Pharmacology Flashcards
Describe lignocaine (as a systemic drug)
Type: Class 1B Antiarrhythmic
Effect: Treat VT and PVC
MOA: block fast VG Na Channels, reduce depolarisation (phase 0) rate, and conduction velocity. Also shortens cardiac AP duration (only Class 1B do this).
PK:
- A: IV only, poor bioavailability
- D: 70% protein bound
- M: hepatic with active metabolite
- E: excreted in urine. t1/2 90 min, but longer if poor hepatic blood flow
Aim therapeutic level 1-5ug/ml
CNS toxicity 5-10
- first excitatory Sx
- then depressive Sx
CVS toxicity >10
How does a-Methyldopa work
analogue for dopamine, causing central noraderenaline release. has mild a1 agonist, and +++ alpha 2 agonism (central), which works on hypothallamus and medulla to inhibit SNS outflow.
(Double check this maybe)
Pharmacodynamics and clinical uses of cholinesterase inhibitors
Carbamates:
- Neostigmine: reverse NM block, treat Myasthenia Gravis, urinary retention. Has stable covalent bonds at esteratic sites leading to prolonged inhibition. Onset 3 mins, peak at 7-11, off set around 2 hours (0.5-4hours)
- Pyridostigmine: Treat MG. onset 30-45 mins offset 4-6h
- Physostigmine: Treat anticholinergic crisis. Well absorbed and can cross BBB due to 3rd amine group. onset 5 min, offset 0.5-2h.
Alcohols: Edrophonium: Rapid Ddx between MG and cholinergic crisis (will make MG better, and cholinergic crisi worse). Weak bonds (electrostatic and hydrostatic). quick onset 1-2 min, quick offset 5-15 min
Selective uncharged ACHEi: donepezil, for alzheimers and cognitive decline.
What are the cholinergic receptors, where are they found
Nicotinic:
- Nn: on pre-ganglionic and post-gangiolonic nerve fibres. in the CNS
- Nm: Skeletal muscle
Muscarinic:
- M1: CNS (memory, analgesia, attention). Gastric ( Hal secretion by parietal cells). Gq Protein coupled receptors. stimulate IP3 and GAG to increase intracellular calcium.
- M2: Heart (SA, AV node of bundle) + smooth muscle + pre-ganglionic nerve cells. Gi protein coupled receptor. inhibits adenocyclase and therefor Protein kinase A –> increase cellular extortion of pottasium, reduced intracellular calcium, hyper polarisation of cell.
- M3: exocrine (sweat, lacrimal, saliva). pancreas (insulin). bronchoconstriction. GI peristalsis, Vascular smooth muscle (EDRF). detrusor muscle (bladder). Uterus contraction. Gq protein coupled receptor
- M4. Gi PCR. effects CNS (inhibitory)
- M5. GqPCR, CNS
Atropine
Anticholinergic.
Naturally occurring, tertiary amine (tropic acid and tropine)
MoA: mAChR competitive antagonist.
- reversible, peripherally and centrally acting (cross BBB)
- minimal effect on nAChR
Racemic mixture
variable oral absorption
oral availability <25% (can be given)
protein binding 50%. VD 2-4L/kg
extensive metabolism by hepatic esterases (caution in hepatic failure)
really excreted.
Half-life 150 minutes
onset 30-60s
peak HR after IV dose 2-4 mins
duration of action 3 hours.
Comes in 600mcg ampoule
dose: 10-30mcg/kg (paeds) repeat 5 minutely to 40mcg/kg max.
Glycopyrrolate
Anticholinergic:
MoA: competitive antagonist for mAChR.
Synthetic tertiary amine (madelic acid + tropine)
only peripherally active (cannot cross BBB)
No isomerism
negligible oral absorption, oral bioavailability 5%.
Distribution: 0.2-0.6L/kg
minimal metabolism
85% excreted unchanged in urine (caution renal failure)
half life 75 minutes
onset 2-3 mins
peak effect (HR) after IV dose 3-9 minutes (slower than atropine)
duration: anti-vagal 3 h, anti-sialogogue 6 h
Comes in 200mcg ampule
dose: 4-10mcg/kg
Hyoscine
Anticholinergic. Naturally occurring tertiary amine.
- Butylbromide (Buscopan)
- hydrobromide (scopolamine)
Racemic mixture (l-isomer), can also come in transdermal patch, tablet.
variable oral absorption, bioavailability <50%
extensively metabolised by liver, renal excretion
fast onset (quicker than atropine, 1-3 minutes)
2h duration of action
compare/contrast Atropine and Glycopyrrolate
How is noradrenaline synthesised
Tyrosine (found in diet) enters post-ganglionic nerve cell via Na/tyrosine transporter
Tyrosine converted to DOPA by tyrosine hydroxylase.
DOPA converted to Dopamine by aromatic amino acid decarboxylase (AAAD)
Dopamine converted to noradrenaline by dopamine beta hydroxylase
noradrenaline then converted to adrenaline in adrenal medulla by phenylethanolomine N methyltransferase (PNMT)
Describe the metabolism of catecholamines
noradrenaline and adrenaline are deaminated by COMT (catechol - o - methyltransferase) to normetanephrine and metanephrine.
MAO (monoamine oxidase) converts metanephrines to VMA (Vanillylmandelic Acid).
NorAd and Adr can also be converted by MAO to dehydroxymandelic acid. which then can be deaminated by COMT to VMA
COMT is in peripheral tissue (liver, kidney, blood.
COMT requires hydroxyl (-OH) group on 3,4, carbon.
MAO is on the surface of mitochondria
What constitutes a catecholamine.
What determines direct and indirect activity
Catechol + ethylamine
Catechol:
- benzyl ring
- OH group on C3 and C4
Ethylamine
- alpha and beta carbons + terminal NH2 (amine) group
Direct activity is determined by hydroxyl (-OH) group on beta carbon and C3 of benzene ring)
Pharmacokinetics of Propofol
A: poor oral availability. IV only
D: rapid distribution. Rapid onset 5-10min. Very high volume of distribution (4L/kg). Highly protein bound 98%. Highly lipophilic. Half life of distribution 1-2 minutes
M: Metabolised by liver CYP450. inactive metabolite
E: urine. elimination t1/2 = 5-12 hours.
Pharmaceutics of Propofol
Preparation:
- 10mg/ml (10ml or 50ml glass vial)
Di-iso-propo-phenyl
Glycerol
Soybean oil
Egg lecithin
Water
Sodium hydroxide
Dose: induction 1-3mg/kg
maintenance 4mg/kg/hr (titration)
MoA: Positive modulation of inhibitory function of GABA which binds to GABA-A receptor. causing inhibition of neural pathways/depolarisation
Pharmacodynamics of Propofol
CNS:
- sedative, hypnosis,
- nil analgesia
- can cause myoclonic movements
- reduce cerebral metabolic rate of O2. reduce CPP and ICP
- anticonvulsant
Resp:
- central respiratory depression
- reduce TV, MV
- impair laryngeal reflexes
- bronchodilator
CVS:
- depressant
- reduced SV, SVR, CO
- HR maintained
- reduced sympathetic response to hypoxia.
GIT
- anti-emesis
Renal
- minimal
SE’s: Pain on injection, propofol infusion syndrome
