Pharmacology Flashcards
Isomerism
Structural - dynamic or static
Stereo - enantiomers or diastereoisomers
Chiral centre
Central atom bound to 4 dissimilar groups
Enantiomer
Stereoisomer with a single chiral centre, producing non-superimposable isomers
Tautomerism
Dynamic change between 2 different forms depending on environmental conditions, often pH
Optical isomerism
Ability to rotate polarised light in different directs
What is the time constant?
Time taken for plasma conc to fall to 0 if initial rate of elimination continued
Reciprocal of the rate constant 1/e
Always longer than half life (half life is shorter by a factor of 0.693)
Clearance
Volume of plasma cleared per unit time
Cl = Input/plasma conc
Cl = Ke x Vd (where Ke is elimination rate constant)
Loading dose - equation
Vd * desired concentration
Maintenance dose - equation
Steady state con x clearance
Zero Order Kinetics
Independent of the conc of reactants
Constant amount
Fixed amount cleared; half life decrease
No steady state reached - accumulation will occur e.g. ethanol
(may be due to maximal enzyme activity - some reactions will initially be first order then at saturation point become zero order e.g thiopentone)
Horizontal line on graph
First Order Kinetics
Dependent on conc of reactants.
Constant proportion
Half life and clearance are constant
Reaches steady state - doesn’t accumulate - propofol
Michaelis-Menten Equation
Predicts rate according to substrate concentration and specific enzyme characteristics
V= Vmax[substrate]/Km + [substrate]
Where Km = substrate conc at which velocity is half of max (equivalent to ED50)
Agonists
Demonstrate affinity and intrinsic activity;
full agonists = 1
partial agonists < 1
Antagonists
Demonstrate affinity but no intrinsic activity
Competitive antagonists:
-same site binding
-shift the dose response to the right, but can achieve the same Emax with increased dose
Non-competitive antagonists
-allosteric binding
-reduce the Emax, effect not overcome by ^^ dose
Mixed agonist/antagonists
Opioids - pentazocine, buprenorphine
Mirtazepine
Pindolol, xameterol
Volume of Distribution
Theoretical volume a drug would have to occupy to produce plasma conc.
Vd= dose/conc
Small non polar molecules distribute freely = large Vd 40L
Small polar molecules exit circulation to ECF = Vd ~ 14L
Large polar molecules trapped in circulation = small Vd 5l
When can Vd be larger than total body water?
This effect can be due to protein binding, plasma degradation, sequestration into other tissues e.g. propofol into adipose
Extraction ratio
The efficiency of an organ in eliminating a drug
If ER is high, then clearance depends only on blood flow.
Phase 1 Elimination Reactions
Makes a substance water soluble, unmasks function group
CYP450 reactions;
oxidation - barbs, benzos, paracetamol, omeprazole
reduction - prednisone to prednisolone
hydrolysis - mao > adrenaline, esterases > remifentanil, atracurium, alcohol dehydrogenase > ethanol to acetic acid
Phase 2 Elimination Reactions
Conjugation with a functional group
Glucuronidation - morphine activation, propofol inactiv
Acetylation - isoniazid, hydralazine
Sulphation - paracetamol
Methylation - catecholamines
Glutathione conjug - paracetamol
TCI Models
Marsh
Developed for plasma effect site
Requires lean body weight
TCI Models
Schnider
Requires ABW, age, height, gender
Smaller initial bolus so safer for old/frail/high ASA
Efficacy
Magnitude of receptor response
Affinity
Ability to bind to receptor
Reciprocal of the equilibrium dissociation constant
Potency
Conc (EC50) or dose (ED50) required to produce 50% max effect
LHS with increasing potency
Tolerance
Decrease in response following repeated administration
-pharmacodynamic: receptor subunit modification
-pharmacokinetic: CYP450 enzyme induction
-behavioural: learning to function
Tachyphylaxis
Hyperacute tolerance after only 1-2 doses
Adverse Drug Reactions
Type A
Augmented
85-90% of ADR
Related to pharmacological effects, dose related.
e.g. cough with ACEI
Adverse Drug Reactions
Type B
10-15% of ADRs
Unpredictable
e.g. MH, sux apnoea
Concentration effect
The phenomenon by which the speed of onset of inhalational anaesthetic agents is increased when they are administered with N2O
The Second Gas Effect
The phenomenon by which the rise in the alveolar partial pressure of nitrous oxide is disproportionately rapid when administered in high concentrations
N2O diffuses into blood faster than N2 diffuses out thereby shrinking the alveolar volume and concentrating the remaining gas
Volatiles
Lipid Solubility
Ability to cross the BBB and exert effect
Potency
High lipid solubility = high potency = low MAC = high OG coefficient
Volatiles
Water Solubility
Ability to dissolve into the blood
Speed of onset
Low water solubility = slow speed of onset = low BG coefficient
MAC
Definition
Minimum alveolar concentration of anaesthetic vapour @ equilibirum required to prevent movement to standard surgical stimulus in 50% of unpremedicated subjects at 1 atm
MAC
Agents in ascending order
Halothane 0.75
Isoflurane 1.17
Enflurane 1.68
Sevo 2
Des 6.6
Xenon 71
N20 105
Factors increasing MAC
Childhood
Hyperthermia/hyperthyroidism
Hypernatraemia
Catecholamines/sympathomimetics
Chronic opioids/ETOH
Acute Amphetamines
Factors decreasing MAC
Neonates/old age
Pregnancy
Hypotension/hypothermia/hypothyroidism
Lithium
Alpha agonists/sedatives
Acute opioids/ETOH
Chronic amphetamines
Critical temp = 36.5
Critical pressure = 72bar
Mol weight = 44
MAC = 105
BP = -88
SVP = 5200
BG = 0.47
OG = 1.4
Nitrous Oxide
Manufactured by heating ammonium nitrate to 250 C
Stored as a liquid in French blue, @ 5 bar
Filling ratio 0.75 (less in warmer climates)
MW = 131
BP = -108
MAC = 71
BG = 0.14
OG = 1.9
Xenon
Odourless, inert gas produced by fractional distillation of air, expensive.
Variable increase in CBF; analgesic; no affect on contractility
Halothane
Halogenated hydrocarbon containing bromine, chlorine and fluorine
Henderson Hasselbach Equation
pH = pKa + log10 [HCO3-]/[H2CO3]
Definition of pH
Negative log10 of H+ concentration - nmol.L
Weak acids ionised above their pKa
Weak bases ionised below their pKa
pKa
The pH at which 50% of the drug is ionised - exists in equal portions of ionised to unionised.
Acidic Drugs
Aspirin
Basic Drugs
Local anaesthetics
Morphine
Drugs that cause uterine contraction
Syntocinon
Ergometrine
Prostaglandin F2 - carbaprost, haemabate
Drugs that cause tocolysis
Salbutamol, terbutaline
Isoflurane/sevoflurane
Magnesium
Ritodrine
GTN
Drugs that cross the placenta - lipid soluble, uncharged
Morphine
Warfarin
Lignocaine
Drugs that prolong neuromuscular block
Antibiotics such as streptomycin, polymxyin and neomycin
Cocaine, procaine and lidocaine
Lithium due to its hypokalaemic effect
Verapmil and lidocaine by open channel block mechanism
Tricyclic antidepressants by closed channel block
Acidosis and hypercarbia
Hypothermia
Tell me about Ketamine…
Phencyclidine derivative.
An acid (3.5-5.5) in solution, poor protein binding (12%), T1/2 of 3 hours.
S(+) enantiomer is 2-4x more potent and less psychoactive than the R(-).
Can be administered PO, IM, IV, PR, nasally as well as intrathecal/extradural.
Not a true IV induction agent as takes more than one arm-brain circulation.
Causes a state of dissociative anaesthesia.
Inc sympathetic outflow causes tachycardia and increased CO - good when sick but not in IHD.
Causes profound bronchodilator so useful adjunct for status asthmaticus.
Also used as infusion for refractory status epilepticus.
What groups of drugs are associated with gynaecomastia?
Oestrogens or drugs with oestrogen like activity - digoxin!!
Drugs that enhance oestrogen synthesis
Drugs that inhibit testosterone synthesis or activity
Drugs that act by unknown mechanisms
These drugs cause gynaecomastia by unknown mechanisms
Methyldopa
Busulfan
Amiodarone
TCAs
Diazepam
Omeprazole
Penicillamine
CCB
ACEI
Alcohol
Marijuana
Heroin
Tell me about mannitol…
An osmotic diuretic filtered at the glomerulus but not reabsorbed, creating an osmotic gradient in the tubule, thus excreted with an osmotic equivalent of water.
Useful to force diuresis in drug overdose, cerebral oedema.
Also has oxygen free radical scavenging properties which may reduce the risk of reperfusion injury.
Tell me about entonox…
Entonox is a 50:50 mix of oxygen and nitrous oxide.
Stored at 137bar in blue cylinders with blue and white quartered shoulders.
It has a pseudocritical temperature of -6 and can separate into its components below this.
It exhibits the Poynting effect - change in properties of a mixture not explained by the properties of the individuals.
What is a prodrug?
A drug with no inherent activity that becomes converted to its active form when metabolised, e.g:
Enalapril - enalaprilat
Diamorphine - 6-monoacetlymorphine
Codeine - morphine
Parecoxib - valdecoxib
What do these drugs have in common?
Cytotoxics
Thiazide diuretics
Furosemide
Ethambutol
Pyrazinamide
Sulphonamides
Salicylates
Cause hyperuricaemia
What are the common side effects of loop diuretics?
High protein bound, secreted into tubular lumen by organic acid transporter
Inhibit the Na+/K+/2CL- co-transporter in the ascending LOH, increasing delivery of Na and H20 to the DCT.
Hypokalaemia
Hyponatraemia
Hypomagnesaemia
Metabolic alkalosis
Long term effects of phenytoin…
Osteomalacia and osteoporosis
Hirsuitism
Gingivial hyperplasia
Ataxia
Alpha half life in a two compartment model…
Initial distribution phase following drug administration, where drug equilibrates between the central and peripheral compartments
Beta half life in a two compartment model…
The time required for the plasma drug concentration to decrease by half during elimination phase
Predominantly influenced by slower compartment
Thiazide diuretics…
Inhibit transluminal NaCL transport in the early DCT
Inhibit NA reabsorption, stimulate excretion of Na, Cl and K - assoc with metabolic alkalosis
Reduce ECF - activates RAAS
Side effects:
Hypokalaemia, hypomagnesaemia, hypochloraemic alkalosis
Hypercalcaemia
Impaired glucose tolerance
Gout
Photosensitivity, rashes, postural hypotension, aplastic anaemia
Drugs that reduce renal concentrating ability…
(cause diabetes insipidus)
Lithium
Gentamicin
Amphotericin B
Demeclocylcine
CYP450 Inducers
Anticonvulsants - phenytoin, carbamazepine
Steroids
Antibiotics - rifampicin, griseofulvin
Nicotine, alcohol, St John’s Wort
CYP450 Inhibitors
Azoles
Antibiotics - macrolides, sulfonamides, metro, cipro, chloramphenicol, isoniazid
Cimetidine
Omeprazole
Sodium valproate
Metabolites of tramadol…
In humans the main metabolic pathways are N- and O-demethylation (phase I reactions) and conjugation of O-demethylated compounds (phase II reactions).
Eleven metabolites are known, five arising by phase I reactions (M1 to M5) and six by phase II reactions (glucuronides and sulfates of M1, M4 and M5).
The five phase I metabolites are
Mono-O-desmethyl-tramadol (M1)
Mono-N-desmethyl-tramadol (M2)
Di-N-desmethyl-tramadol (M3)
Tri-N,O-desmethyl-tramadol (M4) and
Di-N,O-desmethyl-tramadol (M5).
Eighty two per cent of tramadol is excreted unchanged.
Weak acid pKa 11
Vd 4L/kg
>95% protein bound
Onset 60s
Duration 3-5mins
Clearance 25-50ml/kg/min
CSHT 20 mins (up to 8hr infusion)
Propofol
2,6 diisopropylphenol
Highly lipid soluble ilipd emulsion
Egg lecithin, soya bean protein - v low allergy risk in adults
Stimulates GABAa, inhibits NMDA, 5HT3 and D2
Keto and enol forms depend on pH - tautomerism
Vd 2.5l/kg
pKa 7.6
65-80% protein bound
Onset 30s
Duration - rapid
Clearance 3ml/kg/min
Thiopentone
Barbiturate ring
Triexponential decline
Phenobarbitone - inactive metabolite
C/I in porphyria
CVS depressant, drops ICP, CBF, CMRO so good in TBI
Lowers IOP
pKa 4.2 - prepared with propylene glycol
Vd 4.5l/kg
76% protein bound
Onset 10-60secs
Duration 6-10mins
Clearance 870-1700ml/min
85% renal excretion, 15% bile
Etomidate
Imidazole ring
Steroid suppression?
Resp relatively maintained - apnoea, TV down but RR up
CVS -stable, mild drop in MAP
CNS - vasoconstrictor
pKa 7.5
Vd 3L/kg
Onset 30 secs
Clearance 18ml/kg/min
Racemic mixture - S more potent and less psychoactive
Na/Ca influx - K efflux
Ketamine
Phencyclidine derivative
Non-competitive NMDA antagonist
Dissociative anaesthesia - analgesia, amnesia, hypnosis and some LA action
Resp - bronchodilator, preserves reflexes
CVS - inc BP, HR, CO
CNS - inc ICP, emergence phenomena
GI - secretions ++
MSK - increased tone
MW 200.1
BP 58.5
SVP 22.7
MAC 1.8
BG 0.7
OG 80
Sevoflurane (7 X F)
Polyfluorinated isopropyl methyl ether - no chiral centre
Stored with 300pm H2O to avoid Lewis acid reaction
Metabolised by CYP4502E1 - compound A ?toxic
Resp; pleasant odour and non-irritant, good for gas induction
CVS: lowers SVR, BP, coronary and cerebral vascular resistance
CNS: post op delirium in children
MW 168
BP 23.5
SVP 89.2
MAC 6.6
BG 0.42
OG 29
Desflurane (6 X F)
Fluoroinated ethyl methyl ether
Tec 6 vaporiser at 39°C and 2 atm
0.02% metabolised, trifluoroacetic acid, low toxicity
Pungent smell
Low BG means fast onset/offset so good for prolonged surgery
Bad for the environment - highest global warming potential
MW 184.5
BP 48.5
SVP 33.2
MAC 1.17
BG 1.4
OG 98
Isoflurane
Halogenated ethyl methyl ether - chiral centre at position 3
0.2% hepatic metabolism; renal tox is rare; trifluoroacetic acid
maintains CBF up to MAC 1
Coronary steal syndrome
Pungent/irritant but also bronchodilator
Produces CO when reacts with dry soda lime
MW 184.5
BP 56.5
SVP 23.3
MAC 1.68
BG 1.8
OG 98
Enflurane
Halogenated ethyl methyl ether - chiral centre at end
Metabolised to organic and inorganic fluorides
Compound F
MW 131
BP -108
SVP -
MAC 71
BG 0.14
OG 1.9
Xenon
Produced by fractional distillation of air = expensive
CVS: no effect on contractility
CNS: variable increase in CBF, analgesic
MW 197
BP 50.2
SVP 32.3
MAC 0.75
BG 2.4
OG 224
Halothane
Halogenated hydrocarbon
Stored with 0.01% thymol to prevent liberation of bromine
CVS: myocardial depressant - inc vagal tone
CNS - most increase in CBF
Halothane hepatits? releases Br, Cl and F
MW 44
BP -88
SVP 5200
MAC 105
BG 0.47
OG 1.4
CT 36.5°C
CP 72bar
Nitrous Oxide
Manufactured by heating ammonium nitrate to 250°C
French blue cylinders at 51bar, filling ratio 0.75
Tare weight not gauge pressure
Diffusion hypoxia -
Oxidises cobalt in B12 - megaloblasts > agranulocytosis
