P33 Flashcards
Lithium carbonate
Mood stabiliser
Bipolar disorder, mania
Use: Lithium is effective in the treatment of acute mania and in the prophylaxis of manic depression.
MoA: not fully understood, but it is thought that it may substitute for sodium or potassium in the central nervous system.
Lithium is toxic, producing dose-dependent and dose-independent side effects.
SE:
- Diarrhoea, tremor, confusion.
- Renal toxicity
- Decreases thyroid function
- Many drug interactions (particularly diuretics)
- In OD = convulsions, coma and death
Contraindications:
- Significant renal impairment
- Sodium depletion
- Dehydration
- Significant cardiovascular disease
Chlorpromazine
Typical antipsychotic
Actions: antipsychotic. apathy and inertia. decreased aggression. antiemetics.
MOA: competitive antagonism of dopamine D2 receptors in mesolimbic and cortical pathways.
Use: Schizophrenia. Psychosis. manic phase of bipolar. Tourette’s. Nausea and vomiting. Aggression in children.
Side effects: Marked sedation Extrapyramidal symptoms Galactorrhoea.; Gynaemcomastia. Weight gain. Contipation. Dry mouth. Hypotension
Rare: neuroleptic malignant syndrome
Agranulocytosis. hepatotoxicity
Haloperidol
Typical antipsychotic
Actions: antipsychotic. apathy. decreased aggression. antiemetic
MOA: competitive antagonism of dopamine D2 receptors. Increased potency when compared with chlorpromazine
Use: Schizophrenia. Psychosis. Mania. Aggressive behaviour. Tourette’s
Side effects: Marked EPS Hyperprolactinaemia Sedative. Hypotensive Neuroleptic malignant syndrome
Flupentixol
Typical antipsychotic
Action: antipsychotic. antidepressant
MOA: competitive antagonism of dopamine D2 receptors.
Use: schizophrenia. psychosis. bipolar disorders.
Side effects: EPS, hyperprolactinaemia, neuroleptic malignant syndrome
Clozapine
Atypical antipsychotic
Action: antipsychotic. effective against positive and negative symptoms
MOA: Actions of 5HT2, muscarinic, alpha 1 adrenoceptors, H1 receptors antagonists.
Use: schizophrenia. Very effective, often used in resistant patients.
Side effects:
Little EPS, constipation, agranulocytosis, epileptic seizures, weight gain, hyperglycaemia, hypotension
Rare: neutropaenia, thromboembolism, cardiomyopathy, myocarditis, aspiration pneumonia
Olanzapine
Atypical antipsychotic
Action: antipsychotic. effective against positive and negative symptoms
MOA: Actions of 5HT2, muscarinic, alpha 1 adrenoceptors, H1 receptors antagonists.
Use: schizophrenia. Very effective, often used in resistant patients.
Side effects:
Little EPS, constipation, agranulocytosis, epileptic seizures, weight gain, hyperglycaemia, hypotension
Risperidone
Atypical antipsychotic
Actions: antipsychotic. effective against positive and negative symptoms
MOA: Potent antagonists of D2 and 5HT2 and alpha 1 adrenoceptors.
Use: Schizophrenia. Psychosis. Mania.
Side effects: EPS (more than other atypicals), insomnia, sedation, hyperprolactinaemia, weight gain, hypotension, sexual dysfunction, anxiety
Quetiapine
Atypical antipsychotic
Actions: antipsychotic.
MOA: antagonism of D2 and 5HT2 receptors.
Use: schizophrenia and other psychotic states. Bipolar disorder.
Side effects: Weight gain. Hyperprolactinaemia Minor EPS. Constipation. Dry mouth. Sedation. postural hypotension. Rare: neuroleptic malignant syndrome
Sulpiride
Atypical antipsychotic
Actions: antipsychotic.
MOA: Dopamine D2 and D3 antagonism. preferential action on dopamine autoreceptors - less EPS.
Use: schizophrenia
Side effects: hyperprolactinaemia. insomnia. anxiety. weight gain. constipation. dry mouth
Amisulpiride
Atypical antipsychotic
Actions: antipsychotic.
MOA: Dopamine D2 and D3 antagonism. preferential action on dopamine autoreceptors - less EPS.
Use: schizophrenia
Side effects: hyperprolactinaemia. insomnia. anxiety. weight gain. constipation. dry mouth
Aripiprazole
Actions: antipsychotic
MOA: Modifications of dopaminergic transmission. Strongly D2 with partial agonist activity.
Use: schizophrenia. psychosis. manic phase of bipolar
Side effects: fewer side effects than other antipsychotics.
Less weight gain.
Some hypotension and nausea and vomiting.
Lithium
Actions: mood stabiliser
MOA: not well understood. Theory that lithium interferes with membrane ion transport including neurotransmitter uptake
Use: bipolar. mania. effects develop over 3-4 weeks
Side effects:
- Diarrhoea, tremor, confusion.
- Renal toxicity
- Decreases thyroid function
- Many drug interactions (particularly diuretics)
- In OD = convulsions, coma and death
Carbamazepine
Action: antiepileptic. Relieves neuropathic pain. Mood stabiliser
MOA: Blocks Na+ channels to inhibit action potential initiation and propagation. use-dependence of block means that action is preferential on rapid fire neurons
Use: partial and generalised seizures. Not absence seizures. Neuropathic pain. Bipolar disorder
Side effects: drowsiness, headache, mental disorientation, motor disturbances
Rare but serious: agranulocytosis, liver damage, aplastic anaemia
Teratogenic
p450 interaction
Sodium valproate
Actions: anticonvulsant, mood stabiliser
MOA: block of Na channels in inhibit action potential initiation and propagation. Inhibition of GABA transaminase to decrease GABA breakdown
Use: epilepsy. manic phase of bipolar, migraine
Side effects: nausea and vomiting. tremor. weight gain. reproductive dysfunction. hepatic and pancreatic toxicity
Teratogenic
Sertraline
Citalopram
Fluoxetine
Paroxetine
SSRI - Selective serotonin reuptake inhibitor
Action: antidepressant
MOA: Inhibits the reuptake of 5HT3 into neurons
Use: depression, anxiety
Side effects:
- Anxiety,
- Insomnia,
- Nausea,
- Diarrhoea,
- Headache,
- Sexual dysfunction
- Increased risk of suicide in younger patients
- Causes hyponatraemia in the elderly
Duloxetine
Venlafaxine
Serotonin-noradrenaline reuptake inhibitors (SNRI)
Actions: antidepressant
MOA: inhibits the reuptake of 5HT and NA into neurons, increasing transmitter action
Use:
- Major depression
- Anxiety disorders (panic, GAD, OCD, agoraphobia)
- Attention-deficit hyperactivity disorder
- Chronic neuropathic pain
- Fibromyalgia syndrome (FMS)”
Side effects:
- Nausea,
- Headache,
- Sleep disturbance,
- Sexual dysfunction
- Cardiac dysrhythmia, seizure and CNS depression with OD
- Takes a few weeks to see effects
- Increase risk of suicide in younger people
Amitriptyline
Imipramine
Lofepramine
Clomipramine
TRICYCLIC ANTIDEPRESSANT
Actions: antidepressant, neuropathic pain
MOA: Inhibits reuptake of NA and 5HT3 into neurons, increasing transmitter actions
Use: depression, panic disorder, neuropathic pain. enuresis
Side effects: sedation, blurred vision, dry mouth, constipation, urinary retention
- Overdose potentially fatal due to cardiac dysrhythmia, severe hypotension, seizure and CNS depression
- Increased risk of suicide in younger patients
- Clinical effects not seen for a few weeks
Mirtazapine
Presynaptic a2-adrenoceptor blocks
“Presynaptic alpha2-adrenoreceptor antagonist which increases central noradrenergic and serotonergic neurotransmission
Dual mode of action:
- Noradrenergic and specific serotonergic antidepressant (NaSSA)
- That acts by antagonizing the adrenergic alpha2-autoreceptors and alpha2-heteroreceptors as well as by blocking 5-HT2 and 5-HT3 receptors
Use: major depression
SE:
- Anxiety
- Increased appetite/weight
- Arthralgia, myalgia
- Confusion
- GI symptoms
- Dizziness, drowsiness, insomnia
- Dry mouth
- Headache (on discontinuation)
- Postural hypotension
Phenelzine
MOAIs - monamine oxidase inhibitor
Actions: antidepressant
MOA: Irreversibly binds to A and B forms of monoamine oxidase.
MAO-A acts on NA and 5HT
MAO-B acts on dopamine
Inhibiting MAO increases transmitter at nerve endings
Use: atypical depression. social phobia
Side effects: postural hypotension, headache, insomnia, sexual dysfunction
Dry mouth, urinary retention
- OD = convulsions
- Increased risk of suicide in young people
- Dietary TYRAMINE causes hypertensive crisis (Cheese)
- Antidepressant effect due to MAO-A inhibition
Moclobemine
MOAIs - monamine oxidase inhibitor (A only)
Actions: antidepressant
MOA: Irreversibly binds to A forms of monoamine oxidase.
MAO-A acts on NA and 5HT
Inhibiting MAO increases transmitter at nerve endings
Use: atypical depression. social phobia
Side effects: postural hypotension, headache, insomnia, sexual dysfunction
Dry mouth, urinary retention
- OD = convulsions
- Increased risk of suicide in young people
- Dietary TYRAMINE causes hypertensive crisis (Cheese)
- Antidepressant effect due to MAO-A inhibition
Isocarboazid
MOAIs - monamine oxidase inhibitor
Actions: antidepressant
MOA: Irreversibly binds to A and B forms of monoamine oxidase.
MAO-A acts on NA and 5HT
MAO-B acts on dopamine
Inhibiting MAO increases transmitter at nerve endings
Use: atypical depression. social phobia
Side effects: postural hypotension, headache, insomnia, sexual dysfunction
Dry mouth, urinary retention
- OD = convulsions
- Increased risk of suicide in young people
- Dietary TYRAMINE causes hypertensive crisis (Cheese)
- Antidepressant effect due to MAO-A inhibition
Bupropion
DOPAMINE REUPTAKE INHIBITOR
Actions: atypical antidepressant, used in smoking cessation
MOA: inhibits neuronal dopamine reuptake with a lesser effect on NA. Antagonist at nicotinic receptors.
Use: alone or in combination with SSRIs in depression
Side effects: agitation, tremor, dry mouth, nausea, insomnia, skin rashes
Seizures can occur with large doses
Non-pharmacological treatment for bipolar disorder?
In bipolar disorder, as in unipolar major depression, severe symptoms in the current mood episode compel the use of electroconvulsive therapy (ECT).
Treating bipolar patients with ECT is consistent with numerous practice guidelines.
Adverse Drug Reaction (ADR)
“An unwanted or harmful reaction experienced following the administration of a drug or combination of drugs under normal conditions of use and suspected to be related to the drug”
Excludes:
- Therapeutic failures
- Overdose
- Drug abuse
- Non-compliance
- Medication errors
Adverse Drug Event
Untoward occurrence after exposure to a drug that is not necessarily caused by the drug
Adverse drug reaction vs Adverse drug event?
Adverse drug event
- Patient having a road traffic accident while on a specific medication
- Untoward occurrence after exposure to a drug that is not necessarily caused by the drug
Adverse drug reaction
- Patient experiencing anaphylaxis shortly after taking a drug
- An unwanted or harmful reaction experienced following the administration of a drug or combination of drugs under normal conditions of use and suspected to be related to the drug
Adverse drug reaction classification
Type A reactions (augmented):
- Common, 80% of all reactions
- Are predictable from the known pharmacology of a drug
- Exaggerated response to pharmacological action
- Usually dose dependent
- High incidence (morbidity), low mortality.
Type B reactions:
- Idiosyncratic, bizarre or novel responses that cannot be predicted from the known pharmacology of a drug and are associated with low morbidity and high mortality.
Not all ADRs fit into type A and type B categories; therefore, additional categories have been developed.
Type C (continuing),
Type D (delayed use)
These are examples of that type of drug reaction?
- Sedation with antihistamines:
- Blockade of central histaminergic receptor
- Action on serotonin receptors - Constipation with opioids
- Stimulation of mu receptors in GIT - Gastric ulcers with NSAIDs
- Inhibition of prostaglandins which protect stomach
Type A adverse drug reaction
Drug induced parkinsonism
- Drugs that block the action of dopamine = dopamine antagonists
- Atypical antipsychotics have less extrapyramidal symptoms
- Clozapine, olanzapine, risperidone
- Less affinity for D2 receptors
Metoclopramide
D2 receptor antagonist.
Indications:
- Migraine headache treatment
- Prevent N+V
- Increase stomach emptying
- GORD
SE:
- Fatigue
- Diarrhoea
- Restlessness
More serious side effects include:
- Movement disorder like tardive dyskinesia
- Neuroleptic malignant syndrome
- Depression
Causes hyperprolactinemia due to inhibitory effect on prolactin leading to:
- Galactorrhoea, amenorrhoea, breast tenderness
First gen antipsychotics
typical
Haloperidol Chlorpromazine Fluphenazine Flupentixol Sulpiride Loxapine
SE:
- Extrapyramidal:
> Akathisia (severe restlessness)
> Tardive dyskinesia (involuntary choreoathetoid movements, most common is chewing and pouting of jaw)
> Acute dystonia (e.g. torticollis, oculogyric crisis)
> Dystonia (involuntary muscular contraction)
> Pseudoparkinsonism
- Hyperprolactinemia
- Decreased seizure threshold
- Postural hypotension
- Sedation
- Weight gain
- Prolonged QT interval (particularly haloperidol)
- Antimuscarinic
Second gen antipsychotics
atypical
Risperidone Paliperidone Clozapine Olanzapine Quetiapine Aripiprazole Amisulpride
SE: - Metabolic syndrome: > Weight gain > Cholesterol abnormalities > DM II + obesity
- Reduced seizure threshold (greater with atypicals)
- Extrapyramidal (akathisia, dyskinesia, dystonia)
- Salivation
- Myocarditis
- Agranulocytosis, neutropenia [clozapine]
Ibuprofen Naproxen Diclofenac Aspirin Indomethacin
Non-selective NSAIDs (COX inhibitors)
The COX-1 enzyme is constitutive and produces prostaglandins associated with GI cytoprotection. The inhibition of these prostaglandins by traditional NSAIDs increases the susceptibility of the GI tract to risk for damage from gastric acid, pepsin, and bile. COX-1 also is associated with prostaglandin production related to the regulation of platelet function (primarily aggregation) and renal function.
The COX-2 enzyme generally is considered to be inducible. It produces prostaglandin secondary to proinflammatory mediators such as cytokines as a response to pain, fever, and inflammation.
SE:
- Heartburn
- Dyspepsia
- Ulceration
- Bleeding
- Perforation
List penicillins used in combination with a beta-lactamase inhibitor or contain a beta lactam ring
Beta-lactamase inhibitor combo: (tazocin & co-amoxiclav)
Contain a beta lactam ring (imipenem & meropenem, carbopenem antimicrobial agents)
Naproxen + ramipril?
NSAID + ACEi
Combinations of drugs may increase the risk of acute kidney injury, as each has the potential to affect kidney function through different mechanisms.
Angiotensin converting enzyme inhibitors/angiotensin receptor blockers cause a haemodynamic reduction in glomerular filtration rate due to efferent arteriolar vasodilation, and NSAIDs cause inhibition of prostacyclin synthesis leading to renal afferent arteriolar vasoconstriction.
Cytochrome P450 3A4 is responsible for metabolism of:
- Calcium channel blockers
- Benzodiazepines
- HIV protease inhibitors
- HMG-CoA-reductase inhibitors
- Ciclosporin
- Non-sedating antihistamines
And is present in GIT and liver.
What are it’s inhibitors and inducers?
Inhibitors
- Fluconazole
- Clarithromycin
- Erythromycin
- Grapefruit juice
- Ritonavir
Inducers
- Carbamazepine
- Rifampicin
- Rifabutin
- St. John’s wort
Enzyme induction leads to: - Tolerance or decreased effectiveness - Increased doses - Increased metabolism and excretion - Slow development -days to weeks
Enzyme inhibition leads to: - Sensitivity - Decreased doses - Drug accumulation - Rapid development -days
What are the implications of being a CYP2D6 ultra-rapid metaboliser?
CYP2D6 is highly polymorphic, with over 90 known allelic variants.
Codeine is a prodrug and its analgesic properties are not manifest until it is metabolized by CYP2D6, primarily to morphine and and codeine-6-glucuronide. Subjects who are ultra-rapid metabolizers based upon CYP2D6 genotype have higher than expected morphine levels (an initial “overdose”), with more side effects and a shorter than expected duration of pain control.
List opiates which are potentially affected by the CPY2D6 polymorphism.
Codeine
Hydrocodone
Oxycodone
Tramadol
Azathioprine
Antiproliferative immunosuppressant
Action: decreases clonal proliferation of T and B cells during induction phase of immune response
MOA: interferes with purine synthesis. cytotoxic on dividing cells
Use: UC and Crohn’s. prevent organ rejection. chronic autoimmune disease, rheumatoid arthritis, granulomatosis with polyangiitis.
SE: myelotoxicity. GI disturbance. hypersensitivity reactions
NOTE: monitor blood for myelosuppression
Pharmacogenomics vs pharmacogenetics
Pharmacogenetics focuses on single drug-gene interactions.
Pharmacogenomics encompasses a more genome-wide association approach, incorporating genomics and epigenetics while dealing with the effects of multiple genes on drug response
Which electrolyte abnormality could an ACEi and spironolactone cause?
Hyperkalaemia
The four major causes of hyperkalemia due to reduced urinary potassium secretion are?
●Reduced aldosterone secretion
●Reduced response to aldosterone (aldosterone resistance)
●Reduced distal sodium and water delivery as occurs in effective arterial blood volume depletion
●Acute and chronic kidney disease in which one or more of the above factors are present
How is GFR measured?
Although GFR cannot be measured directly, the best method for determining GFR is measurement of the urinary clearance of an ideal filtration marker.
The gold standard of exogenous filtration markers is inulin. Inulin is a physiologically inert substance that is freely filtered at the glomerulus, and is neither secreted, reabsorbed, synthesized, nor metabolized by the kidney. Thus, the amount of inulin filtered at the glomerulus is equal to the amount excreted in the urine, which can be measured. Inulin, however, is in short supply, expensive, and difficult to assay. Furthermore, the classic protocol for measuring inulin clearance requires a continuous intravenous infusion, multiple blood samples, and bladder catheterization.
The most common methods utilised to estimate the GFR are: measurement of the creatinine clearance; and estimation equations based upon serum creatinine such as the Cockcroft-Gault equation, the Modification of Diet in Renal Disease (MDRD) study equations, and the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation.
Oral iron:
- Ferrous sulfate
- Ferrous fumarate
- Ferrous gluconate
Parenteral iron:
- Iron dextran
- Iron sucrose
- Ferric carboxymaltose
- Iron isomaltoside 1000
Parenteral iron is generally reserved for use when oral therapy is unsuccessful because the patient cannot tolerate oral iron, or does not take it reliably, or if there is continuing blood loss, or in malabsorption.
Dietary iron is absorbed from the duodenum and upper jejunum.
Haem dietary sources (fish, poultry, and meat) have a higher bioavailability than do non-haem (vegetable) sources (30 versus 10 percent).
= Ascorbic acid (Vitamin C) enhances the absorption of non-animal sources of iron.
= Phosphates, and phytates inhibit iron absorption.
Absorption of ferric iron is facilitated by several factors:
- Gastric acid, which increases its solubility
- Conversion to ferrous iron by ferric reductase on the brush border of enterocytes, which is enhanced by dietary reducing agents such as ascorbic acid (vit C), fructose and some amino acids,
- Intestinal absorption mediated by the divalent metal transporter (DMT-1), mainly in the duodenum.
Expression of DMT-1 is increased in iron deficiency and in hereditary haemochromatosis.
Within enterocytes, iron is oxidized to the ferric state and transported to the circulation by the protein ferroportin.
In the blood, ferric iron is bound to the globulin transferrin and transported to the bone marrow and iron stores.
Cellular iron uptake occurs via transferrin receptors, and in most cells iron is stored as ferritin (a complex of iron with the apoferritin protein).
