Pharmacology (drugs) Flashcards
Describe the pharmacology of oxygen
Pharmaceutics:
- Chemistry/Class: Oxygen is a diatomic gas with density and viscosity slightly higher than that of air
- Preparation: Clear colourless gas
- Administration + dose: Delivered as inhaled gas through a range of delivery devices; delivered IV (via oxygenated blood, eg ECMO); or given externally (hyperbaric oxygen)
- Indication: supplementation (eg. In hypoxia), prophylaxis (pre-anaesthetic induction), antidote (CO toxicity), therapeutics (antibiotic in deep anaerobic infections - via hyperbaric; decrease volume of air-filled body cavities by de-nitrogenation - ie Ptx/pneumocephalus; management of decompression sickness)
Pharmacokinetics:
- Absorption: most pulmonary absorption (250ml/min with 21% FiO2 at rest), some cutaneous absorption <1mL/min
- Distribution: bound to Hb and dissolved in plasma - distributes to all body tissues
- Metabolism: metabolised in all tissues. Mainly by cytochrome c mitochondrial enzymes. Zero-order kinetics, roughly 200mL/min. Main metabolites are CO2 and H2O, cleared via lungs and kidney
- Excretion: exhaled as CO2, or combined with H2O to produce HCO3- and eliminated in urine
Pharmacodynamics:
- Mechanism of action: Essential component of ATP production
- Onset/Offset: minutes
- Organ effects + adverse effects:
- Airway - oxygen-associated airway irritation (drying out membranes,
- Respiratory - improved delivery to gas exchange membrane in supplementation. Decreases respiratory drive in all individuals & may result in a fatal decrease in those dependent on hypoxic drive. Adverse effect - absorption atelectasis. Toxicity can also occur - free radical formation, which can cause pneumonitis/worsening ARDS due to lipid peroxidation of the alveolar capillary membrane
- CVS - Hyperoxia can cause decreased CO, PVR, PAP + cause coronary vasoconstriction with prolonged administration
- Other - note fire risk (esp in ALS with defib)
Pharmacology of B-agonist bronchodilators
Chemistry: similar in structure to NE + adrenaline. Terminal amine group is modified to confer β2-selectivity
Preparation: Inhaled via MDI, or nebulised. Salbutamol available in IV + PO (liquid)
Dose/indication:
SABAs:
* Symptom relief of asthma + COPD
* Prevention of exercise-induced bronchoconstriction
* Note: IV salbutamol used in threatened/preterm labour - relaxes uterine smooth muscle via uterine β2 receptors
LABAs:
* Maintenance treatment of asthma in patients receiving inhaled or oral corticosteroids (LABA rarely/never used as monotherapy)
* COPD
Kinetics
Absorption: salbutamol 10% inhaled absorption when nebulised
Distribution:
SABAs: protein binding 10% salbutamol (Vd 1.3L/kg); terbutaline 25%
LABAs: salmeterol 96%, formoterol ~64%, indacaterol 95%, 60% olodaterol
Metabolism:
SABA: salbutamol & terbutaline: hepatic to inactive sulfate (salbutamol high HER); levalbuterol metabolised in GIT
LABA: salmeterol & indacaterol hepatic - hydroxylated; formoterol & olodaterol hepatic - glucuronidation
Excretion: mostly excreted in urine; salmeterol & indacaterol in faeces; olodaterol both. Elimination half life of salbutamol ~2h
Dynamics
MoA - Activation of Gs protein coupled receptor pathway (adenylate cyclase –> cAMP –> PKA –> phosphorylative events) - leading to bronchial smooth muscle relaxation
* Lowers intracellular Ca2+ concentration
* Acute inhibition of PLC-IP3 pathway and its mobilisation of cellular Ca2+
Act as functional antagonists (reverse bronchoconstriction irrespective of the contractile agent
Effects/adverse
* Resp: bronchodilation
* CVS: sometimes induces tachycardia in high doses
* Endo: Hypokalaemia (effect on Na/K ATPase), hyperlactaemia
* Other: insomnia, muscle cramps
Pharmacology of antimuscarinic bronchodilators
Chemistry - Atropine + scopolamine are naturally occurring - esters formed by combination of aromatic acid, tropic acid + complex organic bases. All other antimuscarinics are derived from these
* ○ Ipratropium and tiotropium are quaternary ammonium compounds
Preparation - ipratropium - solution or powder for inhalation; tiotropium powder only
Dose/Indication - COPD, asthma
Kinetics
* ○ Absorption - Ipratropium/tiotropium (quaternary muscarinic receptor antagonists) not well absorbed via GIT. <1% inhaled drug id absorbed through bronchial mucosa
* ○ Distribution - Ipratropium Vd = 2.4-4.6L/kg, 20% protein bound
* ○ Metabolism - ipra –> 60% metabolised to inactive ester hydrolysis products; 40% in urine unchanged
* ○ Excretion - urine + faeces; 2 hrs half life
Dynamics
* MoA
○ Competitive antagonists of Ach binding to muscarinic cholinergic receptors - block the effects of endogenous ACh at muscarinic receptors (bronchodilator effect is M3)
○ Ipratropium is non selective (therefore also inhibits M2 receptors at presynaptic neurons, which provides ACh- mediated inhibition of ACh release - ie. It stops negative feedback, resulting in further ACh release into the synapse. This might work to oppose the muscarinic blockade at the postsynaptic neuron (conversely, tiotropium has lower affinity for M2)
○ prevents increase in cGMP (normal causes bronchoconstriction)
* Effects/adverse effects
○ Resp: bronchodilation, increased viscosity of airway secretions
○ CNS - drowsiness, dizziness, confusion
○ CVS - tachycardia
○ GI - constipation
○ Other - dry mouth
Pharmacology of theophylline/aminophylline
Class: Methylxanthines
Chemistry - (theophylline + aminophylline) are methylxanthines similar in structure to common dietary xanthines
○ Aminophylline is a complex of theophylline and ethylenediamine
○ Chemically similar to caffeine
Preparation: PO/PR/IV formulations; Theophylline available in PO form only
Dose/Indication: Acute severe asthma, not responding to other therapies
○ Aminophylline: Loading IV 5mg/kg (rate <25mg/min); maintenance IV 0.5mg/kg/hr (in patients not previously treated with theophylline)
○ Theophylline used in maintenance treatment rarely. Initial 300mg daily
Kinetics
○ Absorption: Rapidly absorbed. Aminophylline has high PO bioavailability (88-96%)
○ Distribution: 50-60% protein bound (albumin), Vd = ~0.5L
○ Metabolism - metabolised in liver - demethylation + hydroxylation; forms active metabolites
○ Excretion - saturation of metabolic pathways occurs near therapeutic range - may have zero-order + first order kinetics. Under first-order, half-life is 8hrs
Dynamics
○ MoA - unclear but several proposed MoA. Onset 1-2hrs PO; 30mins if IV
—- Inhibition of phosphodiesterases - theophylline is a non-selective PDE inhibitor (but inhibition is minimal within the ‘therapeutic range’). PDE inhibition likely explains bronchodilator effect of theophylline, but does not account for clinical benefit in asthma seen at the low concentrations it is used in
—- Adenosine receptor antagonism - may reduce inflammation by blocking A2B Receptor on mast cells (activated by adenosine in asthmatics). This mechanism accounts for serious side effects (blockage of cardiac + central A1 receptors)
□ May promote apoptosis of eosinophils + neutrophils (by A2A antagonism) + T lymphocytes (PDE inhibition)
—- Histone deacetylase (HDAC2) activation enhances anti-inflammatory effects of corticosteroids. This happens at the low concs used in asthma
—- Non-bronchodilator effects - the clinical benefits from theophylline use occur at plasma concs low enough to explained by bronchodilator action. Increasing evidence that theophylline has anti-inflammatory effects in asthma
○ Effect/side effects
§ CNS: headache, nausea, vomiting (due to inhibition of PDE4); at high concs, may have seizures from central A1 receptor antagonism
§ CVS: in high concentrations, cardiac arrhythmias may occur due to PDE3 inhibition & antagonism of cardiac A1 receptors
§ GI: Increased acid secretion (PDE inhibition), abdo discomfort
§ Renal: diuresis (Adenosine A1 inhibition)
Other
○ Large variations in clearance - dosage needs to be individualised by measurement of plasma concentrations
○ Plasma monitoring important. Target theophylline conc 5-10mg/L
○ May have a role in prevention of progression of COPD due to anti-inflammatory effects
Pharmacology of Nitric Oxide
Pharmaceutics
- Class/chemistry: selective pulmonary vasodilator. Inorganic gas
- Preparation: In aluminium cylinders containing 100/800ppm of NO & N2. Pure NO is toxic and corrosive
- Administration/dose: 5-20ppm dosing - injected into patient limb of inspiratory circuit or via continuous flow
- Indication: pulmonary hypertension
Pharmacokinetics
- Absorption: Highly lipid soluble and diffuses freely across all membranes
- Distribution: VOD potentially very large
- Metabolism: Following inhalation, NO combines with oxyhaemoglobin that is 60-100% saturated, producing methaemoglobin and nitrate. During the first 8hrs of NO exposure, methaemoglobin concentrations increase
- Excretion: NO has a half-life of <5s. Main metabolite is nitrate (70%) which is renally excreted
Pharmacodynamics
- Mechanism of action/adverse effects - NO diffuses into vascular smooth muscle and stimulates guanylate cyclase which catalyses the formation of cGMP, which activates a phosphorylation cascade which leads to smooth muscle relaxation and vasodilation
○ Resp - inhibits hypoxic pulmonary vasoconstriction & preferentially increases blood flow through well-ventilated areas of lung
§ Toxicity - exposure to 500-2000ppm results in methaemaglobinaemia and pulmonary oedema. Contamination by NO2 can lead to pneumonitis and pulmonary oedema
○ CVS - NO is avidly bound to Hb and inactivated before reaching the systemic circulation
Pharmacology of Epoprostenol
Pharmaceutics
- Class/chemistry: Inhaled pulmonary vasodilator. Epoprostenol is the synthetic analogue of naturally occurring prostacyclin (PGI2)
- Preparation: as vials containing 500 micrograms of freeze-dried epoprostenol sodium - to be diluted in sodium chloride
- Administration/dose: Can be IV, but usually nebulised as a solution with a glycine buffer
- Indication:
—- pulmonary hypertension –>IV 2ng/kg/min up to 25-40ng/kg/min (titrated to effect; significant variability); neb 10-50ng/kg/min
—- pre-eclampsia
—- Haemolytic-uraemic syndrome
—- anticoagulant during RRT & cardiopulmonary bypass –> 5ng/kg/min
Pharmacokinetics
- Absorption: rapidly absorbed into pulmonary circulation via the lungs
- Distribution: 0.35L/kg
- Metabolism: Degrades spontaneously as well as enzymatically into about sixteen major and minor metabolites
- Excretion: Half life ~ 6 minutes; vasodilation is short lived while platelet inhibition lasts up to 2 hrs
Pharmacodynamics
- Mechanism of action - stimulates adenylate cyclase–> increase in cAMP –> activates PKA –> phophorylates + inhibits MLCK –> smooth muscle relaxation + vasodilation. Increased cAMP in platelets leads to inhibition of platelet phospholipase and COX, and ultimately of platelet aggregation
○ Resp: decrease in PVR and interferes with hypoxic pulmonary vasoconstriction
○ CVS: Relaxation of vascular smooth muscle, leading to decrease in systemic vascular resistance
○ CNS: Cerebral vasodilation - increased cerebral blood flow
○ Haem: powerful platelet inhibitor - bleeding time may double with higher doses
- Other: extends filter life during RRT
Pharmacology of adrenaline
Pharmaceutics
* Class/chemistry: Catecholamine/Endogenous sympathomimetic
* Preparation/administration: Clear, colourless solution in 0.1mg/ml or 1mg/ml - can be administered IV/subcut; 1% ophthalmic solution; aerosol (280mic/MD)
* Indication/Dose:
– Anaphylaxis - 0.1-0.5mg subcut
– Asystole/low CO states - 0.1-1mg IV; 0.01-0.1mic/kg/min as infusion in shock
– Glaucoma
– Local vasoconstrictor (added to LA solutions to prolong duration)
Pharmacokinetics
* Absorption - inactivated with oral administration; slower subcut vs IM. Well absorbed from tracheal mucosa.pKa 9.7
* Distribution - Vd = 0.1-0.2L/kg; 12 % protein bound
* Metabolism - Metabolised rapidly by COMT (liver)–> metadrenaline + noradrenaline; MAO (neurons); final common products (normetadrenaline + VMA) are inactive.
* Excretion - urine; half life ¬2min
Pharmacodynamics
* Mechanism of action - directly acting sympathomimetic amine. Agonist of α + β adrenoceptors, with ¬equal activity at both. At α1 - results in release of IP3 –> vasoconstriction. β1 + 2 –>cAMP
* Effects +/- side effects
– CVS - Positive ionotrope + chronotrope. Increases cardiac output, myocardial O2 consumption, coronary blood flow. May result in tachycardia, dysrhythmias, ischaemia
– Resp - mild resp stimulant (increases both tidal volume and respiratory rate). Potent bronchodilator but tends to increase the viscosity of bronchial secretion
– CNS - Increases cutaneous pain threshold and enhances neuromusclar transmission. Little overall effect on CBF. Cerebral haemorrhage may result
– Renal - decreases renal blood flow by up to 40%, but filtration rate remains mostly the same. Inhibits contraction of pregnant uterus
– Metabolic/other - elevated BSL (increases glucagon secretion, stimulates gluconeogenesis, decreases insulin secretion. Plasma renin increased (B1 effect), plasma conc of FFAs increase (activates triglyceride lipase). Increases BMR by 20-30%
* Special points:
– Dose decrease with volatile anaesthetics (risk of ventricular dysrhythmias - mainly halothane, enflurane + isoflurane)
Pharmacology of Ephedrine
Pharmaceutics
* Class/chemistry: Naturally occurring sympathomimetic amine
* Preparation/administration: Tablets 15/30/60mg, elixir, nasal drops; clear colourless solution for injection 30mg/ml. It has 4 isomers - L-isomer is active
* Indication/Dose:
– Hypotension occurring in general, spinal or epidural anaesthesia - 3-7.5mg (max 9mg), repeated every 3-4 min to a max of 30mg, titrated to response
– Nasal decongestant
– Other: Nocturnal enuresis, narocolepsy, diabetic autonomic neuropathy, hiccups
Pharmacokinetics
* Absorption - rapidly and completely absorbed via all routes
* Distribution - rapidly and extensively absorbed. Vd = 122-320L. Crosses placenta & excreted to breast milk
* Metabolism - resistant to MAO + COMT metabolism. Small amount metabolised to norephedrine (may produce central stimulant effect) in liver
* Excretion - 55-99% excreted unchanged in urine. Half life 6.3hrs
Pharmacodynamics
* Mechanism of action - acts both indirectly (causes release of NA from sympathetic nerve terminals) and directly by stimulating α & β-adrenoceptors
* Effects +/- side effects
– CVS - Similar to adrenaline but more prolonged - positive ionotrope + chronotrope–> increases cardiac output, myocardial work and myocardial oxygen consumption
– Resp - resp stimulant + marked bronchodilation
– CNS - stimulatory effect similar to amphetamine. Increases CBF
– Renal - constricts renal blood vessels - decreases renal blood flow & GFR
– Metabolic - stimulates glycogenolysis, may increase BMR, thermogenesis
Special points:
– Tachyphylaxis occurs with prolonged use. Dysrhythmias with halothane
– Clonidine premedication enhances pressor effects of ephedrine
Pharmacology of noradrenaline
Pharmaceutics
Class/chemistry: Catecholamine/endogenous sympathomimetic
Preparation/Administration: Clear, colourless liquid containing 2mg/ml. Administered via CVC in 40mic/ml conc infusion
Dose: titrated to effect. Usually 0.1-0.4ug/kg/min
Indication: refractory hypotension
Pharmacokinetics
Absorption: Undergoes significant first pass metabolism and is inactive when administered orally
Distribution: VD 0.1-0.4L/kg; 25% protein bound
Metabolism: Endogenous NA is metabolised via 2 pathways:
- oxidative deamination to aldehyde by mitochondrial MAO (in liver, brain, kidney) and
- methylation by cytoplasmic catechol-O-methyl transferase(COMT) to normetanephrine. Predominant metabolite is VMA
Excretion: half-life is 0.57-2.4minutes, 5% of dose excreted unchanged, clearance is 28-100mL/min/kg
Pharmacodynamics
Mechanism of action: non-selective sympathomimetic - acts on α & β adrenoceptors. Effect of action depends on distribution of these receptors throughout the body. It is generally a poor β2 agonist. Adrenoceptors are G-protein coupled receptors (GPCR) and binding causes a chain of downstream effects
- Duration of action: 30-40minutes; tachyphylaxis with prolonged administration
Adverse effects: (inc toxicity)
Link above to organ systems:
- CNS - not much change to cerebral blood flow (mildly reduced) + reduction in O2 consumption.
○ Toxicity/Adverse effects: Anxiety, headache, photophobia
- CVS - positive ionotrope - works on the β1 receptor in heart to increase contractility, however does not increase HR like adrenaline (reflex vagal stimulation leads to compensatory bradycardia). CO remains the same or decreases slightly
○ Vasopressor effect - α agonist causing vasoconstriction and raised peripheral vascular resistance, causing rise in SBP + DBP
○ Coronary vasodilation (unclear how/why - possibly β2 stimulation mediated, although NA usually poor β2 agonist)
○ Adverse: chest pain
- Resp - increased minute volume, very slight bronchodilation
- GU - increases contractility of uterus (may induce fetal bradycardia + asphyxia), increases tone of bladder neck, reduces renal blood flow (GFR well maintained)
- Skin: significant cutaneous vasoconstriction. Adverse: pallor; Toxicity: Gangrene. Extravasation - sloughing + tissue necrosis
And others:
- Serious cardiac dysrhythmias during halothane anaesthetics
- Co-administration with MAOIs or tricyclic antidepressants can precipitate serious hypertensive episodes
Milrinone
Pharmaceutics
* Class: Ionotrope
* Chemistry: Bypyridine molecule
* Preparation/Administration: Clear, colourless solution for injection in 10-20mL glass ampoules (1mg/mL)
* Indication + Dose:
* Severe treatment-resistance congestive cardiac failure
* Low cardiac output states following cardiac surgery (loading dose 50mic/kg over 10min; infusion between 0.375-0.75mic/kg/min titrated to response)
Pharmacokinetics:
* Absorption: -
* Distribution: Vd = 0.3-0.4L/kg; 70-80% protein bound
* Metabolism: 12% glucuronidated in liver; Mostly cleared renally - unchanged
* Excretion: Mostly cleared renally - unchanged; half life 2.3hrs in patients with heart failure, longer in renal dysfunction
Pharmacodynamics:
* Mechanism of action: Selective inhibition of type III cAMP PDE in cardiac + vascular muscle (PDE responsible for cAMP catabolism) –> increased intracellular Ca –> increased contractility in cardiac; decreased vascular contraction
* Effects/Adverse:
* CVS: positive ionotropic effect –> CI increases by 25-30%, decreased SVR + MAP. May increase AV nodal conductance (may lead to increase in ventricular response in pts with atrial flutter or AF)
* Renal: u/o + GFR may increase due to increased CO
* Special notes:
- Decrease infusion rate in renal failure
Pharmacology of vasopressin
(Argipressin is synthetic compound which is identical to endogenous human vasopressin)
Pharmaceutics
Class/chemistry: Naturally occurring nonapeptide prohormone produced in posterior hypothalamus
Preparation/Administration: Available in 3 synthetic analogues: (all clear, colourless liquids)Argipressin in 0.4mg/mL (SC/IV or IM); terlipressin in 0.12 or 0.2mg/mL (terli is also available in a power for reconstitution with 5mL - will form 0.2mg/mL); desmopressin in oral powder of 60/120/240mic, oral tablet of 0.1/0.2mg, clear 4ug/ml solution or IN admin with 0.01%
Indication + Dose:
- Cranial diabetes insipidus & Management of polyuria/polydipsia post hypophysectomy: argipressin 0.1-0.4mg (5-20IU)every 4hrs SC/IM; or 100mic TDS desmopressin, adjusted to response
- Bleeding oesophageal varices: argipressin 0.4mg infusion over 15min; terlipressin 0.5mg/hr for 48hrs
- Perioperative/trauma management of people with haemophilia and VW disease
- Management of catecholamine-refractory shock: Argipression is 0.01-0.04U/min
Pharmacokinetics:
Absorption: desmopressin - 0.08-0.16% of dose is absorbed via PO route; 10% via IN route
Distribution: Largest is terlipressin: 0.5l/kg
Metabolism: Endogenous vasopressin metabolised by vasopressinases (endothelial peptidases)
Excretion: Endogenous vaso has a half life of 10-35 minutes; argi is shorter (10-20), terli is longer (50-70), desmo is 2-3hrs. 65% of argi and desmo is unchanged in urine
Pharmacodynamics:
Mechanism of action: Act on GPCR vasopressin receptor. The effects depend on the distribution of these receptors in different organs
Adverse effects (inc toxicity)
Link above to organ systems:
- CVS: V1 receptors in smooth muscle - activation causes vasoconstriction (via increased intracellular calcium) - increases MAP + SVR. At very low doses, causes vasodilation of pulmonary artery
- GU: reduction in urine output and resolution of polydipsia in DI (V2 in DCT + CDs), activation leads to aquaporin-2 trafficking from intracellular vesicle membranes within renal epithelial cells into apical cell membrane –> water resorption
Pharmacology of dobutamine
Pharmaceutics
- Class/chemistry: Synthetic isoprenaline derivative
- Preparation/administration: 12.5mg or 50mg/mL of dobutamine (diluted prior to infusion)
- Dose/Indication: For low cardiac output states eg: MI, cardiac surgery, cardiomyopathy, PEEP ventilation; cardiac stress testing. Dose: 0.5-50mic/kg/min
Pharmacokinetics
- Absorption: Given IV
- Distribution: 0.2L/kg. Steady state conc.s occur within 8-10minutes when drug given at a fixed rate
- Metabolism: Metabolised by methylation, then glucuronidation
- Excretion: Inactive metabolite is excreted in urine with 20% dose appearing in faeces
Pharmacodynamics
- MoA: Acts directly on catecholamine receptors to activate adenylate cyclase, which catalyses the conversion of of ATP to cAMP
- Link to organ systems:
— CVS – activate cardiac β-1-adrenoceptors. SA automaticity increased and AV nodal conduction velocity also increased. Also has activity at α- and β2-adrenoceptors. It decreases LVEDP and SVR
— CNS – stimulation occurs at high dose ranges. Fatigue/nervousness/headache
Other
Should not be used in people with cardiac outflow obstruction. Tachyphylaxis can occur during prolonged infusion
Pharmacology of levosimendan
Pharmaceutics
- Class/chemistry: Propanedinitrile derivative
- Preparation/administration: Clear, yellow or orange solution for injection – 2.5mg/mL in 5 & 1-mL ampoules
- Dose/Indication: Used for acute heart failure. Loading dose of 6-12mic/kg, then infusion at 0.1-0.2microg/kg/min
Pharmacokinetics
- Absorption: Given IV
- Distribution: 97-98% albumin bound with Vd = 0.2L/kg
- Metabolism: Most undergoes hepatic conjugation
- Excretion: About 54% excreted renally, rest in faeces. Elimination half life is 3 hours
Pharmacodynamics
- MoA: Increases calcium sensitivity by binding to myocardial troponin C, leading to stabilisation and increased duration of calcium binding. This results in increased myocardial contractility without impairment of myocardial relaxation or increased oxygen demand. Also stimulates ATP-sensitive K+ channels leading to vasodilation
- Link to organ systems:
— CVS – Increases myocardial contractility via increased calcium sensitivity without increased myocardial oxygen demand. Also causes coronary and peripheral vasodilation. Hypotension
Pharmacology of amiodarone
Pharmaceutics
* Class/chemistry - Iodinated benzofuran derivative (Class 3 antiarrhythmic)
* Preparation- PO tablets 100mg or 200mg; IV 30 or 50mg/ml amiodarone hydrochloride
* Administration - PO or IV
* Dose - Initial loading dose 5mg/kg in 250mL 5% dextrose. Maintenance 15mg/kg/day. PO dose initially 200mg TDS, which is reduced to 100-200mg daily after 1/52
* Indication - tachydysrhythmias resistant to other treatment + related to WPW syndrome
Pharmacokinetics
* Absorption - bioavailability of 22-86% (Smith) or 35-65% (Katzung)
* Distribution - 96-98% protein-bound in plasma; VD is 1.3-65.8L/kg, according to dose
* Metabolism - largely in liver, to desethyl-amiodarone (has anti-arrhythmic properties and is cumulative)
* Excretion - 1-5% in urine, mostly in bile + faeces
Pharmacodynamics
Mechanism of Action - prolongs cardiac action potential & delays refractory period.
* - partial antagonism of alpha- and beta- agonists by reducing number of receptors or by inhibiting the coupling of receptors to the regulatory subunit of the adenylate cyclase system
* - Delays K+ efflux, depresses Na+ influx & depresses Ca2+ influx
* - Onset of action - within 1hr IV, PO 2-3days-weeks
* - Duration after discontinuation can be weeks to months. Half-life (elimination half-life has slow (3-10days) and rapid (weeks) components)
Link above to organ systems
* - CVS - marked prolongation of the action potential duration (and QT injterval on the ECG) by blockade of intracellular K.
○ Sinus rhythm is slowed secondary to reduction in the slow diastolic depolarisation in nodal cells. Automaticity is depressed and AV nodal conduction is slowed by 25%
○ May get hypotension post IV admin - may be due to action of the vehicle
○ Toxicity: may get bradycardia/complete HB resistant to atropine, Ad & NAd
* - Metabolic - Can get LFT abnormalities & TFT (inhibition of triiodothyronine & enhancement of reverse triiodothyronine production & is a potential source of inorganic iodine. This can result in hypo or hyperthyroidism)
* - Resp - fatal pulmonary fibrosis occurs in 1%
* - Ophthalm - corneal microdeposits. Can cause halo at peripheries & rarely optic neuritis
* - Skin - deposits result in photodermatitis & grey-blue skin discolouration in malar regions
Other:
- Specific to drug - contraindicated in porphyria
Pharmacology of digoxin
Pharmaceutics
* Class/chemistry - Cardiac glycoside. Contains steroid nucleus, Series of sugars at C3 + Lactone ring at C17
* Preparation - Tablets - 62.5mic, 125mic, 250mic, or elixir 50mic/ml; or injection 250mic/mL
* Administration - PO or IV. Should be by slow injection
* Doses - loading dose10-20mic/kg Q6H until desired effect achieved. Then maintenance at 10-20mic/kg daily in divided doses
* Indication - use in AF + Flutter, heart failure, prevention of supraventricular dysrhythmias post thoracotomy
Pharmacokinetics
* Absorption - 65-80% absorbed from PO administration
* Distribution - once in the blood, widely distributed to all organ systems (inc CNS). Heart to serum con is 70:1. Vd = 6-7L/kg
* Metabolism - not extensively metabolised (~16%) in stomach or intestine - mostly excreted unchanged by kidneys
* Excretion - Excretion from kidneys proportional to creatinine clearance (50-70% unchanged). Half life: 36-48hrs
Pharmacodynamics
Mechanism of action -
* - Direct action - binds to and inhibits the action of Na+/K+ ATPase in sarcolemma cell membrane. This causes increased intracellular Na+ & decreased intracellular K+. Na+ displaces bound Ca+, and increased Ca+ results in positive ionotropic action. Decreased K+ leads to slowed AV conduction & decreased pacemaker cell action
* - Indirectly modifies autonomic activity and increases efferent vagal activity
Link above to organ systems
* - CVS - Main action is to increase the force of contraction. HR slowed due to depression of SA node discharge, slowed AV node conduction, increase in the AV nodal refractory period and indirect vagal effect. Rapid IV administration may cause vasoconstriction, leading to hypertension and decreased coronary blood flow. ECG changes - prolonged PR, ST depression, T wave flattening & shortened QT
—– (toxicity) - any dysrhythmia - esp junctional brady, ventricular bigemini, 2nd/3rd degree HB. Reverse tick on ECG
* - Renal - mild intrinsic diuretic effect
* - GI - (toxicity): anorexia, nausea, vomiting, diarrhoea, abdo pain
* - Neuro - (toxicity): headache, drowsiness, confusion, visual disturbances, muscular weakness, coma
Onset of action - PO 1-2hrs; IV 5-60min
Duration - 3-4 days
Other
* - Toxicity - Therapeutic range is 0.6-1.0nmol/L (=0.25 ng/mL) digoxin-specific antibody fragments can treat toxicity. They form complexes with dig molecules then are excreted in urine.
○ Indications for treatment: life-threatening arrhythmia, cardiac arrest, K>5.0
○ Consider treatment when: end organ dysfunction, mod-severe GI symptoms, serum dig >12ng/mL (25nmol/L), significant features of dig toxicity with serum dig > 4nmol/L
○ Formulation - 40mg reconstituted in 4mL. Response in ~20min (0-60)
* - Other specifics
○ Increased risk of dysrhythmias with concurrent sux/pancuronium or B-agonists
○ Increased likelihood of toxicity with: low K, Hyper Na, Hyper Ca, Low Mg, acid-base disturbance, hypoxaemia and renal failure
○ Increased plasma dig levels with coadmin of verapamil, nifedipine, amiodarone, diazepam
○ Cannot be removed by dialysis
