7. CNS drugs Flashcards
MAOis
Avoid
Why
Drugs that should be avoided include:
Adrenaline Noradrenaline Ephedrine Pseudoephedrine Phenylephrine Dopamine Dopexamine Dexamfetamine Pethidine.
The metabolism of sympathomimetics is inhibited which may potentiate their pressor action, and the pressor effect of tyramine (found in mature cheese, meat and yeast extracts) may also be potentiated. Alcoholic and low alcohol drinks should also be avoided
ECG changes w/ TCA ocerdose
The degree of QRS broadening on the ECG is correlated with adverse events and indicates that there is an interventricular conduction defect.
QRS > 100 milliseconds is predictive of seizures.
QRS > 160 milliseconds is predictive of ventricular arrhythmias (e.g. ventricular tachycardia).
Other ECG changes likely include:
Right axis deviation
Terminal R wave >3mm in lead aVR
R/S ratio >0.7 in lead aVR
Sinus tachycardia (muscarinic M1 blockade)
Baclofen
what
gamma-aminobutyric acid (GABA) analogue
spasticity resulting from disease or injury to the spinal cord.
monosynaptic and polysynaptic transmission at spinal level and also depresses the central nervous system
No dir effect at NMJ
High absorb
80% excrete unchanged
- reduce in renal dysfxn
Myalgia
Incrreased & decreased slowly
Hypotonia
autonom dyfx, hypertherm
MgSO4 & pre exlampsia - moa
Though the specific mechanisms of action remain unclear the effect of magnesium sulphate in the prevention of eclampsia is likely multi-factorial.
Magnesium sulphate acts as a vasodilator with actions on both the peripheral vasculature and the cerebral circulation to decrease peripheral vascular resistance and/or relieve vasoconstriction. The most likely mechanism is the effect of magnesium on the cerebral vasculature.
The theory of cerebrovascular vasospasm as the etiology of eclampsia seemed to be reinforced by transcranial Doppler (TCD) studies that suggested that MgSO4 treatment caused dilation in the cerebral circulation.
Additionally, magnesium sulphate may also protect the blood-brain barrier and limit cerebral oedema formation or it may act through a central anticonvulsant action.
Reference:
EPSE
Dopamine antagonists, for example, metoclopramide and haloperidol.
Phenytoin tox a/w
x6
Phenytoin toxicity may occur during long term use and is associated with:
Osteomalacia or osteoporosis
Hirsutism
Gingival hyperplasia, and
Ataxia.
It may result in hypocalcaemia (not hypercalcaemia) due to interference with vitamin D metabolism
may also cause a high mean cell volume (macrocytosis).
nysagmus - dose dependent
Phenytoin
anticonvulsant
Barbiturates in chemical structure, but has a five-membered ring, with the chemical name of 5,5-diphenyl-2,4-imidazolidinedione.
of 252 and a 70% to 100% bioavailability following oral administration (25% after rectal dosage).
highly protein bound drug (70 to 95%), which is metabolised by the liver (non-linear) and genetic variation in the gene controlling metabolism occurs (CYP2C9 and CYP2C19).
elimination half life of 22 hours and is excreted primarily through the bile (<5% in the urine)
TCAs
how many rings
How do they work
Metabolism
Side effects
Tricyclic antidepressants (TCAs) are a group of antidepressant drugs and as the name suggests they have a three ringed structure.
However, there are several newer drugs with 1, 2 and 4 ring structures which have similar actions.
They competitively block the reuptake (not potentiate it) of norepinephrine by postganglionic sympathetic nerve endings. alpha adrenerg block
They also have central nervous system anticholinergic properties and they impair the reuptake of 5-hydroxytryptamine. -= aw tachycardia, palp, arrhy, dry mouth
They are metabolised in the liver and the metabolites are renally excreted.
Side effects are multiple especially in overdose, but in general terms have the features of anticholinergic poisoning, for example, tachycardia, urinary retention, blurred vision.
TCAs take two to four weeks before their effect is apparent, which is much slower than electro-convulsant therapy (ECT).
high protein binding
high Vd
Cross BBB affected wby
Tertiary v quaternary
What crosses
paracetamol
OF the BBloq what crosses
Most drugs cross the blood-brain barrier (BBB) by transmembrane diffusion. Factors which favour passage through the BBB include:
Molecular weight of drug <600 daltons Degree of ionisation (non-polar) Lipid solubility Protein binding, and Tertiary structure. Some drugs are carried across the BBB by saturable transport systems.
Hyoscine hydrobromide is a tertiary amine antimuscarinic with peripheral and central effects. Glycopyrrolate however is a quaternary amine and cannot cross the BBB in significant amounts.
Paracetamol diffuses readily into the cerebrospinal fluid. This fast and extensive transfer enables the rapid central analgesic and antipyretic action of intravenous paracetamol. It has low protein binding and low molecular weight.
1 propranolol
2 metoprolol
3 oxprenolol
particularly lipid soluble and readily cross the BBB. Central nervous system side effects such as nightmares and hallucinations are manifestations of this.
Atenolol is a hydrophilic molecule and has a low incidence of central nervous system side effects.
Carbamazepine
Structurally related to -
Manages
Binds to what to inactivate
Metabolites
Carbamazepine is an anticonvulsant that is structurally related to the antidepressant imipramine and is used in the management of epilepsy and chronic pain conditions, for example, trigeminal neuralgia.
It acts by binding to inactivated (closed) sodium channels, which blocks them from returning to their resting state (also closed), that they must return to before they can open again. Thus the sodium current is progressively reduced until it is insufficient to initiate an action potential.
Oral absorption is rapid and plasma protein binding is approximately 80%. There is a linear increase in plasma concentration with dosage and the elimination half life is 13 - 17 hours.
It is metabolised in the liver to carbamazepine-10,11-epoxide, which is an active metabolite. The metabolite contributes to its anticonvulsant action and neurotoxic side effects, which include
Sedation Vertigo Ataxia Diplopia Nausea Vomiting. Carbamazepine may enhance the metabolism of phenytoin, whereas phenobarbital may enhance the metabolism of carbamazepine.
Gabapentin
enzyme inducer?
Affects
Use?
Dose in renal disease
Gabapentin does not induce cytochrome P450 unlike other anticonvulsants such as phenytoin and phenobarbitone.
Vigabatrin may cause visual field defects which may be irreversible.
Rarely have visual disturbances been associated with gabapentin.
Gabapentin is of no use in petit mal, but is used for add-on therapy in partial or generalised seizures and used in the management of chronic pain conditions.
Therapy does not require monitoring of plasma concentrations but the dose should be adjusted in renal disease.
Chlorpromazine
- Sites effect
Side effects
Affects on cell membrane?
Metabolised?
Chlorpromazine, as its trade name (Largactil) implies, has effects at numerous receptors including dopamine receptors.
It is antagonistic at muscarinic, 5-hydroxytryptamine (5-HT), histamine and alpha (1 and 2) adrenoceptors.
Its sedative effects are known as neurolepsy which are accompanied by a reduction in motor activity and muscle tone. The EEG shows a pattern characteristic of sleep and this sedative side effect limits chlorpromazine’s use as an antiemetic.
Side effects include extrapyramidal symptoms such as dystonias, akathisia and tardive dyskinesia, but it does not commonly cause parkinsonian features (rigidity, akinesia and tremor).
Chlorpromazine has a local anaesthetic effect by stabilising cell membranes and reducing the tendency of nerves to depolarise.
It is extensively metabolised in the liver and many metabolites may be detected in the urine up to 18 months after administration.
Gabapentin - binds to
acts on
Managment of
Gabapentin binds to alpha-2-delta calcium channels subunits, acts on voltage dependent calcium channels and NMDA receptors and also increases the level of glutamate decarboxylase to facilitate conversion of glutamate to GABA.
It is well tolerated.
It is used in the management of partial seizures and chronic pain conditions such as diabetic neuropathy and post herpetic neuralgia.
Its main use as an anticonvulsant is in the management of partial seizures.
PCO2 & CBF
Between 4-8kpa
> 2kPa
Hypercapnia
causes what effect on cbf
what side effects
hypocapnia -
Arterial PCO2 is the most important regulator of cerebral blood flow (CBF). Between PaCO2 values of 4 to 8 kPa (30-60 mmHg) the relationship is virtually linear (not sigmoidal).
A fall in PaCO2 below 2 kPa (15 mmHg) does not result in any further decreases in CBF and conversely, an increase above 20 kPa (150 mmHg) does not result in any further increases in CBF.
Hypercapnia increases CBF by vasodilatation but it may cause an intracerebral steal effect where blood is shunted away from ischaemic areas (in which the vessels are already maximally dilated).
Conversely, hypocapnia constricts vessels and may divert blood to ischaemic areas (reverse steal effect).
Chronic hypercapnia is associated with a return of cerebral blood flow from increased to normal levels.
Phenytoin
Therapetuic range Side effects T1/2 Absorption Metabolism / excretion
Phenytoin has a narrow therapeutic range hence small increases in the dose can cause toxicity.
Side effects include gum hypertrophy, hirsutism, ataxia and hepatic impairment.
It has a long half life and is slowly absorbed from the gastrointestinal tract.
It undergoes hepatic metabolism and renal excretion.
SSRI
Citalopram Fluoxetine Paroxetine Sertraline Fluvoxamine, and Escitalopram.
Venlafaxine is a
serotonin and noradrenaline re-uptake inhibitor.
Imipramine
is a tricyclic antidepressant and their mechanism of action is central inhibition of biogenic amine reuptake, predominantly affecting norepinephrine and serotonin. It is also a competitive antagonist at histamine H1 and H2 receptors.
Reboxetine
is an antidepressant but selectively inhibits noradrenaline re-uptake.
Dexmedetomidine
Acts where
Effects
Describe the stress response in surgery
How is affected by dexmetomidine
Other effects
Immune effects
Super-selective centrally acting alpha-2 adrenoceptor
Sedation, analgesia, anxiolysis, and sympatholysis.
The stress response to major surgery is known to initiate a cascade of biochemical and physiological events by direct activation of the sympathetic nervous and neuroendocrine systems. The extent of surgery will depend on the extent and duration of tissue injury and is reflected by an increased secretion of pituitary hormones and the activation of the autonomic nervous system.
attenuated surgical stress response with lower concentrations of epinephrine, norepinephrine, cortisol and blood glucose.
These findings are consistent with the sympatholytic properties of dexmedetomidine.
Decreases in tumour necrosis factor-alpha (TNF-a), C-reactive protein (CRP), IL-6 and IL10.
Dexmedetomidine has an immunomodulatory effect by increasing the expression of NK cells, B cells, and CD4+ T cells, and the ratios of CD4+:CD8+ and Th1:Th2 during major surgery.
Anticonvulsants
Mechanisms common used
Szz - repitive neuoranl dishcarge - in CNS
Act 2 medechnaism - Na channell -blcok fast inactive stabilisn g pre snymatpc Or Increasing
Phenytoin - block fast Na chanell - - respons bedopl druing prop AP
Block chanell prevent further gen AP - centr to activity
Lamotrigine stabil - pre snaptic - prevent release excite
GABA
FAcilatte
agonist
inhibit gaba transmaise
BZD & bartbituate - facil effect gaba buu opening cl channel in GABA
Allow cl flow down conc grad = Make hyperpol
Valproate act prevent breakdown of GABA _ inhib transminase -
enzyme normally cataulses breakdown
Phenytoin
Anticon - used years
Grand mal ppartial status trigeminal
Ib antarrhytmic - dig tox
Site - Fast Na chanell - depol of Ap
Bind Na - refactor effect at block fire high freq
Dscirim epiletypifc & phys activity
PO / IV
not IM
Narrow TW
Monitor
Idioscyrn Hirsut Acne gum coase ft megalobalst
High dose
ataz nystagmus slur sparaestehsi
Teratogenic - cranifacil growth / mental retard & limb / cardiac defects
D-D interact
Induce hpe oxidase - repsone metab
warfarin, bzd, ocp
Metro, cholarmphen & isonazis - inhib metab
90% po avail
90% protein
Metab liver & inact meatb excetre urine
Sat kinetics @ dose above therapeutic range
Normally follows first order kietics - high doses - 0 order - d/t saturation
Sodium valporate
Anti con - petit mal myolclonin chrhnic pain
Stab inact fast Na sim pheny
Also stim venteal gaba inhib - inhib gaba transaminase
Normally well tolerated - can = nause & gastric irritation Tcypotenia Alopeica Neural tube defx
Well abos
90% prote bound
metab liver -excrete renally
anticonvulsants in pregnancy
Most - carry risk NTD, Teratogenicity & coag disorer
Great risk is if consulions
Counselling antenata screen folate supple
predeliv vit k
Lamotrgine consider safer
