Drugs to cram Flashcards
Phenytoin
Route of Administration
Oral, intravenous
Indications
All forms of epilepsy, except absence seizures
Mechanism of Action
Prolongs VGSC inactivation state
Stops the spread of excitation from focus
Adverse Drug Reactions
CNS effects – dizziness, ataxia, headache, Nystagmus, nervousness
Gingival Hyperplasia (20%)
Rashes – Hypersensitivity (Stevens-Johnson Syndrome 2-5%)
Drug-Drug Interactions
CYP450 Inducer
Many drug interactions, e.g. Warfarin, OCP
Cimetidine -> Phenytoin increase
Well absorbed, 90% Protein Bound
Competitive binding, e.g. with Valproate, NSAIDs
Can exacerbate non-linear PKs
Therapeutic Notes
Phenytoin displays Non-Linear Pharmacokinetics at Therapeutic concentrations (linear at sub-therapeutic levels). This means close monitoring of free plasma levels is required
Carbamazepine
Route of Administration
Oral, rectal
Indications
All forms of epilepsy, except absence seizures
Contraindications
AV conduction problems
Mechanism of Action
Prolongs VGSC inactivation state
Adverse Drug Reactions CNS – Dizziness, drowsiness, ataxia, motor disturbances, numbness, tingling GI disturbances – Vomiting CVS – Variations in BP Hyponatraemia Rashes Rarely myelosuppression – neutropenia
Drug-Drug Interactions
CYP450 Enzyme Inducer
Many drug interactions, e.g. Warfarin, OCP
Protein bound
Another protein binding drug can raise Carbamazepine conc.
Antidepressants (SSRIs, MAOIs, TCAs and TCA) interfere with Carbamazepine’s action
Therapeutic Notes
Well absorbed, 75% protein bound
Linear Pharmacokinetics
Initial t½ is ~30hrs, but is a strong inducer of CYP450s and therefore affects its own Phase I metabolism. In repeated use t½ falls to ~15hrs
Drug monitoring required to adjust dosing due to falling t½
Lamotrigine
Route of Administration
Oral
Indications
All forms of epilepsy
Contraindications
Hepatic impairment
Not first line use in paediatric patients due to ADRs
Mechanism of Action
Prolongs VGSC inactivation state
Adverse Drug Reactions
Less marked CNS dizziness, ataxia, somnolence (drowsiness)
Nausea
Some mild (10%) and serious (0.5%) skin rashes, which limits child use
Drug-Drug Interactions
Adjunct therapy with other anti-epileptic drugs
Oral Contraceptives reduce Lamotrigine plasma levels
Valproate increases Lamotrigine plasma levels (protein binding)
Therapeutic Notes
Increasingly first line anti-epileptic drug
Appears to be safer in Pregnancy
Sodium Valproate
Route of Administration
Oral, intravenous
Indications
All forms of epilepsy
Contraindications
Acute liver disease/hepatic dysfunction
Mechanism of Action
Weak inhibition of GABA inactivation enzymes GABAA
Weak stimulus of GABA synthesising enzymes
Weak VGSC blocker and Weak Ca2+ channel blocker
Adverse Drug Reactions
Generally less severe than with other AEDs
CNS sedation – Ataxia, tremor
eight gain
Hepatic Dysfunction – Transaminases increased in 40% of patients
Rarely hepatic failure
Drug-Drug Interactions
Adjust therapy with other AEDs
Care needed with adjunct therapy, as both Valproate and adjunct PKs are affected. E.g. displaces Lamotrigine and Phenytoin, raising their free plasma concentrations
Antidepressants (SSRIs, MAOIs, TCAs and TCA) inhibit Valproate
Antipsychotics antagonise Valproate, by lowering convulsive threshold
Aspirin displaces Valproate from plasma proteins, raising its free conc.
Therapeutic Notes 100% absorbed, 90% protein bound Linear Pharmacokinetics, t½ = 15hrs Close monitoring of free plasma concentration is required Monitor for hepatic disorders
Benzodiazepines
Examples
Diazepam
Lorazepam
Clonazepam
Route of Administration
Oral, intravenous
Indications
Diazepam / Lorazepam – Status Epilepticus
Clonazepam – Absence seizures, short term use
Anxiety
Contraindications
Respiratory depression
Mechanism of Action
Act at a distinct receptor site on GABA Chloride channel
Binding of GABA or Benzodiazepines enhance each others binding, acting as positive allosteric effectors
Increases Chloride current into the neurone, increasing threshold for action potential generation
Adverse Drug Reactions Sedation Tolerance with chronic use Dependence/Withdrawal with chronic use Confusion, impaired co-ordination Aggression Abrupt withdrawal – seizure trigger Respiratory and CNS depression
Drug-Drug Interactions
Highly protein bound (85-100%)
Some adjunct use
Therapeutic Notes
Well absorbed (90-100%), highly plasma bound (85-100%)
Linear Pharmacokinetics, t½s vary between 15-45hours
Side effects limit first line use
Overdose reversed by IV Flumazenil
Use may precipitate seizure/arrhythmia
Levodopa (L-DOPA)
Route of Administration
Oral (only 1% reaches the brain due to peripheral metabolism)
Indications
Parkinsonism (excluding drug-induced extrapyramidal symptoms)
Contraindications
Closed angle glaucoma
Mechanism of Action
L-DOPA is the immediate precursor of Dopamine and is able to penetrate the blood brain barrier to replenish the dopamine lost in the Neostriatum.
Adverse Drug Reactions Nausea and vomiting Psychiatric side effects (Schizophrenia-like symptoms) Cardiovascular effects (hypotension) Dyskinesia
Drug-Drug Interactions
L-DOPA is given in combination with a peripheral DOPA decarboxylase inhibitor (Sinemet, Madopar), reducing necessary dose, side effects and increase the amount of L-DOPA reaching the brain
Vitamin B6 increases peripheral breakdown of L-DOPA
Therapeutic Notes
Extensive peripheral metabolism of L-DOPA means that large doses have to be given to produce therapeutic effects. These large doses are more likely to bring about adverse effects.
Absorbed in competition with amino acids (note – high protein meals)
90% inactivated in intestinal wall by MAO and DOPA decarboxylase
9% converted to dopamine in peripheral tissues
1% crosses BBB to enter the CNS (competes with amino acids)
Dopamine Receptor Agonists
Examples Bromocriptine Ropinirole Pergolide Apomorphine
Route of Administration
Oral
Apopmorphine is always given subcutaneously
Indications
Used in combination with L-DOPA in an attempt to reduce it’s late adverse effects, or when it does not control symptoms
Mechanism of Action
Agonists for Dopamine D2 Receptors
Adverse Drug Reactions Similar to that of L-DOPA, but more common and more severe Nausea Hypotension Psychiatric symptoms
Therapeutic Notes
Bromocriptine is most used
Monoamine Oxidase Type B inhibitors (MAOIs)
Examples
Selegiline
Route of Administration
Oral
Indications
Used on their own in mild cases of parkinsonism
Used in conjunction with L-DOPA to reduce end-dose ADRs
Mechanism of Action
Selegiline selectively inhibits the MAOB enzyme in the brain that is normally responsible for the breakdown of dopamine. By inhibiting breakdown, the dose of L-DOPA
Adverse Drug Reactions
Nausea
Hypotension
Psychiatric symptoms
Catechol-O-methyl Transferase Inhibitors
Examples
Entacapone
Route of Administration
Oral
Indications
Adjunct to L-DOPA therapy to reduce end-dose ADRs
Contraindications
Phaeochromocytoma
Mechanism of Action
Inhibits the enzyme COMT, which degrades dopamine
Adverse Drug Reactions
Nausea and Vomiting
Abdominal pain
Diarrhoea
Anticholinergics
Examples
Benzatropine
Procyclidine
Orphenadrine
Route of Administration
Oral
Mechanism of Action
Antagonists at the muscarinic receptors that mediate striatal cholinergic excitation
Main action in treatment of Parkinson’s disease is to reduce excessive striatal cholinergic activity
Adverse Drug Reactions
CNS effects – Mild memory loss, acute confusional states
Dry mouth and blurred vision (less common)
Therapeutic Notes
Termination of anticholinergic treatment should be gradual, as parkinsonism can worsen when these drugs are withdrawn
Amantadine
Route of Administration
Oral
Indications
Synergistic effect when used in conjunction with L-DOPA
Mechanism of Action
Stimulates neuronal dopamine release and inhibition of its reuptake
Additional muscarinic blocking actions
Adverse Drug Reactions
Anorexia
Nausea
Hallucinations
Therapeutic Notes
Modest anti-parkinsonian effects, but it is only of short-term benefit, since most of its effectiveness is lost within 6 months
Acetylcholinesterase inhibitors
Example
Pyridostigmine
Indications
Myastesia Gravis
Demenita (moderate to mild gains 1 year)
Prevent breakdown of Ach in synaptic cleft
Can cause muscarinic side effects (parallel those effects seen with excessive release of Ach)
Miosis SSLUDGE Syndrome o Muscarinic side effects o Salivation o Sweating o Lacrimation o Urinary Incontinence o Diarrhoea o GI upset and hypermotility o Emesis
Selective Serotonin Reuptake Inhibitors (SSRIs)
Examples
Fluoxetine (Prozac)
Citalopram
Paroxetine
Route of Administration
Oral (almost completely absorbed from gut)
Indications
Depression
Mechanism of Action
Act with a high specificity for potent inhibition of serotonin reuptake into nerve terminals from the synaptic cleft
Only minimal effects on noradrenaline uptake
Adverse Drug Reactions
Common – Anorexia, nausea, diarrhoea (normally settles in 2-3 weeks)
Rare – Precipitation of mania, tremor, extrapyramidal syndromes
Drug-Drug Interactions
MAOIs – Used in combination can cause potentially fatal serotonergic syndrome of hyperthermia and cardiovascular collapse
Therapeutic Notes
First line treatment for depression
Citalopram is the most selective reuptake inhibitor
Paroxetine is the most potent reuptake inhibitor
Long elimination t½ (once daily dosage), metabolised in the liver
Relatively safe in overdose if taken on their own
Serotonin/Noradrenaline Reuptake Inhibitors (SNRIs)
Examples
Venlafaxine
Duloxetine
Indications
Depression
Contraindications
Hypertensive patients, as Venlafaxine raises blood pressure
Mechanism of Action Inhibit the reuptake of both serotonin and noradrenaline, thus potentiating neurotransmitter activity in the CNS Dose dependent Low dose blocks Serotonin High dose blocks Noradrenaline
Adverse Drug Reactions
Common – Anorexia, nausea, diarrhoea (normally settles in 2-3 weeks)
Rare – Precipitation of mania, tremor, extrapyramidal syndromes
(Similar to SSRIs, but occur with less frequency)
Sleep disturbances
Hypertension
Dry mouth
Hyponatraemia
Drug-Drug Interactions
MAOIs – Used in combination can cause potentially fatal serotonergic syndrome of hyperthermia and cardiovascular collapse
Therapeutic Notes
Second line treatment for depression
Similar to TCAs, but adverse effects are reduced as Venlafaxine has little affinity for histamine or α-adrenoreceptors
Relatively short t½ – may be a withdrawal syndrome on discontinuation
Tricyclic Antidepressants (TCAs)
Examples Amitriptyline Imipramine Clomipramine Lofepramine
Route of Administration
Oral
Indications
Depression
Amitriptyline – Chronic, neurological pain
Clomipramine – Good evidence for OCD treatment
Contraindications Recent MI or arrhythmias (especially heart block) Manic phase Severe liver disease Epilepsy (TCAs lower seizure threshold)
Mechanism of Action
Block serotonin and noradrenaline reuptake. Also have affinity for H1, muscarinic and α1 and α2 receptors.
Adverse Drug Reactions
Noradrenergic uptake block in the heart – Arrhythmias
Muscarinic blocking effects – Dry mouth, constipation
α-adrenergic blocking effects – Postural hypotension
H1 blocking effects – Sedation
Weight gain
Constipation
Therapeutic Notes
Lipid soluble, long t½ (once/twice daily dose), metabolised by liver
