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1

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

2

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

3

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

4

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

5

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

6

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)

7

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

8

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

9

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

10

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

11

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

12

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

13

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

14

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

15

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

16

Monoamine Oxidase Inhibitors (MAOIs)

Examples
Phenelzine
Tranylcypromine
Isocarboxazid

Route of Administration
Oral

Indications
Depression


Mechanism of Action
MAOIs block the action of monoamine oxidase, the enzyme that metabolises monoamines (noradrenaline and serotonin). There are two subtypes, MAOA and MAOB. Inhibition of MAOA gives the best antidepressant efficacy.

Adverse Drug Reactions
Hypertension
CNS stimulation causing excitement and tremor
Dry mouth, blurred vision

Drug-Drug Interactions
MAOIs reduce the metabolism of barbiturates, opioids and alcohol.

Therapeutic Notes
Response to treatment with MAOIs may be delayed for ~3 weeks.

17

Typical (First Generation) Antipsychotics

Examples
Haloperidol
Chlorpromazine

Route of Administration
Oral
Depot (every 2/3/4 weeks)

Mechanism of Action
Dopamine D2 Receptor Antagonist
Sedation – Within hours
Tranquilisation – Within hours
Antipsychotic – Several days or weeks

Adverse Drug Reactions
Extrapyramidal effects – Hours or days
Neuroleptic malignant syndrome – Severe rigidity, hyperthermia, autonomic instability, cognitive changes (delirium). Associated with elevated plasma creatine phosphokinase (CPK). Extremely rare, but very serious ADR of all antipsychotics.
Weight gain
Endocrine changes (e.g. prolactinaemia)
Pigmentation

Toxicity
CNS depression
Cardiac toxicity
Risk of sudden death with high dose
Prolonged QT interval -
>Torsades de points
Risk of sudden death with large dose

Therapeutic Notes
Haloperidol is safe in emergencies

18

Atypical (Second Generation) Antipsychotics

Examples
Olanzapine
Risperidone

Route of Administration
Oral

Mechanism of Action
Higher affinity for 5-HT2A receptors than Dopamine D2 Receptors
Sedation – Within hours
Tranquilisation – Within hours
Antipsychotic – Several days or weeks

Adverse Drug Reactions
Vary between drugs
Olanzapine – Significant weight gain, suppressed “full” signals
Risperidone – Increased prolactin
Sedation
Extrapyramidal side effects at high doses

Toxicity
CNS depression
Cardiac toxicity
Risk of sudden death with high dose
Prolonged QT interval ->Torsades de points
Risk of sudden death with large dose

Therapeutic Notes
Atypical antipsychotics have less extrapyramidal side effects, so are therefore more acceptable to patients
First line treatment in schizophrenia

19

Lithium

Examples
Administered as Lithium Carbonate

Indications
Mood stabiliser (Antimanic and Antidepressant activity)
Prophylaxis of Mania and Depression in bipolar disorder
Augmentation of antidepressants in unipolar depression

Contraindications
Renal impairment (renal excretion)

Mechanism of Action (Theories)
Electrolytes and channels – May compete with Mg2+ and Ca2+ channels
Neurotransmitters – Lithium increase 5HT. Chronic Lithium may reduce 5HT receptor sites
Second messenger systems – Lithium attenuates the effects of neurotransmitters on their receptors, without altering receptor density

Adverse Drug Reactions
Memory problems (learning new information) – 52%
Thirst – 42%
Polyuria – 38%
Tremor (very fine) – 34%
Drowsiness – 24%
Weight gain – 18%
Hair loss
Rashes

Toxic Effects
Vomiting
Diarrhoea
Coarse tremor (progression from fine tremor)
Dysarthria (difficulty speaking)
Cognitive impairment
Restlessness
Agitation

Drug-Drug Reactions
NSAIDs will raise Lithium plasma concentration

Therapeutic Notes
Good evidence for reducing suicides
Drug monitoring for toxic levels in case of toxic effect
Toxicity is treated with supportive measures, anticonvulsants, increased fluid intake/IV fluids, Haemodialysis may be necessary

20

NMDA Antagonists

Examples
Memantine

Common Adverse Drug Reactions
Hypertension
Dyspnoea
Headache
Dizziness
Drowsiness

21

H Pylori Infection

Proton Pump Inhibitor – Omeprazole

Antibiotics – Clarithromycin / Amoxicillin

H2 Antagonist – Cimetidine

22

Proton Pump Inhibitors

Examples
Omeprazole
Lansoprazole
Rabeprazole
Pantoprazole
Esomeprazole

Route of Administration
Oral

Indications
Short term treatment of peptic ulcers
Severe GORD
Confirmed oesophagitis
Eradication of H. Pylori (part of triple therapy)
Zollinger-Ellison Syndrome (Gastrin secreting pancreatic tumour)

Mechanism of Action
Irreversibly inhibit Na/K-ATPase that is responsible for proton secretion from parietal cells.

Adverse Drug Reactions
GI upset, nausea
Headaches
Risk of gastric atrophy with long-term treatment

Drug-Drug Interactions
Omeprazole is a CYP450 enzyme inhibitor
Avoid use with patients being treated with Warfarin, Phenytoin etc.
Therapeutic Notes

PPI action is delayed as not all pumps are active all of the time. Maximum efficacy is after 2-3 days.
Restoration of stomach acid requires de novo synthesis, so after treatment stops it will take a few days for acid to return to normal

23

Histamine H2 Receptor Antagonists

Examples
Cimetidine
Ranitidine

Route of Administration
Oral

Indications
Peptic ulcer disease and GORD

Mechanism of Action
Competitively antagonist H2 receptors, blocking the amplifying action of Histamine on Parietal cells

Adverse Drug Reactions
Dizziness
Fatigue
Gynaecomastia
Rash

Drug-Drug Interactions
Cimetidine is a CYP450 enzyme inhibitor
Avoid use with patients being treated with Warfarin, Phenytoin etc.

Therapeutic Notes
Given at night when acid buffering by food is at its lowest

24

Bulk Laxatives

Examples
Ispaghula
Bran
Methylcellulose

Route of Administration
Oral

Indications
Constipation, particularly when hard stools are present

Contraindications
Dysphagia
Intestinal obstruction (Adhesions, ulceration)
Colonic atony
Faecal impaction

Mechanism of Action
Increases the volume of the non-absorbable solid residue in the gut, distending the colon and stimulating peristaltic movement.

Adverse Drug Reactions
Flatulence
Abdominal distension
GI obstruction

Therapeutic Notes
A normal fluid intake is essential
Clinical effects may take several days to develop

25

Faecal Softeners

Examples
Arachis Oil
Glycerol

Route of Administration
Arachis Oil – Enema
Glycerol – Suppository

Indications
Constipation
Faecal impaction
Haemorrhoids
Anal fissures

Contraindications
Children less than 3 years old

Mechanism of Action
Lubricate and soften stools

Therapeutic Notes
Safe, but not always effective
Relatively slow to take effect

26

Osmotic Laxatives

Examples
Lactulose
Magnesium and Sodium Salts
Movicol

Route of Administration
Lactulose – Oral
Magnesium and Sodium Salts – Rectal
Movicol – Orally with fluid (powder)

Indications
Constipation
Lactulose - Liver failure (reduced production of ammonia)

Contraindications
Intestinal obstruction

Mechanism of Action
Increase water content of the bowel via osmosis
Lactulose – Disaccharide (galactose/fructose) that cannot be hydrolysed by digestive enzymes. The fermentation of lactulose by colonic bacteria gives acetic and lactic acid. This has an osmotic effect

Adverse Drug Reactions
Flatulence
Cramps
Abdominal discomfort
Caution required to prevent intestinal obstruction

Therapeutic Notes
Magnesium and Sodium act quickly and are quite severe, so should be reserved for ‘resistant’ constipation if urgent relief is required
Lactulose takes 48 hours to work
Movicol takes 2-4 days to get relief

27

Irritant / Stimulant Laxatives

Examples
Anthraquinone Group
Senna
Danthron
Bisacodyl

Route of Administration
Oral

Indications
Constipation and bowel evacuation prior to medical/surgical procedures

Contraindications
Intestinal obstruction

Mechanism of Action
Increase gastrointestinal peristalsis and water and electrolyte secretion by the mucosa. Possibly by excitation of sensory enteric nerves.

Adverse Drug Reactions
Colonic atony (thus constipation)
Hypokalaemia (Changing electrolyte balance in the gut)

Therapeutic Notes
Anthraquinone group is the most frequently used.
Senna can be bought O.T.C. (Senokot)
Abuse can be detected via Melanosis Coli (pigmentation of bowel wall)

28

Anti-Motility Antidiarrhoeals

Examples
Codeine (opiate analgesic)
Imodium (opiate analogue)

Contraindications
Inflammatory Bowel Disease – Toxic Megacolon

Mechanism of Action
Act on opioid receptors in the bowel
Reduce motility (increase time for fluid reabsorption)
Increase anal tone and reduce sensory defecation reflex

Adverse Drug Reactions
Nausea, vomiting, abdominal cramps, constipation drowsiness

Therapeutic Notes
Imodium is 40 times more potent than Morphine as an antidiarrhoeal agent, and penetrates the CNS poorly

29

Bulk Forming Antidiarrhoeals

Examples
Ispaghula

Route of Administration
Oral

Indications
Particularly useful for patients with IBS and those with ileostomy

Contraindications
Intestinal obstruction

Mechanism of Action
A relatively small amount of faecal fluid (10-20ml) influences composition. Bulk forming antidiarrhoeals absorb this fluid.

30

Dopamine (D2) Receptor Antagonists (Anti Emetics)

Examples
Domperidone
Metoclopramide
Phenothiazines

Route of Administration
Oral
Rectal (extensive 1st pass metabolism)

Indications
Acute nausea/vomiting
Especially induced by L-DOPA or dopamine agonists

Mechanism of Action
Acts on the Postrema on the floor of the 4th ventricle
Acts on the stomach to increase the rate of gastric emptying

Adverse Drug Reactions
Stimulates prolactin release
Metoclopramide – extra-pyramidal reactions (dystonia) occur in 1%, therefore is avoided in Parkinson’s disease