Pharmacology Flashcards
Volume of Distribution
- volume of distribution is the measure of the apparent space in the body available to contain the drug - it relates the amount of drug in the body to the concentration of the drug in blood/plasma - Vd = amount of drug in body/concentration - proportional to half life (Drugs with high Vd are tightly bound by tissues compared with blood, therefore much higher conc in extravasc tissue than in vasc compartment. Drugs with small Vd are tightly bound to plasma proteins and not tissues.)
Factors that affect Vd
- drug properties - lipid soluability, pKa, pH, protein binding, blood flow - patient properties: age, gender, disease, body composition
What is the importance of Vd in overdose situation?
Drugs with large Vd (TCAs) cannot be dialysed, whereas drugs with small Vd (ASA, lithium) can.
Drugs with a high Vd (>70L/70kg)
Diazepam, B-blockers, TCAs, digoxin, morphine, colonising, fluoxetine, chloroquine, cyclosporin
Drugs with low Vd (< 50L/70kg)
Warfarin, lithium, phenytoin, aspirin, frusemide, valproic acid, tolbutamide, cephalexin
What is a ‘second messenger’?
A second messenger is an intracellular substance which has its concentration altered by a process initiated by an extra cellular ligand. The second messenger then acts to initiate or facilitate an intracellular process. 1. Extra cellular process 2. Transmembrane signalling system 3. Intracellular process
If a drug is distributed in the TBW, what is it’s Vd?
TBW: 0.6L/kg or 42L/70kg
What formula describes drug clearance?
Ratio of rate of elimination of a drug to its concentration in blood/plasma Drug clearance (CL) = rate of elimination/concentration
What is Flow Dependent Elimination?
For drugs that are readily cleared by their organ of elimination (high extraction ratio), the rate of elimination is dependent on rate of drug delivery to the organ, which is determined by blood flow and plasma protein binding. Systemic CL = CLrenal + CLliver + CLother
Name drugs that have flow dependent elimination
Hepatic: lignocaine, propranolol, verapamil, morphine, pethidine
Sites of drug biotransformation
Liver GIT Lung Skin Kidneys
Describe phase 1 biotransformation reaction
Conversion of a parent drug to a more polar/water soluble form by the adding or unmasking of a functional group. Most commonly by oxidation, also reduction and hydrolysis. Hepatic CYP (P450) enzymes are responsible for the majority of phase 1 reactions.
What is meant by enzyme induction in liver biotransformation?
Repeated administration of a substrate brings about either enhanced enzyme synthesis or reduced enzyme degradation causing increased metabolism of the substrate.
Describe the difference between a competitive and an irreversible antagonist
Competitive - in fixed concentration of agonist, increasing conc of antagonist will lead to progressively inhibited response, but an increasing agonist conc can overcome to still evoke maximal response (agonist conc/effect curve shift to right) - high competitive antagonist conc can prevent response completely if agonist conc fixed - eg naloxone, flumazenil, propranolol, isoprenaline, naltrexone, nalmefene Irreversible - binds so tightly/covalently as to make receptor unavailable to agonist - number of remaining receptors may then be too low to allow maximal response to occur regardless of agonist conc (unless spare receptors) - length of effect of irreversible antagonist will reflect turnover of receptors involved rather than rate of elimination of antagonist - phenoxyenxamine, MAOI
What is Total Body Clearance of a drug?
- describes the ability of the body to eliminate a drug - refers to the theoretical volume of plasma emptied of drug per unit time (usually L/h) - total body clearance reflects the sum of all clearance process including renal/hepatic/other
Name 2 drugs that have a high hepatic clearance and explain why this is important.
- lignocaine, morphine, propranolol, pethidine - drugs with high hepatic elimination may only be suitable for parental administration or have significant dosing variations depending on route of administration
What factors determine drug half-life?
- volume of distribution and clearance T1/2 = 0.7 x Vd/Cl - Vd and Cl change with disease states - cardiac, hepatic, and renal failure
Routes of drug administration
- Enteral: sublingual, buccal, oral, rectal - Parenteral: SC, IM, IV, intrathecal, epidural - Inhalational - Topical
Factors affecting the rate of drug absorption from the small intestine
Ionisation status of the drug - solubility of drug, formulation of drug Gut factors - gut surface area, blood flow, intestinal motility (reduced transit time and gut absorption)
What are potential disadvantages of rectal drug administration?
- erratic absorption due to rectal contents - local drug irritation - uncertainty of drug retention
What is drug ‘potency’?
- potency is the measure of how much drug is required for effect - potency refers to the affinity or attraction between an agonist and its receptor - a good measure of drug potency is the EC50 - the concentration that produces 50% of the maximal response
What is drug efficacy?
Efficacy is the maximal effect,response that the drug (agonist) can produce (Emax) when all receptors are occupied, irrespective of the concentration required to produce that response.
Draw a concentration-response curve showing 2 drugs with the same potency but different efficacy
See pic
Draw and explain a dose-response curve for an agonist. Show how this curve is altered in the presence of an irreversible antagonist. How does this differ from a competitive antagonist?
See pic
Factors affecting placental drug transfer
- lipid solubility - molecular size - placental transporters - protein binding - placental and foetal drug metabolism
What is meant by foetal therapeutics? Give examples.
Drug administration to the pregnant woman with the foetus as the target. Examples - corticosteroids (for lung maturation) - phenobarbitone (induce enzymes for glucuronidation of bilirubin) - antiretrovirals (decrease HIV transmission) - antiarrhythmics
In children, what factors change with age and alter pharmacokinetics?
Body Size + Composition - growth of child (doses calculated in mg/kg), adult/neonate water 50/70% extracellular 20/40%, preterm neonate 85% water, influences drugs distributed in extracellular space, fat adults 15% pre term infants 1%, plasma proteins (decreased albumin in neonate, potential for increased toxicity in neonate so if drugs are highly protein bound), jaundiced neonate so (if drug highly protein bound will displace bilirubin and cause kernicterus) Drug Metabolism - most drugs metabolised in liver, only 50-70% of adult values, slow clearance and prolonged elimination half lives Drug Excretion - GFR lower in newborns than older infants, neonate 30-40% of adult values, 3 weeks 50-60%, 6-12 months hit adult values
Define drug elimination half life Formula How does half life help clinically?
Time required to change the amount of drug in the body by 1/2 during elimination T1/2 = 0.7 x Vd/Cl Indicates time to steady state after dose change (50% after 1, >90% after 4)
What is the difference between full agonist and a partial agonist?
High concentrations of full agonists can evoke a maximal response, but partial agonists cannot evoke maximal response at any concentration.
Under what circumstances can a partial agonist act as an antagonist?
In the presence of a full agonist Eg buprenorphine
What factors determine the difference in drug metabolism between individuals?
Genetic - enzyme level differences Age - extremes have dec enzyme activity/cofactors Drug-drug interactions - enzyme induction/inhibition, substrate comp Disease states - hepatic, pulmonary, cardiac, thyroid, inflam Diet - induce/inhibit enzymes Environmental - exposure to enzyme inducers Sex - males inc metabolic rate Liver size & function
What is meant by enzyme induction?
Drug causes an increased rate of synthesis or decreased rate of degradation of enzyme, causing: - accelerated substrate metabolism - decreased pharmacological action of the inducer or co-administered drug
List the various molecular mechanisms of transmembrane signalling.
- Lipid soluble ligand crosses membrane and binds to intracellular receptor 2. Transmembrane receptor protein with ligand binding to extracellular domain regulating intracellular enzymatic activity 3. Transmembrane receptor protein that binds & stimulates protein tyrosine kinase 4. Ligand-gated transmembrane ion channels 5. Transmembrane receptor protein, G protein, intracellular second messenger
Describe the function of the system involving G proteins
Transmembrane signalling system with 3 separate components. Extracellular ligand binds to the specific cell surface receptor. This receptor then activates G protein located on cytoplasmic surface membrane. Activated G protein changes activity of effector element (enzyme/ion channel) leading to a change in concentration of second messenger.
What is first pass metabolism?
After absorption of an orally ingested drug, portal blood delivers drug to liver where it is changed before reaching systemic circulation (metabolised in gut wall/portal blood/liver, excreted into bile). Ie It reduces the bioavailability of a drug.
How can you increase bioavailability?
- Different route of administration - IV, IM/SC, SL, PR (50% bypass), Inh, TD 2. Increase absorption (depending on properties of drug) - hydrophilic, lipophilic, actively pumped into gut
Define drug clearance
- Volume of plasma/blood cleared per unit time, or rate of elimination 2. CL systemic = CL renal + CL liver + CL other
What is the relationship between clearance and the dosing frequency of a drug?
- Knowing the clearance of a drug will allow the dosage to be worked out to achieve the target concentration (to maintain steady state, the dosing rate must equal the rate of elimination). 2. Maintenance dose needs to be adjusted for disease states which affect clearance (eg renal failure). 3. Dosing rates (mg/hr) = rate of elimination (steady state) = CL x target conc
Give an example of dosage adjustment for impaired clearance.
Gentamicin, digoxin in renal failure. Loading dose not affected, maintenance dose reduced or dosage interval increased.
With respect to the biotransformation of drugs, please distinguish between Phase 1 & Phase 2 reactions.
Phase 1 - converts the parent drug to a more polar metabolite by introducing or unmasking functional groups (-OH, -NH2, -SH) - eg: oxidations including cytochrome p450 dependent and independent, deaminations, desulfurations, reductions, hydrolysis Phase 2 - involves conjugation with an endogenous substrate to form a highly polar conjugate - eg: glucuronidation, acetylation, sulfation, methylation, conjugation Both types of reactions result in more polar compounds that are more amenable to urinary excretion.
Does biotransformation generally result in more or less active metabolites?
Usually less active. Detoxification may frequently result in metabolites with residual pharmacological activity or even enhanced activity (activation).
Variables influencing the extent & rate that drugs are absorbed
- Route of administration 2. Nature of absorbing surface - cell membrane (single layer of intestinal epi cells compared to several layers of skin cells) - surface area (lung, small intestine, stomach) 3. Blood flow - blood flow enhances absorption (SL v SC) 4. Drug solubility - lipid soluble drugs 5. Drug formulation - enteric coatings
Explain why aspirin absorption is enhanced by the low pH in the stomach.
Aspirin is an acidic drug (pKa 2.98), relatively unionised in the stomach and more ionised in the small intestine. Ie it is more lipid soluble in the stomach and therefore more easily absorbed.
How does ionisation of a drug affect it’s solubility?
Drugs exist as weak acids or weak bases and in the body they are either ionised or un-ionised. Ionised (charged polar) more water soluble. Un-ionised (non-polar) more lipid soluble
Describe Phase 1 and Phase 2 reactions in drug metabolism.
Process of chemical modification of a drug leading to more hydrophilic, more polar, readily excreted compound. Phase 1 (functionalization): converts parent drug to more polar, often inactive metabolite. Oxidation, reduction, hydrolysis - majority of reaction via cytochrome P450 enzymes. Phase 2 (conjugation): metabolites combine with endogenous glucuronic a, sulphate, acetylcoenzyme A, or glutathione to form more polar metabolite. Phase 1 & 2 can occur alone, sequentially, or simultaneously. Metabolites can be more active or toxic than the parent drugs.
Define bioavailability.
Fraction of unchanged drug reaching systemic circulation following administration by any route. AUC (conc-time) is a common measure of the extent of bioavailability.
Factors that affect bioavailability
Extent of absorption - too hydrophilic/too lipophilic, reverse transporter ass with P-glycoprotein (pumps drug back to gut lumen), gut wall metabolism First pass metabolism - metabolism by liver before it reaches systemic circulation, small additional effect if drug has biliary excretion Rate of absorption - determined by site of administration and drug formulation
How can the effect of first pass metabolism be overcome?
Change route of administration to SL, TD, PR, Inh, IV, IM Increase dose
How does Hartmann’s differ from normal saline?
- addition of sodium lactate, potassium chloride, calcium chloride (+pH adjustment) - Hartmann’s Na 131, K 5, Cl 112, Ca 2, Lactate/bicarb 28mmol - N/saline Na 150, Cl 150
What are the potential advantages of Hartmann’s in resuscitation?
- closer to physiologic re potassium, calcium - less hyperchloraemic - effective bicarbonate (?some slow good effect on acidosis)
Potential complications of IV therapy
- overload/under resuscitation - hypothermia - extravasation - acidosis - electrolyte abnormalities - osmo changes - air embolism - infection - cerebral oedema - haemodilution
What is drug clearance?
- Measure of the ability of the body to eliminate a drug - Rate of elimination in relation to drug concentration - CL = rate of elimination/conc
What factors affect drug clearance?
Concentration - dose & bioavailability Elimination - specific organ function/blood flow & protein binding Organ specifics - major sites of elimination are kidneys and liver, therefore factors that affect these organs’ function/blood flow will have most effect
What is the difference between capacity-limited and flow-dependent drug elimination?
Capacity limited - saturable, zero order kinetics - eg aspirin, phenytoin, ethanol Flow dependent - non-saturable, first order kinetics, organ blood flow, protein binding - eg amitriptyline, isoniazid, labetalol, lignocaine, morphine, propranolol, verapamil
What is the difference between a competitive and irreversible antagonist?
Competitive (naloxone, flumazenil, propranolol, isoprenaline) - in fixed conc of agonist, inc conc of antagonist will lead to progressively inhibited response, but an inc agonist conc can overcome to still evoke max response (agonist conc/effect curve R) - high competitive antagonist conc can prevent response completely if agonist conc fixed Irreversible (MAOI, phenoxyenzamine) - bind so tightly/covalently to receptor makes it unavailable to agonist - number of remaining receptors may then be too low to allow maximal response to occur regardless of agonist conc (unless spare receptors) - length of effect will reflect turnover of receptors involved rather than rate of elimination of antagonist
Define drug elimination half-life
- time required to change the amount of drug in the body by 1/2 during elimination - T1/2 = 0.7 x Vd/clearance - 50% after 1, >90% after 4
How does knowledge of a drug’s half life help us clinically?
- dosing regimes - decay after dose/overdose - time to steady state after dose change
What disease states can affect elimination half-life?
- liver - renal - cardiac disease - eg morphine affected by liver and renal disease
Outline the mechanism of action for aspirin.
Irreversible non-selective cyclooxygenase inhibition (COX 1 & 2) - in platelets, irreversible inhibition of COX 1 results in reduction in thromboxane A2 and inhibition of platelet aggregation for the life of the platelet (10 days) - in tissues, inhibits prostaglandin synthesis (COX 2) resulting in anti-inflammatory action, analgesic and anti-pyretic effects
Describe the pharmacokinetics of aspirin.
- rapidly absorbed from stomach and intestine, aspirin hydrolysed to salicyclic acid in plasma/blood, peak plasma level within 1-2hrs - serum half-life of aspirin is 15 mins, low protein binding, saturable metabolism with increasing doses (switches from first to zero order metabolism) - urinary alkalinisation increases excretion of salicylate and its conjs
Outline the adverse effects of aspirin
- GI upset, GI bleeding (gastritis, peptic ulceration) - Hepatotoxicity - Hypersensitivity reactions (asthma, angioedema, rash) - Prolonged bleeding time from platelet inhibition
Describe the mechanism of action of glyceryl trinitrate
- taken up by vascular smooth muscle - interacts with tissue sulfhydryl groups - releases free radical nitric oxide - activates cGMP - dephosphorylates myosin light chains - reduces intracellular Ca levels - smooth muscle relaxation & vasodilation
What are the clinical effects of nitrates?
- low doses: venodilation leads to decreased preload & stroke volume - higher doses: arterial dilation leads to dec blood pressure as well as dec cardiac output & dec myocardial oxygen demand + dilation of coronary arteries/redistribution of perfusion - improved oxygen delivery to myocardium & resolution of ischaemic pain - adverse effects: postural hypotension, tachycardia, dizziness, headache, flushing, blurred vision, dry mouth, rash
Describe the mechanism of action of ACE inhibitors.
- competitive block conversion of angiotensin 1 to 2 - dec vascular tone from prevention of vasoconstrictor effects of AT2 (main effect) - inhibition of aldosterone secretion caused by AT2 leading to reduced Na & H2 resorption resulted in dec BP
What are the adverse effects of ACE inhibitors?
- dizziness, hypotension - cough - headaches, weakness - loss of taste, nausea, diarrhoea - rash, fever, joint pain - mild hyperK due to dec in aldosterone secretion, ARF
What are some drug interactions that occur with ACE inhibitors?
Diuretics - hypotension General anaesthetics - hypotension Lithium - lithium toxicity NSAIDs - hyperkalaemia & reduced effects of ACE inhibitor K sparing diuretics/K supplements - hyperkalaemia
Describe the pharmacodynamics of therapeutic drugs that modulate the effect of angiotensin
- ACE inhibitors - bind ACE reversibly preventing conversion of AT1 to AT2 - inhibitory action on the renin-angiotensin system stimulating action on kallikrein-kinin system
What are the advantages of AT2 receptor antagonists over ACE inhibitors?
- AT2 inhibitors - competitive antagonists at AT2 receptor - as AT2 inhibitors do not result in production of bradykinins, there is a dec incidence of cough and angioedema - potentially greater effect as enzymes other than ACE can generate AT2
What is the cellular mechanism of action of GTN?
- denitration by glutathione S-transferase - free nitrite ions released and form NO - NO activates guanylyl cyclise leading to increased cGMP and dephosphorylation of myosin and smooth muscle relaxation (precise mechanism unknown)
How does GTN relieve angina pain?
- venodilation leads to reduced venous return, reduce ventricular volume and reduced heart wall tension - this reduces myocardial O2 requirement
Outline the pharmacokinetics of sublingual GTN.
- oral bioavailability is low due to extensive first pass hepatic metabolism by high capacity organic nitrate reductase - rapid and efficient absorption by sublingual or intranasal routes but rapid elimination (t1/2 2-8mins) and duration of action (15-30mins) due to high capacity hepatic metabolism - denitrited metabolites conjugated to glucuronide and excreted in urine
How does GTN exert its effect on smooth muscle?
- nitrite -> NO -> increased cGMP -> relaxation - prostaglandins also involved
What are the clinical effects of GTN?
- venodilation -> reduced venous return -> reduced LVEDV -> reduced LV wall tension -> reduced myocardial oxygen consumption (-> reduced cardiac output in normal people, possibly inc in pathological conditions where pretreatment preload is abnormally high) - arterial dilation -> throbbing headache (relatively ineffective on resistance vessels) - other smooth muscle relaxation (eg amyl nitrate + enhanced erection) - dec platelet aggregation, but no apparent beneficial therapeutic effect in this regard - methaemoglobinaemia from nitrite, but not from GTN
What are the pharmacokinetic features of B-blockers?
- well absorbed - low bioavailability - large volume of distribution - most are metabolised in liver
What are the effects of beta blockers?
- dec in hypertension - negative chronotrope and negative ionotrope - AV block - increased survival after AMI - bronchospasm - dec IO pressure
What are the effects of B-blocker in overdose?
- hypotension, bradycardia, cardiogenic shock, bronchospasm, seizures (cerebrotoxic) - NB propranolol causes arrhythmias through Type 1 antiarrhythmic effects (Na channel block)
What is the mechanism of action of atropine?
Reversible block of cholinergic muscarinic receptors.
Examples of organ effects of atropine.
CNS: dec tremor & rigidity in Parkinson’s disease Eye: mydriasis (pupil dilation) & cycloplegia (ciliary m paralysis - loss of accommodation) CVS: SA (and AV) node, blocks vagal slowing -> rel tachycardia and inc conduction (shorten PR), block coronary vasodilation Resp: blocks M receptors on sm m & secretions GI: blocks motility & secretions GUT: relaxes sm m in ureters & bladder wall (spasm) and slows voiding (retention) Skin: decreases sweating
What are the features of atropine poisoning?
- agitation & delirium - raised temp - blurred vision/mydriasis - dry mouth/flushed skin - tachycardia
At a cellular level, describe the action of Ca channel blockers
Bind at intracellular L type Ca channel
- What are the differences in pharmacodynamics between dihydropyridines and other Ca channel blockers? 2. How are these differing pharmacodynamics reflected in their side effect profile?
- Dihydropyridines (amlodipine) are vascular sm m selective. Verapamil/diltiazem greater effect on cardiac/conducting tissue. 2. Dihydropyridines cause flushing, headaches, & tachycardia. Verapamil causes bradycardia. Both can cause hypotension.
What is the mechanism of action of captopril?
- inhibit converting enzyme peptidyl dipeptidase (which hydrolysis AT1 to AT2 - get dec peripheral vasc resistance; CO & HR same - inactivates bradykinin -> vasodilation, dec peripheral vasc resistance & dec BP
Clinical uses of captopril
- CCF, after MI (better preservation of LVF - reduce post MI remodelling) - hypertension - diabetic nephropathy: diminish protein urea, stabilise renal function - improved intrarenal haemodynamics
Adverse effects of captopril
- hypotension after 1st dose if hypovolaemic, diuretics, NaCl restriction, GI loss - ARF (bilateral renal a stenosis) - hyperkalaemia if renal insufficiency, DM - dry cough, angioedema (bradykinin, substance P) - foetal problems if 2nd/3rd trimester - neutropaenia, proteinuria from high dose captopril - minor: taste change, skin rash, drug fever
- What is the mechanism of action of adenosine? 2. What effect does this have on cardiac conduction?
- enhanced K+ conduction -> marked hyperpolarisation - inhibition of cAMP induced Ca2+ influx -> suppression of Ca dependant action potential 2. - inhibits AV node conduction (at least) - increases AV node refractory period - lesser effect on SA node
What are the cardiac effects of amiodarone at a cellular level?
- prolongs AP duration (by blocking K+ channels) - blocks inactivated Na channels, the AP prolonging action reinforces this effect - blocks depolarised cells > normal cells - mild antisympathetic, no competitive inhibitor of B receptors - weak adrenergic blocker -> slows HR and AV node conduction - weak Ca channel blocker -> inhibits abnormal automaticity, slows sinus rate, increase PR interval
What are the mechanisms of pharmacokinetic drug interaction with amiodarone? Give 2 examples.
Inhibits liver cytochrome metabolising enzymes - digoxin, warfarin levels increase - cimetidine increases amiodarone toxicity by dec hepatic clearance - interacts with statins (atorvastatin/simvastatin, use pravastatin as not P450) - concentration and effects of phenytoin, anaesthetics, cyclosporins, theophylline, procainamide, flecainide, quinidine are increased by amiodarone
Describe the pharmacokinetics of metoprolol
- oral or IV, well absorbed - bioavailability 50% due to first-pass effect - large volume of distribution - Half life 3-4hrs - metabolised in the liver
How does metoprolol differ from propranolol in its action at beta receptors?
- B1 equipotent - B2 50-100 x less potent
How do B-blockers control hypertension?
- not fully understood - negative inotropic and chronotropic effects - slow AV node conduction - antagonises release of renin caused by sympathetic nervous system
Pharmokinetics of atropine
- oral (well absorbed) or IV (usual), neb, topical - widely distributed (including CNS) - half life 2 hours - elimination: 60% excreted renally unchanged - 40% phase 1 & 2 metabolism and renally excreted
At which receptors does atropine act?
- muscarinic (equipotent at M1, M2, & M3) - nicotinic (minimal potency)
Effects of atropine on heart rate
Dose dependant - at lower doses often an initial bradycardia -> blocks prejunctional M1 receptors - tachycardia
Mechanism of action of Calcium Channel Blockers
CCBs bind to receptors on alpha 1/2, gamma, delta subunits of L-type Ca channel - dec freq of opening of Ca channels in response to depolarisation - dec transmembrane Ca current - dec Ca influx -> vascular sm m relaxation, dec contractility in cardiac m, dec SA node pacemaker rate, dec AV node conduction velocity
Toxic effects of CCBs
- CVS: cardiac arrest, bradycardia, AV block, heart failure, hypotension - Minor: flushing, dizziness, nausea, constipation, peripheral oedema
Mechanism of action of atropine
Antimuscarinic at cholinergic receptors
Toxic effects of atropine
Tachycardia, flushing, dry skin/mucous membranes, mydriasis, ileus, urinary retention, acute angle glaucoma, central anticholergic syndrome (delirium with visual hallucinations)
Therapeutic uses for atropine
- symptomatic bradycardias, esp when vagally mediated - OGP poisoning/inocybe mushroom poisoning, drying of secretions - adjunct to reversal of non-depolarising muscle relaxants and sux administration in young infants - antispasmodic - mydriatic (dilation of pupil)
Regarding B agonists, by what cellular mechanism do they exert their effects?
- bind to specific receptor - G-protein activation - stimulate adenyl cyclase - increased cyclic AMP - increased free intracellular Ca - activate protein kinase
Compare the cardiovascular effects of adrenaline and dobutamine
Adrenaline: - has B1, B2 and alpha effects - increased inotrope and chronotrope - peripheral vasoconstriction in most vascular beds - vasodilation in skeletal m beds (B2), may reduce TSVR Dobutamine: - is a selective B1 agonist - increases cardiac output with less reflex tachycardia as it has fewer B2 effects - comes as racemic mixture of +ve and -ve isomers, one isomer has B agonist and alpha antagonist effects, the other has alpha agonist effects
What is flecainide’s mechanism of action?
Na channel blockade (class effect) - predominant action is to inhibit the fast, or sodium, channel which is largely responsible for the rapid upstroke of the myocardial action potential in cardiac conducting tissue Class 1C action - minimal effect on the action potential duration and dissociates from the Na channel with slow kinetics (no effect on QT interval) Decrease the rate of rise of the action potential with little effect on duration
Describe flecainide’s pharmacokinetics.
- well absorbed orally, half life ~ 20hrs - peak plasma drug levels at ~ 3hrs (range 1-6hrs) - Vd ranges from 5 - 13.4L/kg (mean 8.7L/kg) - 30% of a single oral dose (range 10 - 50%) is excreted in urine as unchanged drug, remainder by hepatic metabolism - usual dose 100-200mg daily - SE: hypotension, LV dysfunction
What are the effects of adrenaline on the blood vessels in different tissues? What receptors mediate these effects?
Vascular resistance - cutaneous (alpha) - mucous membranes (alpha) - skeletal muscle (B2, alpha) - renal (alpha, delta) - splanchnic (alpha, B), venous tone (alpha, B)
Describe the effects of adrenaline on other organs besides the heart
Resp - bronchodilation Eyes - pupillary dilation, dec intraocular pressure, dec prod aqueous H GI - relaxation of gastric sm m, dec salivary production GUT - uterine sm m relaxation, bladder relaxation, bladder sphincter contraction, ejaculation Skin - apocrine sweat glands (hands) Liver - enhanced glycogenolysis Lipolysis - inc fatty acids & glycerol in circulation Metabolic acidosis Dec extracellular potassium Leucocytosis Insulin - inhibits or stimulates insulin secretion
The actions of digoxin on the heart at therapeutic levels
Mechanical: Na-K ATPase Electrical: - direct: alters action potential - indirect: autonomic, parasympathetic effects predominate Sensitisation of baroreceptors Central vagal stimulation Facilitation of muscarinic transmission
Are the parasympathetic effects of digoxin uniform throughout the heart?
No. Affect atrial and AV nodal function more than Purkinje or ventricular function.
Sites of action of anti hypertensive drugs (with examples)
Vasomotor centre - clonidine, methyldopa Sympathetic ganglia - trimethaphan Sympathetic nerve terminals - guanethidine, reserpine * B receptors of the heart - B blockers * Angiotensin receptors of blood vessels (?by) - AT2 receptor blockers Alpha receptors of blood vessels (?by) - prazosin * Vascular sm m - hydrallazine, SNP, Ca blockers, GTN * Kidney tubules - diuretics B receptors juxtaglomerular cells - B-blockers * ACE
Describe the molecular action of digoxin
Na+/K+ ATPase (sodium pump) inhibition - binds to alpha subunit which has different isoforms - differing affinities for digoxin in various tissues - low concentration occasionally stimulate the enzyme
What are the cardiac effects of digoxin?
Mechanical: increased contractility due to increased intensity of interaction of actin and myosin filaments due to inc free calcium during systole. Electrical: - Direct: shortening of action potential and therefore shortened atrial & ventricular refractoriness - at toxic levels, resting membrane potential reduced, then as toxicity progresses depolarising afterpotentials - Autonomic: at lower doses parasymp effects predominate
What are the non-cardiac manifestations of digoxin toxicity?
At toxic levels, sympathetic outflow inc - all excitable tissue including smooth muscle and CNS. Relative low sens compared to cardiac. GIT: nausea, vomiting, diarrhoea, anorexia CNS: nausea, vomiting, disorientation, hallucinations, visual disturbances, agitation, convulsions Gynaecomastia
Pharmacokinetics of digoxin
- well absorbed orally - moderate Vd (6.3L/kg) - not extensively metabolised, 2/3 excreted unchanged by the kidneys - 10% population with enteric bacteria that reduce oral bioavail - 20-40% plasma protein bound
Describe succinylcholine and its metabolism
- depolarising neuromuscular blocking drug - hydrolysed by plasma cholinesterase (to succinic acid & choline) - action at motor end plate terminated by diffusion away into ECF
What are the adverse effects of depolarising neuromuscular blockade?
Hyperkalaemia: renal failure, burns >24hrs, demyelination, spinal cord injury, muscular dystrophies, CVA Increased IOP, intragastric & ICP Paralysis & prolonged apnoea CVS: negative inotrope & chronotrope Muscle pain
Describe the mechanism of action of amiodarone
Potassium channel blocker (Class 3) Prolongs refractory period by prolonging action potential duration Na channel blockade (Class 1), blocks inactivated Na channels Weak Ca channel (Class 4) & adrenergic (Class 2) blocking Vasodilator
What are the clinical uses of amiodarone?
Atrial & ventricular arrhythmias Maintaining sinus rhythm in AF Prevention of recurrent VT
Describe the potential adverse effects of amiodarone
Cardiac: bradycardia, heart block, hypotension, negative inotropy. Pulmonary fibrosis Abnormal LFTs & hepatitis Skin and corneal deposits Hypo/hyperthyroidism (blocks peripheral conversion of T4 to T3)
What are the organ effects of nitrous oxide?
CNS: analgesic, amnesic, inc CBF Renal: decreased GFR, inc filtration fraction & inc renal vasc resistance CVS: dose dependant myocardial depression Resp: reduced resp response to CO2 & hypoxia
Mechanism of action of nitrous oxide
Directly activate GABA A receptors - GABA A receptor Cl channel, facilitates GABA mediated inhibition at GABA receptor sites - membrane hyperpolarisation - dec duration of opening of nicotinic receptor activated channels, dec excitatory effect of Ach
Describe the pharmacodynamics of propranolol
- non selective action on beta receptors - membrane stabilising action - antagonises renin release from sympathetic ns - competitive, pure antagonist - others: inhibits sympathetic ns stimulation of lipolysis, inhibits liver glycogenolysis, reduces aqueous humour production, inc VLDL, dec HDL, blocks B2 receptor in bronchial sm m inc airway resistance
How does carvedilol differ from propranolol?
- carvedilol has no local anaesthetic action - causes A1 adrenoceptor block, but effect on beta > alpha - stereoselective metabolism of its 2 isomers occurs
What are the effects of nitric oxide?
- smooth muscle relaxant - platelet inhibitor - immune regulator - neurotransmitter
Potential therapeutic applications of nitric oxide
- Vascular effects - vasc sm m tone & BP, inhibits neutrophil adhesion to vasc endothelium 2. HTN ass with pregnancy - resemble deficiency of NO & PG 3. Resp disorders - via inh for newborns with pulm HTN & ARDS, dec pulm a pressure, improves blood O2, adults with ARDS, poss bronchodilator 4. Septic shock - urinary excretion of NO3, bacterial infection 5. Atherosclerosis - poss antioxidant, block LDL prev foam cell form 6. Platelets - potent inhibitor of platelet adhesion & aggregation 7. Organ transplantation - dec free radical toxicity, inhibits platelet/neutrophil aggregation/adhesion to vasc wall 8. CNS - modifies neurotransmitter release, also negative effects 9. PNS - NO promotes relax of sm m in corpora cavernous a
What is the mechanism of action of glyceryl trinitrate in smooth muscle?
NO release, cGMP increases
How do nitrates relieve angina?
Preload reduction decreases myocardial work
Describe the pharmacokinetics of propranolol.
- high 1st pass liver metabolism - high lipid soluability - B-blockade with variable selectivity - negative inotropic and chronotropic
What B-receptor types are there?
B1, B2, B3
What cellular processes do B-agonist-B-receptor coupling initiate?
Activation of all 3 receptor types results in stimulation of adenylyl cyclase and increased conversion of ATP to cAMP. Mediated by stimulatory coupling protein (Gs) via GDP & GTP
What are the clinical uses of B2 selective agonists?
Respiratory, uterine, and vascular smooth muscle relaxation Skeletal muscle K+ uptake
What is the mechanism of action of warfarin?
- inhibits reduction of inactive Vit K epoxide (KO) to active hydroquinone (KH2) form - blocks gamma-carboxylation of glutamate residues in prothrombin (factor 2) and factors 7, 9, 10 as well as endogenous anticoagulant protein C & S
Why is there a delay in the onset of action of warfarin?
8-12hr delay due partially inhibited synthesis and unaltered degradation of 4 Vit K dependent clotting factors and depends on degradation 1/2 in circulation - eg factor 7 (6hrs), 9 (24hrs), 10 (40hrs), 2 (60hrs)
What pharmacological agents are used in the reversal of warfarin?
- vitamin K - FFP - prothrombin complex - recombinant factor 7a
Describe the mechanisms of drug interactions with warfarin
Pharmacokinetic - enzyme induction and inhibition - altered protein binding Pharmacodynamic - synergism - competitive antagonism (Vit K)
List the classes of drugs used for the management of AF in the ED
- B-blockers (class 2) 2. Ca channel blockers (class 4) 3. Cardiac glycosides (eg digoxin) 4. Class 1c antiarrhythmics (eg flecainide) 5. Class 3 antiarrhythmics (eg amiodarone, sotolol)
Describe the pharmacodynamics of sotolol
Class 2 - non-selective B-blocker Class 3 - prolongs plateau phase
Main side effects of sotolol
Pro-arrhythmic - esp prolongation of QT Torsades CCF Asthma AV blockade
What drug interactions with sotalol prolong the QT?
Drugs with prolong QT - phenothiazines, macrolides (erythromycin), quinolones Anti-depressants - increased risk of torsades Drugs which cause hypokalaemia/hypomagnesaemia inc risk of Torsades Myocardial depressant drugs - inc LVF CCB, class 1a antiarrhythmics - may increase refractory time & contraction
Describe the mechanisms by which drugs interact with warfarin
PK: enzyme inhibition (maj), enzyme induction, altered plasma protein binding,altered abs PD: synergism (impaired homeostasis), competitive antagonism (clotting factor synthesis/concentration)
Give some examples of drugs that increase INR
Aspirin, heparin, corticosteroids, metronidazole, fluconazole, trimethoprim-sulfamethoxazole, 3rd gen cephalosporins, macrolides, amiodarone, SSRIs, tramadol.
Give some examples of drugs that decrease the INR
Vit K, diuretics, barbiturates, phenytoin, carbamazepine, rifampicin, dicloxacillin, azathioprim.
- What are the indications for use of adenosine? 2. How does it work?
- Conversion of paroxysmal SVT to sinus rhythm. 2. Activation of inward rectifier K+ currents and inhibition of calcium currents. Leads to marked hyperpolarisation and suppression of calcium-dependent APs. Effect is direct inhibition of AV nodal conduction and increase in AV node refractory period. This interrupts re-entry pathway through AV node.
How do the specific pharmacokinetic properties of adenosine influence the method of administration?
- very rapid metabolism by adenosine deaminase in red cells and vessel walls = very short elimination t1/2 (<10sec) and duration of action (30sec) - must be given by rapid IV bolusing - if initial dose is ineffective then subsequent dose should be increased (no accumulation occurs)
Describe the mechanism of action of tissue plasminogen activator (tPA)?
- activates plasminogen to form plasmin, resulting in fibrin digestion - preferentially activates plasminogen bound to fibrin by several hundred fold, therefore is considered clot specific - short half life therefore heparin is essential adjunct - naturally occurring
What are the clinical uses of tPA?
- AMI - unstable PE - acute ischaemic stroke - severe DVT, peripheral limb intra-arterial clot
What are the complications of tPA?
Haemorrhage - physiological haemostatic thrombi at site of vascular injury eg GIH - systemic lytic state resulting from formation of plasmin, producing fibrinogenolysis and destruction of other coagulation factors esp 5 and 8.
What is the mechanism of action of atropine?
A reversible muscarinic antagonist. Binds to muscarinic receptor, preventing release of inositol triphosphate (IP3) and the inhibition of adenyl cyclase which are caused by the muscarinic agonists.
Describe the organ effects of atropine.
CNS: decreased tremor in Parkinson’s disease, delirium EYE: mydriasis & cycloplegia CVS: tachycardia RESP: bronchodilation and dec secretions GIT: inc salivary secretion, dec gastric secretion of acid/pepsin/mucin, dec gastric emptying, dec gut transit time GUT: relaxes ureteric & bladder wall sm m and slows voiding Decreased sweating
Describe the mechanism of action of heparin.
- binds to endothelial cell surfaces & plasma proteins - its activity depends on antithrombin - heparin binds to antithrombin, causes a conformational change in the inhibitor, exposing its active site for more rapid interaction with proteases - heparin acts as a cofactors for the antithrombin-proteases reaction - antithrombin inhibits proteases esp thrombin 2a, 9a, 10a by forming stable complexes with them and the presence of heparin accelerates this reaction 1000 x - the binding of AT3 and unfractionated heparin -> degradation of both factor 10a and thrombin
How is heparin reversed?
Stop the drug. Administer antagonist protamine (100 units heparin - 1mg protamine) which binds heparin to form a complex devoid of anticoag activity. Excess protamine anticoag effect.
What are the potential adverse effects of heparin?
Bleeding - elderly women, renal failure more prone Thrombocytopaenia - 1-4%, rare pregnancy, lower rates in paediatrics Allergy Reversible alopecia Accelerates clearing of post prandial lipaemia Long term: OP, spont #, mineralocorticoid deficiency
What are the principle effects of adenosine on cardiac conduction?
- Inhibits AV nodal conduction (inc PR interval) 2. Increases AV nodal refractory period 3. These effects are a result of enhanced K conduction and inhibition of cAMP-induced Ca influx resulting in hyperpolarisation and suppression of Ca-dependent action potentials
Outline the groups of drugs that might be used in asthma & give an example of each.
- Bronchodilators
- Selective beta agonists - salbutamol, salmeterol
- Sympathomimetics - adrenaline
- Muscarinic antagonists - ipratropium, tiotropium
- Methylxanthines - theophylline
- Other - magnesium, ketamine, CCBs
- Anti-inflammatory agents
- Release inhibitors - antihistamines
- Steroids - prednisolone, fluticasone
- Slow anti-inflammatory drugs
- Antibodies - omalizumab
- Leukotriene antagonists
- Lipoxygenase inhibitors - zileuton
- Receptor inhibitors - montelukast
- Heliox
Outline the mechanism of action of corticosteroids in asthma.
Corticosteroids do the following
- Reduce bronchial reactivity
- Inhibition of (lymphocytic & eosinophilic) airway mucosal inflammation
- Increase airway calibre
