Flashcards in Pharmacology Deck (215):
What are pharmodynamics?
What a drug does to the body (biological effects and mechanisms of action).
What are pharmokinetics?
What the body does to a drug (ADME).
What is the action of a drug?
Selective binding of a drug to a target molecule.
What is a ligand?
Small molecule that can bind to a target protein or bio-molecule.
What is a receptor?
Macromolecules that mediate the biological actions of hormones and neurotransmitters. Drugs can bind to these. Integral membrane protein. Single polypeptide with outer NH2 and inner COOH terminals. 7 transmembrane spans and 3 outer and inner connecting loops.
What is an agonist?
A drug that binds to a receptor to produce a cellular response. They possess both affinity and efficacy.
What is a partial agonist?
An agonist with lower efficacy than a full agonist.
What is an antagonist?
A drug which blocks the action of an agonist. They bind to receptors but don't activate them. They possess affinity but lack efficacy.
What is affinity?
The strength of the association between the ligand and the receptor.
If it has a low affinity it will have a fast dissociation rate.
Medium = moderate
High = slow
It equates to the binding step in a reaction.
What is efficacy?
Ability of an agonist to evoke a cellular response. Low efficacy= small response.
It equates to the activation step of a reaction.
What is the EC50 or ED50 of a drug?
the concentration that elicits a half maximal response.
What shape is a linear plot of concentration/response relationship graph?
What shape is the semi logarithmic graph of the concentration/response relationship?
Sigmoidal. It shifts to the right from a hyperbolic graph.
What is the potency of a drug?
The amount it takes to elicit a response. You can have equal efficacies but different potencies.
What is a competitive antagonist?
Binding of the agonist and the antagonist happens at the same (orthosteric) site.
What is a non-competitive antagonist?
The agonist bind to the orthosteric site and the antagonist binds to a separate allosteric site.
What is partitioning?
Movement of drugs from one compartment to another e.g. Vascular to interstitial.
What is dissolution of a drug?
It's solubility in water.
Describe the effects of competitive and non competitive antagonists on concentration/response graphs.
Competitive cause a parallel right shift with no depression.
Non-competitive don't shift right but depresses the response slope.
What does ADME stand for?
Absorption, distribution, metabolism and excretion.
The process by which the drug enters the body from the administration site e.g. Orally - most is absorbed in the intestines and a little in the stomach. Both going into the portal circulation.
The process by which the drug leaves the circulation and enters the tissues perfused by blood. Further blood dependent distribution can occur in the tissues. E.g. Vascular department to interstitial water to intracellular water.
What is drug metabolism?
The process by which tissue enzymes (mostly the liver), catalyse the chemical conversion of a drug to a form that is more easily excreted from the body. E.g. By making parent drugs more polar so they aren't absorbed in the kidneys. It can make drugs less pharmacologically active.
What is drug excretion?
The process that removes the drug from the body (principally the kidneys).
What is elimination?
A term frequently used to describe the linked processes or metabolism and excretion.
What chemical factors control drug absorption?
Solubility, chemical stability (not destroyed in the process of absorption e.g. By stomach acid) and the lipid to water partition co-efficient (drug diffusion across the membrane increases with the lipid solubility).
What is the partition coefficient of a drug?
Ratio of how much of the drug likes to be absorbed in lipid as opposed to water. If it has a large partition coefficient it means it likes to be in lipids.
Describe the movement of a drug with a large partition coefficient compared to a small one?
With a large partition coefficient more particles will diffuse into the membrane. This causes a large concentration gradient between the membrane and intracellular fluid and so quick absorption occurs. Small partition membrane coefficient drugs will be absorbed more slowly.
What is degree of ionisation? And what does it depend on for a drug?
Amount of drug existing in the ionised form.
The pKa of the drug and the local pH.
How do we write down drugs as weak acids and bases in both the ionised and unionised form. What are their ionisation equations.
Acids: AH or A-
AH A- + H+
Reaction driven to the right by increasing pH.
Bases: B or BH+
BH+ B + H+
Reaction driven to the left by decreasing pH.
What is a weak acid?
A proton donor.
What is a weak base?
A proton acceptor.
What is pH?
The concentration of H+ in a solution. The more H+ the more acidic it is.
pH 1 = 10-1
pH 7 = 10-7
Do acid/base ions readily diffuse across the membrane?
No, only B and AH readily diffuse.
What happens to a weak acid in an acidic environment?
If a proton dissociates, it will immediately be replaced due to the high concentration of the surroundings.
What happens to a weak acid in a weakly acidic environment?
It is not likely to be replaced due to the low concentrations in the surrounding environment.
What is the pKa of a drug?
The pH at which 50% or the drug is ionised and 50% isn't.
How do we calculate the degree of ionisation of a drug?
The Henderson Hasselbalch equation.
pH - pKA = log(A-/AH)
pH - pKA = log(B/BH+)
Is aspirin acidic or basic? And what is its pKa?
A weak acid.
pKa = 3.5
Is morphine acidic or alkaline? And what is its pKa?
A weak base.
pKa = 8.
Where does the absorption of weak acids start and why?
In the stomach. The acidic environment means that weak acids can exist mostly in the unionised form (if they dissociate they will quickly re-associate) and so they can diffuse across the plasmalemma.
Where do bases start to be readily absorbed and why?
In the small intestine. The pH is more basic and so the drug remains units ionised form and so can be absorbed.
Where does most drug absorption take place?
The small intestine, due to the large surface area.
Do acidic drugs become more or less ionised in an acidic environment?
Do basic drugs become more or less ionised in a basic environment?
Are weak acid/bases or strong acids/bases better absorbed?
What is the pKa of strong acids?
What is the pKa of a strong base?
What factors affect GI absorption?
GI motility- affected by food and some drugs.
pH at absorption site- some diseases can affect this.
GI tract blood flow - affected by food.
Drug manufacture methods.
Physio chemical reactions- some absorption is altered by calcium rich food.
What is oral availability?
The fraction of a drug that reaches the systemic circulation after oral ingestion I.e. The amount of drug in the systemic circulation divided by the amount ingested.
What is the systemic availability?
The fraction reaching the systemic circulation after absorption. I.e. Amount in the systemic circulation divided by the amount absorbed. Iv drugs have 100% systemic circulation.
What is first pass or pre-systemic metabolism.
When drugs are inactivated by enzymes in the gut wall or liver before reaching the systemic circulation.
What are the two big classes of drug administration and the types included In these categories?
Enteral - oral, buccal/ sublingual and rectal.
Parenteral- iv, IM, subcut, inhalational and topical.
What are the advantages and disadvantages of oral drug administration?
Advantages- easy, convenient, non-sterile route, mostly good absorption.
Disadvantages- variable absorption, some drugs destroyed by acid/enzymes, first pass metabolism and GI irritation.
What are the advantages and disadvantages of buccal drug administration?
Adv- bypasses portal, acid and first pass.
Dis- infrequently used so few drugs available.
What are the advantages and disadvantages of rectal drug administration?
Adv- by passes: portal, acid and first pass metabolism. Good for nocturnal administration.
Dis- infrequently used, awkward for consent and variable absorption.
What are the advantages and disadvantages of IV drug administration?
Adv- rapid onset, continuous infusion, complete availability, good for drugs that would irritate topically.
Dis- must be sterile, sepsis/embolism risk, high drug levels at heart.
What are the advantages and disadvantages of IV/subcut drug administration?
Adv- rapid onset if lipid soluble, depot for slow release drugs.
Dis- painful, can cause tissue damage, variable absorption.
What are the advantages and disadvantages of inhalational drug administration?
Adv- huge surface area, ideal for local effect and good for aerosols and volatiles.
What are the advantages and disadvantages of topical drug administration?
Ideal for local effect. Few dis.
What is a bound drug and where can it move?
A drug that is bound to protein and it cannot move between body fluid compartments.
What fluid compartments can ionised and unionised drugs move between?
Ionised - only between plasma water and interstitial water.
Unionised- free to move between all compartments.
What is the volume of distribution of a drug?
The apparent volume in which a drug is dissolved.
What does a Vd of under 5L mean?
That a drug is retained in the vascular department e.g it is too big to cross the capillary wall or it is protein bound.
What does a Vd of under 15 L mean?
The drug is restricted to extra cellular water.
What does a Vd of over 15L mean?
Indicates the drug is distributed throughout all body water.
What is the CNS?
The brain and spinal cord.
What are the branches of the PNS?
Somatic (efferent), enteric, autonomic and somatic and visceral.
What are afferent signals?
Ones that travel towards the CNS.
What are efferent signals?
Ones that travel away from the CNS.
What are the two branches of the autonomic nervous system?
Sympathetic and parasympathetic.
What are the functions of the autonomic nervous system?
Carries output from the CNS to whole body except skeletal muscles. Regulates involuntary visceral functions. (Some can be controlled with training e.g. Urination).
Describe a sympathetic nerve.
Thoracic/lumbar outflow => short preganglionic neurone => synapse => long postganglionic neurone => effector cell.
Describe a parasympathetic nerve.
Cranial/sacral outflow => long preganglionic neurone => synapse => short postganglionic neurone => effector cell.
Describe the structure of the vagus nerves.
Cranial nerve 3,7,9 and 10. Incredibly long preganglionic nerve. The ganglion is embedded in the organ so the postganglionic is very short.
Why is unique about the adrenal glands sympathetic innervation?
It is preganglionic.
What does cholinergic mean?
Ach is its neurotransmitter.
What does adrenergic mean?
It's neurotransmitter is noradrenaline.
List some of the activities of sympathetic stimulation.
Increased heart rate and force of contraction, relaxes bronchi (via adrenaline release) and decreased mucus production (decreased airway resistance), reduces GI motility and constricts sphincters, release of adrenaline from the adrenal gland and ejaculation.
List some activities of parasympathetic stimulation.
Decreases heart rate, constricts bronchi and increases mucus production (increased airway resistance), increased gut motility and relaxation of sphincters, erection.
Describe parasympathetic innervation of the heart?
None in the heart ventricles. SA node and atria receive innervation and so parasympathetic stimulation only affects heart rate and not contraction.
Describe sympathetic innervation in the respiratory system.
The smooth muscle doesn't have sympathetic innervation but glands do. Sympathetic system makes the medulla release adrenaline which relaxes the bronchi.
List the 9 steps in neurochemical transmission.
Precursor uptake, transmitter synthesis, transmitter storage, depolarisation by action potential, calcium influx through voltage activated channels, calcium induced release of transmitter (exocytosis) receptor activation, enzyme inactivation of transmitter or reuptake.
What is the neurotransmitter of the parasympathetic division.
What is the neurotransmitter of the sympathetic division?
Preganglionic = ach. Post is usually noradrenaline.
Describe the spread of action potential in the sympathetic division.
Ach released from preganglionic, Ach opens ligand gated ion channels (nicotinic Ach receptors) in postganglionic. Action potential spreads down and norad released which activates G protein coupled adrenoreceptors in the target cell.
Describe transmission of action potential in the parasympathetic division.
Ach released from preganglionic, Ach opens ligand gated ion channels (nicotinic Ach receptors) in postganglionic. Action potential spreads down and Ach released which activates G protein coupled muscarinic acetylcholine receptors in the target cell.
What is a ligand gated ion channel?
Transmitter gated ion channel or ionotropic receptors. Glycoproteins subunits around a central ion conducting channel. Allow rapid changes in ion permeability and membrane potential. Agonists bind to them causing either opening or closure.
What do G-protein coupled receptors do?
Couples receptor activation to effector modulation. Slow compared to transmitter gated ion channels.
What is the structure of a G protein?
Peripheral membrane protein. 3 polypeptide units (a,b and y). Has a guanine nucleotide binding site in the alpha subunit that can hold GTP or GDP. Guanosine triphosphate or di
How do G-protein receptors work?
Alpha subunit binds to GDP. Agonist activates receptor, G couples with receptor GDP releases GTP binds. alpha binds with effector and modifies the activity. (BY units move to the middle), agonist can dissociate but signalling can persist. Alpha unit GTP to GDP and Pi and signal turns off. Unit rebuilds to start again.
What is a nicotinic Ach receptor?
Five glycoprotein subunits surrounding a central cation conduction channel. Lots of different unit combinations that are functionally and pharmacologically different.
Describe cholinergic transmission.
Uptake of choline via a transporter. Ach synthesis via choline acetyltransferase (CAT). Ach storage. Depolarisation, calcium influx, calcium induced Ach release and exocytosis. Activation of Ach receptors (nicotinic or muscarinic). Degradation of Ach to choline and acetate by acetylcholinesterase. Reuptake and reuse of choline.
How is the action potential started in the postganglionic nerve?
Sodium rushes in the nicotinic Ach receptor with the Ach, starting sodium potassium mechanism.
Describe cholinergic transmission at parasympathetic neuroeffector junctions.
Synthesis and storage of Ach. Depolarisation of action potential. Calcium influx causing release of Ach and exocytosis. Activation of muscarinic receptors (m1 to m3 subtypes), causing cellular response, degradation and reuptake of choline. The effector is a smooth muscle cell etc.
Describe nor adrenergic transmission at sympathetic neuroeffector junctions.
Synthesis and storage of Na. Depolarisation of action potential. Calcium influx causing release of Ach and exocytosis. Activation of adrenoreceptor subtypes causing cellular response. Reuptake of Na by transporters - uptake one on the nerve and uptake two on the cell. effector is a cardiac cell etc.
What metabolises noradrenaline at neuroeffector junctions?
MAO - monoamine oxidase in the nerve.
COMT- catechol-O-methyltransferase in the effector cell.
What are the G-coupled muscarinic Ach receptor subtypes at parasympathetic neuroeffector junctions?
M1- stimulation of phospholipase C causing increased acid secretion in the stomach.
M2- inhibition of adenylyl cyclase opening of K+ channels causing decreased heart rate.
M3- stimulation of phopholipase C causing increased salivary secretions and contraction of visceral smooth muscle.
Vascular smooth muscle is indirectly relaxed by M3 receptor activation.
Describe the action of beta receptor subtypes at sympathetic neuroeffector junctions.
Beta 1- stimulation of adenylyl cyclase causing increased rate and force of heartbeat.
Beta 2- stimulation of adenylyl cyclase causing relaxion of bronchial and vascular smooth muscle.
Describe the action of alpha receptor subtypes at sympathetic neuroeffector junctions.
Alpha 1- stimulation of phospholipase C, causing contraction of vascular smooth muscle.
Alpha 2- inhibition of adenylyl cyclase causing inhibition of NA release.
What is a heteroreceptor?
A presynaptic receptor that modulates the release of neurotransmitter. Antagonism occurs presynaptically.
Hetero Na receptors antagonist Ach and vice versa.
What do presynaptic autoreceptors do?
Mediate negative feedback inhibition of transmitter release. Agonists decrease release. Antagonists increase release.
How does cocaine act in the autonomic nervous system?
Blocks U1 (uptake 1) increasing the concentration of NA in the synaptic cleft, resulting in increased adrenoreceptor stimulation.
Peripheral action causes vasoconstriction (alpha 1 stimulation) and cardiac arrhythmias (beta 1 stimulation).
How does amphetamine act in the autonomic nervous system?
Is a substrate for U1, it enters and inhibits MAO, it enters the synaptic vesicle and displaces norad into the cytoplasm. norad exits back out of U1 and accumulates in the synaptic cleft. Causes increased adrenoreceptor stimulation.
peripheral action causes vasoconstriction (alpha 1 stimulation) and cardiac arrhythmias (beta 1 stimulation).
How does atropine act in the autonomic nervous system?
Competitive antagonist of muscarinic Ach receptors but not nicotinic. Block M 1,2 and 3 with equal affinity. So exerts a widespread effect by blockade of parasympathetic division of the ANS.
What is the minimum effective concentration (MEC) of a drug?
Critical concentration of a drug needed to have an effect.
What is the maximum tolerated concentration (MTC) of a drug?
The amount that can be taken before there are significant unwanted side effects.
What is the therapeutic window of a drug?
The difference between the MTC and the MEC of a drug. Bigger windows = safer drugs.
What is the therapeutic ratio/index of a drug?
TR = MTC/MEC safe drugs have a high ratio and vice versa.
What do Kabs, Kel,D, Ct and Co stand for? (Only the 1st letter is large the rest are subscript.)
Kabs = absorption rate in a compartment.
Kel = the elimination rate from the compartment.
D = dose.
Ct = the concentration at a later time.
Co = concentration.
How do we calculate the initial concentration of a drug?
Co= D/Vd. (Concentration= mass/volume).
What is first order kinetics?
The rate of elimination (Kel) is directly proportional to the drug concentration).
Drug concentration falls exponentially, not at a constant rate. Drugs that exhibit first order kinetics the dose administered changes the plasma concentration (Cp) but not the Kel (relate of elimination) or half life. The vast majority of drugs have this.
What does Cp stand for?
What is the half life for first order kinetics? (T1/2).
Time taken for the concentration at a later time (Ct) to fall by 50%.
T1/2 = 0.69/Kel. (Rate of elimination).
What is drug clearance?
(Cl) The volume of plasma cleared of a drug in a unit of time. It is a constant relating the rate of elimination to plasma concentration. Only applies to drugs exhibiting first order kinetics. Clearance represents the maintenance dose rate.
What is the maintenance dose rate?
The dose per unit of time required to maintain a given plasma concentration.
What is the steady state in relation to dosing?
When we have steady state dosing, the rate of drug elimination = the rate of administration. Rate of elimination = Cl x Cpss therefore so does the rate of administration. So Cpss= maintenance dose rate / Cl. For drugs that have first order kinetics steady state is reached after 5 half lives.
How do we calculate Cl (clearance)?
Is the sum total of all clearance processes e.g. Renal plus hepatic plus other.
How can we calculate the half life in first order kinetics?
How do we calculate rate of elimination?
Rate of elimination = Cl x Cp.
What is a loading dose?
An initial higher dose of a drug given at the beginning to reach the steady state more quickly, for drugs with long half lives.
What equations do we use to calculate loading dose?
Iv. LD = Vd x target Cp.
PO. LD = (Vd x target CP) /F.
F = the fraction of the drug administered that enters the systemic circulation.
If we double the starting dose of a drug, what does this do to the half life?
It adds one.
What is zero order kinetics?
Elimination is initially constant (straight line) and then changes to zero order kinetics.
What two significant substances have zero order kinetics?
Ethanol and phenytoin.
How to most drugs leave the body?
Either as unchanged (highly charged) compounds or ones transformed into more polar ones by metabolism.
Some drugs are excreted unchanged e.g in parent form.
How does drug metabolism usually proceed?
Phase 1- oxidation, reduction and hydrolysis. (Makes drug more polar by adding a chemically reactive group (handle) permitting conjugation).
Phase 2- conjugation. (Adds a compound increasing polarity).
Describe the two phases of aspirin metabolism?
Aspirin (acetylsalicyclic acid) is changed to salicyclic acid and then conjugated to glucuronide.
What are the steps in renal excretion?
Active tubular secretions.
Passive transient ion by diffusion across the tubular epithelium.
Which drugs can filter across the glomerulus?
Drugs with a molecular weight of less than 20000 (most of them).
Also drugs not bound to proteins.
How do we calculate the rate of clearance by filtration?
CLfil = GFR x Fup (fraction of drug unbound in the plasma).
GFR is normally 120 ml/min.
What is tubular secretion of drugs?
20% goes through the glomerulus but the other 80 of renal plasma is delivered to the peri tubular capillaries in the proximal tubule. These cells have two different transporters that move drugs into the nephron lumen. Organic anion transporters and organic cation transporters. Potentially the most effective mechanism of kidney secretion. Can also excrete protein bound drugs.
What does an organic anion transporter do?
Handles acidic drugs in the proximal tubule e.g. Penicillins.
They have transport maximums for particular drugs.
They can concentrate drugs in the tubule against an electrochemical gradient. Which causes more drug to diffuse across.
Drugs may compete for transporters.
What does an organic cation transporter do?
Transports basic drugs in the proximal tubule e.g. Morphine.
They have transport maximums for particular drugs.
They can concentrate drugs in the tubule against an electrochemical gradient, which causes more drug to diffuse across.
Drugs may compete for transporters.
Describe tubular absorption.
99% secreted by the glomerulus can be reaborbed by the distal tubule by passive diffusion.
What factors influence distal tubule re absorption?
Lipid solubility (high solubility reaborbed and excreted slowly).
Polarity (highly polar excreted).
Urinary flow rate- high rate decreases reabsorption.
Urinary pH - alkaline pH increases acid excretion and vice versa.
Urinary alkalinisation can be used to excrete aspirin in overdoses
What different types of ion channels are there?
Voltage gated - opened by membrane potential.
Ligand gated - opened by chemical substances.
Ones that respond to physical stimuli e.g. Thermal.
What ion channels are responsible for the action potential in neurones?
Voltage activated Na channels (depolarising). Open rapidly. Positive feedback, the opening of some causes the opening of others.
Voltage activated K channels (hyper polarising). Open with a slight delay.
Both activated by membrane depolarisation. Negative feedback, outward flow causes re polarisation turning off the stimulus.
What is an action potential?
Brief electrical signals when the membrane potential momentarily reverses. They move with constant magnitude and velocity (for a given axon). Generated when a threshold is reached. They are all or nothing.
What is the refractory period in relation to Na channels?
Voltage gated Na channels opens in response to depolarisation, but enter an inactivated non-conducting state during maintained depolarisation. Re polarisation is needed for them to close and enter the ready state again.
What is the difference between the absolute and relative refractory period?
Absolute- no stimuli can cause a second action potential (down stroke of wave - channels opened but inactivated).
Relative - stronger than normal stimulus may cause a second potential (there are a mix of inactivated and closed channels). Membrane potential is below resting potential.
What influence the velocity of the action potential?
Passive conductance of the action potentials (axon like a leaky hose). The potential decays with distance and so can only conduct over a certain length of the axon. This is dependent upon the membrane resistance (Rm and the axial resistance (ri).
How can action potential velocity be increased?
Decreasing the axial resistance by increasing the axon diameter.
Increasing the membrane resistance by adding myelin insulation.
What makes myelin in the PNS?
What makes myelin in the CNS?
What are the gaps in the myelin called?
Nodes of ranvier.
How does sympathetic stimulation affect the bronchioles?
Preganglionic neurone stimulates adrenaline release from kidneys. Through nicotinic Ach receptors. Adrenaline then activates the beta 2 g-protein coupled adrenoreceptors in the smooth muscle. Causes air away relaxation, decreased mucus production and increased activity of mucociliary escalator.
What are relievers in asthma?
Short or long acting beta2 adrenoreceptor agonists or CysLT1 antagonists.
What are asthma controllers/preventers?
Glucocorticoids. Chromoglicate and humanised IgE antibodies.
What is the basic function of beta2 adrenoreceptor agonists?
To stimulate beta receptors and block the action of spasmogens. To relax bronchial smooth muscle.
Describe the molecular pathway of beta2 adrenoreceptor agonism.
Stimulation increases Gs? Which increases AC (adenylyl cyclase). This changes ATP to cAMP, which increases PKA (protein kinase A), this causes phosphorylation of MLCK (myosin light chain kinase). Causing relaxation.
What happens when beta2 adrenoreceptors are persistently activated?
The receptors are desensitised. And undergo endocytotic resulting in loss of function.
Describe the PKA (protein kinase A) pathway of beta 2 adrenoreceptor desensitisation.
Adrenoreceptor is activated by agonist. PKA causes phosphorylation of B2 receptor. Agonist is not still bound. Results in Reduced G-protein coupling.
Describe the GRK pathway of B2 receptor desensitisation.
Adrenoreceptor is activated by agonist. GRK causes phosphorylation of B2 receptor. The agonist is still bound, and a Beta arrestin receptor complex is produced. Results in loss of G protein coupling.
How do beta2 receptor agonists cause loss of Gprotein coupling?
They act as a scaffold protein between desensitised receptor and the endocytotic machinery. Receptors get internalised in clathrin coated pits and vesicles and are trafficked to endosomes for recycling or lysosomes for degradation.
What are the features of short acting beta 2 adrenoreceptor agonists?
First line treatment for mild intermittent asthma.
Rapid action- usually 5 mins, peak at 30. Relaxation for 4-6 hours.
Increase mucus clearance and decrease mediator release.
Cause fine tremor and tachycardia.
Name a short acting beta2 adrenoreceptor agonist.
Salbutamol aka albuterol.
When are long acting beta 2 adrenoreceptor agonists used?
For nocturnal asthma due to long half life. Used in conjunction with other treatments when they don't work.
Name a laba.
When should labas not be used?
For acute relief of bronchospasm. As a monotherapy.
What is a concern over laba use?
Chronic use may worsen asthma.
Why are beta 2 agonists selective?
So they don't give unwanted side affects by stimulating cardiac beta 1 receptors.
What class of drugs are contraindicated in asthma patients and why?
Non-selective beta adrenoreceptor antagonists. May antagonise beta 2 receptors causing bronchial constriction.
What is cysteinyl leukotriene (CysLT1)?
CysLTs (LTC4, LTD4 and LTE4) derive from mast cells and infiltrate inflammatory cells causing smooth muscle contraction, mucus secretion and oedema.
How do CysLT1 receptor antagonists work?
Act competitively on CysLT1 receptors blocking their action and stopping bronchial construction.
What are the features of CysLT1 receptor antagonists?
Effective as add on therapy in mild persistent asthma and in combo with other meds in severe asthma. Good against antigen and exercise induced bronchospasm. Delivered orally and generally well tolerated.
When should CysLT1 receptor antagonists not be used and why?
In acute attacks as they have less bronchodilator activity than salbutamol.
Name two CysLT1 receptor antagonists?
Montelukast and zafirlukast.
Name two Xanthines?
Theophylline and aminophylline.
Where are Xanthines naturally found?
Tea, coffee and chocolate.
What are the actions of Xanthines?
Combine bronchodilator and anti-inflammatory actions. They relax smooth muscle, inhibit mediator release from mast cells and increase mucus clearance.
When are Xanthines used?
Second line drugs in combo with beta2 agonists and glycocorticoids. Delivered orally.
What are the adverse effects of Xanthines?
Nausea and vomiting, abdominal discomfort and headache. Have numerous drug interactions and so need serum monitoring.
What two steroid hormones are synthesised by the adrenal cortex?
Glucocorticoids (zona fasciculata) and mineralcorticoids (zona glomerulosa). Synthesised on demand.
What is the main glucocorticoid hormone in man?
What does cortisol do?
Inflammatory response decreases.
Immunological response decreases.
Liver glycogen deposition increases.
Glucose output from the liver increased.
Glucose utilisation decreased.
Protein catabolism increased.
Bone catabolism increased.
Gastric acid and pepsin secretion increased.
What is the main mineralcorticoids?
What do mineralcorticoids do?
Regulate the retention of salt and water by the kidney.
What features do endogenous steroids have?
Both the actions of Glucocoticoids and mineralcorticoids. Only the gluco are useful.
Name a common glucocorticoid.
When should glucocorticoids be used?
Not in acute settings as they have no direct bronchodilator action. Mainstay of prophylactic treatment of asthma, delivered by inhalation.
Where are catecholamines synthesised?
In the adrenal cortex medulla.
Where are androgens made?
In the adrenal cortex reticularis.
What receptors do glucocorticoids use?
Nuclear receptors, specifically GRalpha.
Describe the mechanism of action of glucocorticoids.
Enter cell by diffusion.
Combine with GRalpha in cytosol producing dissociation of inhibitory heat shock proteins.
Activated receptor translocation to nucleus aided by importins.
In the nucleus the activated receptor monomers assemble into homodimers and bind to glucocorticoid response elements (GRE) in the promoter region of some genes.
Genes switched on or off to alter mRNA levels and the synthesis rate of mediator proteins.
What effects to glucocorticoids have that are relevant to asthma inflammation?
Genes regulated by GRE's or modifying chromatin structure. Generally increase transcription of genes encoding anti-inflammatory proteins and decrease transcription of inflammatory proteins. They therefore prevent and resolve inflammation.
What's are acetyltransferases (HATS)?
They acylate his tones, allowing the DnA to unwind allowing transcription.
How do glucocorticoids stop DNA transcription?
They recruit HDACs (histone deacetylases) to activated genes, making them wind up around histones again and so stopping transcription.
List some features of glucocorticoids that are useful in asthma.
They decrease formation of TH2 cytokines.
Prevent production of antibodies.
Reduce the number of mast cells and macrophages.
Prevent allergen induced influx into the lung.
They cause cell apoptosis (eosinophils).
Decrease number of dendritic cells.
Decrease mucus production.
Decrease endothelial cell leakage.
When should glucocorticoids be used?
Not in acute situations as they don't alleviate bronchospasm. Useful in long term treatment especially with LABAs.
Used in mild/moderate asthma. Given by inflammation, effect develops over several days.
What are the most common glucocorticoid adverse effects?
Dysphonia (hoarseness) and oropharyngeal thrush.
What are cromolins?
Infrequently used prophylactic drugs used in childhood asthma. Uncertain mechanism with weak anti inflammatory effect.
Name a cromolin.
Sodium chromoglicate. Inhaled and can reduce both asthma phases but takes several weeks for efficacy to develop and needs frequent dosing. Better in young adults and kids.
What mechanism do the use of monoclonal antibodies have in asthma?
Bonds IgE via Fc receptors to stop attachment to mast cells. Suppressing their response. They reduce the expression of Fc receptors in various cells.
Name a monoclonal antibody used in asthma?
What muscarinic receptors are in the airways? And where?
M1 - ganglia- facilitate transmission mediated by ach acting on nicotinic receptors.
M2- postganglionic neurone terminals, act as autoreceptors reducing Ach release.
M3- smooth muscle, mediate contraction and on glands facilitating diffusion.
What is one of the main goals of pharmacological treatment in COPD?
Reducing parasympathetic activity on muscarinic receptors by using antagonists.
What do muscarinic acetylcholine receptor antagonists do in COPD?
Antagonists of bronchiconstrictor on caused by smooth muscle M3 receptors from parasympathetic fibres. Blockage of M3 and M1 desirable but not M2.
What are the features of muscarinic acetylcholine receptor antagonist?
SAMAs or LAMAs, delivered by inhalation. Onset of action greater than 30 mins. Relax bronchospasm caused by irritation of vagus reflex that liberates ach. They also block ach mediated basal tone. They decrease mucus secretion. Little effect of the development of COPD, mainly palliative. Few adverse effects.
What is ipratropium? And what is a newer alternative?
A non-selective muscarinic acetylcholine receptor antagonist. Tiotropium is new and only blocks M3.
What competitive muscarinic receptor antagonists currently licensed?
SAMA - ipratropium and oxitopium.
lAMA - tiotropium and aclidinium.
All given by inhalation with low systemic exposure due to quarternary ammonium group (c.f. Atropine).
Why is tiotropium superior to ipratropium?
Greatly longer half life at M3 receptors. 34 vs 3 hours.
Why is blockage of M2 receptors not desirable in the airway?
M2 receptors are autoreceptors and so ach inhibits further ach release. If these are blocked, then release will increase.
What is indacaterol?
An ultra-laba. With rapid onset vs salmeterol.
What drug category combination is good in COPD and why?
Muscarinic ACh antagonists and beta 2 agonist combo e.g. Salmeterol and tiotropium. LABA and LAMA. Work by different but complentary mechanisms to relax smooth muscle.
What is PDE4?
Phosphodiesterase 4. Prominent PDE expressed in neutrophils, T cells and macrophages.
What is rofumilast?
Selective PDE4 inhibitor, suppresses inflammation in COPD. Approved for treatment of severe COPD and chronic bronchitis. Has limiting GI side effects.
What drugs are used in rhinitis?
Glucocorticoids (inflammation), H1 and CYsLT1 receptor antagonists, vasoconstrictors and sodium chromoglicate.
How do glucocorticoids help rhinitis?
Reduce vascular permeability and inflammation. Usually applied topically as a nasal spray. Effective monotherapy.
What are examples of glucocorticoids given in rhinitis?
Beclometasone, fluticasone and prednisolone.
What antihistamines can be used for rhinitis?
Loratidine, fexofenadine and cetrizine. All second generation.
How are antihistamines administered for rhinitis?
Orally or as intranasal spray.
How are anti cholinergic drugs administered for rhinitis?
Nasal route. Ipratropium is the only one used.
What CysLT1 leukotriene receptor antagonists is used in rhinitis? How is it administered?