffusing through aqueous pores in the lipid (if they are polar) - carrier molecules - pinocytosis
What is the pH of most drugs
5-9 (weak acids and bases)
Explain the clinical relevance of drugs being either weak acids or weak bases
- drugs exist in ionised and non-ionised form, forming a dynamic equilibrium of which the ratio depends on the pH of the environment and the pKa of the molecules - this alters the lipid solubility of the drug
Use aspirin as an example to explain the pH partition hypothesis
- aspirin a weak acid with a pKa of around 3.4 - when aspirin enters the stomach, which has a pH of less than the pKa of aspirin, it is more readily non-ionised -> aspirin exists mainly in the non-ionised form in the stomach meaning that it can readily diffuse across the lipid bilayer (as it is non-polar) - eventually the aspirin will make it into the small intestine, as the pH of the small intestine is greater than the pKa of aspirin, the aspirin becomes ionised -> now its more difficult to get through the membrane
What is the clinical importance of the pH partition hypothesis when prescribing aspirin
- for quick, short relief (e.g. headaches) give it as a soluble - for slow, long relief (e.g. arthritis) coat it in something that isn’t digested in the stomach
What is ion trapping
- once a drug goes through the liver and into the systemic circulation, the aspirin is in an aqueous environment so you find a proportion of aspirin in an ionised form - it is effectively TRAPPED
State some factors which influence drug distribution
- regional blood flow - extracellular binding (plasma protein binding) - capillary permeability - localisation in tissues
Explain how regional blood flow affects drug distribution
- tissues which are well perfused are likely exposed to a higher drug conc. - blood flow can change with activity such as skeletal muscle tissue
State capillary wall architecture and how it effects distribution?
- continuous -> normal vessels, not particularly permeable - fenestrated -> more permeable - discontinuous
Explain how tissue properties can alter drug distribution
- fat isn’t usually highly perfused - a very lipophilic environment -> drugs which are lipophilic tend to localise in fatty tissue (brain, testes etc)
Name the two major routes of drug excretion
- liver - kidneys
Name other none major routes in which drugs can be excreted
- exhalation/lungs - sweating/skin - GI secretions - saliva - milk - genital secretions
Explain drug excretion by the kidneys
- do most of xenobiotic excretion - the majority of the drug that is excreted will get into the urine via active secretion rather than ultrafiltration -> you can’t filter large, protein-bound drug complexes - glomerulus - drug-protein complexes are NOT filtered - proximal Tubule - active secretion of acids and bases - proximal and Distal Tubules - lipid soluble drugs are reabsorbed
Explain drug excretion by the liver
- biliary excretion allows the concentration of large molecular weight molecules (most antibiotics) that are very lipophilic - active transport systems also secrete drugs into bile - active transport systems are geared for the transport of bile acids and glucuronides into the bile - drugs hitch a ride on this because they are non-polar and have a large molecular weight
How can enterohepatic cycling cause problems
- a drug or metabolite gets excreted into the gut but then it can get reabsorbed and returned to the liver via the enterohepatic circulation -> leading to drug persistence
Why might treatment with IV sodium bicarbonate increase aspirin excretion?
- IV sodium bicarbonate increases urine pH which ionises the aspirin making it less lipid soluble - less aspirin is reabsorbed in the proximal and distal tubules so there is an increase in the rate of excretion of aspirin
Define bioavailability
- the proportion of the administered drug that is available within the body to exert its pharmacological effect
Define apparent volume of distribution
- the volume in which a drug appears to be distributed - an indicator of the pattern of distribution
Define biological half-life
- the time taken for the concentration of the drug (in the blood/plasma) to fall to half its original value
Define clearance
- the volume of plasma cleared of a drug per unit time
a. ionised drug
Define first-order kinetics
- the rate of elimination of a drug where the amount of drug decreases at a rate that is proportional to the concentration of drug remaining in the body
Define zero-order kinetics
- the rate of elimination of a drug where the amount is a constant per unit of time
In terms of kinetics are most drugs first-or zeroth order, state an example of the minority?
- first-order
- alcohol/ethanol is zero-order because alcohol dehydrogenase becomes saturated
Why is drug metabolsim required?
- drugs tend to be lipophilic -> must be metabolised to become more water soluble so hey can be excreted easily
- metabolism tends to eliminate or reduce the pharmacological and toxicological activity -> converts the drug into something more polar and, hence, soluble -> more easily be excreted by the kidneys
Define hepatic first pass metabolism
- metabolic conversion of the drug into something that is different before the drug enters the general circulation (the effect that occurs the very first time the drug passes through the liver)
Name some sites for drug metabolism, noting the major site
- LIVER = MAJOR
- gut
- kidneys
- brain
What is meant by low bioavailability
- when you administer the drug and it is absorbed and taken to the liver, you want it to be released in to the systemic circulation in a pharmacologically active form
- f the metabolism is extensive you may only release a small amount of the active drug into the systemic circulation, this is low bioavailability
Explain when low bioavailabitlity can be a problem and how it can be negotiated
- it releases only a small amount of the active form of the drug meaning that if the problem is in the systemic circulation the conc. may not be higher enough to have an effect
- this can be overcome by giving it intravenously
Name some pre-hepatic sites for first pass metabolism
- intestines
- stomach
- oesophagus and buccal cavity
What type of reactions occur in Phase I Reactions and what are the roles
- oxidation -> create new functional groups
- reduction -> create new functional groups
- hydrolysis -> unmasks functional groups
In what stage are prodrugs converted into their active form
- Phase I Reactions
What happens to the polarity of the drug after phase I reactions
- there is very little change in polarity, if it was lipophilic when it started it will still be pretty lipophilic etc
Where do phase I reactions occur
- primarily in the liver
Exactly what metabolises most of the xenobiotics
- the cytochrome P450 system in the liver
- in humans, the system is made up of 57 enzymes
Specifically, where in cells of the liver is the cytochrome P450 enzyme system located?
- endoplamsic reticulum
State a problem that affects the CYP450 system which occurs with some drugs, explaining why it is an issue. Also name a drug which this occurs with.
- some drugs can inhibit or induce the CYP450 system -> changing the ability of the system to handle certain drugs
- the oral contraceptive pill is a common example -> can loss contraceptive properties with certain other drug combinations
Give the equation for oxidation of a drug mediated by cytochrome P450
Describe the cyclic manner of work of cytochrom P450 oxidation
- the drug binds to the iron in the catalytic site and an electron is donated by NADPH
- this electron is picked up by the P450 complex and reductes Fe3+to Fe2+
- molecular oxygen binds to the catalytic site so P450 has Fe2+ and O2 bound
- Fe2+ loses an electron to become Fe3+ with oxygen picking up the extra electron and becoming unstable
- a second electron is donated by NADPH reducing Fe3+ to become Fe2+
- Fe2+ donates an electron to oxygen (becoming Fe3+) and making the oxygen very unstable, however the drug still hasn’t changed
- the drug is converted into its hydroxylated derivative and loses the reactive oxygen as water by picking up two protons
- drug is released and the P450 returns to the cycle with iron in its oxidised state (Fe3+) ready to undergo the next cycle
Describe the structure of cytochrome P450
- at the centre of P450’s catalytic site there is catalytic iron in its oxidised state (Fe3+)
- all P450 enzymes have a porphyrin ring and iron (Fe3+) at its active site
What kind of reaction do oxidations usually start with?
- hydroxylation catalysed by CYP450
- 9f ever unsure on an enzyme starting an oxidation guess CYP450
What is pentabarbitone?
- a narcotic, will put you to sleep
How many isoforms are found after metabolsim by CYP450
- depends on the drug, can be hundreds
Give an example of a prodrug which is catalysed into active form by CYP450
- acetanlide becomes paracetamol by oxidation of C4 in the benzene ring
Why is acetanlide (paracetamol prdodrug) not for sale?
- anlide is toxic to blood cells
What happens if you oxidate a carbon in a carbon chain?
- forms an alcohol group
What happens if you oxidate a carbon in a benzene ring?
- you form an alcohol group
What happens if you oxidate a carbon attached to a nitrogen?
- N-demethylation -> the carbon group that was attached to the nitrogen disassociates leaving a signle hydrogen behind if it was a tertiary amine, the remnants of the carbon group bind with an oxygen to forming a aldehyde, commonly formaldehyde (HCHO)
What happens if you oxidate a carbon attached to a oxygen?
- O-demethylation -> an alcohol group forms in place of the carbon group when its a teritary structure and the remnants of the carbon group form an aldehyde or a ketone, formaldehyde (HCHO)
Why does codeine have such contrasting effects on people?
- it is metabolised into morphine by the CYP450 complex causing all the relative effects, specifically as a painkiller
- however, some people are a lot better at doing this metabolism compared to others hence to disparity
Name two alternative oxidation of nitrogen than N-demethylation, stating the enzymes that carries it out in humans.
- N-oxidation -> requires the formation of a dative bond, flavin containing monoxygenase
- alcohol oxidation by alcohol dehydrogenase
What is the clinical relevance of flavin containing monoxygenase?
- flavin containing monoxygenase defiiciency (aka fish odour syndrome)
- humans generate trimethylamine in their GI tract (product of protein metabolsim -> rimethylamine smells terrible
- in the liver, flavin containing monooxygenase converts trimethylamine into trimethylamine N-oxide which is odourless and polar so it can be readily excreted in the urine
- a small subset of the population has defective flavin containing monooxygenase so they can’t metabolise trimethylamine and must sweat and breathe it out
What are the consequences of fish odour syndrome?
- strange behavouirs
- smoke or wear lots of perfume to mask the smell
- despression -> very high suicide rate
Where are most reductases found?
- in the gut as they are bacterial enzymes colonising the gut
In phase I reactions are oxidations or reductions more common?
- oxidations are far more common, hydrolysis is even less less common than reduction
In phase I reactions, when does hydrolysis occur?
- when there is an ester or an amide
What enzymes carry out hydrolysis
- esterases = hydrolysis of an ester
- amidase = hydrolysis of an amide
True or false, metabolism of prodrugs activates their pharmacological activity.
- true
True or false, xenobiotic metabolism only occurs in the liver
- false
True or false, hydrolysis is a Phase 1 reaction
- true
Does cytochrome P450 uses NADH+ as cofactor ?
- can do but more readily uses NADPH
True or false, cytochrome P450 contains Cu2+ at its active site
- false
Name the types of reactions that occur in phase II metabolsim
- glucuronidation (most common)
- methylation
- sulphation
- acetylation
- aminoacid conjugation
- gluathione
State the rule about enzymes carrying out phase II reaction.
- the name of the reaction and add transferase to the end of it to find the enzyme name
What are the results of phase II drug metabolsim
- the conjugate that is formed is almost always inactive (morphine is an exception)
- less lipid soluble
- more polar
- easier to excrete
What is the conjugating agent for glucuronidation?
- UDPGA
What occurs in a glucuronidation reaction?
- xenobiotic is catalysed by glucuronyl transferase to form the glucuronide derivative of the xenobiotic
- this derivate is polar so can be removed, usuallt though bile due to large molecular weight
Give an example of a drug that goes through glucuronidation.
- ibruprofen
What kind of drugs go through acetulation?
- drugs with a amino group
- acetylation occurs to an electron rich atom
Explain acetylation reaction as part of phase II drug metabolsim
- produce acetylated derivative of the drug and CoA which then goes into intermediary metabolism
- use acetyl CoA as the high energy intermediate
What happens in methylation as part of phase II drug metabolsim?
- a methyl group is donated to an atom rich atom (N, S or O etc) via the high energy intermediate S-adenosyl methionine using the enzyme methyl transferase
- methylation DECREASES polarity
- in ZH, Z can be N, O or S
As methylation makes molecules less polar and therefore hard to excrete why does it occur?
- for endogenous molecules such as noradrenaline -> allows NA to convert into adrenaline
- only occurs to drugs such as amphetamines which have a similar structure to NA
Which phase II drug metabolism reaction occurs with paracetamol?
- sulphation
What happens in the phase II drug metabolsim reaction sulphation?
- xenobiotic is taken with PAPS which is the sulfate donor and gets sulfated to produce the sulfuric acid derivative of the molecule - the derivative is very polar and water soluble
the reaction is catalysed by sulfotransferases
What is glutathione?
- a tripeptide molecule kept in large quantities in the liver and kidneys that protects the bodies from toxic metabolites such as electrophiles
Which part of a molecule of glutathione is important?
- cysteine because it has the thiol part
True or false, metabolism of lipophilic chemicals facilitates their excretion?
- true
True or false, metabolism of drugs prior to entering the systemic circulation is known as “first pass metabolism”?
- true
True or false, phase 2 metabolism includes reduction and acetylation.
- false, reduction is phase I
True or false, phase II metabolism generally increases the polarity of drugs.
- true, to aid excretion
True or false, conjugation of drugs with glutathione is the most common Phase II route of metabolism.
- false, glucuronidation is
What is the importance of drug metabolsim?
- biological half-life of a drug is reduced
- duration of exposure is reduced
- accumulation of the drug in the body is avoided
- potency/duration of the biological activity of the chemical can be altered
- pharmacology/toxicology of the drug is governed by its metabolism
What are cholinomimetic drugs?
- drugs that mimic the action of acteylcholine in the body
- therefore they are parasympathetic drugs
What are the cholinergic target sites/systems?
- eyes
- salivary glands
- sweat glands
- lungs
- heart
- gut
- bladder
- vasculature
What are the 3 main muscarinic effects on the eye?
- contraction of the ciliary muscle - accommodates for near vision
- contraction of sphincter pupillae (circular muscle of the iris) - this constricts the pupil (miosis) and increases drainage of intraocular fluid
- lacrimation (tears)
What is glaucoma?
- an increase in intraocular pressure -> can cause damage to the optic nerves and retina and can ultimately lead to blindness
Explain the mechanism of angle-closure glaucoma
- aqueous humour is generated by the capillaries of the ciliary body, it flows into the anterior chamber of the eye
- its role is to supply oxygen and nutrients to the lens and cornea because they don’t have a blood supply
- the aqueous humour diffuses forwards across the lens, then across the cornea and it drains through the canals of Schlemm back into the venous system
- in angle-closure glaucoma, the angle between the cornea and the iris becomes narrowed => reduces the drainage of intraocular fluid via the canals of Schlemm
Describe the treatment for angle-closure glaucoma
- muscarinic agonist -> causes contraction of the iris opening up the angle and increasing the drainage of intraocular fluid through the canals of Schlemm (has no effect on fluid production)
Explain the muscarinic effects on the heart.
What are the muscarinic effects on the vasculature?
- most blood vessels do NOT have parasympathetic innervation
- acetylcholine acts on vascular endothelial cells to stimulate NO release via M3 receptors -> NO induces vascular smooth muscle relaxation -> decrease in TPR
What are the overall muscarinic effects on the CVS?
- decrease heart rate
- decreased cardiac output (due to decreased atrial contraction)
- vasodilation (via stimulation of NO release)
- all of these can lead to a sharp DROP BLOOD PRESSURE
State the muscarinic effects on non-vascular smooth muscle
- non-vascular smooth muscle that has parasympathetic innervation responds in the opposite way to vascular smooth muscle - it contracts
· Lungs - bronchoconstriction
· Gut - increased peristalsis/motility
· Bladder - increased bladder emptying
What are the muscarinic effects on exocrine glands?
· Salivation
· Increased bronchial secretions
· Increased GI secretions (including gastric HCl production)
· Increased sweating (SNS-mediated)
Summarise the muscarinic effect on the body
· Decreased heart rate
· Decreased blood pressure
· Increased sweating
· Difficulty breathing
· Bladder emptying
· GI pain
· Increased salivation and tears
Name the two types of cholinomimetic drugs
- Directly Acting
- Indirectly Acting
State what directly acting cholinomimetics are
- muscarinic receptor agonists
Name the two types of muscarninic receptor agonists, with an example for each
o Choline esters (bethanechol)
o Alkaloids (pilocarpine)
Describe the structures of bethanechol and pilocarpine
- both very similar to acetylcholine
State some properties of pilocarpine
- non selective -> stimulates all muscarinic receptors
- good lipid solubility
- half-life of 3-4 hours
Give a disease which is treated with pilocarpine
- glaucomao -> constricts sphincter pupillae and opens up the canals of Schlemm to increase the drainage of intraocular fluid
State the side effects of pilocarpine
- general effects of parasympathetic discharge:
o Blurred vision
o Sweating
o GI disturbance and pain
o Nausea
o Bradycardia
o Hypotension
o Respiratory distress
How are the side effects of pilocarpine avoided?
- can be given successfully as an eye drop -> therefore a very low conc. reaches the systemic circulation
State some properties of bethanechol
· M3 receptor selective agonist, still has an effect on all muscarinic receptors
· It is resistant to degradation by acetylcholinesterase
· It is orally active and has limited access to the brain
· Half-life = 3-4 hours
Why is bethanechol administrated?
- mainly used to assist bladder emptying and enhance gastric motility
What are the symptoms of bethanechol?
o Sweating
o GI disturbance and pain
o Respiratory distress
o Impaired vision
o Nausea
o Bradycardia
o Hypotension
How do indirectly acting cholinomimetic drugs work?
- inhibit acetylcholinesterase -> decrease acetylcholine breakdown -> increase the amount of acetylcholine in the synapse -> increase the effect of normal parasympathetic nerve stimulation
State the categories of indirecty acting cholinomimetic drugs, with examples
- Reversible Anticholinesterases (PHYSOSTIGMINE, Neostigmine, Donepezil)
- Irreversible Anticholinesterases (ECOTHIOPATE, Dyflos, Sarin)
Name the two types of cholinesterass
o Acetylcholinesterase (true or specific cholinesterase)
o Butyrylcholinesterase (pseudocholinesterase)
Describe acetylcholinesterase
o Found in ALL cholinergic synapses (peripheral and central)
o Very rapid action (> 10 000 reactions per second)
o It is highly selective for acetylcholine
Describe butyrylcholinesterase
o Found in plasma and in most tissues but NOT in cholinergic synapses
o Broad substrate specificity - hydrolyses other esters e.g. suxamethonium
o It is the principal reason for low plasma acetylcholine
o Shows genetic variation so different people show different reactions to suxamethonium
What are the effects of cholinesterases at a low dose
o Enhanced muscarinic activity
What are the effects of cholinesterases at a moderate dose?
o Further enhancement of muscarinic activity
o Increased transmission at ALL autonomic ganglia (nAChRs)
· This is because the anticholinesterase increases the acetylcholine concentration at ALL cholinergic synapses, muscarinic and nicotinic
What are the effects of cholinesterases at a high dose?
o Becomes toxic
o Depolarising block at autonomic ganglia and neuromuscular junction
o The nicotinic receptors get overstimulated so they shut down
Describe the general action of Reversible Anticholinesterase Drugs
· They compete with acetylcholine for the active site on acetylcholinesterase
· These drugs donate a carbamyl group to the enzyme, blocking the active site and preventing acetylcholine from binding
· Carbamyl groups are removed by slow hydrolysis (this takes minutes rather than miliseconds)
· This increases the duration of acetylcholine activity in the synapse
Where does physostigmine act?
- postganglionic parasympathetic synapses
What is the half-life of physostigmine
- 30 minutes
What is physostigmine used to treat?
o Glaucoma - increases drainage of intraocular fluid
o Atropine poisoning (common in children who eat atropa belladonna berries)
· Atropine is a competitive muscarinic antagonist
· Physostigmine increases the concentration of acetylcholine at the synapse so that the acetylcholine can outcompete the atropine until the atropine is cleared
Describe the general mechanism of irreversible anticholinemimetic drugs
· Irreversible anticholinesterase drugs are ORGANOPHOSPHATE compounds
· Rapidly react with the enzyme active site, leaving a large blocking group
· The blocking group is stable and resistant to hydrolysis so recovery requires the production of new enzymes (this takes days/weeks)
What are the break down of uses of Irreversible Anticholinesterase Drugs?
· Ecothiopate is the only one in clinical use but the others are used as insecticides and nerve gas
What are the side effects of physostigmine
o Side-effects are that of parasympathetic discharge:
· Sweating
· Blurred vision
· GI disturbance and pain
· Bradycardia
· Hypotension
· Respiratory difficulty
What are the side effects of ecothiopate?
o Side-effects are that of parasympathetic discharge:
· Sweating
· Blurred vision
· GI disturbance and pain
· Bradycardia
· Hypotension
· Respiratory difficulty
What is the mechanism of ecothiopate?
o Potent inhibitor of acetylcholinesterase
o Slow reactivation of the enzyme by hydrolysis takes several days
Name a disease which ecotiopate is used to treat?
o eye drops to treatment glaucoma -> increases the drainage of intraocular fluid and has a prolonged duration of action
What are the effects of Anticholinesterase Drugs on the CNS?
· Non-polar anticholinesterases (physostigmine, nerve agents) can cross the BBB
· LOW doses -> CNS excitation with the possibility of convulsions
· HIGH doses -> Unconsciousness, respiratory depression and death
What happens as consequences of organophosphate poisoning?
- severely toxic
- increase in muscarinic activity –> CNS excitation –> depolarising NM block
What is the treatment of organophosphate poisoning
o INTRAVENOUS ATROPINE
o Patient is put on a respirator because of the respiratory depression
o If found in the first few hours the patient can be given Pralidoxime (IV) - this unblocks the enzymes
B
B
Which of the following drugs has efficacy for the muscarinic acetylcholine receptor?
a. Acetylcholine
b. Atropine
c. Acetyl-cholinesterase
d. Adrenaline
e. Acetate
a. Acetylcholine
What is the other name for nicotinic receptor antagonists?
- ganglion blocking drugs
State the two ways in which nicotinic receptor antagonists function
- blocking the receptor
- blocking the ion channel itself
Do nicotinic receptor antagonists affect the parasympathetic or the sympathetic nervous systems?
- effect the systme which is more dominant within the tissue at that time due to use dependency
Which of the following effects would be observed, at rest, after treatment with a ganglion blocking drug?
a. Increased heart rate
b. Pupil constriction
c. Bronchodilation
d. Detrusor contraction
e. Increased gut motility
a and b, both sympathetic effects as the parasymapthetic is blocked
Why do nicotinic receptor antagonists cause hypotension?
- both vasocnstriction and renin production are inhibited leading to less TPR and water reabsorption
Apart from cauing hypotension, name some other side effects of nicotinic receptor antagonists
- smooth muscle: pupil dilation, decreased GI tone, bladder dysfunction and bronchodilation
- exocrine secretions: decreased secretions
What was the clinical use of hexamethonium?
- 1st anti-hypertensive
- was to general so had horrible side effects so has be superseded by more selective agents
When is trimetaphen used?
- only in surgery when controlled hypotension is required -> because it is very potent but the effcts are very short lived so patient will find after the effects of the aneasthetic have worn off
What other agents are often receptor blockade antagonists?
- toxins and venoms -> often bind irreversible unlike the drugs and prevent channel opening which causes total loss of autonomic function
What is the effect of atropine on the CNS?
Normal dose - little effect
Toxic dose - mild restlessness through to severe agitation
What is the effect of atropine on the CNS?
Normal dose - sedation, amnesia
Toxic dose - CNS depression or paradoxical CNS excitation (associated with pain)
What is the action of tropicamide?
- is a muscarinic receptor antagonist which acts on receptors within the iris of the eye to cause pupil dilation
Name a use for tropicamide
- used in eye exams in order to examine the retina
Explain why muscarinic receptor antagonists are used a anaesthetic pre-medications
- causes airways dilation
- dry the throat by decreasing saliva produciton (reduces the risk of aspiration)
- slightly increases the heart rate
- if correctly chosen (hyoscine) has a sedative effect
What is motion sickness?
- sensory information from the ear (labyrinth) and the eye are both coming in and meeting at the memory centre, the hippocampus
- if there is a mismatch in the two bit of information the hippocampus triggers the vomitting centre (Area postrema - CVO) and nausea begins
How do muscarinic receptor antagonists, such as hyoscine, work a treatment for motion sickness?
- reduce the flow of information from the labyrinth to the brain -> although there is still mismatch the response doesn’t occur so neither does nausea
What is Parkinson’s Disease?
- dopaminergic neurones from the substantia nigra releases dopamine into the striatum which binds to D1 receptors, activating these allows the fine control of movement
- M4 receptor has an inhibitory effect on this process
- in Parkinson’s you lose dopaminergic neurones so there is less stimualtion and therefore a loss of fine control
How can muscarinic receptors antagonists be used in treating Parkinson’s Disease?
- as 60-70% of dopaminergic neurones have been lost the inhibitory effect of M4 receptors are no longer wanted so the antagonists can be used to take out the M4 receptors and the inhibitory effect
- by no means a first line treatment
How does ipratropium bromide work to treat asthma and COPD?
- is a muscarinic recepotr which means it blocks the parasympathetic induced bronchoconstriction
Why is ipratropim bromide used to treat asthma and COPD instead of atropine?
- ipratropim bromide has a large quaternary amine structure which means when given as an aerosol it doesnt cross the lipid membrane of the lungs to exit because of its positive charge -> remains localised
How can muscarinic receptor antagonists be used to treat irritable bowel syndrome
- knocking out parasympathetic effects within the gut reduces smooth muscle contraction, gut motility and secretions to relieve some of the symptoms
Name the unwanted side effects of muscarinic receptor antagonists
- hot as hell -> decreased sweating interferes with thermoregulation
- dry as a bone -> reduced secretions
- blind as a bat -> cyclopegia
- mad as a hatter -> CNS disturbance
Which of the following drugs would you administer to treat an atropine overdose?
a. bethanechol
b. ecothiopate
c. hyoscine
d. physostigmine
e. pralidoxime
d- physostigmine - reversibly blocks anti-cholinesterase so acetyl choline can outcompete the atropine until it is metabolised out of the system
State the role of different adrenoceptors.
- alpha 1 - vasoconstriction, relaxation of GIT
- alpha 2 - inhibition of transmitter release, contraction of vascular smooth muscle, CNS actions
- beta 1 - increased cardiac rate and force, relaxation of GIT, renin release from kidney
- beta 2 - bronchodilation, vasodilation, relaxation of visceral smooth muscle, hepatic glycogenolysis
- beta 3 - lipolysis
What are the affects of stimulating A1 adrenoceptors?
PLC —> IP3 and DAG
What are the affects of stimulating A2 adrenoceptors?
decreased cAMP
What are the affects of stimulating B2 adrenoceptors?
increased cAMP
What do cholinoceptor antagonists do?
- cause the loss of sympathetic functions -> enhance parasymathetic function
What do SNS agonist cause?
- cause the loss of parasympathetic functions -> enhance symathetic function
Describe the selectivity of SNS agonists
- ALL adrenoceptors can be activated by NA and A
- NORADRENALINE is more selective for ALPHA receptors
- ADRENALINE is more selective for BETA receptors
Name 5 directly acting SNS agonists
- adrenaline
- phenylephrine
- clonidine
- dobutamine
- salbutamol
Which is adrenoceptor is adreanline selective too?
- non-selective
Which receptor is phenylephine selective too?
- alpha 1
Which receptor is cloninide selective too?
- alpha 2
Which receptor is dobutamine selective too?
- beta 1
Which receptor is salbutamol selective too?
- beta 2
What does selectivity depend on?
o CONCENTRATION - at low concentrations these drugs will be relatively selective but if you increase its concentration, the chance of binding to other receptors increases
Why is adrenaline used in the treatment of anaphylaxis instead of noradrenaline?
o the key thing to consider here is BREATHING -> the patient breathing must be breathing, even if you have a functioning cardiovascular system, you will have nothing to pump around
o adrenaline acts MORE ON BETA RECEPTORS than noradrenaline and this stimulates bronchodilation and relaxation of the throat muscles
o will also stimulate the heart so you get tachycardia, this will support the blood pressure
o acts on alpha receptors and causes vasoconstriction
o via the beta 2 receptors, slows down the release of histamine from the mast cells
What are the symptoms of hypersensitivity?
o endothelial cells within the membranes of the blood vessels move apart so you get a lot of fluid moving into the tissues -> leads to a fall in circulating fluid volume -> fall in bp -> ANAPHYLACTIC SHOCK and collapse of the circulatory system that leads to unconsciousness
o contraction of bronchial smooth muscle and constriction of the muscles around the throat -> causing respiratory distress
o constriction of smooth muscle in the GI tract causing vomiting and diarrhoea
In what instances would you use adrenaline for treatment of pulmonary disorders?
- obstructive conditions -> asthma emergency or acute bronchospasm
- selective beta-2 agonists are preferable
What is adrenaline used to treat?
- allergic reactions and anaphylactic shock
- pulmonary obstructive conditions -> astham and acute bronchospasm
- glaucoma
cardiogenic shock
- spinal anaesthesia
- local anaesthesia
In what pulmonary event would adrenaline be given as a treatment?
- cardiogenic shock - the sudden inability of the heart to pump sufficient oxygen-rich blood (occurs in MI or cardiac arrest)
o beta 1 receptor is the main target -> positive inotropic action
When is adrenaline given in which the main target site is alpha 1?
- spinal and local anaestheisa
Why is adreanline given with spinal anaesthsia
o anaesthetising through the spine takes away the sympathetic output to the peripheral resistance vessels
o meaning you get relaxation of peripheral resistance vessels so the patient won’t be able to maintain their blood pressure
- giving a little bit of adrenaline at the same time you can constrict the blood vessels so you can maintain the blood pressure
Why is adrenaline given with local anaesthesia?
o adrenaline causes constriction of the blood vessels in the local area thus preventing the clearance of the anaesthetic from the area
o if the anaesthetic was given without adrenaline then it will wear off faster
What are the side effects of adrenaline?
- Secretions - reduced and thick
- CNS - minimal
- CVS Effects:
o Tachycardia, palpitations, arrhythmias
o Cold extremities, hypertension
o OVERDOSE - cerebral haemorrhage, pulmonary embolism
- GIT - minimal
- Skeletal muscle - tremor
Out of the unwanted effects of adrenaline a important to monitor?
- CVS
Describe the selectivity of phenylephrine
- very selective to alpha 1
- minorly selective to alpha 2
- no really selectivity to beta 1 or 2
Phenylephrine is structually similar to adrenaline, so why is it ever used?
- more resistant to COMT degradation so stays in the system for a bit longer
What are the clinical uses of phenylephrine?
o Vasoconstriction
o Mydriatic (dilates pupil)
o Nasal Decongestant -> vasoconstriction in nasal sinus -> less fluid leakage -> less blockage
What is aside effect of phenylephrine which must be watched out for?
- hypertension due to vasoconstriction of vessels
Describe the selectivity of clonidine
- very selective to alpha 2
- moderately selective to alpha 1
- no really selectivity to beta 1 or 2
Describe the mechanism of action of clonidine
- clonidine will stimulate the pre-synaptic alpha 2 receptors -> has a negative effect on the synthesis and release of noradrenaline
- less noradrenaline -> less stimulation at the effector organ -> less vasoconstriction -> fall in TPR and bp
What are the clinical uses of clonidine
- hypertension
- migraines
- glaucoma
Excluding blood vessels, where else are alpha 2 receptors found and explain whether clonidine acts on them
- the brain
- clonidine has a central action on the brainstem
o within the brainstem it works on the baroreceptors in this pathway and reduces the sympathetic drive coming out of the brain
o the reduction in sympathetic activity -> reduced TPR and noradrenaline release at the nerve terminal thus reducing TPR further
Describe the selectivity of isoprenaline
- selective for beta 1 and beta 2
- no selectivity for alpha 1 or alpha 2
Why is isoprenaline clinically relevant seeing that it is structually similar to adrenaline?
- less susceptible to uptake 1 and MAO breakdown -> much longer plasma half-life (2 hours)
What are the clinical uses of isoprenaline?
- Cardiogenic Shock
- Acute Heart Failure
- Myocardial Infarction
What is the issue with using isoprenaline to treat cardiac problems?
- you are trying to restore cardiac output
- beta-2 receptors in vascular smooth muscle which causes dilation of the blood vessels in the muscles -> pooling of blood within the muscles -> decreased venous return -> via baroreceptors, you get REFLEX TACHYCARDIA
- the caused effect is opposite to what you are trying to achieve
Describe the selectivity of dobutamine
- selective to beta 1
- some selectivity to beta 2
- very light selectvitiy to alpha 1 or alpha 2
What are the clinical uses of dobutamine
o Cardiogenic Shock
o Acute Heart Failure
o Myocardial Infarction
Why is dobutamine used for cardiac disorders instead of isprenaline
- lacks reflex tachycardia because it is selective for beta 1
- short plasma half-life (2 minutes) so gives a lot of control
How is botutamine administrated?
- IV infusion
Describe the selectivity of salbutamol
- beta 2 selectivity
- some selectivity to beta 1
- not selective for alpha 1 or alpha 2
What are the clinical uses of salbutamol?
- asthma
- threatened premature labour
How does salbutamol work as a treatment for asthma?
· Beta-2 mediated relaxation of bronchial smooth muscle
· Inhibition of release of bronchoconstrictor substances from mast cells
· The inhaler gives relatively localised effects on the lungs
· You can also give salbutamol as tablets to control asthma - for chronic asthma conditions in hospital
How does salbutamol work as a treatment for threatening premature labour
- beta-2 mediated relaxation of uterine smooth muscle -> prevents abortion of a foetus
What are the side effects of salbutamol?
o Reflex tachycardia
o Tremor
o Blood sugar dysregulation
Name two indirectly acting SNS agonists?
- cocaine
- tyramine -> the cheese reaction
WHat is the mechanism of cocaine?
- Uptake 1 blocker for dopamine and noradrenaline
- gives a high by causing an increase of dopamine in the synapse
What are the actions/side effects of cocaine on the CNS?
- low doses: euphoria, excitement, increased motor activity
- high doses: activation of chemotactic trigger zones -> vomiting, CNS depression, respiratory failure, convulsions and death
What are the actions/side effects of cocaine on the CVS?
- low doses: tachycardia, vasoconstriction and raised blood pressure
- high doses: ventricular fibrillation and cardiac arrest
What is the mechanism of tyramine?
- a dietary amino acid - commonly found in cheese (hence being dubbed the cheese reaction) , red wine and soy sauce
- it acts as a false neurotransmitter -> isn’t a problem in normal people (except from stimulating dreams)
- tyramine acts as a weak agonist at the effector organ at which the noradrenaline will be stimulating the receptors while aslo piggy backing on the uptake systems and competing with NA for the uptake 1 site
- this means that you get more NA hanging around in the synapse before displacing NA from the vesicles
- normally, this displaced NA will be broken down by MAO but the tyramine competes with the NA for the binding site on the MAO
- this means that there is less break down of the NA that has been displaced from the vesicles -> builds up and leaks out into the synaptic cleft
What kind of people have to be careful of tyramine?
- people on MAO inhibitors (e.g. to control depression)
What is the problem with the combination of tyramine and MAO inhibitors?
- patients on MAO inhibitors have their MAO capabilities completely blocked
- this inhibits the breakdown of NA -> accumulation of NA in the synapse that leads to a hypertensive crisis
- patients on MAO inhibitors are told to avoid cheese, red wine and soy sauce and anything else that has high concentrations of tyramine
What do alpha 1 adrenoceptors cause?
- vasoconstriction, relaxation of the GIT
What do alpha 2 adrenoceptors cause?
- inhibit transmitter release
- contraction of vascular smooth muscle
- CNS actions
What do beta 1 adrenoceptors cause?
- increase cardiac force and rate
- relaxation of GIT
- renin release from the kidneys
What do beta 2 adrenoceptors cause?
- bronchodilation
- vasodilation
- relaxation of visceral smooth muscle
- hepatic glycogenolysis
What do beta 3 adrenoceptors cause?
- lipolysis
What is different about alpha 2 receptors compared to other adrenoceptors?
- appear on neurones and pre-synapses
- act as a negative feedback regulator to prevent prolonged action
What receptors are targeted by carvedilol?
- alpha 1 and beta 1
What receptors are targeted by labetalol?
- alpha 1 and beta 1
What receptors are targeted by prazosin?
- alpha 1
What receptors are targeted by propanolol?
- beta 1 and 2
What receptors are targeted by atenolol?
- beta 1
What diseases provide the main clinical uses of SNS antagonists and false transmitters?
· Hypertension
· Cardiac Arrhythmias
· Angina
· Glaucoma
What is the major controller of blood pressure?
- renin release -> angiotensin II and aldosterone
Name the targets for anti-hypertensive treatments.
· Sympathetic nerves that release the vasoconstrictor noradrenaline
· Kidneys - regulates blood volume and vasoconstriction
· Heart
· Arterioles determine peripheral resistance (alpha 1 mediated vasoconstriction)
· CNS - determines blood pressure set point and regulates some systems involved in blood pressure control and the autonomic nervous system
Why were cardioselective beta antagonists made?
- most of the POSITIVE effects are from Beta 1 blockade and most of the NEGATIVE effects are from Beta 2 blockade
What are the target sites for beta blcokers?
o act as anti-hypertensives mainly because of their antagonism of beta 1 adrenoceptors
- in the heart to reduce heart rate and cardiac output but this effect disappears with chronic treatment - the heart resets itself
- KIDNEYS to REDUCE RENIN PRODUCTION - PRIMARY EFFECT
o beta 2 antagonism may be important, but it is not clear to what extent due to decreased noradrenaline
o act in the CNS, if lipid soluble enough, to reduce sympathetic tone (beta 1 and 2)
Back
Name some side effects of beta blockers?
- bronchoconstriction
- cardiac failure -> caused by slowing the heart too much
- hypoglycemia
- fatigue -> due to reduced cardiac output and reduced muscle perfusion
- cold extremities -> loss of beta receptor mediated vasodilation of cutaneous vessels
- bad dreams
Name 4 disease that if a patient is suffering from should not be given no-selective beta blockers?
o ASTHMA
o COPD
o CARDIAC FAILURE
o DIABETES -> masks symptoms of hypoglycemia - don’t even know they are haing an attack
- all due to beta 2 blockade
What is the mechanism of action of Nebivolol?
- binds to beta 1 receptors
- causes NO release
How does Sotalol function?
- binds to beta 1 and 2
- inhibits K+ channels
What is the selectivity of Propanolol?
- non-selective beta antagonist
What are the effects of Propanolol?
- at rest, propranolol causes very little change in heart rate, cardiac output or arterial pressure
- in exercise that you see the effects of propranolol on these variables
Does Propanolol have any negative effects?
- all the typical adverse effects, caused by beta 2 antagonism
What is the selectivity of Atenolol?
- historically called cardioselective beta blockers -> are selective for beta-1
How does Antenolol bring about its effects?
- mainly antagonises the effects of noradrenaline in the heart
- also affect any tissue with beta 1 receptor e.g. kidneys
What does Atendolol’s selectivity depend on?
- its concentration -> therefore it isnt safe to give to asthmatic patients despite having less of an effect on the airways
When might Sotalol be the best anti-hypertensive?
- when the hypertension is associated with an arrhythmia
What are the advantages of Atanolol over Propanolol?
- Atanolol is beta 1 specific so doesn’t cause the side effects
What are the targets for Carvedilol?
- mixed beta and alpha -> beta 1, beta 2 and alpha 1
What is the advantage of Carvedilol?
- alpha 1 blockade -> additional vasoconstrictor properties
What advantage does carvedilol have over atenolol and propranolol?
- reduces the vasoconstriction due to targeting of alpha 1
What are the affects of alpha receptors?
- a1-receptors -> postsynaptic on vascular smooth muscle -> vasoconstriction
- a2-receptors -> presynaptic autoreceptors inhibiting NE release
What is the selectivity of Phentolamine?
- non-selective alpha antagonist
How does Phentolamine act as a anti-hypertensive agent?
- causes vasodilation due to alpha 1 blockade
What is the problem with Phentolamine?
- blockade of presynaptic alpha-2 receptors removes the inhibitory effect of the alpha-2 receptors on noradrenaline release -> increase in noradrenaline release -> enhances the reflex tachycardia that appears with any blood pressure lowering agent
- increased GIT motility
- diarrhoea
o NO LONGER IN CLINICAL USE
What is the selectivity of Prazosin?
- highly alpha 1 selective antagonists
What is the effect of Prazosin?
- vasodilation
- less tachycardia than non-selective antagonists since they do NOT increase noradrenaline release from nerve terminals
- cardiac output decreases, due to a fall in venous pressure due to dilation of capacitance vessels
- hypotensive effect is dramatic -> the postural hypotension is troublesome
- unlike other anti-hypertensives, alpha-1 antagonists cause a decrease in LDL and an increase in HDL cholesterol -> becoming popular again as an anti-hypertensive agent
Name 6 beta blockers.
- Propanolol
- Pindolol
- Atenolol
- Carvedilol
- Nebivolol
- Sotalol
Name 2 alpha blockers.
- Phentolamine
- Prazosin
What is the current role of beta and alpha blockers in the treatment of heart failure?
- not front-line treatment
- are add ons if 2 or 3 methods don’t work
Why do alpha 2 receptors and baroreceptors reduce the effectiveness of phentolamine?
- removes inhibitory effect of alpha 2 receptors on noradrenaline release -> increase NA release -> enhanced reflex tachycardia to low bp
Name a false transmitter used to treat hypertension.
- Methyldopa
What is the mechanism of action os Methyldopa?
- Methyldopa is taken up by the noradrenergic neurons and is decarboxylate and hydroxylated to form the false transmitter - alpha-methyl noradrenaline
- it is NOT deaminated within the neuron by MAO and tends to accumulate in larger quantities than noradrenaline therefore it displaces noradrenaline from the synaptic vesicles
- is less active than noradrenaline on alpha-1 receptors so is LESS EFFECTIVE AT CAUSING VASOCONSTRICTION
- more active on presynaptic alpha-2 receptors, this means that the auto-inhibitory feedback mechanism operates more strongly and reduces noradrenaline release below normal levels
- has some CNS effects, it stimulates the vasopressor centre in the brainstem to inhibit sympathetic outflow
What are the other effects of Methyldopa?
o Renal and CNS blood flow is well maintained so it is widely used in patients renal insufficiency or cerebrovascular disease
For what group of people is Methyldopa recommended?
o pregnant women because it has no adverse effects on the foetus despite crossing the blood-placenta barrier
What are the adverse effects of Methyldopa?
- dry mouth
- sedation
- orthostatic hypotension
- male sexual dysfunction
o It is RARELY USED -> causes postural hypotension
What is the main cause of myocardial ischaemia?
- arrhythmias
Which drug is used in the majority of arrhythmias?
- Propanolol
What class of drugs are used to treat arrhythmias?
o beta antagonists (beta blockers)
- an increase in sympathetic drive to the heart via beta-1 can precipitate or aggravate arrhythmias due to its control on the pacemaker current and AV conductance
- refractory period of the AV node is increased by beta antagonists -> interferes with AV conduction in atrial tachycardias and slows down ventricular rate -> even if with strange re-entry type electrical activity in the damaged tissue, it wont stimulate another heart beat because it’s still in the refractory period
Define Angina.
- pain that occurs when the oxygen supply to the myocardium is insufficient for its needs
Where are the most common places to feel pain with angina?
- chest
- arms
- neck
What tends to bring angina on?
- exertion
- excitement
Describe Stable Angina.
o due to a fixed narrowing of the coronary vessels e.g. atheroma
o pain on exertion, but is enough flow for normal activity
Explain what is meant by Unstable Angina?
o pain with less and less exertion, culminating with pain at rest due to atheromatous plaque beginning to rupture
o you get a platelet-fibrin thrombus associated with the ruptured atheromatous plaque but without complete occlusion of the vessel
o high risk of infarction
What causes Variable Angina?
o coronary artery spasm -> associated with atheromatous disease
What drugs can be used to treat Angina?
o decrease heart rate and cardiac contractility -> decreased CO -> decreased systolic blood pressure
o at low doses, beta-1 selective antagonists, METOPROLOL, reduce heart rate and myocardial contractile activity without affecting bronchial smooth muscle -> reduce the oxygen demand whilst maintaining the same degree of effort
What is Glaucoma?
o an increase in intraocular pressure due to aqueous humour produced by the blood vessels in the ciliary body via the actions of carbonic anhydrase
What is directly related to the amount of aqueous humour that is produced?
o blood flow in the ciliary body
o blood pressure
State the path of aqueous humour?
o posterior chamber -> through the pupil -> anterior chamber -> trabecular network in the canal of Schlemm
What type of drugs are used to reduce the rate of aqueous humour formation?
o beta-blockers
How do beta blockers help with migraines?
- maintains good blood supply to the CNS so reduces the risks of a migraine
In what nerves do you find neuromuscular transmission?
- somatic
Describe neuromuscular transmission?
o motor nerves are Cholinergic
- action potential –> depolarisation of the membrane –> opening of voltage sensitive calcium channels –> calcium influx –> vesicles exocytosis
- acetylcholine is synthesised from Acetyl CoA and Choline by choline acetyltransferase (CAT) (only found in cholinergic nerve terminals)
- the targets for the acetylcholine at neuromuscular junctions are the nicotinic acetylcholine receptors on the END PLATE
- nicotinic receptors are ion channel linked, when you stimulate the receptor you get a change in conformation and an influx of sodium ions
- this results in a depolarisation of the membrane called the end plate potential
- this is a GRADED potential - depends on how much acetylcholine is released and how many receptors are stimulated
- once the end plate potential reaches a threshold then it generates an action potential that propagates in both directions from the end plate
- the acetylcholinesterase, which breaks down the acetylcholine once it’s had its effect, is bound to the basement membrane in the synaptic cleft
- acetylcholinesterase breaks down acetylcholine to acetate and choline
What are the two main subsets of nicotinic acetylcholine receptors?
o ganglionic (aka neuronal)
o muscle
Describe the distribution of nicotinic receptors.
o span the membrane and have both intra- and extra-cellular components
How many subunits make up a nicotinic acetylcholine receptor?
o 5
What is the significance of there being two alpha subunits when it comes to receptor activation?
o both must bind to acetylcholine before it becomes activated
Name a drug which targets the central processes with the CNS?
- baclofen/diazepam -> GABA receptor agonist
When is diazepam useful?
o is a benzodeizepam -> used to treat spasticity following strokes or due to cerebral palsy
How do local anaesthetic work?
- prevent conduction of action potentials down motor neurones
How can local anaesthetics cause muscle weakness?
- if it injected too close/directly into a motor neurone
Name both two therapeutic drugs and one toxin that can interfere with acetylcholine release?
- therapeutic = hemicholinium and calcium entry blockers
- toxin = botulinium toxin
What are the two types of neuromuscular blocking drugs?
- depolarising
- non-depolarising
Name a depolarising and a non-depolarising drug which acts at the motor end plate?
- depolarising - suxamethonium
- non-depolarising - tubocurarine
Where is Dantrolenes sit of action?
- inhibits calcium release within the muscle fibres themselves -> prevents propagation – acts as a spasmolytic
Where is the site of action of neuromuscular blocking drugs?
- post-synaptic -> act on nicotinic receptors on the motor end plate
What are non-depolarising NM blocking drugs?
- competitive nicotinic receptor antagonists
What are depolarising NM blocking drugs?
- nicotinic receptor agonists
Do NM blocking drugs affect consciousness?
- no
Do NM blocking drugs affect pain sensation?
- no
What must be done to help patients when on NM blocking drugs?
- assisted respiration
Describe the structure of a non-polarising NM blocking drug?
- big molecules with relatively restricted movement around the bonds
Describe the structure of a polarising NM blocking drug?
- small molecules with rotationally movement around the bonds
What is the structure of suxamethonium?
- two bonded acetylcholine molecules
- due to the flexibility one molecule can bind to two alpha subunits -> therefore stimulating the receptor
Describe the mechanism of action of suxamethonium.
- causes an extended end plate depolarisation -> isn’t metabolised as quickly as acetylcholine so remains bound for longer
- this leads to a depolarisation block of the NMJ (aka phase 1 block) due to overstimulation
How are NM blockers administrated?
- IV shot – slowly seeps into muscle fibres
What does suxamethonium cause?
- fasciculations (individual fibre twitches) -> leads to flaccid paralysis (up to 5 minutes)
What metabolises suxamethionium?
- pseudocholinesterase in the liver and plasma
What are the uses of suxamethinium?
- endotracheal intubation -> relaxes skeletal muscle of the airways
- muscle relaxant for electroconvulsive therapy -> treatment for severe clinical depression if talking therapy and anti-depressants haven’t worked
Name 4 unwanted effects of suxamethonium.
- post-operative muscle pain
- bradycardia
- hyperkalaemia
- raised intraocular pressure
What causes the post-operative muscle pain after suxamethonium use?
- initial fasciculation ripping the muscle slightly
How does suxamethium cause bradycardia?
- direct muscarinic action in the heart
- generally avoid as suxamethonium is given after general anaesthetic which has atropine (competitive muscarinic antagonist) with it
Name 3 types of people who should not be given suxamethonium.
- burn patients
- soft tissue injury
- eye injuries or glaucoma
What is the mechanism of action of tubocurarine?
- competitive acetylcholine receptor antagonist
- 70-80% is required to achieve full relaxation of muscles as it prevents the potential from reaching the threshold
What are the effects of tubocurarine?
- fasciculations (individual fibre twitches) -> leads to flaccid paralysis (40-100 minutes)
In which order does skeletal muscle relax in when administrated with tubocarinine?
o extrinsic eye muscles (relaxes first, gets back to normal last)
o small muscles of the face, limbs, pharynx
o respiratory muscles (relaxes last, gets back to normal first)
- return in the opposite order
What are the uses of tubocarinine?
- relaxation of skeletal muscle during surgery -> means less anaesthetic is needed
- permit artificial ventilation
What reverses the actions of non-polarising NM blockers
- anti-cholinesterases (neostigmine) -> increase acetylcholine conc.
Describe the pharmacokinetics of tubocurarine.
- does NOT cross the BBB or placenta
- NOT metabolised at all -> excreted in the urine (70%) and the bile (30%)
- if there is any impairment in hepatic or renal function then it increases the duration of action of tubocurarine
What is atracurium?
- a non-depolarising NM blocker used instead of tubocurarine (same mechanism) in patients with hepatic or renal impairment
- a chemically unstable molecule - due to the pH of the plasma it gets hydrolysed into two inactive fragments -> duration of action isn’t affected by functionality
What are the unwanted effects of tubocurarine?
o ganglion block - it could block some of the nicotinic receptors in the ganglia
o histamine release from mast cells
- hypotension -> due to ganglion blockade and histamines acting on the H1 receptors on the vasculature and cause vasodilation
- tachycardia -> may lead to arrhythmias -> is a reflex in response to the hypotension or blockade of vagal ganglia
- bronchospasm -> caused by the histamine release
- excessive secretions (bronchial and salivary) -> caused by the histamine release
- apnoea -> why you always assist respiration in someone who’s taking tubocurarine
Which of the following effects would be observed with a non-depolarising neuromuscular block?
A: Initial muscle fasciculations
B: Irreversible nAChR blockade
C: The block would be enhanced by anti-cholinesterase drugs
D: A flaccid paralysis
E: Increased arterial pressure
- D
The clinical use of neuromuscular blocking drugs will most likely involve interference with which of following physiological processes?
A: Kidney function
B: Consciousness
C: Body temperature regulation
D: Pain sensation
E: Respiration
- E
Describe action potentials of the heart.
- several channels are important in regulating the sinoatrial action potential
- If Channel is responsible for allowing the action potentia to propagate -> is a sodium channel that opens at the most negative potential -> initially sodium influx occurs until a certain amount of depolarisation and then the calcium channels open
- calcium channels come in TWO forms: -> T type = transient and L type = long lasting
- opening of the calcium channels increases the depolarisation
- potassium channels opening is responsible for repolarisation
How does the sympathetic nervous system bring about an increase in herat rate?
- beta adrenoceptors are coupled with adenylate cyclase and cause an increase in cAMP -> is important in opening the If channel
- sympathetic nervous system is responsible for causing this increase in cAMP and it also has a positive effect on calcium entry
How does the parasympathetic system slow heart rate?
- parasympathetic nervous system is negatively coupled with adenylate cyclase via muscarinic receptors -> promotes the opening of potassium channels and prolongs repolarisation
What 4 factors influence myocardial oxygen demand?
- heart rate
- afterload
- contractility
- preload
Name three drugs which can slow heart rate.
- beta blockers
- calcium channel antagonists
- ivabradine
How do beta blockers slow heart rate?
- block beta receptors -> less cAMP is made so less downstream signalling -> longer initial depolarisation phase before calcium channels open
How do calcium channel antagonists reduce heart rate?
- block calcium channels (L-type) in the plasma membrane -> reduced calcium influx of external calcium -> reduced influx of calcium from the sacroplamic reticulum
What part of cardiac myocytes holds the most calcium?
- sarcoplasmic reticulum
How does ivabradine reduce heart rate?
- blocks sodium channels (If) -> delays depolarisation to threshold levels
Name 2 drugs that can reduce cardiac contractility.
- beta blockers
- calcium channel blockers
Name the 2 classes of calcium channel antagonists, also state the major difference between the two.
- rate slowing -> act on the CARDIAC and smooth muscle
- non-rate slowing -> act on the smooth muscle
What is the major consequence of non-rate slowing calcium channel antagonists?
- reflex tachycardia -> profound vasodilation triggers baroreceptors which signal to the heart
What is the mechanism of action of organic nitrate?
- organic nitrates are substrates for nitric oxide production
- enters endothelial cells and promote NO production -> NO then diffuses into the vascular smooth muscle and causes smooth muscle relaxation by activating guanylate cyclase
Name a condition in which organic nitrates are commonly prescribed.
- angina when there is profound atherosclerosis reducing the blood flow to the heart
What is the mechanism of potassium channel openers?
- promote potassium efflux so smooth muscle becomes hyperpolarised -> has a reduced ability to contract -> overall it promotes smooth muscle contraction/vasodilation
How do organic nitrates and potassium channel openers influence the myocardial oxygen supply/demand relationship?
- increase coronary blood flow
- vasodilation reduces TPR hence reduces afterload -> heart has less work to do against the resistance
- venodilation, which reduces venous return to the heart and hence reduces preload and contractility
- reduction in afterload and preload causes a decrease in myocardial oxygen demand
What are the effects of beta blockers?
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- decreased heart rate and contractility
What are the effects of calcium channel antagonists?
- decreased heart rate and contractility
What are the effects of organic nitrates?
- increased coronary blood flow, decreased preload and afterload
What are the effects of potassium channel openers?
- increased coronary blood flow, decreased preload and afterload
What is the effects ivabradine?
- decreased heart rate
Name treatments for angina.
- beta blocker or calcium antagonist as background anti-angina treatment
- ivabradine is a newer treatment
- nitrate as symptomatic treatment (short acting)
What are the side effects of beta blockers?
- worsening of cardiac failure (CO reduction) -> in angina with HF beta-blockers will reduce the work the heart has to do but, because of the HF it is dangerous -> CO goes down -> HF is worsened
- bradycardia (heart block) -> due to less conduction through AV node
- bronchoconstriction (blockade of β2 in airways)
- hypoglycaemia (in diabetics on insulin) due to decreased glycogenolysis/gluconeogenesis
- cold extremities and worsening of peripheral arterial disease (β2 blockade in skeletal muscle vessels) -> beta-2 receptors cause vasodilation, especially in peripheral tissue -> e.g. blood flow to the hands is dependent on beta-2 mediated vasodilation
- fatigue
- impotence (sexual dysfunction)
- depression
- CNS effects (lipophilic agents) e.g. nightmares
If a beta blocker is being used as a treatment for heart failure what properties should you look for?
- use a beta blocker whihc has vasodilator properties -> should have equal affinity for beta 1 and 2 receptors or also antagonise a 1 receptors -> e.g. pindolol or carvedilol
Name two groups of patients that shouldn’t be given beta blockers.
- asthmatics -> due to bronchoconstriction
- diabetics -> due to hypoglycaemic properties
What are the side effects of rate limiting calcium channel blockers?
- bradycardia and AV block (Ca2+ channel block)
- constipation -> less gut contractions
Name a rate limiting/slowing calcium channel blocker.
- verapamil
What are the side effects of non-rate slowing calcium channel blockers?
- ankle oedema -> vasodilation means more pressure on capillary vessels
- headache/flushing
- palpitations -> baroreceptor reflex response
- vasodilation/reflex adrenergic activation
Name a non-rate slowing calcium channel blocker.
- dihyrdopyridines
Describe the simple classification of arrhythmias based on the site of origin.
- supraventricular arrhythmias (e.g. amiodarone, verapamil) – can be atria/nodal tissue
- ventricular arrhythmias (e.g. flecainide, lidocaine)
- complex (supraventricular + ventricular arrhythmias) (e.g. disopyramide)
What is Vaughan-Williams classification.
- classification of anti-arrhythia drugs
o CLASS I: Sodium channel blockade
o CLASS II: Beta-adrenergic blockade
o CLASS III: prolongation of repolarisation (membrane stabilisation, mainly due to potassium channel blockade)
o CLASS IV: Calcium channel blockade
What is the problem with the Vaughan-Williams classification system?
- despite still being used by most cardiologist lots of of modern dugs don’t fit it -> many drugs cross classes, particularly Na and K channel blockers -> couldn’t be classified -> e.g. amiodarone
What is the mechanism of adenosine?
- nodal tissue via the A1 receptor -> negative effects on cAMP -> decreased Ca channel opening and prolonged K channel opening -> prolonged depolarisation and slower repolarization -> helps to normalise tachyarrhythmia to normal sinus rhythm
- vascular effects -> stimulation of adenylate cyclase à increased cAMP -> associated with relaxatiob of smooth muscle
What is the use of adenosine?
- supraventricular tachyarrhythmias
What is the mechanism of action of verapamil?
- depresses SAN automatically and subsequently AV node conduction
What is the use of verapamil?
- reduction of ventricular responsiveness to atrial arrhythmias
What is the mechanism of amiodarone?
- complex action involving beta-blocking, calcium and potssium channel effects
- major effects are attributable to potassium channel blockade
What are the uses of amiodarone?
- supraventricular and ventricular tachyarrhythmias -> often due to re-entry problems
What are the adverse effects of amiodarone?
- accumulates in the body -> t½ 10 - 100 days causing:
- photosensitive skin rashes
- hypo- or hyper-thyroidism
- pulmonary fibrosis
What is re-entry rhythms?
- when APs meet they tend to cancel each other out
- in healthy tissue APs would pass down on either side, and if they crossed paths, they would MEET and CANCEL EACH OTHER OUT. This ensures that the AP proceeds in one direction.
- tissue blocks leads to re-entry rhythm -> if the tissue with a block has undergone its repolarisation phase, APs can reactivate the tissue -> tachyarrhythmia
How are re-entry rhythms overcome?
- work against it to prolong repolarisation -> the re-entry AP comes into the tissue and reaches the AP point, the tissue hasn’t repolarised yet -> the AP just dies and can’t be propagated -> reduce some of these arrhythmias
- done with a potassium channel blocker like AMIODARONE
What is the mechanism of cardiac glycosides?
- inhibition of Na-K-ATPase -> increased intracellular Ca2+ via effects on Na+/Ca2+ exchange -> positive inotropic effect
- central vagal stimulation by digoxin causes increased refractory period and reduced rate of conduction through the AV node (parasympathetic NS slows the heart)
o overall they slow the heart rate and improve ventricular contraction -> improves CO and restores normal rhythm
What are the uses of cardiac glycosides?
- AF and flutter lead to a rapid ventricular rate that can impair ventricular filling (due to decreased filling time) and reduce CO
- digoxin reduces the conduction of electrical impulses within the AV node via the vagal stimulation -> fewer impulses reach the ventricles and ventricular rate falls
Why does hypokalaemia lower the threshold for digoxin toxicity?
- digoxin competes with potassium -> if you have little potassium in your blood, then digoxin over-inhibits
What is the treatment pathway for hypertension?
Name the 3 major stimuli for renin production.
- decreased renal Na absorption
- decreased renal perfusion pressure
- increased sympathetic activity
What are the actions of angiotensin II?
o very powerful vasoconstrictor à increased TPR
o direct and indirect effects on the kidney
- directly affects kidney to promote salt and water retention à increased blood volume
- indirectly affects kidney by stimulating aldosterone production -> aldosterone acts on the kidney
o sympathetic activation
o thirst activation
Name an ACE inhibitor.
- enalapril -> any drug ending with pril
What are ACE inhibitors used to treat?
- hypertension
- heart failure
- post-myocardial infarction
- diabetic nephropathy
- progressive renal insufficiency
- procaution for patients at high risk of cardiovascular disease
How do ACE inhibitors treat hypertension?
- an effect on TPR -> angiotensin II is a vasoconstrictor -> blocking it will reduce TPR -> decrease BP
How do ACE inhibitors treat heart failure?
- angiotensin II increases salt and water retention -> drives up blood volume -> increase in venous return
- ACE inhibitors decrease venous return in HF patients -> reduce work of the heart and decreased congestion in the system -> stress on heart alleviated
What can angiotensin II receptor blockers be used to treat?
- hypertension
- heart failure
- very similar to ACE inhibitors -> have the same effects -> decreased TPr and decreased venous return
What are the side effects of ACEi and ARBs?
- GENERALLY WELL TOLERATED. SIDE EFFECTS:
- cough -> ACEi only -> prevents the breakdown of bradykinin -> builds up and stimulates coughing
- hypotension
- urticaria/angioedema (rare)
- hyperkalaemia
- foetal injury
- renal failure in patients with renal artery stenosis -> angiotension can’t bind to efferent arteriole so glomerulus pressure isn’t maintained
What is the mechanism of smooth muscle contraction?
- membrane depolarisation opens voltage-gated Ca2+ channels (VGCCs)
- Ca2+ enters & binds to calmodulin (CaM)
- Ca2+-CaM complex binds to & activates myosin light chain kinase (MLCK)
- MLCK mediated phosphorylation -> smooth muscle contraction
Why are CCBs or thiazide diuretics used instead of ACEi or ARBs in the elderly adn Afro-Caribbean population?
elderly = uncoupling of BP from the RAS system as you get older -> more due atherosclerosis etc
- afro-Caribbean = to low plasma renin activity
Why would you give an alpha blocker in resistant hypertension?
- alpha 1 adrenoreceptor antagonists are used as a last resort as antihypertensive treatment
- alpha 1 receptor is the predominant vasoconstricting receptor in the vasculature -> blocking alpha 1 receptors reduces vasoconstriction -> reduce TPR -> decrease BP
Why do people abuse drugs?
primarily centred on the reward pathway (mesolimbic dopamine system) in the brain
- reward pathway is a collection of dopaminergic neurones that originate in the ventral tegmental area and project down to the ventral striatum -> in particular the nucleus accumbens
Describe endothelial dysfunction in atherosclerosis.
- endothelium becomes dysfunctional -> problem because the endothelium is responsible for producing a lot of mediators
- characterised by a series of early changes that precede lesion formation -> changes include greater permeability of the endothelium, up-regulation of leucocytes, endothelial adhesion molecules and migration of leucocytes into the artery wall
Describe fatty streak formation in atherosclerosis.
- fatty streak is the earliest recognisable lesion of atherosclerosis and is caused by the aggregation of lipid-rich foam cells -> derived from macrophages and T lymphocytes within the tunica intima
- later on the lesions will also include smooth muscle cells
- are usually formed in the direction of blood flow
- most fatty streaks don’t actually develop into serious atherosclerosis, but it is an early stage and begins very early in human life
Describe the unwanted effects of different NSAID target sites.
Describe the structure-activity relationship of opiates, focus on morphine.
- tertiary nitrogen = analgesia by permits receptor anchoring -> extending the side chain to 3+ carbons generates an antagonist
- tertiary nitrogen allows the molecule to bind the receptor by giving it affinity and permits receptor anchoring -> side chain attached to the nitrogen determines the efficacy
- 2 alcohol groups have a role in binding -> not as much as the tertiary nitrogen
How do the structures of heroin and codeine differ to that of morphines?
- heroin = diacetylmorphine
- codeine = methylmorphine
What is the general rule about potency of opiods and their lipid solubility?
o more lipid soluble = more potent
- exception to this is codeine
Describe the metabolism of morphine.
- morphine produces active metabolites -> morphine-6-glucoronide is the most potent active metabolite of morphine (10% of the blood levels of morphine at any one time) -> active metabolites are less likely to cause the negative (e.g. repsiratory depression) than morphine -> individuals who don’t metabolise morphine very well are more likely to have negative side effects
Describe the pain pathway.
- pain is sensed peripherally, and is recognised by sensory neurones -> relay this information to the spinal cord -> spinothalamic neurones relay this information to the thalamus -> doesn’t process the information, but it directs it to the cortex
- thalamus also directly activates the descending pain tolerance pathway -> simultaneously, the cortex has an additional impact on the pain tolerance pathway
- the PAG region is the integrating centre for the pain tolerance pathway -> receives all information and determines output, it relays to the NRM (effector arm)
- thalamus switches the PAG on automatically -> not long after, the cortex modulates this signal*
- the NRM, descending neurones leave to suppress the feelings of pain that are reaching the brain
- the NRPG is an auto-feedback element of the brain -> is away of switching on pain tolerance without any higher centre functioning at all -> isn’t as powerful as PAG, but is still an important
- most of the information goes to the thalamus, but some filters through the NRPG and automatically switches on pain tolerance*
How does the locus coreleus affect pain?
- is the sympathetic nervous system effector -> is largely independent of the analgesia system
- if your stress pathway is activated, the LC is active -> automatic signal to dampen down pain
- when you injure yourself playing sport, it doesn’t hurt very much at the moment in time -> makes sense in terms of flight or fight
- if the SNS is active it suppresses pain information from the periphery to the brain
How is pain modulated in the dorsal horn?
- certain amount of signal comes down and reaches the dorsal horn, to suppress information moving from periphery to brain
- substantia gelatinosa is a mini brain in the spinal cord -> processing and modification of the signal takes place
Describe the cough pathway.
How do opioids cause nausea?
- via a direct effect at the chemoreceptor trigger zone
- GABA keeps the CTZ suppressed -> opioids switch this inhibition off -> CTZ signals to the medullary vomiting centre, and you feel nauseous
What is the mechanims of glucocorticoids in IBD?
- glucocorticoids act at multiple points in the inflammation seen in bowel disease
- can inhibit the production of IL-1 and TNF-alpha by dendritic cells. Dendritic cells are thought to have an important role in IBD
- are very potent anti-inflammatory and immunosuppressive actions of GCs -> when given systemically, chronic glucocorticoid administration causes many unwanted effects
Describe Type A adverse drug reactions.
- reaction is often an extension of the pharmacologic effect of the drug that we already know about -> therefore usually predictable and often dose dependent
- responsible for at least two-thirds of ADRs
- can either have a linear increase in toxicity (digoxin) or can have a tipping point which once over can have detrimental effect (paracetamol)
How is psychoses split?
Describe GABA metabolism.
- GABA transaminase (GABA-T) is the enzyme in the first step - GABA -> succinic semialdehyde
- second enzyme is succinic semialdehyde dehydrogenase (SSDH) to produce succinic acid
- succinic acid goes back into the TCA cycle in the cells and as glutamate also arises from the TCA cycle -> a GABA shunt is formed
- around 10% of the activity of the TCA cycle is involved in generating GABA as a transmitter
Describe the synthesis of dopamine.
- production of dopamine = L-tyrosine -> L-DOPA -> dopamine
- dopamine is stored in vesicles at the synaptic terminal
- process utilises the enzymes -> tyrosine hydroxylase (rate limiting) and DOPA decarboxylase
What are the two routes of administration of general anaesthetics?
Explain the blood:gas partition co-efficient and how it effects the level of control and anaesthetist has?
- if you fill the lungs with anaesthetic agent, this anaesthetic will diffuse across into the blood
- if it dissolves POORLY in the blood (has a low blood:gas partition coefficient) a fairly large proportion remains in gaseous form within the blood -> agent transfers into the brain very effectively
- component that is dissolved in the blood (in a liquid form) will diffuse poorly into the brain
o for control you want an anaesthetic agent that has a low blood:gas partition coefficient, because this makes it MORE available to the brain and because if it is POORLY DISSOLVED IN THE BLOOD (low blood:gas partition coefficient), it is EASIER to clear it from the brain - simply remove the source and it will quickly diffsue out
Describe prokaryotic nucleic acid synthesis.
- dihydropteroate (DHOp) is produced from paraaminobenzoate (PABA) by DHOp synthase, and converted into dihydrofolate (DHF)
- tetrahydrofolate (THF) is produced from DHF by DHF reductase -> THF IS IMPORTANT IN DNA SYNTHESIS
Describe the structure of a virus.
- viruses have nucleic acid (genetic material), which is either RNA or DNA -> this is protected by a coat of proteins (capsid)
- bigger viruses also have a lipid envelope and envelope proteins
