A- Main Study Deck Flashcards
Re: Providone/Iodine as an antispectic/disinfectant - what are its main action, onset/duration, advantages & limitations and spectrum of activity?
Main action: Oxidative damage.
Onset/Duration: Onset: Iodine is bacteriocidal in 1 minute and kills spores in 15 minutes. However in povidine compounding it has a delayed onset/Duration: No sustained effect
Advantages:
1. Sporicidal
2. Cheap
3. Broad spectrum
Most effective for intact skin
Limitations:
1. Hypersensitivity reactions
2. Delayed onset without residual activity
3. Stains clothes and dressings
Spectrum of activity:
- Bacteria (G+ve and –ve and acid fast)
- Sporicidal
- Viruses
- Fungi
Ineffective against:
Prions
Hydrophilic viruses
Other:
Can be used as antiseptics or disinfectants (latter contains more iodine)
4 types of lung receptors (peripheral afferents)
Respiratory
- Pulmonary stretch receptors - discharge in response to distension of lung & activity is sustained with lung inflation - ie. They show little adaptation
- Irritant receptors - Rapidly respond to airway irritants - eg. Cigarette smoke/noxious gases/cold air
- J receptors - respond to chemicals injected into the pulmonary circulation –> results in rapid, shallow breathing
- Bronchial C fibres - respond to chemical injected into the bronchial circulation –> results in rapid, shallow breathing
Hering-Bruer reflex
Respiratory
Stimulation of pulmonary stretch receptors results in slowing of respiration due to increase in expiratory time
[Opposite is true for expiration]
Normal compliance
Respiratory
100mL/cmH2O
* C(lung)= 200mL/cmH2O; C(chest wall) = 200mL/cmH2O
Specific compliance = 0.05/cmH2O
Malignant hyperthermia incidence
Pharmacogenetics
1:5,000 - 1:50,000
What is porphyria?
Pharmacogenetics
Mutation of haem synthesis enzymes which causes a build-up of neurotoxic intermediate metabolites (porphyrin precursors) in response to various drugs (anticonvulsants, antibiotics, thiopentone)
○ Autosomal dominant
Malignant hyperthermia mechanism
Pharmacogenetics
Mutation of the ryanodine calcium channel receptor which causes a hypermetabolic crisis in response to volatile anaesthetics
Malignant hyperthermia signs/symptoms
Pharmacogenetics
○ Initial - tachycardia, masseter spasm, hypercapnoea, arrhythmia
○ Intermediate - hyperthermia, sweating, combined metabolic and respiratory acidosis, hyperkalaemia, muscle rigidity
○ Late - rhabdomyolosis, coagulopathy, cardiac arrest
Malignant hyperthermia Mx
Pharmacogenetics
Cease volatile, start TIVA, give dantrolene 2.5mg/kg increments to 10mg/kg, Rx of complications
Atypical plasma cholinesterase/pseudocholinesterase
Congenital/acquired/both/neither?
Pharmacogenetics
Fails to metabolise suxamethonium and causes “sux apnoea”
○ Congenital - autosomal recessive
○ Acquired - due to loss of plasma cholinesterase. Can occur in pregnancy, organ failure (hepatic, renal, cardiac), malnutrition, hyperthyroidism, burns, malignancy, drugs (OCP, ketamine, lignocaine and ester Las, metoclopramide, lithium)
○ Note: acquired disease will have normal dibucaine no but just decreased quantity of enzyme
How to test for atypical plasma cholinesterase/pseudocholinesterase?
Pharmacogenetics
○ Measured by dibucaine number. Dibucaine is an amide LA, which inhibits plasma cholinesterase. Greater inhibition indicates a less severe mutation - so normal:normal dibucaine no = 80 (80% inhibited). Dibucaine resistant:resistant has a no of 20 (20% inhibited)
G6PD deficiency
Pharmacogenetics
Mutation of glucose 6-phosphate dehydrogenase which produces acute haemolysis in response to oxidative stress due to dapsone, methylene blue, fluoroquinolones, antimalarialas and rasburicase
Normal cardiac output and cardiac index values
CO = 5L/min; CI = 2.5-4L/min
LaPlace’s Law (cardiac)
sigma = Pr/2h
where sigma = myocardial wall stress
P = transmural pressure
r = radius
h = ventricular wall thickness
Features of SA node and ventricular myocyte action potentials: resting, threshold, peak potentials
Ventricular myocyte:
* Resting potential: -90mV
* Threshold: -70mV
* Peak: +50mV
SA node:
* Max diastolic (nil real resting potential): -70mV
* Threshold: -40mV
* Peak: +20mV
Structure of fast cardiac Na+ channel
2xβ subunits
1x α subunit
* Has 4 domains - I-IV
* The N- & C- terminus are both intracellular
* Each domain has 6 transmembrane segments linked by intracellular and extracellular peptides
–Extracellular peptides linking segments 5-6 form the ion pore (responsible for ion selectivity - the Ca channel has similar structure but is Ca selective)
–Domain IV undergoes a conformational change in response to voltage & opens the pores (activation gate - ‘m’)
– The intracellular peptide loop connecting domain III & IV forms the inactivation gate ‘h’
What membrane potential does the absolute refractory period of a cardiac action potential go up to?
Absolute refractory period is up to ~-50mV. At this value, some fast Na+ channels have recovered from inactivation enough to permit response to stimulation
Time constant equation
(tau) = compliance x resistance
What are the functions of the FRC?
- Oxygen reservoir - prevents rapid changes in alveolar oxygen tension and arterial oxygen content by maintaining gas exchange throughout expiration
- Maintenance of small airway patency (N2 splinting)
- Optimising respiratory workload - compliance maximal at FRC, WOB required from FRC is minimal
○ Keeps tidal volume over steep part of lung compliance curve - Minimises pulmonary vascular resistance & hence RV afterload/work/oxygen demand
What are the factors affecting FRC
Normal WOB
0.35J/L
Oxygen requirement of breathing
The oxygen requirement of breathing at rest is 2-5% of VO2 or 3ml/min
(tidal breathing uses <2% of BMR)
Normal osmolarity
~285mOsm/kg
Baroreceptor reflex
- Sensor/stimulus: carotid sinus & aortic arch - circumferential and longitudinal stretch receptors detect change in BP
○ Decreased BP decreases firing rate of baroreceptor- Afferent: glossopharyngeal + vagus
- Processor: NTS & Caudal ventral medulla/RVLM
○ Decreased BR firing rate –> decreases GABA secretion from caudal VM. This decreases inhibition of sympathetic output from RVLM (ie SNS activity increased) - Efferent/effectors: vagus nerve + sympathetic chain
○ Peripheral vessels - a1 mediated vasoconstriction
○ Decreased vagal input into SA - Effect: increased HR and BP in response to fall in BP
- Note: Tends to override Bainbridge reflex when it comes to atrial stretch in hypovolaemia (except in spinal anaesthesia, where reverse Bainbridge reflex may predominate)
Bainbridge reflex
- Sensor/stimulus: Stretch receptors in atria + pulmonary artery measure changes in pressure
- Afferent: vagus
- Processor: NTS & CVM
- Efferent:
○ Sympathetic fibres to heart
○ Vagal efferents to gardiac ganglion - Effects
○ Increased RA pressure produces an increase heart rate
Chemoreceptor reflex
- Sensor/stimulus: Carotid and aortic body detect low PaO2 and/or high PaCO2
- Afferent: glossopharyngeal + vagus
- Processor: NTS + Nucleus ambiguus
- Efferents/effectors:
○ Sympathetic fibres to heart and peripheral smooth muscle
○ Vagal efferents to cardiac ganglion - Effects:
○ Primary effects - bradycardia, hypertension
○ Secondary effects - increased preload due to increased ventilation, thus activation of Bainbridge –> increased heart rate
○ Activation of pulmonary stretch receptors –> activation of Hering-Breuer reflex –> increases HR
Cushing reflex
- Sensor/stimulus: intracranial pressure/cerebral ischaemia is detected by some unknown sensor
- Afferent:
○ Fibres from the medullary mechanosensory areas, to sympathetic ganglia
○ Fibres from cerebral hemispheres, which exert descending inhibitory control on the medullary vasomotor sensor - Processor: rostral ventrolateral medulla
- Efferents/effectors: Sympathetic fibres to heart and peripheral smooth muscle
- Effects:
○ Hypertension + tachycardia
○ Secondary - baroreflex mediated bradycardia
- Afferent:
Bezold-Jarisch Reflex
- Sensor/stimulus: Multiple and heterogeneous stimuli interact with receptors in all cardiac chambers, including:
○ Mechanical: pressure and stretch (thus, inotropy preload and afterload)
○ Chemical: veratrum alkaloids, ATP, capsaicin, snake venom, other venoms- Afferent: unmyelinated C-fibres of vagus
- Processor: NTS
- Efferents/effectors: sympathetic fibres to heart and peripheral smooth muscle, vagus via cardiac ganglion
- Effects: hypotension (vasodilation) & bradycardia
Occulocardic reflex
- Sensor/stimulus: mechanoreceptors on the globe and in facial muscles detect pressure on the globe
- Afferent: long and short ciliary nerves to trigeminal nerve (via Gasserian ganglion) to sensory nucleus of TN. From here, short internuclear fibres to NTS
- Processor: NTS
- Efferents/effectors: vagus nerve via cardiac ganglion to SA + AV node
- Effects: bradycardia, if severe, to the point of arrest
Diving reflex
- Sensor/stimulus: pain, temperature, chemical and mechanosensitive stretch receptors detect pressure to globe of eye, pain in trigeminal nerve distribution, cold temperature, or noxious stimulus of anterior ethmoidal nerve
- Afferent: trigeminal nerve
- Processor: NTS (vagal response), Rostral medulla (sympathetic response), ventral response (apnoea)
- Efferents/effectors: Vagus nerve via cardiac ganglion to SA, AV nodes; phrenic nerve to respiratory muscles
- Effects: bradycardia, cerebral vasodilation + systemic vasoconstriction, apnoea
○ Net effect is to prevent aspiration and maximise blood flow to CNS at the expense of skin, muscle and splanchnic organs
Barcroft-Edholm Reflex
- Sensor/stimulus: Emotional distress/orthostatic changes, increased ITP (eg. Defecation, cough/sneeze, laughter)
- Afferent: unknown
- Processor: ?NTS/Nucleus ambiguus
- Efferents/effectors: vagus & SNS to SA, AV nodes, peripheral smooth muscle
- Effects: Vagal - bradycardia, sympathetic - systemic vasodilation
SvO2 from tissue beds: jugular, muscles, renal, IVC, SVC, Hepatic
Jugular - 55%
Muscles - 72%
Renal - 81%
IVC - 71%
SVC - 79%
Hepatic - 66%
Normal mixed venous PO2 & SvO2
40mmHg & 70-75%
Energy consumption of 1 MET
1 MET = 3.5 ml O2/kg/minute
Aortocaval compression syndrome
- Seen as early as wk 20
- Compression of IVC by gravid uterus - decreases venous return & reduced CO
* Blood returns to heart via paravertebral epidural veins draining into azygous
* Uterine perfusion diminished secondary to increased uterine venous pressure - Compression of aorta may be present & associated with uterine arterial hypotension + reduced uteroplacental perfusion
- Can be relieved by positioning mother to left side
Changes in afterload during pregnancy
Afterload (reduced) –> TPR decreases by 30% by wk 12& 35% (by 20th wk, then remains at 30% below non-pregnant values)
* Vasodilation mediated by progesterone, prostaglandins & downregulation of alpha-receptors
* SBP + DBP - decrease (~10%) & reach nadir at 20wks
* Vascular system as whole becomes more refractory to vasoconstrictors
* Note re: RV afterload
□ CVP + PCWP - remain stable throughout pregnancy. PCWP balance by decreased PVR
Changes in preload during pregnancy
○ Preload (increased) –> By term, maternal blood volume increased by 35-40% (approx 1-1.5L)
§ Plasma volume increases by 45% - Na + H2O retention by oestrogen stimulation of RAAS
§ RBC volume increases by 20% due to renal erythropoietin synthesis
§ Disproportionate rise in plasma volume vs red cell mass accounts for fall of haematocrit to 33% (“anaemia of pregnancy”)
Changes in CO, HR and SV during pregnancy
CO increases by 40-45% by 12-28wks, peaks at 50% 32-36wks, then reaches 47% at term
- Heart rate: HR increases by 17% at end of first trimester,(increases to 25% at middle of third trimester);
- Stroke volume increases by 20-30% (predom in 1st trim)
Changes to distribution of CO in pregnancy (regional flow changes)
- Distribution (regional flow changes)
○ Renal blood flow - increases by 80% in first trimester (may fall slightly towards term)
○ Large proportion of blood flow is directed to uteroplacental circulation, that increases its blood flow 10-fold to 750mL/min at term
○ Increased blood flow to breasts, GIT, skin
Physical and mechanical changes to heart during pregnancy
Physical/mechanical changes:
- LV mass increases by 40g by 3rd trimester
- Heart is more rotated to left
○ May see Q waves + TWI in inferior leads
- Colloid oncotic pressure falls by 14% - may predispose to oedema
CVS changes during PARTUITION + Post delivery:
- Pressure:
○ Maternal SBP + DBP increase 10-20mmHg during uterine contraction- Volume:
○ Each uterine contraction squeezes ~300mL blood from uterus into central maternal circulation - Cardiac output:
○ CO increases by ~15% during latent phase of labour, by 30% during the active phase & 45% during the expulsive stage
○ Immediately after delivery, CO ~60-80% above pre-labour values as a consequence of autotransfusion & increase venous return associated with uterine involution - CO & SBP/DBP return to non-pregnant values by 2 wks post delivery
- Volume:
How long after birth do pregnancy-induced respiratory changes settle?
After birth:
* FRC and RV return to normal within 48h
* Vt returns to normal within 5 days
Effect of pregnancy on lung mechanics
- Compliance
○ increased adipose tissue and breast mass –> decreased chest wall compliance (lung compliance unchanged)- Resistance
○ Increases in early pregnancy - mucosal oedema
○ Progesterone-mediated bronchodilation - decreased resistance in later pregnancy (35%)
- Resistance
Storage functions of the liver
- Storage
- Metabolic fuel: Glycogen- ~100g & fat
- Fat soluble vitamins
○ Vitamin A → stored in stellate cells –> converted to retinol (active form). Contains 1-2yr supply
○ Vitamin D → ~ 1-4 month supply
○ Vitamin E & vitamin K - minimal - Vitamin B12 + folate (50% of body’s storage for both)
- Trace elements - iron (as ferritin), zinc, copper, selenium
- Blood reservoir - ~ 500mL of blood
Synthetic functins of the liver
Synthetic
- Plasma proteins- albumin, α+ β globulins, fibrinogen
- Nutrients - glucose, ketones, lipids, cholesterol, amino acids
- Regulatory molecules (thrombopoetin, angiotensinogen)
- Bile acids → stored in gallbladder
Metabolic functions of the liver
Metabolic
- Carbohydrate metabolism
○ Liver is a glucostat –> maintains strict BSL
§ in conditions of ↑ glucose, glycogenesis & FFA synthesis will normalise BSL
§ in conditions of ↓ glucose, gluconeogenesis will normalise BSL
- Lipid metabolism → free fatty acids (FFA). synthesised & packaged with as lipoproteins be transported to adipose tissue for storage
§ FFA oxidation will also produce energy.
- Protein Metabolism - amino acids can be transaminated, deaminated or decarboxylated to give acetyl- CoA
Detoxification/excretory functions of the liver
Detoxification & excretion
- Immunological detoxification:
○ Kupfer cells act as scavengers & phagocytes & secrete prostaglandins
- Ammonia → urea conversion via urea cycle
- Conjugation of bilirubin & excretion in bile
- Processing of drugs via:
○ Phase I (oxidation & hydrolysis) and
○ Phase II (conjugation) reactions
Length, diameter, origin and termination of trachea
Length: 10-16cm
Diameter: (internal) 2.5cm
Origin: C6
Termination: carina, T4 (sternal angle)
Classify generations of bronchial tree
Generation 1-4 - Bronchi (cartilaginous)
Generation 5-14 - bronchioles (non-cartilaginous)
Gen 15-18 - Respiratory bronchioles (some gas exchange)
Gen 23 - alveolar sacs
Describe the muscles in the larynx involved with phonation, inspiration, expiration and effort closure
Muscles - various muscles attaching to the various structures. Important movements:
* Phonation: cricothyroid (brings cords together by moving thyroid down), interarytenoid (transverse + oblique), vocalis (subset of muscles from thyroarytenoid) - mediates tension in vocal ligament to modulate pitch
* Inspiration: + cricoarytenoid (posterior + lateral) - rotate arytenoids outwards
* Expiration: thyroarytenoid adduct cords to increase resistance and provide intrinsic PEEP (3-4 cmH2O), which maintains patency of small airways & maintains FRC
* Effort closure - aryepiglottic muscles contract strongly to act as a sphincter, allowing airway to withstand up to 120cmH2O pressure
What is Dalton’s Law
Dalton’s Law:
* In a mixture of gases, the pressure exerted by each gas is the same as the pressure exerted if the gas was the only gas in that mixture:
* PTOTAL = PGas1 + PGas2 + PGas3
What is Boyle’s Law?
Boyle’s Law:
* For a fixed mass of gas at constant temperature, the pressure (P) and volume (V) are inversely proportional, such that P ×V = k, where k is a constant.
Henry’s Law
Henry’s Law
* The amount of a given gas dissolved in a given liquid is directly proportional to the partial pressure of the gas in contact with the liquid:
P = Hv × M
Where
* P is pressure
* M is the molar concentration of gas
* Hv is Henry’s Proportionality Constant
Graham’s Law
Graham’s Law:
* The rate of diffusion is inversely proportional to the √MW
Fick’s Law of diffusion
Fick’s Law of diffusion:
* Passive movement of molecule from an area of high concentration to low
- There are many different iterations of Fick’s Law
- V_gas∝A/T D (P_1− P_2)
V_gas = Flow of gas D∝ Solubility/√MW MW = molecular weight A = surface area P_1 − P_2= difference between partial pressure in alveolus vs capillary T = diffusion distance (or thickness of membrane)
Third gas law (Gay-Lussac’s Law)
The pressure of a fixed mass of gas at constant volume is directly proportional to its absolute temperature (P/T = k).
Avogadro’s Law
Equal volumes of gases at the same temperature and pressure contain the same number of molecules (6.023 × 1023, Avogadro’s number).
Universal (Ideal) Gas Law
The state of a fixed mass of gas is determined by its pressure, volume and temperature (PV = nRT)
The Bohr equation for measuring dead space
VD/VT = (FACO2 - FECO2) / FACO2
Where:
VD = dead space volume VT = tidal volume FECO2 = fraction of expired CO2 FACO2 = fraction of alveolar CO2 *Note: Enghoff modification: P_A 〖CO〗_2 is substituted by P_a 〖CO〗_2 as arterial CO2 is measurable (and arterial CO2 is the mixed product of all lung units (theoretically representative of the average CO2 of all alveoli put together))
Alveolar gas equation
PAO2 = (FiO2 × (Patm - PH2O)) - (PaCO2 / RQ)
Where PAO2= Partial pressure of alveolar oxygen FiO2 = fraction of inspired oxygen Patm = Atmospheric pressure (usually 760 mmHg) PH2O = partial pressure of water vapour at the alveolus (usually 47 mmHg) PaCO2 = Partial pressure of arterial carbon dioxide RQ = respiratory quotient, usually 0.8
Oxygen content equation
(sO2 × ceHb × BO2 ) + (PaO2 × 0.03)
Where: ceHb = the effective haemoglobin concentration (conc of hb species capable of carrying & releasing O2) PaO2 = the partial pressure of oxygen in arterial blood 0.03 = the content, in ml/L/mmHg, of dissolved oxygen in blood (for a PaO2 of 100 mmHg, the O2 content is 0.03 × 100 = 3ml/L BO2 = the maximum amount of Hb-bound O2 per unit volume of blood (normally 1.39 of dry Hb, or 1.30 in "real" conditions) sO2 = oxygen saturation:
The shunt equation
Qs/Qt = (CcO2 - CaO2) / (CcO2 - CvO2)
Where
Qs/Qt = shunt fraction (shunt flow divided by total cardiac output)
CcO2 = pulmonary end-capillary O2 content, same as alveolar O2 content
CaO2 = arterial O2 content
CvO2 = mixed venous O2 content
Starling equation
J_v=L_p S [(P_c − P_i) - σ(π_c− π_i)
Where:
Jv = filtration rate
Lp = Hydraulic permeability
S = Surface area
Pc = Capillary hydrostatic pressure
Pi = Interstitial hydrostatic pressure
σ = Reflection coefficient (protein permeability, range 0-1)
πc = Intracapillary plasma oncotic pressure
πi = Interstitial oncotic pressure
*Note: LpS = K = kf = capillary filtration constant* **Note2: πi becomes πegl in the revised Starling model to represent the endothelial glycocalyx layer**
Starling forces in lung
○ LpS - surface area ~140m2 (compared to 4000-7000m2 in systemic circulation)
○ Pc = 4-12mmHg
○ Pi = interstitial hydrostatic pressure - essentially equal to alveolar pressure = atm pressure. Increases during PPV
§ Surfactant decreases hydrostatic pressure by decreasing surface tension
○ πc = 25mmHg throughout circulation; affectd by blood protein count
○ πi = ~3mmHg at alveoli
○ σ= 0.5-0.7 in lung
Normal airway resistance
2mLH2O/L/s
MoA of aminoglycosides
- Bind to 30s Ribosomal subunit, which interferes with protein synthesis by causing misreading and premature termination of mRNA translation.
- Diffuse through porin channels in the outer membrane into periplasmic space. Transport through inner membrane is oxygen dependent (/electron dependent). Antimicrobial activity is markedly reduced in anaerobic conditions (eg. Abscess).
- Concentration dependent killing - higher the concentration, the greater the rate at which bacteria are killed.
- Post-antibiotic effect exists (bactericidal effect persists after conc<MIC). The duration of this effect is also concentration dependent
Define antispectic and disinfectant
- Disinfectants are chemical agents or physical procedures that inhibit or kill microorganisms
- Antiseptics are disinfectants with sufficiently low toxicity to host cells that can be used directly on skin, wounds or mucosa
Re: alcohol as an antispectic/disinfectant - what are its main action, onset/duration, advantages & limitations and spectrum of activity?
Main action: Likely act by denaturing proteins. Optimal bacteriocidal concentration is 60-90%
Onset/duration Rapid/ Lack residual action because they evaporate completely
Advantages: Evaporative effects are useful when sinks with running water are not available
Limitations: Flammable- must be allowed to dry fully before diathermy or laser surgery 2. Corneal damage; 3. Skin drying; 4. Ineffective against C. Dif spores
Spectrum of activity: - Gram positives and negatives, Acid fast bacteria are susceptible, - Lipophilic viruses may be susceptible, Many fungi
Ineffective against: Spores and prions. Hydrophilic viruses are less susceptible
Re: Chlorhexidine as an antispectic - what are its main action, onset/duration, advantages & limitations and spectrum of activity?
Main action:Cationic biguanide -strongly adsorbs to bacterial membranes causing leakage of small particles and precipitation of cytoplasmic proteins
Onset/Duration: Delayed/Sustained residual activity
Advantages: Resistant to inactivation by blood and organic material; Low skin irritation
Limitations:
1. Neurotoxic
2. Delayed effect
3. No direct spore activity
4. Agents in moisturisers, neutral soaps, and surfactants may neutralised its action
Spectrum of activity
- Bacteria (G+ve>G-ve)
- Moderate fungal and viral activity
- Inhibits spore germination
Ineffective against
Spores and prions
Hydrophilic viruses are less susceptible
Other
Can be combined with 70% alcohol
Preferred antiseptic for central venous access
Not absorbed orally
What is the speed of sound in tissue
1540m/s
Define potency
(of a drug)
- Potency is defined as the concentration (EC50) or dose (ED50) of a drug required to produce 50% of that drug’s maximal effect/a specified response in 50% of the population
○ Two drugs may have the same efficacy but one may achieve the effect at a lower dose
○ A drug with lower EC50 or ED50 has higher potency
Define efficacy
(of a drug)
- Efficacy - a measure of the magnitude of the effect once the drug is bound
○ Different agonists produce varying responses, even when occupying the same proportion of receptors
○ Efficacy can be expressed numerically - as a ratio of the drug’s maximal efficacy to the maximal efficacy of some known potent agonist (aka intrinsic activity or maximal agonist effect)
What is a competitive antagonist?
A compound that competes with endogenous agonists for the same binding site - it may be reversible or irreversible
○ In the presence of a competitive antagonist, the Emax of the agonist is unaffected, but the potency is reduced
What is a non-competitive antagonist?
A compound that binds at a different site to the natural receptor and produces a conformational change that prevents receptor activation
Define FRC
The volume of air in the lungs at end of expiration during tidal breathing. It is the point at which alveolar pressure = atmospheric pressure, and is equal to expiratory reserve volume (ERV) plus residual volume (RV).
What is the blood supply, venous & lymphatic drainage + nerve supply of the larynx?
Blood supply:
- Upper half: superior branch of the super thyroid artery
- Lower half: inferior branch of the inferior thyroid artery
Venous drainage:
- Upper half: superior branch of the superior thyroid vein
- Lower half: inferior branch of the interior thyroid vein –> brachiocephalic vein
Nerve supply:
All muscles are supplied by the recurrent laryngeal nerve except cricothyroid muscle, which is innervated by the external laryngeal
Lymphatics
- Upper and lower groups of deep cervical nodes
What is the Hagen-Poiseuille equation?
- This is specific to laminar flow (fastest velocity at centre of vessel, little to no movement at periphery)
What is Reynold’s number
If Re<2000, flow more likely to be laminar, 2000-4000 = transitional & >4000 turbulent
What is the alveolar gas equation?
Define PaO2, SaO2 and CaO2
- PaO2 = partial pressure of oxygen in arterial blood (measured value, in mmHg)
- This is the pressure that ‘dissolved’ oxygen (ie oxygen unbound to Hb) exerts on the measuring oxygen electrode
- Although the pressure of oxygen is an important indicator of Hb saturation and total oxygen content, it is not a measure of content (ie mass or volume)
- SaO2 = oxygen saturation (measured value, in %)
- This is the percentage of all the heme sites in all the available haemoglobin that is taken up by an oxygen molecule
- Similarly to above, this is an important surrogate measure for oxygen availability however is also not a measure of content
- CaO2 = blood content of oxygen (can be measured directly, or calculated by the oxygen content equation, in mL of oxygen/100ml or 1000mL of blood - ie mL/dL or mL/L)
- This measures total oxygen content (dissolved plus bound)
Recount the following gas laws:
- Boyle’s
- Charles’
- Third gas law (Gay-Lussac’s law)
- Avogadro’s Law
- Universal (Ideal) gas law
- Henrys Law
- (own question)*
Write the definitions for flow, pressure, compliance and work of breathing
(own question)
Recount the following laws:
- Alveolar gas equation
- Oxygen content of blood
- Shunt equation
- (Own question)*
Define closing capacity
The maximal volume of gas in the lungs at which small airways begin to collapse in dependent parts of the lung
Define latent heat of vapourisation
The heat required to convert a substance from liquid to vapour at a given temperature. Latent heat of vapourisation decreases as ambient temperature increases, and is reduced to zero at the critical temperature of that substance.
Define vapour pressure & Saturation vapour pressure
- Vapour pressure = pressure exerted by a vapour above the surface of a liquid.
- The more solutes you add to a solution, the lower vapour pressure, at any given temp + pressure
- Saturation vapour pressure = pressure exerted by a vapour in equilibrium with liquid of the same substance. It is influenced by temperature and pressure
- AKA equilibrium vapour pressure. It is the point at which the rate of evaporation = rate of condensation
- Substances with a higher vapour pressure is more volatile. (eg. Sevo has SVP of 157mmHg at sea level, room temp vs H2O which is 18.6mmHg)
- SVP increases with increasing temp - at body temp, H2O SVP is 47-48mmHg
Define boiling point temperature
The temperature at which vapour pressure equals atmospheric pressure. A lower atmospheric pressure will result in a lower boiling point temperature
* Note: evaporation different to boiling - evaporation takes place from surface; bubbles form within the liquid when boiling.
Define critical temperature
- Critical temperature is the temperature above which it is not possible to liquefy a given gas by increasing its pressure
- A substance is a gas when it is above its critical temperature, and a vapour when it remains in gaseous phase below its critical temperature
- Nitrous has a critical temp of 36.5o and a critical pressure at this temp of 73atm. At 20O (temp of normal operating room), its critical pressure is 55atm
Define critical pressure
Minimum pressure which would suffice to liquefy a substance at its critical temperature
Define critical point
The point of minimum pressure and maximum temperature at which both a gaseous and a liquid phase of a given compound can coexist
Define specific critical volume
Volume of space occupied by 1kg of a gas at its critical point
Define absolute humidity and relative humidity
- Absolute humidity is the mass of water vapour present in a given volume of air.
- Relative humidity is the percentage ratio of the mass of water vapour in a given volume of air to the mass required to saturate that given volume of air at the same temperature
Define filtered load
The amount of a substance filtered per unit time
Define buffer
Any weakly ionised acid or base in equilibrium with its fully ionised salt that can resist changes in pH when a stronger acid or base is added.
List the ISF buffers
Bicarbonate
Phosphate (note: conc too low)
Protein (note: conc too low)
List the blood buffers
HCO3
Hb
Plasma protein
Phosphate (note: conc too low)
List the urinary and bone buffers
Urinary:
- Phosphate
- Ammonia
Bone:
- Ca carbonate
List the CSF buffers
HCO3 (important as low proteins, & negligible PO4)
How is haemoglobin metabolised?
RBCs phagocytosed by macrophages in liver or spleen, or haemolysed in circulation. Heme is degraded to bilirubin, Fe 2+ is recycled
Synthesis of haemoglobin?
Heme synthesised in mitochondria & cytosol of immature RBCs, globin synthesised by ribosomes in cytosol
Prothrombin time: normal range, therapeutic values, coagulation pathway assessed, method & abnormal in?
Normal range
10-13s
Therapeutic values
20-30s (warfarin)
Coagulation pathway assessed
Extrinsic & common
Method
- Sample collected in citrated blood tube & centrifuged (only plasma analysed)
- Recombinant tissue factor added
Abnormal in:
○ Problems with:
§ Vit-K dependent factor eg.warfarin
§ FVII eg. haemophilia
§ Factor Xa eg. apixaban
§ Thrombin eg. dabigatran
APTT: normal range, therapeutic values, coagulation pathway assessed, method & abnormal in?
Normal range
30-40 sec
Therapeutic values
usually 50-90 or 60-100s
Coagulation pathway assessed
Intrinsic & Common
Method
- Collected + centrifuged as per PT
- Phospholipid & negatively charged FXII activator added
Abnormal in:
- Factor deficiency (XII, XI, X, IX, II), heparin therapy, direct thrombin inhibitor therapy, direct Xa inhibitor therapy, antiphospholipid syndrome
Activated Clotting Time (ACT): normal range, therapeutic values, coagulation pathway assessed, method & abnormal in?
Normal range
110-130sec
Therapeutic values
200sec for ECMO, 400sec for bypass
Coagulation pathway assessed
Whole clotting cascade & platelet function
Method
- Whole fresh blood collected
- Point of care test - contact activator (eg. Kaolin) added
- Endogenous platelets are used as the source of phospholipid
Abnormal in:
Any coagulopathy. Most useful when there is one single predictable source of clotting dysfunction
What is the activator for Fibtem?
Cytochalasin D (platelet inhibitor) - isolates fibrinogen testing
What is the activator for Extem?
tissue factor
What is the activator for Intem?
Phospholipid & ellagic acid
What is the activator for Heptem?
Ellagic acid & heparinase
Contents of prothrombinex
- 500IU of Factor IX
- 500IU of Factor II (prothrombin)
500IU of Factor X
Contents of FFP
- Factor VII (will reduce PT)
- Factor IX, XI (will reduce aPTT)
- Factor X, II
200IU of Factor VIII per adult dose
How is prothrombinex prepared?
Adsorption of coagulation factors from plasma onto an ion exchange medium –> selective elution
How is FFP prepared?
Separation (by centrifuge) from whole blood, either by donation or by apheresis. Must be prepared within 6-18hrs
Dose of prothrombinex?
25-50IU/kg
Warfarin: INR < 2 - 20U/kg, 2-4: 30U/kg, >4: 50U/kg
How much Glycogen + fat is stored in the liver? (in g)
Glycogen: 100g
Fat: 75g
Amount of fat soluble vitamins stored in liver?
○ Vitamin A → stored in stellate cells –> converted to retinol (active form). Contains 1-2yr supply
○ Vitamin D → ~ 1-4 month supply
○ Vitamin E & vitamin K - minimal
What are the primary and secondary bile acids?
Primary: Formed in liver from cholesterol (by action of cholesterol 7α hydroxylase)
□ Cholic + Chenodeoxycholic acid
Secondary: formed by bacterial action on primary bile acids
□ Deoxycholic + Lithocholic acid
Define tolerance
Tolerance is the requirement of higher doses of a drug to produce a given response
Classify the mechanisms of tolerance
- Pharmacokinetic tolerance
- Pharmacodynamic tolerance
○ Receptor downregulation
○ Receptor deactivation
○ Receptor subunit modification
○ Second messenger systems
○ Drug target depletion - Physiological tolerance
- Learned/behavioural tolerance
- Others:
○ Sensitisation
○ Cross-tolerance
- Pharmacodynamic tolerance
Describe pharmacokinetic tolerance
Persistent exposure makes drug clearance mechanisms more active; classically by induction of metabolic enzymes (eg. Effect of ethanol on CYP450 enzymes)
Describe pharmacodynamic tolerance
Persistent exposure to the drug produces and adaptive homeostatic response that results in a decreased pharmacological effect
○ Receptor downregulation - receptors are inactivated or endocytosed in response to sustained stimulation
○ Receptor deactivation - receptor protein is phosphorylated in response to excess stimulus (eg. Nicotine and nicotinic receptor)
○ Receptor subunit modification - modified receptor complex is selectively expressed, with diminished selectivity for the drug but maintained sensitivity for the endogenous ligand (eg. GABA-A receptor and benzodiazepines)
○ Second messenger systems - deactivation of post receptor second messenger systems (eg. B-agonists)
Drug target depletion - some key molecule is used up in the drug action. Subsequent drug dosing will have diminished effect until the key molecule is regenerated (eg noradrenaline depletion due to ephedrine therapy)
Describe physiological tolerance
Tolerance to the effects of the drug rather than to the drug itself at the receptor level. Physiological adaptive mechanisms may maintain homeostasis. Eg. Vasodilator antihypertensives may be offset by increased heart rate and CO, which maintains BP
Describe behavioural tolerance
The development of learned behavioural adjustments that compensate for the drug’s effects
Describe sensitisation
“reverse tolerance” - subsequent dosing increases the drug effect (eg. Amphetamines)
Describe Cross-tolerance
Development of tolerance to multiple drugs belonging to the same class, after exposure to only one of them (eg. Nitrates)
Define tachyphylaxis
Decreased response to a drug with repeated short-term use. It occurs over minutes-hours & cannot easily be overcome with increase dose
Classify antihypertensives
(DR SVC)
Diuretics
- Carbonic anhydrase Inhibitors
- Loop diuretics
- Thiazides
- K+ sparing diuretics
RAAS antagonism
- ACE Inhibitors
- ARBs
- Direct renin inhibitors
Sympatholytics
- alpha blockers
- beta blockers
- mixed alpha + beta
- centrally acting (eg clonidine)
Vasodilators
- Arterial - hydralazine
- Arterial + venous - nitrates
Ca channel blockers
Renin: description, production + role
○ 37 kDa proteolytic enzyme with half life 40-120min
○ Produced in and released from juxtaglomerular (granular) cells in juxtaglomerular apparatus
Role:
○ Cleaves angiotensiongen into angiotensin-I
○ Rate-limiting step in RAAS
Renin: stimuli for release + regulation
Stimulus for release:
○ ↓ Na delivery to macula densa
○ ↓ blood pressure or renal perfusion pressure (sensed by intrarenal baroreceptors) –> likely cell stretch-mediated mechanism of renin release
○ Activation of β1 receptors on juxtaglomerular cells
Inhibits release:
○ Negative feedback: ↑ Renin –> ↑ Angiotensin II (ATII) –> binds AT1 receptors on juxtaglomerular cells –> ↓ renin secretion
Adrenaline: Class, preparation + administration
L1
- 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)
Adrenaline: indications + dose
L1
- Indication/Dose:
– Anaphylaxis - 0.1-0.5mg subcut
– Cardiac arrest - 1mg IV;
– Low CO states: 0.01-0.1mic/kg/min as infusion in shock
– Glaucoma
– Local vasoconstrictor (added to LA solutions to prolong duration)
Adrenaline: absorption + distribution
L1
- 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
Adrenaline: metabolism + excretion
L1
- Metabolism - Metabolised rapidly by COMT (liver)–> metadrenaline + noradrenaline; MAO (neurons); final common products (normetadrenaline + VMA) are inactive.
- Excretion - urine; half life ¬2min
Adrenaline: mechanism of action
L1
- 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
Onset: immediate
Duration: 1-5min
Adrenaline: PD effects + precautions
L1
- 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)
Ephedrine: Class/chemistry
L2
Naturally occurring sympathomimetic amine
Ephedrine: indications/dose
L2
- 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
Ephedrine: Absorption + distribution
L2
- Absorption - rapidly and completely absorbed via all routes
- Distribution - rapidly and extensively absorbed. Vd = ~4L/kg. Crosses placenta & excreted to breast milk
Ephedrine: metabolism + excretion
L2
- 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 6hrs
Ephedrine: mechanism of action
L2
- Mechanism of action - acts both indirectly (causes release of NA from sympathetic nerve terminals) and directly by stimulating α & β-adrenoceptors
Onset: rapid
Duration: 1hr
Ephedrine: PD effects + precautions
L2
- 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
Noradrenaline: Class & preparation/administration
L1
Class/chemistry: Catecholamine/endogenous sympathomimetic
Preparation/Administration: Clear, colourless liquid containing 2mg/ml. Administered via CVC in 40mic/ml conc infusion
Noradrenaline: Indications + Dose
L1
Dose: titrated to effect. Usually 0.1-0.4ug/kg/min
Indication: refractory hypotension
Noradrenaline: Absorption + distribution
L1
Absorption: Undergoes significant first pass metabolism and is inactive when administered orally
Distribution: VD 0.1-0.4L/kg; 25% protein bound
Noradrenaline: metabolism + excretion
L1
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 ~2minutes, 5% of dose excreted unchanged
Noradrenaline: Mechanism of action
L1
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
- Onset: immediate
- Duration of action: 5-10minutes; tachyphylaxis with prolonged administration
Noradrenaline: PD effects + precautions
L1
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
Levosimendan: Class, preparation/administration
L3
- Class/chemistry: Propanedinitrile derivative
- Preparation/administration: Clear, yellow or orange solution for injection – 2.5mg/mL in 5 & 1-mL ampoules
Levosimendan: Dose/Indication
L3
Severe decompensated heart failure unresponsive to other therapies.
Cardiogenic shock post cardiac surgery in pts with EF <40%
Infusion at 0.05-0.2microg/kg/min. Used for ~24/24
Levosimendan: Mechanism of action
L3
- 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
Levosimendan: PD effects + precautions
L3
— CVS – Increases myocardial contractility via increased calcium sensitivity without increased myocardial oxygen demand. Also causes coronary and peripheral vasodilation. Hypotension
Dobutamine: Class, preparation/administration
L3
- Class/chemistry: Synthetic isoprenaline derivative
- Preparation/administration: 12.5mg or 50mg/mL of dobutamine (diluted prior to infusion)
Dobutamine: Dose/Indication
L3
For low cardiac output states eg: acute heart failure & cardiogenic shock. Dose: 2.5-20mic/kg/min (~100-3000mic/min)
Dobutamine: MoA
L3
Predominately selective β-1 agonist, weak β2 agonist. Acts directly on catecholamine receptors to activate adenylate cyclase, which catalyses the conversion of of ATP to cAMP
Dobutamine: PD effects + precuations
L3
— 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
Metaraminol: Class/chemistry
L2
Synthetic sympathomimetic amine
Metaraminol: Indication/dose
L2
Adjunct in treatment of hypotension. 0.5-2mg bolus dose. Infusion 0.5-10mg/hr
Metaraminol: Absorption + Distribution
L2
Absorption: -
Distribution: Does not cross BBB. Vd = 4L/kg; 45% PB. Distributes into catecholamine storage vesicle - persists for days
Metaraminol: Metabolism + Excretion
L2
Metabolism: Not metabolised
Excretion: Eliminated slowly over hrs/days - distribution t1/2 rapid. Half life - minutes
Metaraminol: MoA
L2
Direct and indirect acting sympathomimetic. Agonist effect at alpha-1 adrenoceptor, but also some beta-adrenoceptor activity. Causes noradrenaline release from intracytoplasmic stores, in addition to causing adrenaline release
Duration of action - 20-60min; onset 1-2min
Metaraminol: PD effects + precautions
L2
- CVS - Sustained increase in systolic and diastolic blood pressures due to increase in systemic vascular resistance. Reflex bradycardia. Indirect increase in coronary artery flow
- CNS - cerebral blood flow decreased
- Renal - renal blood flow decreased
Other:
- Excessive hypertension may occur when administered in patients with hyperthyroidism or those receiving MAOIs
Isoprenaline: Class/chemistry
L3
Synthetic catecholamine
Isoprenaline: Indication/dose
L3
Complete heart block, bradycardia with haemodynamic compromise
0.5-10mic/min1
Isoprenaline: MoA
L3
Non-selective Beta-adrenergic agonist. Its actions are mediated by membrane-bound adenylate cyclase and subsequent formation of cAMP
Onset: immediate
DoA: 10-15min
Isoprenaline: PD effects + precautions
L3
- CVS - Positive ionotrope + chronotrope –> increased CO; decreased, PVR (B2 effect) & DBP
- Side effects = tachycardia, hypotension, arrhythmias, angina
- Resp - Potent bronchodilator
- CNS - CNS stimulant
Other
- Tachyphylaxis may occur with prolonged use
Dopamine: Class/chemistry
L3
Naturally occurring catecholamine
Dopamine: Indication/dose
L3
Low cardiac output states, especially post cardiac surgery. Initial 2-10mic/kg/min; maintenance up to 50mic/kg/min
Dopamine: MoA
L3
Stimulates adrenergic and dopaminergic receptors. Lower doses mainly dopaminergic stimulating (renal + mesenteric vasodilation), higher doses both dopaminergic & β1 stimulating, large doses stimulate α-adrenergic receptors
Onset: 5 min
Duration: <10min
Dopamine: PD effects + precautions
L3
- CVS - Dose dependent - increased ionotropy, CO, coronary BF (beta effects); increased vasoconstriction, SBP (alpha effects)
- Resp - may decrease ventilatory response to hypoxia
- CNS - Nausea (direct stimulation of CTZ). Does not cross BBB
- Renal - in low doses, marked reduction in renal vascular resistance –> increases flow. Diuresis via D1 receptors at luminal and basal membranes of PCT
Other
- Reduce dose in people who have taken recent MAOIs
Phenylephrine: Class/chemistry
L3
Synthetic sympathomimetic amine
Phenylephrine: Indications/dose
L3
hypotension, nasal decongestant, mydriatic agent. 50-100microg bolus doses
Phenylephrine: MoA
L3
Direct acting selective alpha-1-adrenoceptor agonist (nil B-effects)
Duration of action 15-20min IV; onset immediate
Phenylephrine: PD effects
L3
- CVS - rapid increase in SBP + DBP, SVR. Reflex brady - may reduce CO
- CNS - mydriasis
- Renal - RBF decreased
Vasopressin: Class/chemistry & preparation/administration
(And analogues)
L1
(Argipressin is synthetic compound which is identical to endogenous human vasopressin)
Class/chemistry:
- Naturally occurring nonapeptide prohormone produced in posterior hypothalamus
Preparation/Administration:
Available in 3 synthetic analogues: (all clear, colourless liquids)
- Argipressin in 20IU/mL (SC/IV or IM) - draw up into 20U/20mL
- terlipressin
- desmopressin in oral, IV, IN
(Note - analogues L2)
Vasopressin: Indications + Dose
(And analogues)
L1
- Management of catecholamine-refractory shock: Argipression is 0.6-2.4IU/hr
- Cranial diabetes insipidus & Management of polyuria/polydipsia post hypophysectomy: 100mic TDS desmopressin, adjusted to response
- Bleeding oesophageal varices: terli: 0.5mg/hr for 48/24
- Perioperative/trauma management of people with haemophilia and VW disease
Vasopressin: Absorption + distribution
(And analogues)
L1
Absorption: desmopressin - 0.08-0.16% of dose is absorbed via PO route; 10% via IN route
Distribution: Argi: Vd = 0.14L/kg, not protein bound. Largest is terlipressin: 0.5l/kg
Vasopressin: Metabolism + excretion
(And analogues)
L1
Metabolism: Endogenous vasopressin metabolised by vasopressinases (endothelial peptidases). Argi = 35% metabolised, desmo - minimal, terli - completely metabolised
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
Vasopressin: MoA
(and analogues)
L1
Act on GPCR vasopressin receptor
- V1 = GqPCR - act via PLC –> IP3 + DAG –> increase IC Ca
- V2 = GsPCR - activated AC –> cAMP –> increase IC Ca
Onset 1-2min
Duration up to 20min
Vasopressin: PD effects + precautions
(And analogues)
L1
- 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
- Endo: release of ACTH from pituitary
Milrinone: Class/chemistry & preparation/administration
L1
- Class: Ionotrope
- Chemistry: Bypyridine molecule
- Preparation/Administration: Clear, colourless solution for injection in 10-20mL glass ampoules (1mg/mL)
Milrinone: Indication + Dose
L1
- 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)
Milrinone: Absorption + distribution
L1
- Absorption: -
- Distribution: Vd = 0.3-0.4L/kg; 70-80% protein bound
Milrinone: Metabolism + excretion
L1
- 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
Milrinone: MoA
L1
- 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
Milrinone: PD effects + precautions
L1
- 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
Other
- Decrease infusion rate in renal failure
Classify antihypertensives
(mnemonic: DR SVC)
- Diuretics (see renal)
- RAAS antagonists
- ACE inhibitors
- ARBs
- Direct renin inhibitors- eg.Aliskiren
- Sympatholytics
- B-blockers
- A-blockers
- Mixed A + B
- Centrally acting (eg clonidine)
- Vasodilators
- Arterial
- Arterial + venous
- Ca- Channel antagonists
ACE inhibitors: Indications + dose
L3
- Indications: Hypertension, HFrEF, Post MI, diabetic nephropathy
- Examples:
- Captopril (dose range 6.25mg-max 150mg/24hrs. Usually 12.5mg BD for HTN),
- perindopril (2.5mg arginine = 2mg erbumine. Usually 4-5mg (max 8-10mg daily)),
- ramipril dosing same as perindopril arginine
ACE inhibitors + ARBs: MoA
L3
ACEIs: Blocks ACE which catalyses conversion of angiotensin I–> angiotensin II
ARBs: Block AT1 receptor (10000-fold more selective for AT1 than AT2). Inhibits biological effects of AngII, similar to ACEIs
ACE inhibitors & ARBs: PD effects + adverse effects
L3
Organ effects:
- CVS: ↓vasoconstriction & ↓hypertrophic remodelling (less ATII) & ↑ bradykinin levels (decrease breakdown) –> stimulates PGs –> vasodilation
- Renal: ↑ natriuresis
Adverse effects:
- Hypotension,
- cough (accumulation of lung bradykinin),
- hyperkalaemia (in pts taking K+ sparing diuretics)
- Note: ARBs: ARF, less cough
Contraindicated in pregnancy (teratogenesis, fetal hypotension, anuria, renal failure)
ARBs: Indications + dose
L3
Hypertension, some ACEs approved for diabetic nephropathy, valsartan for HF
Dose:
- Irbesartan (150mg daily - max 300mg)
- candesartan (4mg daily to max 32mg)
- telmisartan (40mg - max80mg)
List receptor mediated mechanisms of drug action
-
Alter ion permeability - act on ligand gated ion channels (membrane spanning complexes that can form a transmembrane channel for ions). Types:
– Pentameric -> 5 membrane spanning units (eg, nicotinic Ach receptor at NMJ - Na+ flux, GABA A receptor - Cl- flux)
– Ionotropic glutamate -> NMDA, AMPA and kainate iontropic ligand gated ion channels. They form Na, K and (NMDA only) Ca channels when glutamate binds
– Purinergic receptors -> activated by purines such as adenosine & ATP. Permeable to Na, K and Ca -
Produce intermediate messengers - act on membrane bound systems which transduce signal from an extracellular ligand to an intracellular signal transmitted by intermediate messengers. Eg:
○ G proteins (most common) - eg, Nad and Adr
○ Tyrosine kinase - eg, insulin
○ Guanylyl cyclase
- Membrane bound - eg. atrial natriuretic peptide on its receptors
- Soluble - eg. NO -
Regulate gene transcription
○ Steroids & thyroid hormones act on intracellular receptors to alter the expression of DNA and RNA
List the non-receptor mediated mechanisms of drug action
-
Physiochemical properties
○ Antacids - neutralise gastric acid
○ Chelating agents (eg, resonium - on gut K) -
Enzymes
○ Concentration of the substrate normally metabolized by the enzyme is increased, and product of reaction is decreased
○ Eg, ACE inhibitors (captopril, enalapril) prevent the conversion of ACEI to ACEII & bradykinin into its breakdown fragments -
Voltage gated Ion channels
○ Involved in the conduction of action potentials in excitable tissues
○ Eg, local anaesthetics (eg, lignocaine) block Na channels, calcium channel blockers (eg, diltiazem) acts on vascular smooth muscle ion channels - Alteration on transport proteins - eg. Frusemide on NKCC2
-
Prodrugs
○ Require conversion to activated form by a metabolic pathway
Eg. Levodopa –> dopamine
GTN: Class/chemistry
L2
Class: Organic nitrate
Chemistry: Ester of nitric acid
GTN: Indications/Dose
L2
- Stable, unstable, variant angina
Dose: 0.3mg s/l; 0.4-0.8mg s/l buccal spray; 5-10mg/24 transdermal; - LV failure secondary to MI
- Perioperative control of BP
Start 5-10mic/min. Increase up to 200microg/min IV infusion (sometimes up to 400mic/min)
GTN: Absorption + distribution
L2
Absorption: Rapid + efficient s/l (40%). POBA 3%
Distribution: PB 60% Vd ~2L/kg
GTN: Metabolism + excretion
L2
Metabolism: by liver + RBCs to mono- & di-nitrates + nitrites - all have lower activity than parent
Excretion: 80% urine. T1/2 1-3min
GTN: MoA
L2
Metabolised to NO –> stimulates guanylate cyclase in vascular smooth muscle –> increased cGMP–> phosphorylation cascade–> relaxation
Onset: 1-3min s/l or ~100s IV
Duration:15-30min s/l or 3-5min IV
GTN: PD effects + precautions
L2
CVS: at low doses, venodilation –> veno + arterial at higher doses. Decreases afterload, decreases myocardial O2 demand, increases myocardial oxygen supply. Reflex tachycardia in normal individuals
CNS: ICP may increase due to cerebral vasodilation
Other:
40-80% of IV GTN adsorbed onto plastic giving-sets (needs non-PVC)
Sodium Nitroprusside: Class/chemistry
L2
Class: Inorganic nitrate
Chemistry: Central Fe atom with 5 cyanide groups + 1x NO
Sodium Nitroprusside: Absorption + Distribution
L2
Absorption: -
Distribution: Vd up to 0.2L/kg (EC space)
Sodium Nitroprusside: Indications/dose
L2
IV infusion 0.5-6microg/kg/min
- Hypertensive crisis
- Aortic dissection prior to surgery
- LV failure
Sodium Nitroprusside: Metabolism + Excretion
L2
Metabolism:
* Rapid non-enzymatic hydrolysis in RBCs –> 5x cyanide ions per molecule of SNP
* –> 1x cyanide reacts with methaemoglobin –> cyanomethaemoglobin
* –> 4x cyanides enter plasma –> 80% react with thiosulfate –> thiocyanate (catalysed by hepatic rhodanese). Remainder of cyanide reacts with hydroxycobalamin to form cyanocobalamin
Excretion: Metabolites excreted unchanged in urine. T1/2 2 min (thiocyanate 2 days)
Sodium Nitroprusside: MoA
L2
Interacts with sulfhydryl groups on smooth muscle membrane –> releases NO –> vasodilation
Onset: 1-2min
Duration: 3-7min IV
Sodium Nitroprusside: PD effects + precautions
L2
CVS: decreases SBP, CO well maintained. Decrease Myocardial O2 consumption. Causes both veno - and arterio dilation
Resp: attenuates HPV in lungs
CNS: cerebral vasodilation, increased ICP. Shifts autoregulation to left
Other
Can be removed by haemodialysis
Needs to be protected from light
Can get cyanide toxicity
Hydralazine: Class/chemistry
L3
Antihypertensive
Pthalazine derivative
Hydralazine: Indications/dose
L3
- acute severe hypertension
- Pre-eclampsia
IV 5-10mg, administered slowly. May repeat 20-30min later. IVI initially 200-300microg/min, maintenance 50-150microg/min - chronic moderate to severe hypertension - PO 50-200mg daily in divided doses
Hydralazine: MoA
L3
Activates ATP sensitive K+ channels –> inhibits opening of voltage gated Ca channels by hyperpolarising membrane –> electromechanical decoupling + inhibition of contraction
Onset: 5-20min when given IV
Duration: 2-6hrs
Hydralazine: PD effects + precautions
L3
CVS: predominately arteriolar vasodilation –> decreases SVR. Compensatory tachycardia
CNS: CBF increases
Metabolic: increases plasma renin
Other:
Additive hypotensive effects with volatiles
Clonidine: Class/chemistry
L3
Antihypertensive
Aniline derivative
Clonidine: Indications/Dose
L3
0.05-0.6mg PO (max 900microg/day), IV 0.15-0.3mg
- Hypertension
- Migraine
- Chronic pain, opiate and alcohol withdrawal
- premedication in anaesthesia
Clonidine: MoA
L3
Stimulates alpha 2 (200:1 ratio alpha 2:alpha1 affinity) receptors (pre-synaptic) –> decreases NAd release –> decreased sympathetic tone. GiPCR–> decrease cAMP –> dec Ca2+ influx & Ca-mediated NAd release
Analgesic effect - activation of alpha 2 R in dorsal horn of spinal cord (inhibits neurotransmission)
Onset: Within 5min IV
Duration: 3-7hrs when given IV
Clonidine: PD effects + precautions
L3
CVS: transient increase in BP (stimulation of alpha1), then sustained decrease. SVR decreased with long term treatment
CNS: Decreases cerebral blood flow + IOP. Depressant effect on spontaneous sympathetic outflow & afferent A delta- & C-fibre mediated somatosympathetic reflexes
Sedation
Analgesia
Prazosin: Indications/Dose
L3
0.5mg -1mg BD or TDS initially. Maintenance 3-20mg in divided doses
- Hypertension
- CCF
- Raynauds (1-2mg BD)
- BPH
Prazosin: MoA
L3
Inhibits post synaptic alpha1 receptors –> GqPCR –> inhibits PLC –> decreased IP3 + DAG –> decreased intracellular {Ca2+]
Onset: 30-90minutes
Duration: 10-24hrs
Prazosin: PD effects + precautions
L3
CVS: decrease in SVR without reflex tachycardia
Genitourinary: Improvement in urinary flow
Adverse: orthostatic hypotension, rarely tachycardia
What does β1 activation result in?
(systems)
β1 receptors:
* Distribution: mostly cardiac
* Effects:
○ CVS
§ ↑ SA node firing rate, ↑ HR
§ ↑ contractility
§ ↑ conduction velocity
§ ↑ AV node automaticity
○ Renal
§ ↑ renin secretion by the kidney
○ GI
§ ↓motility and tone of the stomach
What does β2 activation result in?
(systems)
β2 receptors:
* Distribution: Smooth muscle
* Effects:
○ Resp:
§ Bronchodilation
○ CVS:
§ Vasodilation of vascular beds (coronary arteries, arteries of abdo viscera, renal arteries)
§ Mild cardiac effects – β2 receptors make up 25% of total cardiac β receptor population
○ GI:
§ ↓motility + tone of stomach, intestine
§ Gallbladder relaxation
○ Skeletal muscle effects:
§ Increased K+ uptake
§ Glycogenolysis à Hyperlactataemia
○ Metabolic/endocrine
§ ↑glycogenolysis & gluconeogenesis in liver, insulin secretion, lipolysis, thermogenesis
What does β3 activation result in?
(systems)
β3 receptors:
* Bladder (detrusor) relaxation
* ↑ water & solute resorption at the kidney
* ↑ lipolysis and thermogenesis at the adipocyte
* Modulation of cardiac contractility
* Relaxation of uterine contractions
Adrenergic agonists: General pharmacokinetics
A - no available or inactivated PO (brush border COMT)
D - 0.1-0.2L/kg (Except aramine & ephedrine 4L/kg
M - COMT & MAO (aramine & ephedrine not metabolised)
E - urine
Non-adrenergic agonists: kinetics
D - V (0.14) <M (0.4); PB V(0)<M (70)
M - V(liver + kidney)>M (liver - not much)
E - Urine
Which β-blockers are:
- non selective
- β-1 selective
- combined α+β
- non selective
–> Prop + Sot - β-1 selective
–> Bisop, Esmo, Aten, Metop, Nebiv - combined α+β
–> Carvi + labet
Which β-blockers have membrane stabilising activity?
PMN
- prop
- metop
- nebiv
Which β-blockers have instrinsic sympathomimetic activity?
- labet
- acebut
- pindo
Labetalol: Class/chemistry
L2
B-blocker/ antihypertensive
Racemic mixture of 4 stereoisomers
Labetalol: Indications + dose
L2
Dose: 100-800mg PO BD; 5-20mg bolus IV or titratable infusion 20-160mg/hr
- Hypertensive emergencies
- All grades of hypertension
Labetalol: Absorption + distribution
L2
A: Rapidly absorbed but extensive FPM. BA 10-90%
D: 50% PB; Vd up to 15L/kg
Labetalol: Metabolism + Excretion
L2
M: Metabolized by the liver via CYP3A4 and CYP2D6 – inactive compounds
E: Elimination half-life of 5-8 hours. Excreted in the urine and feces.
Labetalol: MoA
L2
Non selective B-blocker with α1 blockade. Has some intrinsic sympathomimetic activity.
Alpha:beta 1:3 PO or 1:7 IV
Onset: IV – 5-30min
Duration: IV – 50min
Labetalol: PD effects + precautions
L2
CVS: beta-1 & beta-2 blockade in cardiac tissue à decreased HR & contractility
Alpha-1 block à vasodilation à
20% decrease BP
Decreases HR + CO by ~10%
Renal: decreased renal VC à increased RBF à GFR unchanged
Carvedilol: Indications/Dose
L3
- Hypertension - PO initial 12.5mg daily –> 25mg (max 50mg)
Chronic heart failure with reduced ejection fraction - initial 3.125mg BD to max 25mg BD
Carvedilol: MoA
L3
Non selective B-blocker with α1 blockade, No ISA.
Onset: 30-60min
Duration: Long (t1/2 = 7-10hrs)
Carvedilol: PD effects + precautions
L3
CVS: ↓CO, ↓HR, ↓ reflex orthostatic tachycardia, vasodilation, ↓PVR, ↑ANP
Renal: ↓renal VC, ↓ plasma renin
Describe the anatomical course of the pulmonary circulation
Describe the anatomy of pulmonary vessels
- Pulmonary arteries can be classified:
○ Elastic (large, contain elastin)
○ Transitional (increasing amounts of circumferential muscle fibres)
○ Muscular (enough muscle to allow vasoreactivity)
○ Non-muscular (small endothelial vessels)
○ Capillaries (form a vascular sheet) - Pulmonary veins - thinner walled, contain more collagen + less elastin
- Pulmonary arteries and veins travel with bronchi (+ nerves + lymphatics) in bronchovascular bundles (à peribronchial cuffing)
Normal PA pressures
(systolic + diastolic)
PA systolic pressure = 18-25mmHg
PA diastolic pressure = 8-15mmHg
Normal pulmonary capillary and venous pressures
Pulmonary capillary pressure = 4-12mmHg
Pulmonary venous pressure = 6-12mmHg
Define venous admixture
A volume of blood that needs to be added to pulmonary end capillary blood to explain the observed difference between pulmonary end capillary oxygen content and arterial oxygen content
Venous admixture - normal value
Normal shunt fraction/venous admixture is 3%
Berggren equation
ie. shunt equation
- Shunt fraction –> ratio of venous admixture to total cardiac output
○ Q_s/Q_t = ((Cc_(O_2 ) −Ca_(O_2 )))/((Cc_(O_2 )− Cv_(O_2 )))Where:
§ Q_s= shunt blood flow
§ Q_t = cardiac output (so Qs/Qt = shunt fraction)
§ Cc_(O_2 ) = pulmonary end-capillary blood O2 content
§ Ca_(O_2 ) = arterial O2 content
§ Cv_(O_2 ) = mixed venous blood O2 content
Amiodarone: Class/chemistry + Preparation/administration
L1
- Iodinated benzofuran derivative (Class 3 antiarrhythmic)
- PO tablets 100mg or 200mg; IV 30 or 50mg/ml amiodarone hydrochloride
Amiodarone: Dose/Indication
L1
- tachydysrhythmias resistant to other treatment + related to WPW syndrome
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
- cardiac arrest: shockable rhythm. 300mg IV every 3 cycles
Amiodarone: Absorption + distribution
L1
- 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
Amiodarone: Metabolism + Excretion
L1
- Metabolism: largely in liver, to desethyl-amiodarone (has anti-arrhythmic properties and is cumulative)
- Excretion: 1-5% in urine, mostly in bile + faeces
T1/2 variable - up to 60days
Amiodarone: MoA
L1
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: 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)
Amiodarone: PD effects + other
L1
CVS - marked prolongation of the action potential duration (and QT interval 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%
- Other: Contraindicated in porphyria
Amiodarone side effects: CVS
○ Hypotension - Vasodilation w ↓ SVR (due to polysorbate 80)
○ ↓ CO - Decreased cardiac contractility
○ May get bradycardia/complete HB resistant to atropine, Ad & NAd
Amiodarone side effects: Resp
○ Pulmonary fibrosis
§ Tends to occur during chronic therapy
§ May be rapidly progressive and fatal
§ Risk factors: underlying lung disease, high doses, recent pulmonary insults (e.g. pneumonia)
§ Rx: Withdrawal of drug; high dose glucocorticoids [MIMS]
Amiodarone side effects: nervous system + occular
○ Peripheral:
- Peripheral neuropathy [MIMS]
□ Typically exposure-dependent (long term; high dosage)
□ Sensory > motor neuropathy (glove and stocking paraesthesia; disequilibrium)
□ Incomplete resolution on drug withdrawal
○ Central effects:
§ Tremor
§ Dizziness
§ Vertigo
Ocular:
○ Corneal microdeposits (almost ubiquitous, but usually asymptomatic) [Katzung, Goodman and Gilman’s]
§ Occasional visual changes (e.g. halos in peripheral visual fields) [Katzung, Goodman and Gilman’s]
○ Optic neuritis w blindness [Katzung, Goodman and Gilman’s]
Amiodarone side effects: MSK/Cutaneous
- Musculoskeletal system:
○ Proximal myopathy [MIMS] - Cutaneous:
○ Photodermatitis (photosensitivity) [Katzung]
○ Grey-blue discolouration in sun-exposed areas [Katzung] - Thrombophlebitis
Amiodarone side effects: Endocrine
- Endocrine effects:
○ Blocks peripheral de-iodination of T4 to T3 [Katzung]
○ Hyperthyroidism
○ Hypothyroidism (Wolf-Chaikoff effect)
○ Amiodarone-induced thyroiditis (types 1 and 2)
Amiodarone side effects: drug interactions
- Pharmacokinetic interactions:
§ Enzyme inhibition:
□ CYP3A4
□ CYP2C9
§ Efflux pump inhibition (PGP): - Pharmacodynamic interactions:
§ Negative chronotropes/dromotropes: risk of bradyarrhythmias
§ Synergistic QTc prolongation with other agents
Amiodarone side effects: GI
○ Nausea and vomiting
○ Hepatic:
○ Drug-induced liver injury
§ Δ AST, ALT, ALP
§ Rarely, acute liver failure
○ Hypersensitivity hepatitis [Katzung]
Class IA antiarrhythmic mechanism + example
Mechanism
Effect on (ventricular myocyte) AP:
- Moderate ↓ in phase 0 slope, ↑ APD, ↑ ERP
Effect on ECG:
- ↑ QRS + QT interval
Example
Quinidine
Procainamide
Na channel blockers (moderate)
Class IB antiarrhythmics: mechanism + example
Mechanism
Effect on (ventricular myocyte) AP:
- Small ↓ in phase 0 slope, ↓ APD, ↓ ERP.
Effect on ECG:
- minimal
Preferentially affects ischaemic or depolarised Purkinje and ventricular tissue
Example:
“I’d buy Liddy’s Mexican Tacos”
Lidocaine, mexiletine
Phenytoin
Na channel blockers (weak)
Class IC antiarrhythmics: mechanism + example
Mechanism
Effect on (ventricular myocyte) AP:
- Significantly ↓ Phase 0 slope; No effect on ERP or APD in Purkinje and ventricular tissue
Effect on ECG:
- Significant ↑ in QRS duration, therefore ↑ Qtc
- Significantly prolongs ERP in AV node + accessory bypass tracts, therefore ↑ PR interval
Example
“Can I have fries please”
Flecainide, propafenone
Na channel blockers (Strong)
Class II antiarrhythmics: mechanism + example
Mechanism
Effect on (pacemaker) AP:
- ↓ SA & AV nodal activity (↓cAMP & Ca2+ currents)
- Suppress abnormal pacemakers - ↓ slope of phase 4
Effect on ECG:
- AV node particularly sensitive - ↑ PR interval
Example
Metoprolol
B-blockers
Class III antiarrhythmics: mechanism + example
Mechanism
Effect on (ventricular myocyte) AP:
- ↑APD, ERP,
Effect on ECG:
- ↑QT interval
Example
Amiodarone
Sotalol
K channel blockers
Class IV antiarrhythmics: mechanism + example
Mechansim
Effect on (pacemaker) AP:
- ↓conduction velocity, ↑ERP
Effect on ECG:
- ↑PR interval
Example
Verapamil
Diltiazem
Ca channel blockers
Lignocaine: Class/chemistry + Administration/preparation
L1
Class/chemistry
Sodium channel blocker
Tertiary amine
pKa 7.9, ionisation 25%
Administration/preparation
- Multiple routes - IV, S/c, IT, epidural, topical
- 1-2% IV solution for injection, topical gel
- Combined formulations with adrenaline
Lignocaine: Dose/Indication
L1
- Local anaesthetic (3mg/kg to max 200mg)
- Class Ib antiarrhythmic - Rx for ventricular tachydysrhythmias - IV bolus 1mg/kg over 2 min, Inf 20-50mic/kg/min
Lignocaine: Absorption + distribution
L1
Absorption
Absorption of LAs related to site of injection, dose, VCs (delay absorption)
Distribution
~ 70% PB (alpha-1 glycoprotein); VD = ~1L/kg
Lignocaine: Metabolism + excretion
L1
Metabolism
Liver with multiple metabolites. Some lower seizure threshold, some with antiarrhythmic properties
Elimination
Half life ~100min
<10% in urine
Lignocaine: MoA
L1
Diffuse into cells in unionised form, combine with H+ –> enters internal opening of Na+ channel and combines with receptor –> decreases Na+ conductance –> prevents depolarisation of cell membrane
Acts on Nav1.5 subunit of fast voltage gated Na channels
Onset: 1-5min local infiltration; rapid IV
Duration: ~1-2hrs local (increased with adrenaline); 10-20min IV
Lignocaine: PD effects + other
L1
CVS: decreases rate of rise of phase 0 of ventricular AP, slows AP propagation + reduces automaticity. In toxicity, it decreases PVR & contractility –> hypotension + CV collapse
Resp: Bronchodilation. Resp depression in toxicity
CNS: biphasic effect - excitation then depression
Other
Not removed by dialysis
Flecainide: Class/chemistry & dose/indication
L3
Class/chemistry
Antiarrhythmic Class 1c
Dose/indication:
PO 50-100mg BD (max 400mg daily)
IV 2mg/kg (max 150mg)
- SVT
- Suppression of irritable foci eg. ventricular tachycardia + ectopics
- In treatment of re-entry dysrhythmias eg WPW
- In treatment of pAF
Flecainide: MoA
L3
Sodium channel blocker. Reduces maximum rate of depolarisation –> slows conduction. Has greatest effect on His-Purkinje system + ventricular myocardium
Flecainide: PD effects + other
L3
CVS: markedly slows phase 0 of action potential, but decreases ERP - may be proarrhythmogenic. Increases QRS duration, PR prolongation
CNS: may have visual disturbances
Adverse effects
May exacerbate heart failure, ventricular dysrrhythmias, increases non-fatal cardiac arrest
Amlodipine: Dose/indication
HTN, angina
2.5-5mg daily (max 10mg daily)
Verapamil: Class/chemistry
L3
Class IV antiarrhythmic
Non-dihydropyridine/phenylalkylamine
Verapamil: Dose/Indication
L3
240-480mg BD-TDS;
- Hypertension
- Angina
- pSVT, AF, flutter - 2.5-10mg IV
Verapamil: MoA
L3
Competitive blockade of slow Ca2+ channels, leading to decrease Ca2+ influx into vascular smooth muscle and myocardium
Onset: PO 10-20min; IV 3-5min
Duration: PO 6-8hrs; IV 0.5-6hrs
Verapamil: PD effects + Other
L3
CVS: decreases automaticity and conduction velocity, increases refractory period. Decreases SVR, potent coronary artery vasodilator
CNS: cerebral vasodilation
Adverse effects
Dizziness, flushing, nausea, first or second degree heart block
Other
Avoid co-administration with dantrolene
Nimodipine: Class/chemistry
L2
Ca2+ channel blocker - dihydropyridine
Nimodipine: Preparation/administration & Dose/Indications
IV infusion and tablets (30mg)
D/I
- Prevention of cerebral vasospasm secondary to subarachnoid haemorrhage
- Dose: 60mg Q4H; IV 1mg/hr for first 2hrs –>2mg/hr 5-14 days
- Migraine
- Drug-resistant epilepsy
Nimodipine: PD effects + other
L2
CNS: headache, cerebral vasodilation, increased CBF
CVS: hypotension, bradycardia
GI: nausea
Nimodipine: Absorption + distribution
L2
Absorption
Rapidly and well absorbed, significant FPM - BA low (30%)
Distribution
Highly protein bound, large Vd (1-2L/kg)
Nimodipine: Metabolism + excretion
L2
Metabolism
Liver
Excretion
Urine
t1/2 up to 6hrs
Nimodipine: MoA
L2
Modulates opening of Ca2+ channels on vascular smooth muscle (?preferential action on cerebral vasculature) –> prevents Ca2+ influx –> vasodilation
Sotalol: Class/chemistry
L3
B-blocker/antiarrhythmic
Sotalol: Dose/Indication
L3
Usually ~80mg BD initially
- AF, maintenance of sinus rhythm
- SVT
Ventricular arrhythmias
Sotalol: MoA
L3
Non-selective B-blocker - prolongation of atrial action potentials. K+ channel blocker - prolongs phase 3 of ventricular AP
Onset: 1-2hrs PO
Sotalol: PD effects (+ adverse effects)
L3
CVS: slows heart rate, decreases AV nodal conduction, increased AV nodal refractoriness, prolongation of atrial and ventricular action potentials
Adverse effects
Bradycardia, chest pain, palpitations, dizziness, fatigue, headache, dyspnoea
Digoxin: Class/chemistry
L3
Cardiac glycoside. Contains steroid nucleus
Digoxin: Dose/Indication
L3
Doses - loading dose 250-500microg every 4-6hours to effect (max daily dose 1.5mg). Then maintenance at 125-250microg daily
Indication - use in AF + Flutter, heart failure, prevention of supraventricular dysrhythmias post thoracotomy
Digoxin: MoA
L3
- Direct action - binds to & inhibits Na+/K+ ATPase in sarcolemma cell membrane–> ↑ intracellular Na+ & ↓ intracellular K+. ↑Na/Ca exchange via INCX - ↑ intracellular Ca–>ionotropy. Decreased K+ leads to slowed AV conduction & ↓ pacemaker cell action
- Indirectly modifies autonomic activity & ↑ efferent vagal activity
Onset: PO 1-2hrs; IV 5-60min
Duration of action: 3-4 days; Half life: 36-48hrs
Digoxin: PD effects
L3
- CVS - ↑ ionotropy. ↓ HR (depression of SA node discharge, AV node conduction), ↑ AV nodal refractory period & indirect vagal effect. Rapid IV administration may cause vasoconstriction, leading to HTN & ↓ CBF. 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
Digoxin: toxicity - levels, antidote, risk factors
L3
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
Adenosine: Class/Chemistry + Preparation/administration
L2
Naturally occurring nucleoside
Clear, colourless solution 3mg/mL
Adenosine: Dose/Indication
L2
- Diagnosis and treatment of paroxysmal SVT. Initially 3-6mg IV, followed by 12mg at 1-2min intervals until effect observed
Adenosine: relevant PK
Metabolism - absorbed from plasma into RBCs –> phosphorylated to AMP or deaminated to inosine. T1/2 <10sec
Adenosine: MoA
L2
Direct agonist at A1 and A2 receptors. Adenosine activates acetylcholine sensitive K+ current in the atrium and sinus & AV nodes - shortens APD, hyperpolarisation + slowing of normal automaticity
Onset 10 seconds
Duration 10-20 seconds
Adenosine: PD effects + adverse effects
L2
CVS: depression of SA & AV nodal activity; coronary vasodilation - endothelial A2 receptors
Resp: increase in depth + rate of respiration. May induce bronchospasm
CNS: infusion results in increased CBF
Adverse effects:
Facial flushing, dyspnoea, chest discomfort
Magnesium (antiarrhythmic): Class/chemistry + Preparation/administration
L1
Mg2+ 2nd most abundant intra-cellular cation
Mg2+ oxide, chloride, sulphate
PO & IV
IV MgSO4 (50% Mg & inorganic sulphate, 40mmol/100ml), ampoule 10mmol/5ml
Magnesium (antiarrhythmic): Dose/indication
L1
Dose: depends on Mg2+ level, 10-20mmol over 20/60
Eclampsia & pre-eclampsia
Premature labour
Low Mg2+
Ventricular dysrhythmias incl TDP
Asthma
Magnesium (antiarrhythmic): Absorption + distribution
L1
Absorption:
BA: 25-65%
Distribution:
ECF: 1% (0.7-1mmol/L)
Bone: 60%
ICF: 39% (15-20mmol/L)
30% bound to albumin
Magnesium (antiarrhythmic): Metabolism + Elimination
L1
Metabolism
Dissociates into active Mg2+
No metabolism
Bound to bone or filtered into kidneys
Elimination:
Renal
90% reabsorbed in TAL LOH
Magnesium (antiarrhythmic): MoA
L1
Same role of endogenous Mg2+
Multiple mechanisms
* Reduces membrane excitability e.g. muscle & nerve
* Reduces NT release cholinergic & adrenergic synapses
Ca2+ antagonist -> relax smooth muscle
Onset: immediate after IV
Magnesium (antiarrhythmic): PD effects
L1
- CVS: Direct vasodilator - ¯ SVR, ¯ BP, ¯ cardiac conduction & force of contraction, ¯ HR, ¯ catecholamine release
- Resp: Bronchodilator
- CNS: ¯ catecholamine from adrenal medulla & adrenergic nerve terminals, CNS depressant, Anti-convulsant, Cerebral vasodilator
- GIT: Osmotic laxative -> diarrhoea
- GU: Renal vasodilator, Diuretic
- O&G: ¯ uterine tone & contractility
Magnesium (antiarrhythmic): toxicology
L1
N&V, facial flushing, CNS depression, areflexia, respiratory depression. Reverse with Ca2+
Plasma level (mmol/L) Effect
<0.7 Arrhythmia
4-6 Nausea, ¯ reflexes, speech impaired
6-10 Muscle weakness, resp depression, ¯ HR
>10 Cardiac arrest
Atropine: Class/chemistry + preparation/administration
L1
Class: Anticholinergic
Chemistry: Racemic mixture of D- and l-hyoscyamine (l- form is active)
Prep/admin: Clear, colourless solution for injection in 0.5/0.6mg/mL and 3mg in 10mL
Atropine: Dose/Indication
L1
- Bradycardia with haemodynamic compromise - 0.5-1mg - repeat 3-5minutely
- Counter the muscarinic effects of anticholinergic agents
- During CPR
- treatment of organophosphate poisoning, tetanus
Atropine PK: Absorption + distribution
L1
A: Well absorbed IM
D: 50% PB; Vd = 2-4L/kg. Crosses BBB & placenta
Atropine PK: Metabolism + elimination
L1
M: Hydrolysed in liver and tissues to tropine + tropic acid
E: T1/2 = 2.5hrs, excreted in 24hrs in urine
Atropine: MoA
L1
Competitive antagonism of acetylcholine at muscarinic receptors (GPCR)
Onset: immediate
Atropine: PD effects
L1
CVS: tachycardia, increased CO. Decreases AV nodal conduction time
Resp: Bronchodilation, secretions reduced, RR increases
CNS: CNS excitation or depression can occur
GI: antiemetic, decreases gastric motility
Metabolic: reduces sweating, BMR increases, suppresses ADH secretion
Midazolam: Class/chemistry + Preparation/administration
L1
Class: sedative/anxiolytic
Chemistry: Imidazobenzodiazepine
Preparation: Vials 5mg/5ml
Administration: IV + IM
Midazolam: Dose/Indications
L1
- Induction of anaesthesia - 0.15-0.2mg/kg
- Sedation in ICU- 0.03-0.2mg/kg/hr
- Termination of seizures
Midazolam: Absorption + distribution
L1
A: Poor bioavailability 44%
D: 96% protein bound (albumin) with Vd = 0.8-1.5L/kg
Midazolam: Metabolism + Excretion
L1
M: Extensively hepatic (CYP3A4). Hydroxylated and forms many active metabolites
E: Renally excreted as hydroxylated metabolites
T1/2 = 2hrs; CSHT 70-80min post 8hr infusion
Midazolam: MoA
L1
Targets (between α & γ subunits) GABA-A receptors in CNS – enhances inhibitory effect of GABA (increased permeability to Cl-) Different receptor subtypes are responsible for the nuances in effects of the different benzos
Onset: IV 1-5min; Duration: ~1hr for sedation
Midazolam: PD effects
L1
- CNS: sedation, hypnosis, anterograde amnesia. CMRO2 & CBF decrease
- CVS: decrease in SVR, decrease in BP with compensatory increase in HR
- Resp: Can cause apnoea, impairs ventilatory response to hypercapnoea
Phenytoin: Class/chemistry + Admin/prep
L2
Class: Anticonvulsant/Hydantoin.
Chemistry: Little difference in activity between isomers
Fosphenytoin is the water-soluble prodrug
pKa 8
**Admin/prep: **
PO - 25/50/100/300mg capsules, syrup of 6mg/ml
IV - clear, colourless solution 50mg/mL
Phenytoin: Dose/Indications
L2
- Prophylaxis and treatment of GTC + partial epilepsies
- Status: IV 15-20mg/kg with additional 5mg/kg post 12hrs if needed
- 4-5mg/kg (usually 200-500mg) in 1 or 2 doses in epilepsy - Arrhythmias (especially from dig toxicity) - 3-5mg/kg
- Trigeminal neuralgia
Onset: 0.5-1hr IV; PO 2-24hrs
Phenytoin: Absorption + Distribution
L2
A: Absorption is slow via PO + IM routes. (Note IM may cause muscular damage) Bioavailability is 85-95%
D: 90-93% protein bound in plasm - Vd = 0.5-0.7l/kg
Crosses BBB + placenta
Phenytoin: Metabolism + excretion
L2
M: In liver. Large genetic variation in rate of metabolism.
- Hydroxylated derivative –> conjugated to glucuronide
- Exhibits zero order elimination just above therapeutic range
E: 70-80% renally excreted by active tubular secretion as the major metabolite, 5% unchanged
- t1/2 = 9-22hrs in the first-order kinetics range
- plasma concentration increases disproportionately with increased dosage
Phenytoin: MoA
L2
- Blocks voltage and use dependent Na+ channels. Also delays outward K+ flux & Ca2+ flux
- High affinity binding site for phenytoin in CNS, so likely endogenous binding site
Phenytoin: PD effects
L2
CNS - stabilises the seizure threshold by preventing the speed of seizure activity, rather than abolish a primary discharging focus. Tonic phase can be abolished, but clonic seizure may be exaggerated/prolonged. Toxicity - nausea/vomiting, drowsiness, behavioural difference, tremor, ataxia, nystagmus, paradoxical seizures, peripheral neuropathy + cerebellar damage
CVS - class IB antiarrhythmic properties + enhances AV nodal conduction. Hypotension may complicate rapid IV administration of the drug; complete heart block, VF & asystole
Metabolic/other -Hyperglycaemia, hypocalcaemia + LFT derangement (suppresses ADH secretion)
Haem - megaloblastic anaemia (folate deficiency with chronic use)
Phenytoin: special points (interactions + monitoring)
L2
Drug interactions
- Increase phenytoin toxicity: metronidazole + isoniazid
- Reduces effect of benzodiazepines, pethidine + warfarin. May also decrease the MAC of volatiles
- May enhance CNS toxicity of Las
Therapeutic drug monitoring
Limited correlation b/w therapeutic efficacy and plasma conc but may be useful to confirm toxicity or compliance
Levetiracetam: Dose/Indication
L3
- Single agent (or adjuvant) for seizures (myoclonic, partial, generalised epilepsy)
- 250mg BD, then increase to 500mg in 2/52 (titrate to max 1.5g BD)
- Loading dose in status 60mg/kg (to max 4.5g)
Levetiracetam: MoA
L3
Not well understood
- interact with SV2A (synaptic vesicle protein) to decrease release of neurotransmitters
Peak effect ~ 5-30min IV
Levetiracetam: PD effects + other
L3
CNS: Sedation, anticonvulsant
Adverse effects:
- Ataxia, fatigue, dizziness, somnolence
- Psychiatric disturbances - aggression, paranoid
Other:
- Does not interact with CytP450
- Dose reduce in renal failure
Sodium Valproate: Dose/Indication
L3
- Primary generalised seizures
- Initially 600mg daily in 2 doses. Maintenance 20-30mg/kg in 2 doses(max 2.5g daily) - Chronic pain of non-malignant origin
- 200-400mg BD for migraine prevention - Bipolar disorder. Dosing similar to epilepsy
Sodium Valproate: MoA
L3
Inhibits GABA transaminase + succinate semialdehyde dehydrogenase (enzyme that metabolise GABA)
Blocks voltage-gated ion (Na+, K+ & Ca2+) channels
Sodium Valproate: PD effects + other
L3
CNS: anticonvulsant, minimal sedation
Metabolic: infrequently, hyperammonaemia
Toxicity: liver dysfunction, decreased GCS, thrombocytopaenia, coagulation dysfunction
Adverse effects: weight gain, oedema, coagulation dysfunction, hepatic impairment, pancreatitis
Lamotrigine: Dose/Indication
L3
Partial and generalised seizures - initial 25mg –> 100-200mg/day
Lamotrigine: MoA
L3
Inhibits voltage gated Na+ channel & reduce release of glutamate
Lamotrigine: PD effects + other
L3
CNS: Anticonvulsant
Adverse:
Headache, nausea, diplopia & tremor, rarely aseptic meningitis, HLH, SJS
Phenobarbital: Dose/Indication
L3
- Epilepsy
- PO 60-240mg daily nocte - Status epilepticus
- 10-20mg/kg (max 1g) infused at <60mg/min. Repeat after 6hrs if needed
Phenobarbital: MoA
L3
Enhance the binding of GABA to GABAA receptors. Extends the amount of time the chloride ion channel is open by interacting with GABAA receptor subunits.
Phenobarbital: PD effects + other
L3
CVS: can cause bradycardia,hypotension, syncope
CNS: CNS depression, confusion, dizziness, drowsiness
GI: constipation, nausea, vomiting
Resp: can get apnoea (especially with rapid IV use), hypoventilation, respiratory depression
Other:
Concentration monitoring 10-40mg/L or 24-180micrmol/L
Previously used as anaesthetic - but now rare use due to haemodynamics
Propofol: Class/chemistry
L1
Class: Sedative/hypnotic
Chemistry: Alkylphenol derivative. 2,6-diisopropylphenol
Propofol: MoA
L1
Not well understood. Potentiates inhibitory neurotransmitters (GABA + glycine) - presumably GABA-A agonism
Propofol: Preparation/administration
L1
Opaque, white liquid. 1% liquid emulsion (1mg/mL). Excipients include:
- soy bean oil, Egg lethicin
- NaOH (to adjust pH)
- EDTA (disodium edetate), which retards bacterial growth
- glycerol
Administered IV
Propofol: Indication + Dose
L1
- Induction + maintenance of general anaesthesia 1.5-3mg/kg bolus, followed by 4-12mg/kg/hr
- 50% dose increase for children, and dose reduce for elderly - Sedation in ventilated ICU patients - 1-3mg/kg/hr (max 4mg/kg/hr)
- Intractable nausea + vomiting in chemotherapy patients
- Termination of status epilepticus
Propofol: Absorption/Distribution
L1
A: 98% protein bound in plasma with VD = 4L/kg. Highly lipophilic. pKa ~11
D: Short distribution half life. Has initial effect (alpha phase) before distribution to tissues.
Propofol: Metabolism/Excretion
L1
M: There are 2 metabolic pathways
- glucuronide metabolite (inactive) by liver
- hydroxylated metabolite (quinol) which is sulfated and glucuronidated by cyt P450
Extrahepatic metabolism (40%)
Inter-individual variability effects which pathway it is metabolised.
E: Metabolites are renally excreted. Quinol metabolite can cause green discolouration of urine + hair.
Maximal CSHT ~20min
Propofol: PD effects + other
L1
CVS: Bradycardia, decreases cardiac output by 20% (decreases systemic vascular resistance due to production and release of NO & blunts baroreceptor reflex)
CNS: Causes hypnosis/sedation. Some people may have initial jerking movements (? Imbalance in subcortical inhibitory/excitatory centres), anticonvulsant, decreases CBF, ICP, CMRO2, antiemetic
Resp: Causes decrease in tidal volume, apnoea, decreased response to hypercarbia + hypoxia, decreases laryngeal reflexes
Other:
Toxicity - propofol infusion syndrome - rhabdo, renal failure, multi-organ failure
Ketamine: Class/chemistry + Preparation/administration
L1
**Class: **Sedative
**Chemistry: **Phencyclidine derivative. Racemic mixture (S-enantiomer more potent). Soluble in water
**Preparation/ Administration: **
50, 100mg/ml
IV, IM, IN, Oral (lozenges)
Ketamine: Indication + Dose
L1
**Induction: **1-2mg/kg
**Procedural sedation: **0.2-0.5mg/kg every 5-10minutes
Analgesia: 0.25-0.5mg/kg bolus, then 0.05-0.25mg/kg/hr
Ketamine: Absorption/ Distribution
L1
A: BA (oral 25%), nasal (50%), IM (93%)
D: 20% PB, Vd = 3L/kg
Ketamine: Metabolism/Excretion
L1
M: CYP450 - Norketamine (25% activity of parent)
E: Elim half life 2hr; 90% in urine
Ketamine: MoA
L1
NMDAR non-competitive antagonist at NMDAR
Inhibition of glutamate
Onset: 1min; Duration 10-15min
Ketamine:
L1
**CVS: **Stimulates SNS, increases HR, CO, BP - however is a direct myocardial depressant. S-ketamine - less myocardial depressant effect
**CNS: **Dissociative anaesthesia, analgesia. May increase CMRO2
**Resp: **Bronchodilation, respiratory rate. Airway reflexes intact
**AS: **increases salivation
**GI: **causes nausea + vomiting
