Pharmacology Flashcards
Phases of human drug clinical testing
Phase 1 - normal volunteers
Phase 2 - target population compared with control drug
Phase 3 - similar to phase 2 but larger groups
Phase 4 - post-marketing surveillance
Subdivisions of pharmacology
PHARMACOKINETICS
- absorption
- distribution - depends on capillary permeability, drug solubility (lipophilic drugs easier), binding to plasma proteins
- metabolism
- excretion
PHARMACODYNAMICS
PHARMACOTHERAPEUTICS
TOXICOLOGY
Biotransformation
Makes drugs more polar - as lipophilic properties hinder elimination
2 phases:
Metabolism - oxidation, reduction, hydrolysis
- via cytochrome p450
Conjugation with - glucuronate (paracetamol/morphine), glutathione, sulfate (COCP), acetic acid (hydralazine and isoniazid)
- in liver cytosol
Volume of distribution
Ratio of amount of drug in the body to its plasma concentration
Large Vd in lipophilic drugs, indicating that most of the drug is being sequestered in some tissue
Drug interactions
Enzyme inductors - increase cytochrome p450
- SCRAP GP
Sulfonylureas, Smoking
Carbamazepine, Corticosteroids
Rifamycins (Rifampicin, Rifabutin)
Alcohol (Chronic)
Phenytoin
Griseofulvin
Phenobarbital
Enzyme inhibitors - inhibit CYP450
- VIDEOCASE
Valproate
Isoniazid
Disulfiram
Erythromycin, Clarithro (not Azithro)
Omeprazole
Cimetidine
Allopurinol
Sulfonamides
Ethanol (Acute)
Enterohepatic circulation - reduced by ampicillin
GIT flora - reduced by ampicillin
Drug bioavailability influenced in pregnancy
↑ circulating volume
↑renal blood flow so ↑ renal clearance
↑ 3rd space
↑ fat content
↓ albumin and binding proteins
↑ gastric emptying time
↑ liver metabolism (but no change to liver blood flow)
Teratogens
A drugs - Anticonvulsants, Antibiotics, Anticoagulants, Antimetabolites, Androgens, Alcohol, Antipsychotics
< Day 20 - limb defects
Day 20 - anencephaly
Day 34 - transposition of great vessles
Day 36 - cleft lip
Day 42 - VSD, syndactyly
Day 84 - hypospadias
Most drugs cross the placenta, except…
HIT
Heparin
Insulin
Tubocurarine
Drugs that cause abortion
MET
Misoprostol
Ergotamine
Thrombolytics
FDA risk of substance to fetus
A - no fetal risk - proven by LOTS of data
B - animal studies failed to demonstrate risk, no adequate studies in women
C - animal studies show adverse effect, no adequate studies in women, benefit of drug outweighs potential risk
D - evidence of risk of human teratogenicity, potential benefits outweigh potential risk
X - evidence of risk of human teratogenicity, potential risk outweighs benefits of drug
Drugs and breastfeeding
Most drugs enter breast
Drugs not excreted in breast milk - warfarin, aminoglycosides (eg gentamicin)
Dopamine agonists
FDA category B
Prolactin antagonist - ↑dopamine ↓prolactin
↓milk production
For pituitary tumours, parkinsons disease, inhibition of lactation, hyperprolactinaemia
eg bromocriptine, cabergoline
Domperidone
Dopamine antagonist
To stimulate lactation (↑prolactin secretion), ↑gastric motility
Also used for anti-emesis, parkinsons disease
Does NOT cross blood brain barrier
Morphine
FDA category C
Acts on μ-opioid receptors in brain, substantia gelatinosa of spinal cord, GIT
Gives - analgesia, sedation, euphoria, dependence, resp depression, pinpoint pupils, constipation, sphincter of Oddi spasm
Antidote is naloxone or NMDA antagonists (ketamine)
Metabolized in liver, kidney, brain
Heroin
FDA category X
= diacetylmorphine, diamorphine
Prodrug of morphine, more potent
More lipophilic, so crosses BBB more easily
Binds to μ-opioid receptors
Effects - euphoria, drowsiness, CNS depression
Fetal effects are non-teratogenic, but include placental infection, FGR, preterm birth, fetal death
Neonatal narcotics syndrome - usually 48hr- up to 4weeks of birth, see CNS hyperirritability, high-pitched crying, resp distress, poor feeding, seizures
Fentanyl
FDA category C
μ-opioid agonist
Short acting
100x more potent than morphine
Can cross placenta
Lidocaine
FDA category B
Blocks fast voltage-gated sodium channels to prevent neurone depolarisation
Antiarrhythmic
2hr half-life
Metabolized by liver
Toxicity - circumoral (oral) paraesthesia, tinnitus, blurred vision, seizures, loss of consciousness, cardiorespiratory compromise, ECG changes
Risk of cardiotoxicity highest if underlying conduction issue eg WPW
Maximum dose
- without adrenaline 3mg/kg
- with adrenaline 7mg/kg
Cocaine
= benzoylmethylecgonine
From leaves of coca plant
CNS stimulant, appetite suppressant, topical anaesthetic, SSRI, potent vasoconstrictor
Metabolized most in liver, can detect metabolite in urine within 4hr intake up to 8days post
Side effects - tachycardia, hallucinations, bronchospasm, crack lung syndrome, MI, tooth decay, bruxism
Fetal effects - vasoconstriction of uterine/placental/umbilical artery -> FGR, fetal death, abruption, Prune-belly syndrome, hydronephrosis, reduced HC, gastroschisis
Tramadol
FDA category C
Centrally acting analgesic
Weak μ-opioid agonist, serotonin releasing agent, noradrenaline reuptake inhibitor, nicotinic acetylcholine receptor antagonist, M1 and M3 muscarinic acetylcholine receptor antagonist
Maximum dose 400mg/day
Ethanol
FDA category X
Organic compound where hydroxyl functional group is bound to carbon atom, product of glucose fermentation
C2H5OH
CNS depressant, γ-aminobutyric acid (GABA) receptor agonist
Metabolized in liver by alcohol dehydrogenase to acetaldehyde
0.05% blood alcohol -> euphoria
0.08% -> upper legal driving limit
0.1% -> CNS depression
0.4% -> death
Ethanol abuse
Maximum for males 140-210g/week
For females 84-140g/week
(14 units average)
Blood - anaemia, thrombocytopenia, ↑triglycerides
Cardiac - cardiomyopathy, stroke, HTN
GIT - chronic gastritis, pancreatitis, liver cirrhosis and hepatitis, fatty liver, oropharyngeal cancer
Pregnancy - miscarriage, aneuploidy, structural congenital abnormalities
+ Wernicke-Korsakoff syndrome, polyneuropathy, delirium tremens
Fetal alcohol syndrome
Permanent birth defect
Growth - low birth weight, short stature
Craniofacial - smooth philtrum (upper lip indentation), thin upper lip, small palpebral fissures
CNS structural - microcephaly, agenesis of corpus collosum, cerebellar hypoplasia
Neurodevelopmental abnormalities - epilepsy, impaired fine motor skills, neurosensory hearing loss, LDs, cognitive defects
Types of antibiotics
Bactericidal
- interrupt cell wall / membrane / enzymes
- kill bacteria, or in low doses act as bacteriostatic
Bacteriostatic
- inhibit cell growth and reproduction by inhibiting protein production, DNA synthesis, cellular metabolism
- high doses become bactericidal
Interfere with folate metabolism
- sulfonamides inhibits conversion of benzoic acid to folate
- dihydrofolate reductase inhibitors eg trimethoprim, methotrexate, pyrimethamine
Penicillin
Derived from penicillium fungi
5 groups
- β-lactams
- β-lactamase resistant
- broad-spectrum penicillins eg amox, ampicillin, co-amox
- antipseudomonal penicillins eg ticarcillin, piperacillin
- mecillinams
Sulfonamides
2 groups - sulfonylureas (eg gliclazide) and thiazide diuretics
Competitive inhibitor of dihydropteorate synthetase (enzyme in folate synthesis)
Side effects - porphyria, Stevens-Johnson syndrome, toxic epiderminal necrolysis, blood - agranulocytosis, haem anaemia, thrombocytopenia
Nitrofurantoin
FDA category B
Bactericidal
Excreted by kidneys
Poor tissue penetration so not for treating pyelo or renal abscess
SEs of pulmonary fibrosis, neonatal haemolysis if antenatal
Bacteriostatic
Clindamycin - binds to 50s ribosome, anaerobe cover, SE of pseudomembranous colitis, excreted in breast milk, catB
Chloramphenicol - binds to 50s ribosome, broad spectrum, SE aplastic anaemia, excreted in breast milk, catC
Macrolides eg azithro/clarithro/erythro - binds to 50s ribosome and accumulate within leukocyte, SE colitis, excreted in breast milk, catB
Tacrolimus - SEs cardiac/hepato/nephro toxicity, breast feeding should be avoided, catC
Tetracycline eg doxy - binds to 30s ribosome, broad spectrum, breastfeeding ok, catD
Trimethoprim (sulfonamides) - inhibits folate, compatible with breastfeeding, catD
Bactericidal antibiotics
Rifampicin - inhibits DNA dependent RNA polymerase, gram +ve cover, heptatotoxic, compatible breastfeeding, catC
Vancomycin/teicoplanin - inhibits cell wall synthesis, gram +ve cover, nephro/ototoxic, poor gut absorption, catB
B-lactam penicillin - gram +ve cover, neurotoxicity, compatible with breastfeeding, catB
Metronidazole - inhibits nucleic acid synthesis, covers anaerobes, catB
Quinolone (cipro, levofloxacin) - inhibits bacterial DNA gyrase, broad spectrum, breastfeeding avoided, catC
Aminoglycerides eg gentamicin - gram -ve cover, nephro/ototoxic, compatible with breastfeeding, catC
UTI treatment in pregnancy
If <35/40
- pivmecillinam 400mg stat then 200mg TDS for 5-7 days
- or if pen allergic, nitro 100mg BD 7 days
If near term >35/40
- cefalexin 500mg TDS 7 days
(if severe pen all then discuss)
Never trimethoprim in 1st T (teratogenic)
Antifungals
Fungal cell wall is made of ergosterol
But human cell wall made of cholesterol
So antifungals work on ergosterol
SEs - nephrotoxicty, hepatitis, anaphylaxis
Aciclovir
Antiviral drugs do not destroy target pathogens but inhibit pathogen development
Guanine analogue
Prodrug - converted into active form in viral cell by thymidine kinase
Inhibits viral DNA polymerase
Primarily for herpes infections
Poor water solubility, poor oral bioavailability
Elimination half life 3hrs
Renally excreted
Antifungals
Polyene group - eg nystatin
- inhibits synthesis of ergosterol
- catB
Imidazole group - eg ketoconazole, clotrimazole, fluconazole
- inhibits synthesis of ergosterol
- catC
Allylamines - eg terbinafine
- inhibits enzyme required for ergosterol synthesis
- catB
Caspofungin - inhibits cell wall glucan synthesis
Neuraminidase inhibitors
For treatment and prophylaxis of influenza virus A and B
Both FDA catC
Zanamivir (relenza)
- inhaled, with minimal oral bioavailability, can cause bronchospasm in asthma
Oseltamivir (tamiflu)
- prodrug, 75% oral bioavailability, metabolized in liver then renally excreted
- SEs Stevens-Johnson syndrome, neuropsychiatric disorders
Ribavirin
FDA cat X
For treatment of respiratory syncytial virus infection, hep C
Prodrug, 45% oral bioavailability, long half life as RBCs concentrate drug and can’t excrete it
Purine analogue
SEs - haem anaemia, teratogenic
Antiretrovirals
For treatment of retroviral infections eg HIV
Aims to achieve viral load <50 RNA copies/ml plasma
Nucleoside reverse transcriptase inhibitor
- so prevents synthesis of double-stranded viral DNA
- tenofovir - catB
- zidovudine, lamivudine - catC
Non-nucleoside reverse transcriptase inhibitor
- nevirapine, etravirine - catB
- efavirenz - catD
Protease inhibitor
- inhibits protease activity
- saquinavir, ritonavir - cat B
Integrase inhbitors - realtegravir - catC
Entry inhibitors - maraviroc - catB
HAART
HAART (highly active antiretroviral therapy) includes combination of at least 3 drugs belonging to at least 2 classes of antiretrovirals
SEs - lactic acidosis, hyperglycaemia, hepatitis, pancreatitis, peripheral neuropathy
Used in tx for HIV when:
- CD4 T-lymphocyte count is 200-350cells/mm3 in asymptomatic patients
- viral load > 10,000 HIV RNA copies/ml plasma
- severely symptomatic
Drugs to prevent HIV transmission from mother to fetus
HAART if not on antiretroviral therapy prior to pregnancy
- commence 20-28weeks, then discontinue after delivery
- zidovudine PO to neonate up to 6w of life, START (short term)
Alternatively, zidovudine monotherapy
- only antiretroviral drug specifically for use in pregnancy but NOT in 1stT
Women who conceive on HAART should continue through pregnancy
Antimalarial drugs
Chemo-prophylaxis
- not 100% effective
- causal or suppressive
- mefloquine or malarone safe in pregnancy
- doxycycline (teeth discolouration and bone growth disruption) and primaquine (fetal haemolysis) contraindicated
Mefloquine
FDA catC antimalarial, = Lariam
Recommended chemo-prophylaxis in pregnant women, can be used in 1stT
Also drug of choice in chloroquine-resistant falciparum malaria
Works to suppress RBC stage of malarial parasite
Metabolized in liver
Half life 2-4 weeks
Excreted by bile and faeces
Side effects - depression, insomnia, hallucinations, seizures
Oxytocin
FDA catA
Nanopeptide of 9 amino acids
Synthesized in supraoptic and paraventricular nucleus
Stored and released by the posterior pituitary gland
Non-neuronal sources of oxytocin - retina, thymus, adrenal medulla, pancreas, Leydig cells, corpus luteum, placenta
6 min half life
Excreted in bile and urine
Acts on G-protein receptors which require magnesium and cholesetrol
Destroyed in GI tract
Regulates circadian rhythm, uterine contraction, letdown reflex
Maternal oxytocin triggers transient inhibitory switch in GABA signalling from excitatory to inhibitory in fetal brain during delivery
Can give - intranasal, IM or IV
Side effects of oxytocin
CNS - SAH, seizures
CVS - tachycardia, HTN, increased CO, arrhythmia
GU - pelvic haematoma, uterine rupture
Biochemical - oliguria, natriuresis, hyponatraemia, water intoxication
Prostaglandins
20carbon lipid molecules (with 5 carbon ring) derived from fatty acids
Produced by all nucleated cells except lymphocytes
Act as local messengers, = paracrine hormones
Functions - many, including contraction and relaxation of smooth muscle
Obstetric - IOL, TOP, management of PPH
Prostaglandin E1 - eg misoprostol - for PPH and TOP
Prostaglandin E2 - eg dinoprostone - for IOL by ripening the cervix
Prostaglandin F2α - eg carboprost synthetic or dinoprost natural - for IOL, TOP, treatment of PPH
Misoprostol
FDA catX
Synthetic prostaglandin E1 analogue
40 min half-life
Prevention of NSAID-induced gastric ulcers
- inhibits secretion of gastric acid by parietal cell via G-protein coupled receptor mediated inhibition of adenylate cyclase (decreased intracellular cAMP)
- increases secretion of gastric mucus
- increases gastric mucosal blood flow
And for labour induction
SEs - uterine rupture, hyperstimulation, amniotic fluid embolism, diarrhoea, vomiting, headache
Dinoprostone
FDA catC
Prostaglandin E2 analogue for ripening of cervix
Transient pyrexia associated - within 15-45mins, return to usual temp 2-6hours after discontinuiation
Ergometrine
FDA catX
Chemically similar to LSD
Works on 5HT1, dopamine and α-adrenergic receptors
Functions - vasoconstrictor, constricts intracranial extracerebral vessels, uterine contraction, relieves migraine
SEs - ergotism (St Anthony’s fire, prolonged vasospasm -> gangrene, hallucinations, abortion), diarrhoea and vomiting
Contraindications - IOL, 1st/2nd stages of labour, vascular disease, severe cardiac disease, severe HTN
Tocolytics
4 types:
Oxytocin receptor antagonist (eg atosiban)
β2 agonists (salbutamol, terbutaline, ritodrine)
Calcium channel blockers (nifedipine)
NSAIDs (indometacin)
Atosiban
Tocolytic - oxytocin receptor antagonist
IV administration
Contraindications - PET, IUD, IU infection, APH, PROM after 30w
SEs - vomiting, tachycardia, hypotension, headache, hot flushes, hyperglycaemia, fever
β2-agonists
Tocolytic, FDA catB
Ritodrine - 2h half life, PO
Terbutaline - 6h half life, PO/INH/SC
Salbutamol - 2h half life, PO/INH/IV
SEs - fluid retention, increased myocardial workload, increased HR, gluconeogenesis of liver and muscle, glycogenolysis, hyperglycaemia, hypokalaemia, muscle cramps, headache
Nifedipine
Ca channel blocker tocolytic
No anti-arrhythmic activity
2h half life
Excretion via urine and bile
Unlicensed in pregnancy (catC)
SEs - hypotension, vasodilatation, tachycardia, dependent oedema, dyspnoea
CIs - cardiogenic shock, aortic stenosis, recent MI
Hydralazine
FDA cat C
Antihypertensive agent, as vasodilator of arterioles > venules
Antioxidant
Metabolized by acetylation
Fast acting
SEs - SLE, fluid retention, diarrhoea, headaches
Methyldopa
FDA cat D
Antihypertensive agent as α2 agonist, competitive inhibitor of DOPA decarboxylase (so less L-DOPA into dopamine)
Prodrug - active metabolite is α-methylnorephinephrine metabolized in liver
SEs
- CVS - rebound HTN, angina, postural hypotension
- GIT - dry mouth, hepatitis, pancreatitis
- neuro - Parkinsonism, Bell’s palsy
- bone marrow suppression - leukopenia, thrombocytopenia, haem anaemia
- increased prolactin - gynaecomastia, amenorrhoea
- psychological - depression, anxiety
Labetalol
FDA cat C
Mixed α1β blocker
8h half life
Only used in 3rdT
Associated with FGR and neonatal hypoglycaemia
Maxdose 2.4g/day
Calcium channel blockers
Antihypertensive in pregnancy
Non-dihydropyridine
- verapamil (C), diltiazem (D)
Dihydropyridine (vascular selective)
- nimodipine (C)
- nifedipine (C, preferential on cerebral arteries, used in vasospasm post SAH)
Antihypertensives to be avoided in pregnancy
ACEis (eg ramipril)
- cause CVS congenital malformations, impaired fetal renal function (oligohydramnios), skull defects
Thiazide diuretics
- neonatal thrombocytopenia if 3rdT
Statins (FDA cat X)
- CNS and limb defects
Antiepileptic drugs and teratogenicity
Epilepsy ↑ risk of teratogenicity regardless of medication
- background risk 2%
- if maternal epilepsy 4%
- if on medication 6-8%
Associated with NTDs, cleft palate, cardiac defects, urogenital defects, neonatal coagulopathies
Should be on 5mg folic acid
Vitamin K at birth
Carbamazepine
FDA cat D - safest antiepileptic in pregnancy
Fetal levels 50-80% of maternal serum levels
Also used in bipolar disorder and trigeminal neuralgia
Valproate
FDA cat D
Drug of choice for primary generalized epilepsy
Worst teratogenic profile amongst antiepileptic drugs
Fetal consequences - FGR, hyperbilirubinaemia, hepatotoxicity, transient hyperglycaemia, NTDs, cardiac anomalies, craniofacial defects, urogenital defects, limb defects
Phenytoin
FDA cat D
Lowers serum folate
Fetal consequences - fetal anticonvulsant syndrome, cleft palate, microcephaly, cardiac abnormalities, mental retardation
Not assoc with NTDs
Maternal side effects - nystagmus, paraesthesia, megaloblastic anaemia, TEN
Newer classes of antiepileptic drugs
Lamotrigine (catC)
- also used in bipolar disorder
- crosses placenta and is excreted in breast milk
- if on COCP as well then reduced AED effect
Topiramate (catC)
Levetiracetam (catB)
Gabapentin (catB)
Magnesium sulfate
CatB
Used in arrhythmias, asthma, eclampsia
SEs - CNS depression, resp depression
Antidote 10ml 10% calcium gluconate
Diazepam
CatD
Positive allosteric modulator of GABA
Used in status epilepticus, + insomnia, anxiety, restless leg, alcohol withdrawal
If taken in 3rdT - neonatal benzodiazepine withdrawal syndrome (hypotonia, reluctance to suckle, cyanosis, impaired metabolic response to cold), floppy infant syndrome
Antidote is flumazenil
Warfarin
FDA cat X
Synthetic derivative of coumarin
Interferes with vitamin K dependent clotting factors (2, 7, 9, 10)
Initial effects thrombogenic due to decrease in protein S and protein C, then anticoagulant
High protein binding
Antidote is FFP, vitamin K, prothrombin complex concentrate
2% teratogenic risk
Maternal SEs - skin necrosis, fat embolus, purpura fulminans
Warfarin embryopathy
- 5% of fetuses if warfarin at 6-12weeks
- dose dependent
- skeletal abnormalities, heart defects, short proximal limbs and phalanges
Unfractioned heparin
FDA cat C
One unit heparin = 0.002mg pure heparin
Naturally occurring anticoagulant in mast cells and basophils
Activates antithrombin III, causing inactivation of thrombin and factor Xa
SEs - heparin induced thrombocytopenia, osteoporosis, alopecia, hyperkalaemia
Antidote - protamine sulfate
Does NOT cross the placenta, NOT secreted in milk
LMWH
FDA cat B
Smaller risk of osteoporosis compared to unfractionated heparin
Monitor effects via anti-factor Xa activity, no need to monitor APTT coagulation parameter
Enoxaparin - 0.6mg/day prophylactic, 1mg/kg therapeutic
Dalteparin - 75units/kg prophylactic, 100units/kg therapeutic
Tinzaparin - 75units/kg prophylactic, 175units/kg therapeutic
Tissue plasminogen activator
t-PA, anticoagulant
Catalyses conversion of plasminogen to plasmin
(plasmin is fibrinolytic enzyme)
Encoded by PLAT gene on chromosome 8
Streptokinase is form of tPA
Recombinant t-PAs include alteplase, reteplase
Antidote is aminocaproic acid (antifibrinolytic)
Anticoagulants if heparin contraindicated
Danaparoid - inhibitor of activated factor X
Lepirudin - direct thrombin inhibitor
Fondaparinux - inhibitor of activated factor X
Gastro-oesophageal reflux drugs
H2 receptor blockers (catB)
- block action of histamine on parietal cells in stomach
- eg cimetidine (avoid, anti-androgen), ranitidine (safer)
PPIs
- irreversibly block H/K-ATPase of gastric parietal cell
- reduces gastric acid secretion by 99%
- omeprazole (C), lansoprazole/pantoprazole (B)
- risk anencephaly, and B12 deficiency in long-term use
Antacids
- to neutralize stomach acidity
- eg magnesium hydroxide, calcium carbonate (rennie), aluminium hydroxide (gaviscon, safest in pregnancy)
Antiemetics
Cyclizine (B) - H1 receptor antagonist, and central anticholinergic action
- SEs - dry mouth, drowsiness, antimuscarinic and extrapyramidal effects
Metoclopramide (B) - dopamine D2 receptor antagonists, 5-HT3 receptor antagonist, 5-HT4 agonist, gastroprokinetic agent
- SEs - extrapyramidal effects, hyperprolactinaemia, agranulocytosis, SVT, neuroleptic malignant syndrome, tardive dyskinesia, oculogyric crisis
- NOT licensed in <20yo
Promethazine is histamine H1 antagonist
Ondansetron (B) - 5-HT3 receptor antagonist
- SEs constipation
Prochlorperazine (C) - potent typical antipsychotic
- SEs tardive dyskinesia, seizures, neuroleptic malignant syndrome
Laxatives
Bulking agents
- bran, methylcellulose, fybogel
Stool softeners
- docusate
Osmotic agents
- lactulose (catB), sorbitol, glycerine, sodium phosphate
Stimulants
- senna (catC), bisacodyl, microlax enema, castor oil
Loperamide
FDA cat B
Antidiarrhoeal
μ-opioid agonist, but only acts on receptors in large intestine
Does not cross BBB hence no opioid effects on CNS
NSAIDs
Mostly catD
Non-selective inhibitor of COX-1 and COX-2
Also antipyretic
Acetic acid derivatives - indometacin, diclofenac, ketorolac
Enolic acid derivatives - piroxicam, meloxicam
Fenamic acid derivatives - mefenamic acid, flufenamic acid
Propioninc acid derivatives - ibuprofen, naproxen
Selective COX-2 inhibitors - celecoxib, rofecoxib
Indometacin
FDA cat C
NSAID
Inhibits synthesis of prostaglandin by inhibiting COX1 and COX2 enzymes
Used to treat PDA postnatally
Side effects if given antenatally - premature closure of ductus arteriosus, NEC, neonatal pulmonary HTM, neonatal renal damage
Aspirin
FDA catD
aka acetylsalicylic acid
Antipyretic, anti-inflammatory, antiplatelet (irreversibly inhibits synthesis of thromboxane A2)
SEs - gastritis, Reye’s syndrome (under age 12), metabolic acidosis in overdose, neonatal haemorrhage if within 5d of delivery (so stopped at 36w gestation), miscarriage under 12w (but low dose is used in treatment of recurrent miscarriage?)
Steroids
FDA C
Antenatal corticosteroid treatment in preterm deliveries is associated with reduction in rates of RDS, IV haemorrhage, neonatal death
SEs - hyperglycaemia, leukocytosis, Cushing’s, peptic ulcers, osteoporosis, psychiatric disturbance
Betamethasone 12 mg IM x 2 doses or dexamethasone 6 mg IM x 4 doses are the steroids of choice to enhance lung maturation
Hydrocortisone used to prevent adrenal crisis in patients who are taking prednisolone >7.5mg/day for >2 weeks, if undergoing surgical procedures, starvation, labour
5-aminosalicylic acid
FDA cat B
Mesalazine, sulfasalazine
For treatment of ulcerative colitis, crohn’s
SEs - agranulocytosis, hypospermia
Chemo-therapeutic agents
Alkylating agents, cat D
- cisplatin, carboplatin, cyclophosphamide, chlorambucil
Antimetabolites (interfere with DNA production during S phase of cell cycle)
- azathioprine (purine analogue), 5-fluorouracil (pyramidine analogue), methotrexate (antifolate)
Alkaloids (block cell division by preventing microtubule function)
- vincristine, vinblastine
Topoisomerase inhibitors
- topotecan
Antineoplastic
- doxorubicin
Azathioprine
Cat D
Purine analogue, interferes with purine synthesis
Prodrug, active metabolite is 6-mercaptopurine and 6-thioionosinic acid, metabolized by xanthine oxidase
SEs - bone marrow suppression, carcinogenic
Mycophenolate mofetil
Cat C
Interferes with purine synthesis by inhibition of inosine monophosphate dehydrogenase
Prodrug - active metabolite is mycophenolic acid
Less toxic than azathioprine
Methotrexate side effects
FDA cat X
Bone marrow suppression - anaemia, leukopenia, thrombocytopenia
GIT - hepatitis, pancreatitis, pharyngitis, gingivitis, stomatitis
Cardioresp - pericarditis, pericardial effusion, pulmonary fibrosis
Thrombosis - DVT, retinal vein thrombosis, central thrombosis
Carbimazole
Prodrug, active form is methimazole
Prevents thyroid peroxidase enzyme from coupling and iodinating tyrosine residues on thyroglobulin
Reduces production of T3 and T4
SEs - agranulocytosis (bone marrow suppression)
Fetal risk - cat D
Propylthiouracil
Inhibits thyroperoxidase enzyme
Inhibits peripheral conversion of T4 to T3 by inhibiting tetraiodothyronine 5 deiodinase enzyme
SEs - agranulocytosis
Fetal risk - cat D (preferred over carbimazole as lower placental transfer and excretion in breast milk)
Metformin
Biguanide agent
Suppresses hepatic gluconeogenesis (AMP-activated kinase)
Increases insulin sensitivity
Enhances peripheral glucose uptake
Increases fatty acid oxidation
Not metabolized and excreted unchanged in the urine
Reduces overall mortality by 30% when compared to insulin
Reduces LDL cholesterol and triglycerides
SEs - hypoglycaemia, lactic acidosis, GI upset
Fetal risk - catB
Glibenclamide
Sulfonylurea class drug
Stimulates insulin release by inhibiting ATP-sensitive K channels in pancreatic β cells
Metabolized by liver
SEs - hypoglycaemia, cholestasis
Cat B
Rosiglitazone
Thiazolidinedione agent
Decreases insulin resistance and leptin levels by binding to peroxisome proliferator-activated receptors in fat cell nucleus
SEs - MI risk, stroke, bone fractures, macular oedema, hepatotoxic
Cat C
Repaglinide
Meglitinide agent
Stimulates insulin release by inhibiting ATP-sensitive K channels in pancreatic β cells
SEs - hypoglycaemia, weight gain
Cat C
Acarbose
Reduces rate of digestion of complex carbohydrates by inhibiting α-glucosidase enzyme in small intestines
Inhibits pancreatic amylase
Metabolized in GIT
SEs - flatulence, diarrhoea
Cat B
Vildagliptin
Dipeptidyl peptidase-4 inhibitor
SE - pancreatitis
Cat B
Exenatide
Incretin
Glucagon-like peptide agonist
Increases pancreatic insulin secretion
Suppresses pancreatic release of glucagon
SEs - pancreatitis, ?increase thyroid ca risk
Cat C
Mifepristone
FDA cat X
Competitive progesteronic receptor antagonist
Half life around 20hours
Causes cervical softening and dilatation, decidual degeneration, release of endogenous prostaglandins, increased sensitivity of myometrium to prostaglandins
Anti-glucocorticoid and anti-androgen
Used for emergency contraception (delays ovulation and prevents implantation), and MTOP (up to 9weeks, 600mg)
Contraindicated in severe asthma, chronic adrenal failure, ectopic pregnancy, acute porphyria, hepatic impairment, renal impairment
Cyproterone acetate
FDA cat X
Anti-androgen - suppresses action of testosterone and DHT on tissues, suppresses LH
Used in BPH, prostate ca, priapism, hirsuitism
Weak progestogenic activity (for hot flushes)
Suppresses synthesis of cortisol, aldosterone, oestrogen
SEs - hepatotoxicity, low cortisol, low aldosterone (so hypoNa hyperK), gynaecomastia, galactorrhoea, osteoporosis, thrombosis (if with oestrogen)
Tibolone
aka Livial
Selective tissue oestrogenic activity regulator
Used as HRT, osteoporotic prevention
Oestrogenic, progestogenic, androgenic properties
Functions - relives climacteric symptoms, prevents osteoporosis, no endometrial stimulation, non-oestrogenic effects on breast tissue
Selective oestrogen receptor modulators
SERMs
- raloxifene, tamoxifen, clomifene
Have both oestrogen and anti-oestrogen activity
Excreted via faeces
Used for prevention of osteoporosis, decreasing risk of breast ca
SEs - thrombosis, endometrial ca, hot flushes
Danazol
Derived from synthetic ethisterone (modified testosterone)
Weak androgenic activity
Gonadotrophic antagonist
Acts on pituitary gland and inhibits LH and FSH causing inhibition of ovarian steroidogenesis, resulting in decreased secretion of oestradiol
Does not affect pituitary hormones
Used to treat endometriosis, uterine fibroids, menorrhagia
Does not cause osteoporosis
Can masculinize a female fetus
SEs - fluid retention, weight gain, masculinisation
Buserelin
GnRH agonist
Acts on pituitary gland and inhibits LH and FSH causing inhibition of ovarian steroidogenesis, resulting in decreased secretion of oestradiol
Used to treat prostate and breast ca, endometriosis, uterine fibroids
Maximum duration of treatment is 6 months
SEs - menopausal symptoms, osteoporosis
Combined oral contraceptive pill
Mechanism - inhibits ovulation (suppresses LH and FSH) and increases viscosity of cervical mucus}
Contraindications - pregnancy, post partum (<6w breastfeeding, <3w non-breastfeeding), smoking >15/day above the age of 35, BMI >35, arterial disease, HTN (160/95), valvular heart disease with pulm HTN or subacute bacterial endocarditis, VTE, migraine with aura, breast ca, cirrhosis, Raynaud’s, SLE
Can be used in cervical, endometrial, ovarian ca
First generation high dose oestrogen 50μg
Second generation 30-35μg eg microgynon
- both with levonorgestrel or norethisterone
Third generation with new forms progesterone (desogestrel)
- increase risk VTE
- reduce risk acne, headache, weight gain, breast symptoms, breakthrough bleeding
Missed pill rule COCP
If <3 pills (or 2 if taking low oestrogen content pill)
- take missed pill, no need for extra precaution
If >3pills missed (2 if taking low oestrogen content COCP)
- take missed pill, extra precaution for 7 days
- if in 3rd week then omit pill-free interval
- if in 1st week use emergency contraception
VTE and cancers risk on COCP
Background risk 5 / 100,000
On 2nd generation COCP 15 / 100,000
On 3rd generation COCP 25 / 100,000
In pregnancy 60 in 100,000
Decreased risk ovarian cancer (50% if use >10yr) and endometrial cancer (50%, benefits lasting 20yr after discontinuing
Increased risk breast ca (risk back to normal after 10yrs stopped) and cervical cancer
Progesterone only contraception
Inhibits ovulation
- low-dose progesterones inconsistently inhibits ovulation in 50% of cycles
- intermediate dose (cerazette) inhibit in 97-99% of cycles
- high dose (Depo-provera) completely inhibit ovulation and follicular development
And increases viscosity of cervical mucus
Side effects - irregular bleeding, weight gain, breast discomfort, acne, depression
Amenorrhoea in 20% POP, regular bleeding 40%, erratic bleeding 40%
Can be used within 3w PP without any extra precautions
Contraindications - pregnancy, undiagnosed PV bleeding, liver tumour, acute porphyria, breast ca in last 5yrs
Missed pill rule in POP
Short time frame (3hr) for all except cerazette (12h)
After missed pill take missed/late pill, use extra precautions for 48hours
Parental progesterone-only contraception
Depo-Provera = medroxyprogesterone acetate IM
Norethisterone enantate IM infection
Implanon = etonogestrel-releasing implant effective up to 3y
Reliable inhibition of ovulation
Depo-Provera
IM, lasts 12-14weeks
Give 5days PP in non-breastfeeding women (higher risk of menorrhagia sooner)
SEs - weight gain in 70%, osteoporosis (avoid for more than 2yr), delayed return to fertility by 6-18mo
Often get irregular bleeding, but amenorrhoea in 60% by 12months
Decreases serum oestrogen level due to complete inhibition effect on ovulation
Assoc with reduction in bone density within first 2y use
Reduces risk of endometrial ca by 80%
Implanon
Etonogestrel 68mg
Lasts 3yr
Serum levels of progesterone reach ovultaion-inhibiting levels by 24hr from insertion
90% start to ovulate within 3w removal
Bleeding patterns - amenorrhoea in 20%, prolonged bleeding in 20%, infrequent bleeding in 5%
Insertion of coils
Can be immediate after 1st or 2ndT TOP
From 4w PP
At any time in menstrual cycle
Extra precuation not needed for copper coil at all, or for mirena if inserted on day1 of cycle
Risk of expulsion 5%, common in first year
Risk of uterine perforation 0.1%
Risk of pelvic infection greatest in first 20days
Copper coil IUD
Copper is toxic to ovum and sperm, inhibits fertilisation and implantation
Irregular or heavy bleeding common in first 3-6months
Licensed for 7-10years
Mirena IUS
Compartment gradually releases levonorgestrel
Mediated via progestogenic effect on endometrium, so endometrial atrophy, increase in phagocytic cells, increase cervical mucus viscosity, 75% continue to ovulate
Licensed for 5 years for HMB, 8 years for contraception
Irregular bleeding common in first 6 months, then 65% amenorrhoea at 12months
Emergency contraception
Levonorgestrel 1500μg
- within 72hr UPSI
- 95% effective in first 24hr
- inhibits ovulation for 5-7days if taken prior to ovulation
- double dose if taking enzyme inducers
- SEs - nausea, bleeding
EllaOne = ulipristal acetate 30mg
- selective progesterone receptor modulator
- up to 120hours after UPSI
- inhibits ovulation, suppresses growth of follicles, delays endometrial maturation
Copper IUD
- within 5days UPSI or 5days ovulation
