CPT Flashcards
Def: pharmacokinetics
Study of factors which determine the amount of drugs at their sites of biological effect at various times.
Includes
ADME
Absorption
Distribution
Metabolism
Excretion
Def: Pharmacodynamics
What the drug does to the body
Def: clearance
Volume of plasma cleared of a drug per unit time
Def: half-life
Time taken for drug concentration to decline to half its original valu
Depends on volume of distribution and clearance
Def: volume of distribution
Volume into which a drug appears to distribute
Theoretical volume that would be necessary to contain the total amount of a drug administered at the same concentration that it is observed in the blood plasma.
High for lipid-soluble drugs
Low for water-soluble drugs
What factors can increase the volume of distribution?
Higher Vd indicates a greater amount of tissue distribution.
High lipid solubility (non-polar drugs), low rates of ionisation or low plasma binding capabilities have higher volumes of ditribution than drugs which are more polar, more highly ionised or exhibit high plasma binding.
Vd may be increased by renal failure (due to fluid retention) and liver failure (due to altered body fluid)
Vd=
Total amount of drug in body/drug blood plasma concentration
What is first order kinetics?
Clearance of durg is always proportional to plasma concentration
Most drugs are in this category
What is zero order kinetics?
Clearance of drug is not always proportional to plasma concentration
Saturation of metabolism-> constant rate of elimination regardless of plasma levels
Give some examples of drugs with zero order kinetics
Phenytoin
Salicylates
Ethanol
What is bioavailability?
Percentage of the dose of a drug which reaches the systemic circulation
100% for IV administration
How long is ~ required for a drug to reach a steady state?
Around 5 half lifes
What does a loading dose do?
Reduces the time needed to reach a steady state, useful if long or short half life
What are some drugs that use loading doses?
Phenytoin
Digoxin
Amiodarone
Theophylline
What are the indications for therapeutic drug monitoring?
Ix lack of drug efficacy (possibility of poor compliance)
Suspected toxicity
Prevention of toxicity
What are three drugs that must have therapeutic drug monitoring?
Aminoglycosides
Vancomycin
Li
What are some dugs that have therapeutic monitoring?
Phenytoin
Carbamazepine
Digoxin
Ciclosporin
Does Warfarin undergo therapeutic drug monitoring?
Not monitored per se, it is the biological effect that is monitored rather than the plasma drug level
What is first pass metabolism?
Metabolism and inactivation of a drug before it reaches the systemic circulation
i.e. pre-systemic elimination
Occurs in gut wall and liver
Gives some examples of drugs that undergo FPM
Propranolol
Verapamil
Morphine
Nitrates
What are the pathways of drug metabolism and elimination?
Excreted unchanged by the kidney e.g. frusemide
Phase 1 metabolism and then renal excretion
Phase 2 metabolism and then renal excretion
What is phase 1 metabolism
Creation of reactive, polar functional groups.
Oxidation: usually by cytochrome P450 system
Reduction and hydrolysis
What is phase 2 metabolism?
Production of polar compounds for renal elimination
Either the drug or its phase 1 metabolite
Conjugation reactions: glucuronidation, sulfonation, acetylation, methylation
What is the principle method of elimination?
Renal, depends on GFR
How many subtypes of CyP450 are there?
>11
What is the most important CyP?
What proportion of drugs does it metabolise?
CyP3A4
>30% e.g. CCBs, beta blockers, statins, benzos
What is the second most important CyP?
What proportion of drugs does it metabolise?
CyP2D6
>20% e.g. antidepressants, some beta blockers, opiates
Prodrugs: –>
L-DOPA
Dopamine
Prodrugs: –>
Enalpril
Enalprilat
Prodrugs: –>
Ezetimibe
Ez-glucuorinde
Prodrugs: –>
Methyldopa
alpha-methylnorepinephrine
Prodrugs: –>
Azathioprine
6-mercaptopurine (by xanthine oxidase)
Prodrugs: –>
Carbimazole
Methimazole
Prodrugs: –>
Cyclophosphamide
4-hydroxycyclophosphamide
What are pharmacogenomics?
Genetically determined variation in drug response
What is the significance of acetylation in terms of pharmacogenomics?
Fast vs slow acetylators e.g. fast in Japan vs Europe
Variations in acetylation affects which drugs?
Isoniazid
Hydralazine
Dapsone
Which CyP doesn’t have polymorphisms?
CyP3A4
What is the signifcance of G6PDD?
Oxidative stress-> haemolysis
What are some drugs that can precipitate haemolysis in G6PDD?
Quinolones, primaquine, nitrofurantoin, dapsone
How can ADRs be classified?
Type A
Type B
Long term ADR
Delayed ADR
Features of Type A ADR
Common, predictable reactions
Dose-related but may occur at therapeutic doses
Consequences of known pharmacology of the drug
Features of Type B ADR
Rare, idiosyncratic reactions
Usually not dose related
E.g. allergies and pharmacogenetic variations
Features of LT ADR
Dependence, addiction
Withdrawal phenomena
Adaptive changes e.g. tardive dyskinesia
Features of delayed ADR?
Carcinogenesis
Teratogenesis
What are the drug determinants of ADR?
Pharmacodynamics
Pharmacokinetics
Dose
Formulation
Route of administration
Rate of administration
What are the patient specific determinants of ADR
Age
Co-morbidities
Renal- digoxin, aminoglycosides
Hepatic: warfarin, opiates
Organ dysfunction
Genetic predisposition
Examples of drug that can cause T1HS?
Penicllins, contrast media
Anaphylaxis
Examples of drugs that can cause T2HS?
e.g. causing haemolysis
Penicillins, cephalosporins, oral hypoglycaemics
Methyldopa
Examples of drugs that can cuase T3HS reactions
Immune-complex
Serum sickness-like reaction
Penicillins, sulphonamides
Examples of drugs that can cause T4HS
Cell-mediated
Topical Abx, antihistamine cream
What are pseudoallergies?
Pharmacological ADRs not immune
NSAID pseudoallergy
Bronchospasm
Shift metabolism from prostaglandins-> leukotrienes-> bronchoconstriction
May occur in non-asthmatic populations but commoner if asthmatic
ACEI pseudoallergy
Cough and angioedema (anaphylactoid)
ACEI inhibit bradykinin metabolism
Drugs associated with withdrawal
Opiates
Benzos
Corticosteroids
Def: rebound
Worse on withdrawing the drug than before starting
Drugs in which rebound ADR may be seen?
Clonidine
Beta-blockers
Corticosteroids
Adaptive LT ADR?
Neuroleptics-> tardive dyskinesia
Delayed ADRs
Oestrogens
Endometrial Ca
Breast Ca
Delayed ADRs
cytotoxics
Leukaemia
Drugs causing immune urticaria
Penicllins
Cephalosporins
Drugs causing non-immune urticaria?
Contrast
Opiates
NSAIDs
Drugs causing erythema multiforme?
SNAPP
Sulfonamides
NSAIDs
Allopurinol
Phenytoin
Penicllin
Drugs causing erythema nodosum
Sulponhamides
OCP
Drugs causing photosensitivity?
Amiodarone
Thiazides
Sulfonylureas
Drugs causing fixed eruptions
Erythromycin
Sulphonamides
Drugs causing lupus like reactions
Hydralazine
Isoniazid
Penicillamine
Drugs causing cholestatic hepatotoxicity
Clavulanic acid (may be delayed)
Fluclox: may be delayed
Erythromycin
Sulfonylureas (glibenclamide)
OCP
Tricyclics
Chlorpromazine, prochlorperazine
Drugs causing hepatocellular damage
Paracetamol
VPA, phenytoin, CBZ
Rifampicin, Isoniazid, Pyrazinamide
Halothane
Methotrexate
Statins
Drugs causing chronic hepatitis
Isoniazid
Methyldopa
Methotrexate
Drugs causing gallstones
OCP
Drugs causing pancytopenia/aplastic anaemia
Cytotoxics
Phenytoin
Chloramphenicol
Penicillamine
Phenothiazines
Methyldopa
Drugs causing neutropenia
Carbamezapine
Carbimazole
Clozapine
Sulfasalazine
Drugs causing thrombocytopenia
Valproate
Salicylates
Chloroquine
Drugs causing peripheral neuropathy
Isoniazid
Vincristine
Amiodarone
Nitrofurantoin
Penicilliamine
Drugs causing pulmonary fibrosis
Bleomycin
Busulfan
Amiodarone
Nitrofurantoin
Sulfasalazine
Methotrexate
Methysergide
Drugs causing gynaecomastia
Spironolactone
DIgoxin
Verapamil
Cimetidine
Metronidazole
Drugs causing SIADH
Carbamezapine
Cyclophosphamide
Chlorpropamide
SSRIs
TCAs
Drugs causing gingival hypertrophy
Nifedipine
Phenytoin
Ciclosporin
Drugs causing prolonged QT
FVN MATCH
Fluoroquinolones: ciprofloxacin
Venlafaxine
Neuroleptics: phenothiazines, haldol
Macrolides
Anti-arrhythmics 1a/III: quinidine, amiodarone, sotalol
TCAs
Histamine antagonists
Cholinergic side effects
SBLUDGEMS
Caused by?
Salivation
Bronchoconstriction
Lacrimation
Urination
Diarrhoea
GI upset
Emesis
Miosis
Sweating
e.g. anti-cholinesterases
Anti-muscarinic side effects
CUMBBD
Constipation
Urinary retention
Mydriasis
Blurred vision
Bronchodilation
Drowsiness
Dry eyes/skin
Causes of anti-muscarinic side effect profile?
Ipratropium
Anti-histamines
TCAs
Anti-psychotics
Procyclidine
Atropine
Causes of dopamine excess
L-Dopa
Da agonists
Clinical features of dopamine excess?
Behaviour change
Confusion
Psyhcosis
Causes of dopamine deficit
Anti-psychotics
Anti-emetics: metoclopramide, prochlorperazine
Features of dopamine deficit?
EPSEs
Increased prolactin
Neuroleptic malignant syndrome
Cerebellar disease
DANISH
Dysdiadochokinesia, dysmetria, rebound
Ataxia
Nystagmus
Intention tremor
Scanning dysarthria/slurred speech
Hypotonia
Pharmacological causes of cerebellar syndrome
EtOH
Phenytoine
Causes of EPSEs?
Typical antipsychotics
Rarely: metoclopramide, prochlorperazine: especially in youing women
Dyskinesias and dystonias are common with anti-parkinsonian drugs
Mechanism of EPSEs?
D2 block in the nigrostriatal pathway
Excess AChM- hence the effect of anti-AChM
What are the types of EPSEs?
Parkinsonian
Acute dystonia
Akathisia
Tardive dyskinesia
Neuroleptic malignant syndrome
Explain mechanism of EPSEs
Features of Parkinsonian EPSEs?
Occurs within months
More common in the elderly
Bradykinesia tremor, rigidity
Rx of parkinsonian EPSEs?
Procyclidine
Features of acute dysonia
Occurs within hours-days of starting drugs
Commoner in young males
Involuntary sustained muscle spasm
e.g. lock jaw, spasmodic torticollis, oculogyric crisis
Rx in acute dystonia?
Procyclidine
Features of akathisia
Occurs within days to months
Subjective feeling of inner restlessness
Rx of akathisia?
Propranolol (crosses BBB)
Features of tardive dyskinesia?
Rhythmic involuntary movement of head, limbs and trunk
Chewing, grimacing
Protruding, darting tongue
Occur in 20% of those on long term neuroleptics
Rx in tardive dyskinesia?
Switch to atypical neuroleptic
Clozapine may help
Procyclidine worsens symptoms
Features of neuroleptic malignant syndrome
4-10d after initiation or change of dose
Mostly in young males
Motor: severe muscular rigidity
Mental: fluctuating consciousnsess
Autonomic: hyperthermia, increased HR, sweating, hyper/hypotensive
Blood: rasied CK, leukocytosis
Rx neuroleptic malignant syndrome?
Dantrolene: inhibits muscle Ca release
Bromocriptine/apomorphine: reverse Da block
Cool patient
Where do pharmaceutical drug interactions take place?
Outside the body
Mainly with IV drugs being mixed together
e.g. Ca and NaHCO3-> precipitation
What are the pharmacokinetic forms of drug interactions
Altered absorption
Displacement from plasma proteins
Metabolism- inhibitors and inducers
Excretion
Give an example of altered absorption
Tetracyclines and quinolones with Ca, Fe, Al
Drugs chelate the metals and are not absorbed
Give an example of drug displacement from plasma proteins
Warfarin + some NSAIDs
often clinically insignificant as clearance increases proportionally with displacement
What are some enzymes that can be inhibited by drugs?
P450
Xanthine oxidase: allopurinol
DOPA decarboxylase: carbidopa
Acetaldehyde dehydrogenase: disulfiram, metronidazole
How do diuretics affect Li?
Reduce Li clearance
How do loop diuretics affect aminoglycosides
Increase aminoglycoside ototoxicity
What are some examples of indirect drug interactions
Diuretics and steroids-> increase risk of digoxin toxicity by reducing K
NSAIDs and warfarin increase risk of GI bleed
Abx and warfarin increase bleeding risk as Abx kill GI microflora that make Vit K
What are some important P450 inducers
PC BRAGS
Phenytoin
Carbamezapine
Barbiturates
Rifampicin
Alcohol (chronic)
Griseofulvin
St John’s Wort
What are some important P450 Inhibitors?
VIP C CEO GFF
Valproate
Isoniazid
Protease inhibitors
Ciprofloxacin
Cimetidine
Erythromycin and clarithromycin
Omeprazole
Grapefruit juice
Fluconazole, fluoxetine
What are some important drugs metabolised by p450?
COWEST
Ciclosporin
OCP
Warfarin
Epileptic drugs: phenytoin, CBZ
Statins
Theophylline
What classes of drugs increase Warfarin action?
Enzyme inhibitors
EtOH
Simvastatin
NSAIDs
Dipyridamole
Amiodarone
What drugs reduce warfarin action?
Enzyme inducers
What drugs do diuretics potentiate?
ACEI
Li
Digoxin
What do k-sparing diruetics do with ACEI?
Increase risk of hyperkalaemia
Pharmacokinetics of the edlerly: Distribution
Reduce body water- increased {water soluble drugs}
Increased body fat- {reduced fat soluble drugs}
Reduced albumin- [increased protein bound drugs]
Reduced weight: therefore at standard dose- {increased]
Pharmaokinetics in the elderly: metabolism
Reduced oxidation
Reduced FPM
Reduced induction of liver enzymes
Therefore with age there is an increased t1/2 of hepatically metabolised drugs
Pharmacokinetics in the elderly: elimination
Reduced GFR
Reduced tubular secretion
Bottom line of pharmacokinetics in the elderly
Increased age tends to lead to greater and longer drug effects
Altered organ sensitivity in the elderly
ANS
Defective compensatory mechanisms
Reduced beta receptor density: therefore reduced effectiveness of drugs targeting them
Altered organ sensitivity in the elderly:
CNS
Increased sensivity to anxiolytics and hypnotics
Altered organ sensitivity in elderly:
Reduced cardiac function
Reduced perfusion of liver and kidneys: reduced function: reduce metabolism or elimination of drug
What are some issues with compliance in the elderly
Confusion
Reduced vision
Arthritic hands
Living alone
Polypharmacy
What are the major problem drugs in the elderly affecting the CVS?
Anti-HTNs
Digoxin
Diuretics
What are the major problem drugs in the elderly affecting the CNS?
Anti-depressants
Anti-parkinsonian
Hypnotics
Pharmacokinetics in the neonate
A: reduced gastric motility
D: immature BBB
Increased body water: {reduced water soluble drug]
Reduced body fat [increased fat soluble drugs]
Reduced albumin {increased]
M:
Reduced P450 activity
Reduced conjugation
E:
Reduced GFR and tubular secretion
Bottom line: reduced age leads to greater and longer drug effects
Mechanisms of teratogen action?
Orally active= crosses placenta
Implantation-> abortion
Embryonic-> structural defets
Fetogenic-> relatvely less dangerous
Common teratogens and their effects
ACEI: affect kidney growth
AEDs: NTDs
LI: Ebstein’s anomaly
Anti-folate e.g. trimeth-> NTDs
Tetracyclines-> stains teeth
Warfarin: cardiac defects, reduced IQ, saddle nose, blindness
Statins
What are some drugs to avoid in late pregnancy and why?
Asprin: haemorrhage, kernicterus
Aminoglycosides: CN8 damage
Anti-thyroid: goitre, hypothyroidism
Benzos: floppy baby syndrome
Chloramphenicol: grey baby syndrome
Warfarin: haemorrhage
Sulphonylureas: kernicterus
Mx of HTN in pregancny
NB don’t prescribe ACEI to fertile young women
Labetalol
Methyldopa
Nifedipine
Hydralazine
Mx of DM in pregnancy
Poor glucose control associated with increased congenital abnormalities
Use insulin and or metformin
Mx of epilepsy in pregnancy
Folic acid pre-conception
Drug level tends to fall in pregnancy
Increased risk of malformations
Increased risk of haemorrhagic disease of newborn
Avoid VPA
Use LTG or CBZ
Atnicoagulation in 1st trimester
LMWH
Anticoagulation in 2nd trimester-36w
LMWH or warfarin
Anticoagulation 36w- term
LMWH
Mx of anticoagulation term onwards
Warfarin
Sedatives and breast feeding
Drowsiness
Anti-thyroid and breast feeding
Goitre
Tolbutamide and breast feeding
Hypoglycaemia in infant
What are some important drugs affected by renal impairment?
DGAAC
Digoxin
Gentamicin
Atenolol
Amoxicillin
Captopril
Digoxin in renal impirment
T1/2: 36-90 hours
Low therpaeutic index, shoulde be monitored
Nausea, xanthopsia, gynaecomastia
AV tachyarrythmias, heart block
Digoxin toxicity
Gentamicin in renal disease
T1/2:2.5-> 50h
MUST be monitored
Increased risk of toxicity if reduced Na e.g. diuretics or dehydrated
Hearing and vestibular issues
Nephrotoxicity
Gentamicin
Atenolol in renal disease
T1/2: 6->100hours
CI to atenolol
Asthma/bronchospasm
Severe heart failure
PVD
Bradycardia, hypotension
Worsening of PVD and HF
Confusion
Atenolol toxicity
Amoxicillin in renal disease
T1/2 2-> 15hrs
Toxcity:
seizures (in meningitis, impaired BBB), rashes
Hypotension
Taste distrubrance
Cough
reduced GFR
Angioedema
Captopril toxicity
What form of VitD should be used in renal impairment?
Alfacalcidol (1 alpha-hydoxylated)
What are some important nephrotoxic drugs?
Gentamicin
Li
Ciclosporin
ACEI/ARB
NSAIDs
Gentamicin: renal toxicity mechanism
Renal tubular damage-> accumulation-> increased nephro and ototoxcicity
MUST monitor levels
Li: renal toxicity mecahnism
Inhibits Mg-dependant enzymes e.g. adenylate cyclase
ADH requires adenylate cyclase therefore Li causes nephrogenic DI
Also causes direct tubular damage
Must monitor drug levels
How does Li cause nephrogenic DI
ADH requires adenylate cycle, an Mg-dependant enzyme inhibited by Li
Ciclosporin: renal toxciity mechanism
Reduced GFR: reversible
Damages renal tubules: irreversible
P450 substrate
Consider monitoring
ACE/ARB nephrotoxcity mechanism
Reduce GFR: inhibit efferent arteriolar vasoconstriction may be profound in RAS or CoA
NSAIDs: nephrotoxicity mechanism
Reduce GFR: prevent afferent arteriolar vasodilation
Leading to papillary necrosis
What should be considered in prescribing in hepatic impairment
Albumin levels
Clotting factors synthesis
Reduced FPM
Reduce alpha 1 acidic glycoprotein
Encephalopathy
Hepatorenal syndrome
Prescribing in hyopalbuminaemia
Increased proportion of free drug
e.g. phenytoin, CBZ, predniosolne, diazepam, tolbutamide
Redcued FPM, what Rx should be assessed
Opiates
Phenothiazine
Imipramine
What are some drugs bound by alpha-1acidic glycoprotein
Chlorpromazine
Quinidine
Imipramine
What is a consideration in hepatic encephalopathy regarding Rx
Sedatives/opiates-> coma
Caution with drugs that may cause constipation
Anxiolytis: temazepam safest due to short t1/2
TCAs safer but avoid MOAIs
Considerations in Rx with hepatorenal syndrome
Withdraw nephrotoxic drugs
Modify doses of renally-excreted drugs
What are some drugs causing cholestatic heaptotoxicity
Clavulanic acid: may be delayed
Fluclox: may be delayed
Erythromycin
Sulfonylureas
OCP
Tricyclics
Chlorpromazine, prochlorperazine
What drug is associated with gallstones?
OCP
What drugs are associated with chronic hepatitis
Isoniazid
Methyldopa
What drugs are associated with hepatocellular damage
Paracetamol
VPA, Phenytoin, CBZ
Rifampicin, isoniazid, pyrazinamide
Halothane
Methotrexate
Statins
Drugs and doses used as morning after pill
Levonorgesterl 1.5mg PO STAT
Ulipristal 30mg PO STAT
MOA of beta agonists
Act at bronchial B2 receptors:
SM relaxation and reduce secretions
Side effects of beta agonist bronchodilators
Tachycardia
Tremor
Interactions of beta agonist bronchodilators
Reduce K in high doses with corticosteroids, loop/thiazide diuretics/theophylline
SABA features
Short acting, fast onset
2-4 hrs
Give 2 examples of SABA
Salbutamol (ventolin)
Terbutaline (Bricanyl)
MOA muscarinic antagonist bronchodilation
Bronchodilation
Mucus secretion
Side effects of muscarinic antagonist bronchodilators
Dry mouth
Caution re muscarinic antagonist bronchodilators
Closed angle glaucoma
Prostatic hypertrophy
Features of SAMAs
3-6hrs
Short acting
e.g. SAMA
Ipratropium (Atrovent)
e.g. LAMA
Tiotropium (Spiriva)
e.g. of ICS
Beclometasone: Becotide
Budenoside: Pulmicort
Fluticasone: Flixotide
What is symbicort?
Budenoside and fomoterol
Gives examples of LABA
Salmeterol
Formoterol
What is seritide
Fluticasone and salmeterol
MOA of ICS
Act over weeks to reduce inflammation:
Reduce cytokine produciton
Reduce prostaglanding/leukotriene synthesis
Reduce IgE secretion
Reduce leukocyte recruitment
Prevent long term decline in lung function
Side effects of ICS
Oral candidiasis
High doses may lead to typical steroid SEs
Fluticasone vs other ICS
2x as potent: use lower dose
Symbicort usage
Can be used as a preventer or a reliver because of formoterol’s fast onset
Use of ICS advice
Use a spacer
Rinse mouth after use
Theophylline MR
Aminophylloine
Drug class
Methylxanthines
Methylxanthine MOA
PDE inhibitors: increase cAMP-> bronchodilation
Side effects of methylxanthines?
Nausea
Arrhythmias
Seizures
Hypokalaemia
Interactions of methylxanthines leading to reduced levels
Smoking
EtOH
CYP inducers
Interactions of methylxanthines to increase levels
CCBs
CYP inhibitors
Additional detail re methylxanthines
Aminophylline is IV form:
give IVI slowly
Too fast -> VT
Monitor with ECG and check plasma levels
CYP metabolism
NB if pt already on theophylline cannot have IV aminophylline
MOA
Montelukast
Zafirlukast
Leukotreine receptor antagonists
Block cysteinyl leukotrienes
Side effects for leukotriene R antagonists
?Churg Strauss
What are leukotriene antagonists particulalrly useful for?
NSAID and exercise induced asthma
Roflumilast MOA
PDE-4i
Side effects roflumilast
GI
CI for roflumilast
Severe immunological disease
Omalizumab MOA
Humanised anti-IgE mAb
Features of omalizumab
SC injection every 2-4w
Used for severe asthma
Carbocysteine
Mucolytic
Side effects of carbocysteine
GI bleed (rare)
CI carbocystiene
Active peptic ulceration
Dornase ALFA (Dnase) MOA
used in?
Mucolytic
CF
Non-sedating H1R antagonists
Certrizine
Loratidine
Fexofenadine
Sedating H1R inverse agonists (antagonists)
Chlorphenamine
Inverse agonist
In the field of pharmacology, an inverse agonist is an agent that binds to the same receptor as an agonist but induces a pharmacological response opposite to thatagonist. A neutral antagonist has no activity in the absence of an agonist or inverse agonistbut can block the activity of either
Side effects of H1R inverse agonists
hypotension
Arrhythmia: long QT
Older agents: drowsiness
Anti-AChM
CI for H1R inverse agonists
Severe hepatic disease
Caution in H1R inverse agonists
Long QT
BPH
Closed-angle glaucoma
LMWH in pregnancy
Does not cross the placenta
ST effects of pred in asthma
Candidiasis
Hypokalaemia
What is important to remember re LMWH in pregnancy
Must remember to stop it due to risk of osteoporosis
Indapamide
Thiazide like diuretic
Which 2 of the following are most likely to cause hyponatraemia
INdpamide
Perindopril
Rivaroxaban
Amlodipine
Citalopram
Simvastatin
Paracetamol
Indapamide- will cause sodium loss-> hyponatraemia
Citalopram-> SIADH (obscure adverse effect)
Periondopril will cause hyponatraemia but hyperkalaemia
Why should you take short acting statins at night (simvastatin)
Because cholesterol synthesis is thought to happen prinicipally during the night
%w/v units
grams in 100 millilitres gives you the percentage
v/v %
millilitres in 100 millllitres
Abciximiab
2b3a antagonist
Cough ADR in ACEi
Dose independent
Colchicine in gout
Recommended in patients with HF as unlikely to make HF worse.
Diclofenac should not be used as it has a high risk of cardiovascular events
1:1000 adrenaline
1mg per ml
1:10000
0.1mg per ml
Mx of acute dystonia
Procyclidine 5mg IM
What is the limit of morphine per 24h
200mg/24 hours
Which medication is often associated with gout
Thiazide diuretics: increase Na clearance at the expense of uric acid excretion
Two common side effects of metronidazole
N+V
Furred tongue
Metallic taste in mouth
Reversal of warfarin overdosing with Vit K PO or IV
IV and PO both same onset of action
If plan is to restart warfarin, give IV as PO action takes longer to turn off than IV
What drugs require obligatory TDM?
Aminoglycosides
Vancomycin
Lithium
What are some drugs that commonly have TDM?
Aminoglycosides
Vancomycin
Lithium
Digoxin
Phenytoin
Does Warfarin have TDM?
Technically not as it is not the [plasma] being monitored, rather the biological effect
What are the 3 pathways of drugs through the body?
Excreted unchanged by the kidney e.g. furosemide
Phase 1 metabolism-> kidney or phase 2
Phase 2 metabolism: undergoes phase 2 transformation and then excreted
Phase 1 metabolism=
Oxidation
Reduction
Hydrolysis
Molecule itself is directly altered usually by cytochrome p450 (oxidation)
Phase 2 metabolism
Either the original drug or its modified form is then conjugated e.g. glucuronidation, sulphation, acetylation
This tends to make compound more polar, allowing excretion more readily
What is the most important cytochrome subtype
CYP3A4: accounts for 30% of prescribed drugs e.g. CCBs, statins, BZDs
CYP2D6
Next most important cytochrome, metabolises 20% of drugs e.g. antidepressants, beta blockers, some opiates
CYP1A2 metabolises
Paracetamol
Caffeine
Theophylline
CYP2C9 metabolises
Warfarin
Ibuprofen
CYP2C19 metabolises
Diazepam
Omeprazole
Enalpril
Prodrug, ACEi
converted to enlaprilat
Azathioprine
Prodrug, converted to 6-mercaptopurine
Ezetimibe
Ez-glucuorine
Converted to the glucuronide in the liver which is the active form. This reaches the lumen of the small intestine where it blocks cholesterol absorption
What is the single most important determinant in the elimination of most drugs?
GFR
What is pharmacogenetics?
The study of genetically determined varaitions in the response to drugs
What is the significance of acetylation polymorphisms?
A small number of drugs are metabolised by acetylation, there are fast and slow acetylators, which is genetically determined and which may have different side-effects
Drugs that udnergo acetylation include isoniazid, hydralazine, dapsone
What are some examples of variations in clinical pharamacogenetics?
Pseudocholinesterase
G6PD
Porphyria
Significance of pseudocholinesterase
Patients lacking this enzyme had prolonged recovery after anaesthesia
Type A ADRs
Predictable reactions
Common
Dose-related but can occur at therapeutic doses
Consequence of known pharmacology of drugs
What is a type B ADR
Idiosyncratic reactions
Rare to very rare
Usually not dose related
Include true allergies
Include some pharmacogenetic variations
What are long term ADR?
Dependence/addiciton e.g benzos
Withdrawal phenomena inc rebound e/g/ clonidine
Adaptive changes e.g. typical antipsychotics-> tardive dyskinesia
What are delayed ADR
Carcinogenesis
Teratogenesis
ABCDE classification of ADRs
Augmented pharmacological effect
Bizarre
Chronic
Delayed
End of treatment
What are the drug determinants of ADRs?
Pharmacodynamics:
pharmacokinetic properties e.g. digoxin
Dose e.g. beta blockers
Formulation e.g. digoxin
ROA e.g. phenytoin
Rate of administration e.g. aminophylline
Digoxin excretion
Renally
ROA phenytoin
Oral- rarely CV problems
IV: bradycardia/hypotension
Rate of administration aminophylline
Given too quickly-> ventricular arrythmia
liver disease + opiates
Increases risk of hepatic encephalopathy and worsening liver failure
What are some examples of pseudoallergies
Non-immune mechanisms, pharmacolgoical
e.g. salicylates, other NSAIDs-> bronchospasm. shift metabolsim from prostaglandins to leukotrienes which leads to bronchospasm
ACEi-> cough, angioedema (anaphylactide)
Drugs causing urticaria
Penicllins, contrast media, opiates
Drugs causing erythema multiforme
Penicllins, sulfonamides
Drugs causing erythema nodosum
Sulfonamides, OCP
Drugs causing photosensitivity
Amiodarone
Thiazides
Sulfonylureas
Drugs causing fixed eruptions
Erythromycin
Sulfonamides et.c
Drugs causing lupus-like reactions
Penicllins, isoniazid, hydralazine
Fixed eruption
Drug causes rash in a fixed distribution
Drug stopped, if restarted rash appears in same distribution
Drugs causing intrahpeatic cholestasis
Phenothiazines (formerly used as an antihelminthic)
TCA
Sulfonylurea
Erythromycin
Clavulanic acid (may be delayeed)
Carbimazole
Anabolic steroids (dose related)
Drugs causing hepatocellular damage
Isoniazid
Pyrazinamide
Methyldopa
TCA
Phenytoin
All of the above can occur from acute or chronic use
Pracetamol (dose dependant)
Methotrexate (dose dependant) (causes liver fibrosis)
Drugs causing chronic hepatitis
Isoniazid
Methyldopa
Drugs causing gallstones
Fibrates
Oestrogens
Drugs causing pancytopenia (aplastic anaemia)
Cytotoxics (Type A)
Type B:
Chloramphenicol( (1/10000, tends to be lethal)
Phenytoin
Peniclliamine
Phenothiazines
Drugs causing neutropenia
All type B
Carbamazepine
Carbimazole
Clozapine
Mianserin- withdrawn
Sulfasalazine
Mianserin
It is classified as a noradrenergic and specific serotonergic antidepressant (NaSSA)
Drugs causing thrombocytopenia
All type B
Chloroquine
Captopril
Quinidine
Salicylates
VPA (most important)
Drugs causing peripheral neuropathy
Amiodarone
Nitrofurantoin
Penicillamine
Isoniazid
Dose dependant:
Vincristine
Cis-platin
Drugs causing pulmonary fibrosis
BBC MAN
B-Bleomycin
B-Busulfan
C-Cyclophosphamide
M-Methylsergide
A-Amiodarone
N-Nitrofurantoin
Methotrexate
Azathioprine enzyme moniotring
Azathioprine is a purine analogue that interferes with DNA synthesis and inhibits the proliferation of quickly growing cells, especially cells of the immune system. It is used as an immunosuppressant in patients undergoing organ transplantation, and its metabolite 6-mercaptopurine is used in the treatment of autoimmune diseases and acute lymphoblastic leukemia.
During metabolism, hypoxanthine-guanine phosphoribosyltransferase (HGPRT) converts 6-mercaptopurine to cytotoxic 6-thioguanine nucleotide analogues, while thiopurine methyltransferase (TPMT) inactivates 6-mercaptopurine through methylation to form 6-methylmercaptopurine.
Approximately 11% of the population has reduced TPMT activity and 0.3% of the population has true deficiency of TPMT. [1] In these patients, active 6-mercaptopurine accumulates, and a larger proportion of 6-mercaptopurine is converted to the cytotoxic 6-thioguanine nucleotide analogues, which can lead to bone marrow toxicity and myelosuppression
Withdrawal reactions
important drugs
Opiates
BZDs
Corticosteroids
Rebound reactions
common drugs
Clonidine
Beta-blcokers
Corticosteroids
Oestrogen carcinogenesis
Endometrial ca
?breast ca
Types of clinical trials
Phase 1: normal volunteers (50)
Phase 2: patients, open study (200)
Phase 3: clinical trials: DB-RCT
Phase 4: post marketing
What are the 3 methods for detecting ADR post approval
Post-marketing: yellow card
Cohort studies
Prescription event monitoring
Black triangle drugs
Newly licensed usually <2y
Report any suspected adverse reaction
Established drugs in yellow card scheme
Only report serious adverse reactions: fatal, life-threatneing, needing hospital admission, disabling
What are pharmacetuical drug interactions
Ones taking place outside the body
Generally IV drugs being mixed together e.g. Ca and bicarbonate precipitating out
Always read instruction
Altered absorption: drug interactions
Tetracyclines, quinolones + Ca, Fe, Al
Altered absorption if given with any metal due to chelation
Think about drug timing
Displacement from plasma proteins
Most important
Warfarin + NSAIDs
Cytochrome p450 inhibitors
SICKFACES.COM Group
Sodium VPA
Isoniazid
Cimetidine
Ketoconazole
Fluconazole
Alcohol- binge drinking
Chloramphenicol
Erythromycin and other macrolides
Sulfonamides
Ciprofloxacin
Omeprazole
Metronidazole
Grapefruit juice
Allopurinol + 6 mercaptopurine
Makes it more cyotoxic
Cheese reaction
MAOI and cheese-> hypertensive reaction. e.g. cheese, marmites (foods containing tyramine)
P450 inducers
CRAP GPS
Carbamezapine
Rifampicin
Alcohol (chronic)
Phenytoin
Griseofulvin
Phenobarbitone
Sulphonylureas
Diuretics + lithium
Increased Na clearance but decreased Li clearance
Loop diuretics + aminoglycosides
Inihbit each others excretion and increase toxicitiy, particularly ototoxicity
What are some exmaples of indirect interactions?
Diuretics, corticosteroids + digoxin (low K)
NSAIDs and warfarin: damage to stomach, increased risk of GI bleed
Antibiotics and warfarin. reduced gut bacteria (involved in K production)
How can renal disease impact pharmacology
Drugs that are eliminated by the kidney
Drugs that are metabolised by the kidney
Nephrotoxic drugs
What are the clinically most important drugs effected by renal impairment
DIgoxin
Gentamicin
Atenolol
Amxocivillin
Captopril
Nause
Dysrhythmias
Anthopsia
Breast enlargement
Digoxin
Ototoxcitiy
Nephrotoxicity
Increased risk of toxicity in hyponatraemia and dehydration
Gentamicin
Bradycardia
Confusion
Hypotension
Fatigue
PVD
Heat failure at higer doses
Atenolol
Hypotension
Reduced GFR
Cough
Taste distrubance
Angioedema
GI distrubance
Captopril
When dose amoxicllin toxicity become important and why
Generally nontoxic
In patients with renal impairment the half life of the drug is substantially increased( 14h)
In patients with menigitis, the BBB is disrupted and this allows amoxiillin to accumulate in the CSF
These patients may develop seizures.
The allergic manifestation of drugs may also appear more commonly in this group of patients
Dry cough proportion of ACEi patients
15%
What is an important drug metabolised by the kidney and the significance of this?
Vit D3 (cholecalciferol- formed in skin). Vit D (made by uv irradiation of ergosterol)
Both forms are activated sequentially. 25a in liver
1a in the kiney
to yield 1,25 di(OH)D3 and 1,25 di(OH)D2
Mechanism of 2o hyerparathyroidism
Hypocalcaemia with relative conseuqence of hypophosphataemia lead to hyperparathyroid
Consequnece of failure in VtiD/ renal pathway
Gentamicin mechanism of nephrotoxicity
Renal tubular damge
Important in that damage occus with an accompanying degree of reduciton in GFR leading to gentamicin accumulation.
Causes a cycle.
Importance of appropriate gentamicin TDM
LI mecahnism of nephrotoxicity
Nephrogenic DI: through inhibiting Mg dependent enzymes (adenylate cyclase) which is activated in renal tubule by ADH.
and
Tubular damage
Cyclosporin A mechanism of nephrotoxicity
Reduced GFR
and
Tubular function
Used in renal transplant immunosuppression. Physician needs to distinguish between rejection episode causing decline in renal function or cyclosporin toxicity.
Cyclosporin AEs
TDM
Hypertension
Reduced GFR
Mechanism of ACEi nephrotoxicity
A2Rs located principally on the efferent arteriole. Have a vasoconstrictive effect.
If you administer ACEi which blocks biosynthesis of AngII or you give ARB there will be dilatation of the efferent arteriole.
As a consequent of that, renal blood flow through glomerulus increases.
However, the pressure within the glomerular tuft decreases.
The GFR is dependent on the perfusion pressure within the glomerular tuft, as perfusion pressure reduces, GFR reduces.
If a patient has a pathological reduction in pressure in the afferent arteriole e.g. RAS,(or more rarely in CoARc sited proximally to the renal arteries) there is a danger that if you inhibit ACEI/ARB for the pressure within glomerular tuft to reach pathologically low levels with a consequent critical reduction in GFR.
NSAIDs mechanism of toxicity
Inhibit COX and reduce PG concentration.
In the kidney and renal vasculature, most of the PGs are vasodilator. Effects are mediated by prostaglandin E2 and prostacycline.
These molecules regulate the diameter of blood vessels around the glomerulus.
LT use of NSAIDs. particularly in patients with preexisting renal damage, may result in a further reduciton in GFR and Na retention.
May also cause papillary necrosis. Papilla receives blood supply from surrounding bvs that require PGs to maintain their diameter, thus patients receiving high concentrations of NSAIDs may develop relative ischaemia of the renal papilla-> necrosis if sustained. Necrotic papilla may become detached from renal cortex, fall into renal pelvis and block ureturs
What are the hepatic synthetic functions important in pharmacology
Albumin: hypoalbuminaemia may increase proportion of the free drug, more of a problem if drug clearance is reduced.
e.g. Diazepam, tolbutamide, phenytoin
A1-acidic glyocoprotein: binds basic drugs
e.g. quinidine, chlorpromazine and imipramine
Reduced synthesis of Clotting factors
Warfarin and synthesis of Vit-K dependant clotting factors
What are the Vit K dependent clotting factors?
2, 7, 9, 10
What are drugs that should be prescribed with care in current or recent encepahlopathy?
Opiates (most important):
prolonged elimination, may precipitate encephalopathy
Anti-psychotics: phenothiazine and butyrophenones
Anxiolytes and hyponotics: oxazepam and temazepam are safest
Antidepressants: TCAs are safest, avoid MAOs: idiosyncractic hepatotoxicity
Hepatorenal syndrome precipitated by
Opiates
Major tranquilisers etc.
Patient with hepatic disease and declining renal function
?hepatorenal syndrome
R/v drug chart and withdraw drugs that may be contributing
What are the groups of drugs that are likely to present problems in patients with liver disease?
Those with high FPM
High plasma protein binding
Low TI
Those with CNS depressant effect
Importance of drugs with extensive FPM
Normally only a small proportion of ingested blood enters blood, liver disease-> very reduced FPM
e.g.
Clormethiazole
Chlorpromazine
Imipramine
Morphine
Pethidine
Importance of drugs with high plasma protein binding in context of liver disease
Combination of high protein binding and reduced elmination likely to precipitate a prolbem
e.g.
Chloral hydrate
Phenytoin
Importance of durgs with low TI in context of liver disease
Any incapacity of liver to metabolise drug and reduce toxic levels likely to precipiate toxicity
e.g. barbiturates
Importance of drugs with CNS effect in context of liver disease
Principally because of capacity to control through autonomic NS the important CV and respiratory functions likely to become hypotensive, develop bradycardias and stop breathing.
Drugs include opiates, phenothiazine and othrers with known sedative effects
How can the mecahnisms of hepatotoxicity be classified?
Non-covalent
or
Covalent
What are the mechanisms of non-covalent hepatotoxcitty?
Occur as a consequence of the activity of cytochrome p450.
During these reaction oxygen radicals can be generated e.g. peroxides, superoxides, hydroxyl radicals. Highly reactive molecular species that may damage the structure of lipids, aas and other molecules.
Normally glutathione is there to protect the cell and serves as free radical scavenger, however in established liver disease glutathione may become depleted and this may increase the propensity of oxudative products to cause issues
What is the mechanism of covalent hepatotoxicity
Involve adduct formation between drug/metabolite and DNA/proteins/lipids within the cell
What are the common hepatotoxic drgus?
Hepatocellular necrosis:
Paracetamol- reactive intermediate
Halothane: repeated use
Anticonvulsants Carbamazepine, phenytoin and valproate
MAOIs, isoniazid, nitrofurantoin, sulphonamides
Hydralazine, methyl dopa
Cholestasis:
Chlorpromazine
Sulphonylureas (glibenclamide)
Carbimazole
This drug has 100% bioavailability in an oral formulation
A.
Metformin
B.
Captopril
C.
Levodopa
D.
Amiodarone
E.
Gentamicin
F.
Methotrexate
G.
Isoniazid
H.
Ciprofloxacin
I.
Phenytoin
J.
Diltiazem
Ciprofloxacin
Probenecid competitively inhibits the secretion of which drug?
A.
Lithium
B.
Beclometasone
C.
Penicillin
D.
Metronidazole
E.
Theophylline
F.
Azathioprine
G.
Suxamethonium
H.
Lignocaine
I.
Propofol
J.
Dapsone
Penicillin
A.
Lithium
B.
Beclometasone
C.
Penicillin
D.
Metronidazole
E.
Theophylline
F.
Azathioprine
G.
Suxamethonium
H.
Lignocaine
I.
Propofol
J.
Dapsone
A prodrug that interacts with allopurinol
Azathioprine
Drug metabolised by acetylation, used to treat leprosy
Dapsone
Smoking increases the metabolism of this drug.
A.
Lithium
B.
Beclometasone
C.
Penicillin
D.
Metronidazole
E.
Theophylline
F.
Azathioprine
G.
Suxamethonium
H.
Lignocaine
I.
Propofol
J.
Dapsone
Theophylline
An anti-platelet drug that may cause a rare thrombotic syndrome that is characterised by a classic triad
Clopidogrel
A drug used to treat Wilson’s disease, that may cause a myasthenia gravis-like syndrome
Penicillamine
A centrally acting antihypertensive that may give rise to a positive Coombs test
Methyldopa
If this antidepressant is given with amiodarone it increases the risk of an arrhythmia
Amitryptilline
If this drug is given to a patient with bipolar affective disorder, there is increased risk of toxicity of a particular mood stabiliser
Frusemide
Which drug causes ‘floppy baby syndrome’?
Diazepam
Which drug, when given to a mother in the late stages of pregnancy, can cause a low platelet count in the neonate?
Bendroflumethiazide
Which drug causes Ebstein’s anomaly in the baby?
Li
Effects of this drug on the fetus include frontal bossing, midface hypoplasia, saddle nose, cardiac defects, short stature, blindness and mental retardation.
Warfarin
Drug that may cause liver adenoma.
A.
Penicillamine
B.
Sumatriptan
C.
Oral contraceptive
D.
Cimetidine
E.
Hydroxychloroquine
F.
Methotrexate
G.
Rifampicin
H.
Cyclophosphamide
I.
Atenolol
J.
Diclofenac
Rifmapicin
Renally excreted drug that can cause impotence, nightmares and type 2 Diabetes
atenolol
Renally excreted drug used to treat Zollinger Ellison Syndrome
Cimetidine
Detemir
Longer acting insulin that binds to albumin in the circulation
Glargine
Longer acting aa-altered insulin, thus prolonged absorption from subcutaneous tissue
Action of insulin at the liver
Switches off hepatic glucose output:
gylcogenolysis
gluconeogensis
Inhibits ketogenesis
Action of insulin at adipose tissue
Increaes lipoprotein lipase activity:
reduces hypertriglyceridaemia
Increases GLUT4 activity-> glucose stored as fat
Decreased lipolysis: reduced [glycerol], [non-esterified fatty acids reduced]
Insulin action at muscle
Decreased proteolysis: decreased aa delivery to liver for gluconeogenesis
Increased GLUT4 activity-> [reduced glucose]
Can a bolus of insulin be useful?
Short t1/2 of IV insulin means bolus is never useful. Should be given by infusion
When is human insulin used?
IV
Features of basal-bolus QDS insulin
Short acting with breakfast
Second dose with lunch
Third with evening meal
Intermediate insulin given OD
ACTrapid given 15 mins before meal
Intermediate given before patient goes to bed
Preprandial glucose
Doesn’t tell you how much insulin is needed
Post prandial tell you how much you should have given
Fasting glucose
Tells us how much long acting needs to have been given night before
Issues with actrapid
Human insulin.
Forms hexamers under skin and is abosrbed over 3-4h
Needs to be given 15 mins before meal
Can lead to late post prandial hypoglycaemia
Can lead to immediate post-prandial hyperglycaemia that may lead to diabets cx
Insulin lispro
Short acting insulin that has modified aa so doesn’t form hexamers under skin
Faster onset and shorter duration of action
Can be given at beginning of food or even after food.
Possible T2D insulin regimes
Long acting insulin + sulphonylurea
BD mixtrrd
Full basal bolus
Insulin + metformin
Advantage of metformin and insulin
Didn’t gain weight that is seen in intensive insulin alone
Glucagon in EtOH induced hypo
May not be as effective as EtOH uses glycogen in metabolism
Dietary advice in T2DM
Control total calories/increase exercise
Reduced refined carbohydrate
Increase complex carbohydrate as a proportion of carbohydra
Reduce fat as proportion of caloires
Increase unsaturated fat as a proprotion of fat
Increase soluble fibre
Address Na intake
Oriistat dose
120mg TDS
Metformin
Insulin sensitiser
Biguanide
Increases hepatic insulin sensitivity
Inhibits hepatic gluconeogenesis
Insulin sensitiser
Biguanide
Increases hepatic insulin sensitivity
Inhibits hepatic gluconeogenesis
Metformin
Metformin iniitial dose
500mg BD
Side effects of metformin
GI disturbance: nausea and diarrhoea
Lactic acidosis (rare)
Do not use if severe liver, severe cardiac, or mild renal failure (elevated Cr + radiological contrast media)
Act on beta cell to acutely cause insulin release independent of glucose concentration
Stimulate second phase insulin secretion
Sulphonylureas
Metaglinides
Sulphonylurea MOA
Act on insulin secretagogue
Act on beta cell to acutely cause insulin release independent of glucose concentration
Stimulate second phase insulin secretion
Starting dose of sulphonylureas
2.5mg BD
Draw MOA of sulphonylureas
Cx of sulphonylureas
Hypoglycaemia: can be severe, prolonged, or even fatal
Especially a problem in elderly, alcoholics and those with poor nutirtion- not enough stored glyocgen
Weight gain
Rarer complications: rashes, blood dyscrasia
Hypoglycaemia: can be severe, prolonged, or even fatal
Especially a problem in elderly, alcoholics and those with poor nutirtion- not enough stored glyocgen
Weight gain
Rarer complications: rashes, blood dyscrasia
Sulphonylureas
What are the non-sulphonylurea secretagogues?
Repaglanide
Nataglinide
Gliclazide
Glibenclamide
Sulphonylureas
MOA Thiazolidinediones
Reduce lipotoxicity
Increase muscle insulin sensitivity
Favourable fat distribution
Suppression off fatty acid release through PPARg agonism
Reduce lipotoxicity
Increase muscle insulin sensitivity
Favourable fat distribution
Suppression off fatty acid release
All rthrough PPARg agonism
Thiazolidinediones
Rosiglitazone
Pioglitazone
Glitazone: PPARg agonists
MOA PPARg
Act on intranuclear PPARg
Adipose tissue>liver and muscle
Affect lipoprotein lipase, FA transporter, CoA synthase, GLUT4
Insulin resistance reduced
Act on intranuclear PPARg
Adipose tissue>liver and muscle
Affect lipoprotein lipase, FA transporter, CoA synthase, GLUT4
Insulin resistance reduced
PPARg agonist e.g. glitazone
Side effects of pioglitazone
Peripheral weight gain
Oedema
Should not be used with insulin
E.g. of alpha glucosidase inhibitors
Acarbose
MOA acarbose
Delay oligosaccharide absorption
S/E acarbose
Flatulence
MOA GLP-1
Inhibit glucagon release
Cause acute insulin release
Stimulate insulin biosynthesis
Improve beta cell differentiation
Inhibit glucagon release
Cause acute insulin release
Stimulate insulin biosynthesis
Improve beta cell differentiation
GLP1
Pramitide MOA
Slow gastric eptying
Inhibit glucagon release
Cause acute insulin release
Why should thyroxine be introduced gradually, especially in the elderly
Can exacerbate pre-existing ischaemic heart disease
What are the risks of suppressing TSH
Osteopenia/osteoporosis
AF (especially in older patients)
Should not aim to suppress TSH, should aim to bring it within normal range
Mx of low uptake thyroxtocisosis
Use beta blockers as thionamides won’t work
Sore throat on carbimazole
Warn patient to stop due to risk of agranulocytosis
When is 131I not used in thyroid disease
Opthalmopathy/tracheal compression
MOA Mg Triscillate
Antacid
Neutralises gastric acid
MOA AI hydroxide
Antacid
Neutralises gastric acid
MOA Gaviscon
Alginate
Reduces reflux: increased stomach content viscosity
Forms a raft on top of stomach contents
MOA
Omeparzole
Lansoprazole
Pantoprazole
PPIs
Activated in acidic pH
Irreversibly inhibit H/K ATPase
More effective than H2R antagonsits
MOA
Cimetidine
Ranitidine
H2 R antagonists
Reduce gastric parietal cell H secretion
MOA
Misoprostol
Prostaglandin analgoue
Acts on parietal cells to reduce secretion
Side effects:
Mg Triscillate
Diarrhoea
Side effects: AI hydroxide
Constipation
Side effects: PPIs
GI distrubance
Headache
Side effects: H2R antags
Mainly with cimetidine: GI disurbance
Side effects:
Misoprostol
Diarrhoea is very common
Interactions:
Mg Triscillate
Interfere with drug absorption- take separately
Interactions:
AI hydroxide
Interfere with drug absorption- take separately
Interactions:
PPIs
P450 inhibitor
Interactions:
Cimetidine
P450 inhibitor
Additional notes:
Mg Triscillate, AI hydroxide
Take when symptoms occur/expected
Additional notes:
PPIs
Masy mask symptoms of gastric carcinoma
Additional notes:
H2R antags
May mask symptoms of gastric Ca
Additional notes:
Misorpostol
Mainly used to prevent NSAID-associated PUD
Often in combination with NSAID e.g. diclogenac + misoprostol= arthrotec
MOA:
Bran Ispaghula
Bulk laxatives
Increase feacal mass-> increased peristalsis
MOA:
Docusate
Glycerin (PR)
Senna
Picosulfate
Stimulant laxatives
Increase intestinal motility
MOA:
Lactulose
Macrogol
Phosphates
Mg Salts
Osmotic laxatives
Increse stool water content
MOA:
Liquid paraffin
Stool softener
Side effects:
Bulk forming laxatives
Bloating
Side effects:
Liquid paraffin
Reduced ADEK absorption
Granulomatous reactions
Contraindication to all laxatives
Bowel obstruction
What is co-danthrusate
A mild stimulant laxative used in Rx of opioid induced constipation
MOA:
Hyoscine butylbromide (Buscopan)
Antimuscarinic- antispasmodic
MOA:
Mebeverine
Peppermint oil
Antispasmodic
MOA:
Loperamide
Opioid receptor agonist
Doesn’t cross BBB therefore no central effects
MOA:
Sulfasalzine
Mesalazine
5-ASA
Unknown MOA
MOA:
Budesonide
Steroid
More potent than prednisolone
High FPM therefore less systemic effects
MOA:
Infilixmab
Chimeric anti-TNF mAB
MOA:
Etanercept
P75 TNFRFc fusion protein
MOA:
Adalimumab
Human anti-TNF mAb
Side effects:
Hyoscine
Anti-AChM SEs: dry mouth, palpitations
Side effects:
Loperamide
Abdo cramps
Side effects:
5-ASAs
Sulfasalzine has increased SEs:
blood dyscrasias
hepatitis
rash, urticaria
Oligospermia
pulmonary fibrosis
Side effects:
Infliximab, etanercept, adalmimuab
Severe infections
TB
Allergic reactions
CCF
CNS demyelination
Points of interest:
5-ASA
Monitor FBC
Topical in distal disease
Points of interest:
Budesonide
Use to induce remission in ileal crohn’s
Points of interest:
Biologics used in IBD
Screen for TB before parenteral admin
Give hydrocortisone to reduce allergic SEs
SABAs
Salbutamol
Terbutaline
LABAs
Salmeterol
Formoterol
MOA:
beta agonists
Act @ bronchial B2 receptors- smooth muscle relaxation
reduced mucus secretion
MOA:
Muscarinic antagonists
Bronchodilation
Mucus secretion
SAMA
Ipratropium
LAMA
Tiotropium
E.g. ICS
Beclometasone
Budesonide
Fluticasone
Symbicort
Budesonide + formoterol
Seretide
Fluticasone + salmeterol
MOA:
ICS
Act over weeks to reduce inflammation
Reduce cytokine production
Reduce prostaglanding/leukotriene synthesis
Reduce IgE secretion
Reduce leukocyte recrutiement
Prevent long term decline in lung function
MOA:
Theophylline
Aminophylline
Methylxanthines
PDE inhibitors: increse cAMP-> bronchodilation
MOA:
Montelukast
Zafirlukast
Leukotriene antagonists
Block cysteinyl leukotirenes
MOA:
Roflumilast
PDE4 inhibitor
MOA:
Omalizumab
Humanised anti-IgE mAb
MOA:
Carbocystine
Mucolytic
MOA:
Dornase ALFA
DNAse (mucolytic)
MOA:
Certirizine/loratidine/fexofenadine
Chlorphenamine (piriton)
Selective H1R inverse agonists aka H1 antagonists
What are the non-sedating antihistamines
Certirizine
Des/ loratidine
Feoxfenadine
Give an example of a sedating antihistamine
Chlorphenamine
Side effects:
H1R partial agonists
Hypotension
Arrhthmia: long QT
Older agents:
drowsiness
Anti-AChM
Side effects:
Carbocystiene
GI bleed (rare)
Side effects:
Roflumilast
GI
Side effects:
Leukotriene antagonsits
?Churg-Strauss
Side effects:
Methylxanthines
Nausea
Arrhythmias
Seizures
Hypokalaemia
Side effects:
ICS
Oral candidiasis
High doses may -> typical steroid SEs
Side effects:
Muscarinic antagonsits
Dry mouth
Side effects:
Beta agonsits
Tachycardia
Tremor
CI:
Muscarinic antagonists
Closed angle glaucoma
Prostatic hypertrophy
CI:
Roflumilast
Severe immunological disease
CI:
Carbocysteine
Active peptic ulceration
CI:
H1R inverse agonsists
Severe hepatic disease
Caution:
long QT
BPH
Closed angle glaucoma
Interactions:
Methylxanthines
Reduced levels:
smoking, EtOH, CyP inducers
Increased levels:
CCBs
CyP inhibitors
Interactions:
Beta agonsits
Reduced K in high doses with corticosteroids, loop/thiazide diuretics
Theophylline
Additional info:
Salbutamol
Can be given IV in acute severe asthma
Additional info:
ICS
Decreases risk of complications: use spacer, rinse mouth after use
Fluticasone is 2x as potent so use at lower dose
Symbicort can be used as a reliever or a preventer because of formoterol’s fast onset
Additional info:
Methylxanthines
Aminophylline is IV form
Give IVI slowly, too fast-> VT
Monitor with ECG and check plasma levels
Additional info:
Leukotriene antagonsits
Particularly useful for NSAID and exercise induced asthma
Additional info:
Omalizumab
SC injection every 2-4w
Used for severe asthma
Use: carbocystine
COPD
Use: DNAse
CF
Standard dose:
Amoxicillin
500mg TDS PO
Standard dose:
Clarithromycin
500mg BD PO
Standard dose:
Trimethoprim
200mg BD PO
Standard dose:
Co-amox
1.2g TDS IV
Standard dose:
Simvastatin
20mg OD Nocte PO
Standard dose:
Nifedipine MR
20mg OD PO
Standard dose:
Lisinopril HTN
10mg OD PO
Standard dose:
Lisinopril HF
2.5mg OD PO
Standard dose:
Bisorprolol HF
1.25mg OD PO
Standard dose:
Paracetamol
1g QDS PO
Standard dose:
Codeine phosphate
30mg every 4h PRN PO
Max 240mg daily
Standard dose:
Tramadol
50mg ever 4h PRN PO
Ma 300mg daily
Standard dose:
Enoxaparin
Treatment: 1.5mg/kg/24h SC
Prophlyaxis: 40mg OD SC
MOA:
Cyclophosphamide
Alkylates DNA
Affects B cells> T cells
MOA:
Cisplatin
Alkylates DNA
MOA:
Azathioprine
Blocks de novo nucleotdie synthesis
Affects T cells > B cells
MOA:
Mycophenolate mofetil
Blocks de novo nucleotide synthesis
Affects T cells > B cells
MOA:
Methotrexate
Dihydrofolate reductase inhibitor
MOA:
Chlorambucil
Alkylates DNA
Antiproliferative agents
Cyclophosphamide
Cispaltin
Azathioprine
Mycophenolate mofetil
Methotrexate
Chlorambucil
Inihibitors of cell signalling
Ciclosporin
Tacrolimus
Sirolums
MOA:
Ciclosoprin
Tacrolimus
Calcineruin inhibitors
Block IL-2 production
MOA:
Sirolimus
Blocks mTOR pathway
What are the anti-T cell monoclonal antibodies
Murnomab-CD3
Basiliximab
Toilizumab
Abatecept
MOA:
Muromonab-CD3
Blocks CD3 on T cells
MOA:
Basiliximab
Blocks CD25R (alpha chain of Il-2R)
MOA:
Tocilizumab
Blocks IL-6 R
MOA:
Abatecept
Anti CTLA-4 Ig
Blocks costimulation of T cells
MOA:
Prednisolone
Inhibits phosophilapse A2:
Reduces platelet activating factor
Reduced arachidonic acid
Reduced trafficlking of phagocytes (hence transient increase in phagocyte count)
Lymphopenia, apoptosis of T+V cells
MOA:
Ustekinumab
Binds to p40 subunit of IL-12 and IL-23
MOA:
Rituximab
Anti-CD20
Redcues B cells (not plasma cells)
used for lymphoma and autoimmune disease
MOA:
Alemtuzumab
Binds to CD-52
Used in CLL
MOA:
Natalizumab
Anti-a4 integrin
Used in MS and Crohn’s
Side effects:
Cyclophosphamide
Bm suppresswion
Haemorrhagic cystitis
Alopecia
Sterility
Side effects:
Cisplatin
BM suppression
Severe n/v
Nephrotoxic
Ototoxic
Peripheral neuropathy
Side effects:
Azathiorpine
Bm suppression
Hepatotoxicity
n/v/d
Arthralgia
Side effects:
Mycophenolate
BM suppression
Skin malignancy
GI upset
Side effects:
Methotrexate
Pulmonary fiboris
Hepatotoxic
Mucositis
Side effects:
Chlorambucil
BM suppression
EM-> SJS
Side effects:
Ciclosporin
Nephrotoxic
Hepatic dysfunction
Tremor
Hypertrichosis
Gingival hypertrophy
Encephalopathy
Side effects:
Tacrolimus
Nephrotoxic < cf ciclosporin
Diabetogneic
Neurotoxic > cf ciclopsoinr
Side effects:
Sirolimus
Dyslipidaemia
Side effects:
Pred
Diabetes
Central obesity
Adrenal suppression
Cataracts
Glaucoma
Pancreatitis
Osteopororis
Cushingoid
Hirstutism
Neutrophilia
Interactions:
Azathioprine
Allopurinol-> increased toxicity
Interactions:
Methotrexate
Increased toxicity with NSAIDs, ciclosporin, Crohn’s
Interactions:
Ciclosporin
Tacrolimus
P450 inhibitors
Use:
Cyclophosphamide
Cancer
RA
SLE
Systemic sclerois
Wegener’s
Use:
Cisplatin
Cancer
Use:
Azathioprine
Prevent Tx rejection
Steroid sparing agent: IBD, SLE, RA
Use:
Mycophenolate
Prevent Tx rejection
AI disease
Use:
Methotrexate
Cancer
RA
Psoriasis
Crohn’s
Use:
Chlorambucil
Cancer e.g. CLL
Use:
Ciclopsporin
Prevent Tx rejection
GvHD
UC
RA
Psoriasis
Use:
Tacrolimus
Prevent Tx rejection
Additional info:
Cyclophosphamide
Give mensa to prevent haemorrhagic cystitis
Activated by p450
Additional info:
Cisplatin
Carboplatin is associated with less severe SEs
Requires pre-admin hydration
Additional info:
Azathioprine
Do TPMT assay before use
50% of patients intolerant of azathioprine tolerate 6-MP
Additional info:
Methotrexate
Give folinic acid to reduce risk of myelosuppression
Monitor U+E, FBC, LFT
Additional info:
Ciclosporin
Monitor LFTs
What are the important cytotoxic classes
Aklyating agents
Antimetabolites
Cytotoxic Abx
Microtubule inhibitors
Topoisomerase inhibitors
Immune modulators
MAbs
Tyrosine kinase inhibitors
Endocrine modulators
Alkylating agents
Cyclophosphamide
Chlorambucil
Busulfan
Cisplatin
MOA alkylating agents
DNA x-linking
Base mis pairing
Excision of alkylated DNA-> strand breaks
Antimetabolites
Methotrexate
5-FU
Cytotoxic Abx
Anthracycline: doxorubicin, daunorubicin
Bleomycin
MOA cytotoxic Abx
Intercalate with DNA
Free radical formation
MT inhibitors
Vinca alklaoids: vincristine, vinblastine
Taxanes: paclitaxel
Topoisomerase inhibotrs
Etoposide
Immune modualtors
Thalidomide, lenalidomide
Trastuzumab
Anti-Her 2: breast Ca
Bevacizumab
Anti-VEGF
Cetuximab
Anti-EGFR (CRC)
Rituximab
Anti-CD20 NHL
Tyrosine kinase inhiibots
Erlotonib
Imatinib
Sinitimib
Erlotinib
Lung Ca
Imaitinb
CML
Sunitinib
RCC
Common side effects of CTx
N/v: prophylactic anti-emetics
Alopecia
Neutropenia: 10-14d post chemo
Extravasation of chemo agents:
pain, burning brusing at infusion site. Stop infusion, give steroids, apply cold pack. Liaise early with plastics
Hyperuricaemia
Oral mucositis
Specific problems:
Cyclophosphamide
Haemorrhagic cystitis: give mensa
Hair loss
BM suppression
Specific problems:
Doxorubicin and other anthracylcines
Cardiomyopathy
Extravasation reactions
Specific problems:
Bleomycin
Pulmonary fibrosis
Specific problems:
Vincristine
Peripheral neuropathy
Don’t give intrathecal
Specific problems:
Paclitaxel
Peripheral neuropathy
Hypersensitivity
Pre rx with anti-histamines and steroids
Specific problems:
5-FU
Palmar-plantar erythrodysthesia
Mucositis
Mx of chemo-induced emesis
Low risk: domperidone/metoclopramide started pre Rx
High risk:
ondanestron + dex + aprepitant
Breast Ca: FEC
5- FU
Epirubicine
Cyclophospamide
Breast Ca: CMF
Cyclophosphamide
Methotrexate
5-FU
Testicular teratoma: BEP
Bleomycin
Etoposide
cisPlatin
CTx ovarian
Carboplatin
Pacliatzel
R-CHOP
NHL
Ritxuimab
Cyclophosphamide
Hydroxydaunomycin (doxorubicin)
Oncovin
Pred
ABVD
HL
Adriamycin
Bleomycine
Vinblastine
Dacarbazine
Advies with pred
Don’t stop steroids suddenly
Consult doctor when unwell
Increase does with illness or stress
Carry steroid card
Avoid OTcs e.g. NSAID
Osteoporosis and PUD prophylaxis (Ca+ vit D, bisphosphonates, PPI)
SEs of steroids
GI:
Candidiasis, PUD, oesophageal ulceration, pancreastitis
Cardio:
HTN, CCF
MSK:
Proximal myopathy
Osteoporosis
Endo:
Growth suppression, HPA suppression, Cushing’s
Metabolic:
Na and fluid retention
Raised PMN
Reduced K
CNS:
Depression, psychosis
Eye:
Cataracts, glaucoma
Immune:
Increased susceptibility to infection
Liver transplant regime
Tacrolimus
Azathioprine
Pred: withdraw at 3m
Renal transplant regime
Pre-op:
Alemtuzumab
Post op
Pred
Tacrolimus LT
Drugs used in rheumatic disease
5-ASAs
Methotrexate
Hydroxychloroquine
Penicllamine
Infliximab
MOA:
Hydroychloroquine
Reduced activation of dendritic cells
Anti-Gout Drugs
Colchcine
Allopurinol
Feboxustat
Probenecid
Rasburicase
MOA:
Allopurinol
XO inhibitor
MOA:
Feboxustat
XO inhibitor
MOA:
Probenecid
Urcisouric
MOA:
Rasburicase
Recombinant uric oxidase
MOA:
NSAIDs
Non-selective COX inhibitors
Analgesic
Antipyretic
Anti-inflammatory
MOA:
Celecoxib
Selective COX2 I
Rank NSAIDs from least to most toxic
Ibuprofen
Diclofenac
Aspirin
Naproxen
Indomethacin
Ketoprofen
Neuromusuclar durgs
Stigmines
Baclofen
Dantrolene
MOA:
stigmines
Anticholinesterases:
Increase ACh in the synpatic cleft
Enhacne neuromuscular transmission
A 55-year-old man develops a rash two days after starting a new medication. The rash is mildly pruritic and mainly affects the arms, torso and neck. The palms of his hand are shown below:
© Image used on license from DermNet NZ
Which one of the following drugs is most likely to have been started?
Levetiracetam
Olanzapine
Carbamazepine
Fluoxetine
Diazepam
This patient has developed erythema multiforme which is a known complication of carbamazepine use.
