Drug Summary
Cancer Pharmacology
Alkylating Agents – add an alkyl group to DNA preventing transcription and replication.
Eg Nitrogen mustards SE: N&V, bone marrow depression, haemorrhagic cystitis
Folic Acid Analogues – impairs the conversion of dihydrofolate to tetrahydrofolate thus inhibiting
DNA replication. Eg Methotrexate SE: Bone marrow depression, damage to epithelium
of GIT, pneumonitis, nephrotoxicity
Pyrimidine Analogues – are structurally analogous to pyrimidine nucleotides and can be incorporated
into the DNA and prevent elongation of the new strand. Eg 5-fluorouracil SE: GIT
epithelial damage, myelotoxicity, cerebellar disturbances
Purine Analogues – inhibit purine synthesis, decreasing DNA replication and new strand formation
Eg Mercaptopurine SE: myelosuppressive,
Anti-mitotic Agents – bind to tubulin of the mitotic spindle microtubules causing cell arrest in
metaphase. Eg Vincristine SE: paraesthesias (sensory changes), neuromuscular
abnormalities, myelotoxicity
Antibiotics – either create free radical species or causing breaks in the DNA strands
Eg Doxorubicin SE: cardiac damage, dysrhythmias, HF, hair loss
Hormone Receptor Antagonists – blocks receptors on tumours removing the stimulus for growth, antioestrogenic action on mammary tissue and oestrogenic effects on plasma lipids,
endometrium and bone Eg Tamoxifen SE: breast tenderness, N&V, anorexia, retention
of salt and water with oedema and increased thromboembolism
Hypertension Pharmacology
α-Blockers – bind α-adrenoceptors in vessels preventing nor-adrenalin mediated vasoconstriction and
decreasing blood pressure. Eg Prazosin, doxazosin SE: postural hypotension, flushing,
tachycardia, nasal congestion, impotence
ACE Inhibitors – inhibit ACE in the lungs causing less angiotensin II mediated vasoconstriction but
more bradykinin due to decreased breakdown. Eg Enalapril, captopril SE: hypotension,
dry cough, rash CI: RAS à RF
Angiotensin II receptor Antagonists – block angiotensin II at its receptors causing decreased
vasoconstriction, hypertrophy and fibrosis. Eg Candersartan, losartan SE: not many
β-blockers – Selective blockers for b1 adrenoreceptors cause negative inotropy (contractility) and
chronotropy (rate), non- selective blockers for b2 cause asthma bronchoconstriction Eg
Metoprolol (B1 selective) SE: fatigue, cold peripheries, bronchoconstriction, cardiac
failure, depression, hypoglycaemia
Ca channel entry blockers – block entry of calcium into cells causing decreased SM contraction and
decreased conduction through SA and AV nodes. Eg Nifedipine, Verapamil SE:
headaches, constipation, heart block, cardiac failure
Centrally acting drugs – α2 agonist that acts in the brain to decrease sympathetic outflow and vascular
constriction. Eg α-methyldopa, clonidine SE: drowsiness, orthostatic hypotension,
oedema and wt gain, rebound hypertension
Diuretics – increase Na+ excretion and water that follows but cause cause hyperglycaemia due to K
loss. Eg Thiazide diuretics SE: urinary freq, gout, glucose intolerance, hypokalaemia,
hyponatraemia, thrombocytopenia
Endothelin Antagonists – blocks Endothelin which has similar effects to Angiotensin II
(vasoconstriction, hypertrophy, fibrosis). Eg Bosentan
Renal Pharmacology
Osmotic Diuretics – are filtered at the glomerulus but are not able to be reabsorbed. This causes an
osmotic gradient into the tubule lumen. Eg Mannitol SE: headache, N&V, transient
expansion of extracellular fluid, hyponatraemia
Carbonic Anhydrase Inhibitors – Inhibits brush border carbonic anhydrase and prevents reabsorption
of NaHCO3 and therefore water. Eg Acetazolamide
Loop Diuretics – inhibit the Na+K+2Cl- symport in the thick ascending loop of Henle thus preventing
Na+ absorption and resulting in a swap of Na+ for K+ in the DCT. Eg Frusemide SE:
hypokalaemia, metabolic alkalosis, hypovolaemia
Thiazide Diuretics – inhibit the Na+ and Cl- co-transporter in the distal convoluted tubule thus
preventing Na+ and water absorption. Eg Chlorothiazide SE: hypokalaemia, metabolic
alkalosis
+
K Sparing Diuretics – inhibits the apical membrane Na+ channel in the collecting ducts that works
with Na+/K+ ATPase to absorb Na+ and secrete K+. Eg Amiloride SE: hyperkalaemia,
metabolic acidosis, skin rash
Aldosterone Antagonists – inhibits the binding of aldosterone to mineralocorticoid receptors in the
collecting ducts thus preventing Na+ and water reabsorption. Eg Spironolactone SE: GI
upsets, hyperkalaemia, metabolic acidosis, gynaecomastia, menstrual disorders, testicular
atrophy
Asthma Pharmacology
1. Bronchodilators – “relievers” cause relaxation of contracted bronchial smooth muscle
a) β2-adrenoceptor agonists Eg Salbutamol (short acting), Salmeterol (long acting)
b) Anti-muscarinic drugs
Eg Ipratropium
c) Xanthines
Eg Theophylline
2. Glucocorticoids – "preventers" reduce underlying airway inflammation
a) Anti-inflammatory glucocorticoids
Eg Beclomethasone (inhaled)
Eg Prednisolone (oral)
Eg Hydrocortisone (IV)
b) "Anti-allergic drugs"
Eg Sodium cromoglycate
c) Leukotriene receptor antagonists Eg Montelukast
Heart failure pharmacology – always use a β-blocker, ACE inhibitor and a diuretic
Drugs that Increase Force of Contraction - Inotrope
1. Digoxin – cardiac glycoside positive inotrope that inhibits the action of Na+/K+-ATPase and
therefore increases intracellular calcium SE: N&V, cardiac arrhythmias, confusion
2. Dobutamine – β1-adrenoceptor agonist positive inotrope that increases cAMP levels and
intracellular Ca2+ SE: dysrhythmias
3. Phosphodiesterase Inhibitors – inhibit phosphodiesterase thus decreasing breakdown of
cAMP and therefore increasing intracellular Ca2+
4. Levo-Simendan – calcium sensitiser that increases cross bridge interactions therefore
increasing force of contraction.
Drugs that Decrease Afterload
1. α-Blockers – bind α-adrenoceptors in vessels preventing nor-adrenalin mediated
vasoconstriction and decreasing blood pressure. Eg Prazosin SE: hypotension, flushing,
tachycardia, nasal congestion, impotence
2. ACE Inhibitors – inhibit ACE in the lungs causing less angiotensin II mediated
vasoconstriction but more bradykinin due to decreased breakdown. Eg Enalapril
3. Angiotensin II receptor Antagonists – block angiotensin II at its receptors causing decreased
vasoconstriction, hypertrophy and fibrosis. Eg Candersartan
4. Ca channel entry blockers – block entry of Ca2+ into cells causing decreased SM contraction
and decreased conduction through SA and AV nodes. Eg Nifedipine, Verapamil
5. Endothelin Antagonists – blocks Endothelin which has similar effects to Angiotensin II
(vasoconstriction, hypertrophy, fibrosis). Eg Bosentan
Drugs that are Diuretics
1. Loop Diuretics – inhibit Na+K+2Cl- symport in thick ascending loop of Henle thus preventing
Na+ absorption and resulting in a swap of Na+ for K+ in the DCT. Eg Frusemide
2. Thiazide Diuretics – inhibit the Na+ and Cl- co-transporter in the distal convoluted tubule thus
preventing Na+ and water absorption. Eg Chlorothiazide
Others
1. β-blockers – Selective blockers for b1 adrenoreceptors cause -ve inotropy and chronotropy,
non-selective blockers for b2 cause asthma bronchoconstriction. Eg Metoprolol (selec)
2. Aldosterone Antagonists – inhibits the binding of aldosterone to mineralocorticoid receptors in
the collecting ducts thus preventing Na+ and water reabsorption. Eg Spironolactone
3. TNF-α Antagonists – reduces the inflammatory aspect of heart failure. Eg Etanercept
4. A and B Naturietic Peptides – secreted by the atria in response to pressure and increase the
excretion of sodium into the urine. Eg Nesiritide B
5. NEP inhibitor – dual inhibitor of ACE and Neutral endopeptidase (NEP) which breaks down
natriuetic peptides thus increases concentrations of ANP and BNP. Eg Omapatralate
New compounds
1. Growth hormone
2. Vitamins – reduce oxidative stress in heart and vessels.
3. PARP inhibitors – nuclear enzyme that repairs single strand DNA breaks using ATP
4. Stem cells – repair cells damaged by MI
5. Anti-inflammatories – suppress the immune system
Antiarrhythmic Drugs (Vaughan Williams Classification)
Class I – Na+ channel blockers, prevent rapid influx of Na+ therefore decrease nerve conduction with
use-dependent block. Eg Quinidine Ia (SE: blurred vision, dry mouth, constipation and urinary
retention in men), Lignocaine Ib (SE: drowsiness, disorientation, convulsions), Flecainide Ic
(SE: can increase sudden death assoc with VF in MI pts)
Class II – B-blockers, selective blockers for b1 adrenoreceptors cause negative inotropy and
chronotropy, non-selective blockers for b2 cause bronchoconstriction. Eg Metoprolol (select)
Class III – K+ channel blockers, that prolongs the cardiac action potential by inhibiting repolarisation,
therefore prolonging the refractory period. Eg Amiodarone (SE: photosensitive skin rashes,
blue skin, hypo and hyper thyroid, pulm fibrosis, corneal deposits, neurological and GIT
disturbances) , L-Sotalol (SE: Torsades de pointes and beta blocker SE CI: asthmatics)
Class IV – Ca2+ channel antagonists, block entry of Ca2+ into cells causing decreased SM contraction
(vasodilation) & decreased conduction through SA and AV nodes. Eg Nifedipine, Verapamil
Class V – Others
Adenosine – opens K+ channels leading to hyperpolarisation and slowing the rate of
rise of the pacemaker potential and inhibiting ectopic foci
Digoxin – stimulates vagal activity causing AcH release which slows conduction through the
AV node and decreases fibrillation
AMI pharmacology
Streptokinase – antigenic protein extract from β-haemolytic Streptococci that indirectly activates
plasminogen to plasmin for clot lysis SE: bleeding, GI haemorrhage, stroke, allergic reactions,
hypotension CI: internal bleeding, haemorrhagic CVA, bleeding diatheses, pregnancy, HT,
surgery
Tissue Plasminogen Activator (tPA) – endogenous activator of plasminogen to plasmin for clot lysis
and is not antigenic SE: bleeding, stroke CI: as above
Heparin – binds via a pentasaccharide unit to antithrombin III which inhibits thrombin and factor Xa
from converting fibrinogen to fibrin in the intrinsic clotting pathway SE: haemorrhage,
thrombosis, thrombocytopenia, osteoporosis, hypoaldosteronism
Warfarin – inhibits conversion of the inactive epoxide form of vitamin K to the active reduced form
of the vitamin thus producing incomplete factors II, VII, IX X for the extrinsic clotting pathway
SE: haemorrhage, hepatotoxicity. Potentiate warfarin effects: liver disease; agents which inhibit
hepatic drug metabolism eg cimetidine, metronidazole, amiodarone; drugs that inhibit platelet
function eg NSAIDs; drugs that replace warfarin eg NSAIDs, chloral hydrate; drugs that inhibit
reduction of vit K eg cephalosporins and drugs that decrease availability of vit K eg antibiotics
and sulphonamides. Agents that lessen effects: pregnancy, hypothyroidism, drugs that induce
hepatic p450 enzymes eg rifampicin, carbomazepine, barbiturates and drugs that reduce
absorption eg cholestyramine
Aspirin – irreversibly inactivates cyclo-­‐oxygenase enzyme production of thromboxane A2 (promotes platelet aggregation) thus decreasing the risk of myocardial infarction SE: GIT bleeding, salicylism (tinnitus, vertigo, decreased hearing and N&V), skin rash, worsen asthma, Reye’s syndrome in children (liver disorder and encephalopathy), hyperventilation, hyperpyrexia CI: worsens warfarin, interacts with probenecid and sulphinpyrazone so should not be used in gout Glyceryl Trinitrate (GTN) – forms NO which activates guanylyl cyclase to increase conversion of
GTP to cGMP which causes relaxation of smooth muscle and vasodilation SE: postural
hypotension, headache, tolerance
Ischaemic heart disease pharmacology – use either a β-blocker, Ca2+ channel blocker or GTN
Glyceryl Trinitrate (GTN) – vasodilator of peripheral veins, which decreases preload by pooling of blood and decreased venous return therefore decreasing the oxygen demand of the myocardium
β-­‐adrenoceptor antagonists – negative inotrope which slows HR and increases period of diastole during which coronary arteries are open and blood flow to left ventricular tissue increases Eg Propranolol SE: bronchoconstriction, cardiac failure, cold extremities, fatigue, depression Calcium channel blockers – block entry of Ca2+ into cells causing decreased SM contraction
(vasodilation) & decreased conduction through SA and AV nodes. Eg Nifedipine, Verapamil
Drug treatment of blood cholesterol Statins – inhibit HMG CoA reductase mediated intracellular cholesterol synthesis, causing increased hepatocyte LDL receptor expression and cholesterol uptake from the blood. Eg Simvastatin SE: GIT disturbance, insomnia and rash, rare: myositis, hepatitis, angio-­‐
oedema Colestipol and cholestyramine – bind bile acids within the intestine, which stimulates increased production of bile acids from cholesterol in the liver. SE: nausea, abdo bloating, constipation, diarrhoea Fibric acid derivatives – decrease production and increase clearance of VLDL-­‐triglycerides Eg Gemfibrozil and bezafibrate SE: myositis (rhabdomyolitis), myoglobinuria, ARF Nicotinic acid – decreases hepatic lipoprotein synthesis SE: flushing, palpitiations, GIT disturbances Fish oils – decreases production of VLDL-­‐triglycerides and substitutes for arachidonic acid in cell membranes forming thromboxane A3 (causes less platelet aggregation than A2) Benzodiazepine pharmacology: anxiolytic and hypnotic agents
Gamma-aminobutyric acid (GABA) is an inhibitory neurotransmitter in the CNS which binds to
neuron GABA receptors causing increased Cl- influx and thus neuron hyperpolarisation and inhibition
Temazepam – insomnia, anxiolytic, hypnotic, short acting
Diazepam – anti-Anxiety, muscle relaxant, iv as anticonvulsant, long acting
Midazolam – anaesthetic premedication, short acting
Chlonazepam – anti-convulsant, anxiolytic (esp mania), long acting
SE: In acute OD: prolonged sleep, serious CVS and resp depression; Therapeutic effects: drowsiness,
confusion, amnesia, impaired coordination; Tolerance and Dependence: withdrawal causes anxiety,
tremor, dizziness, loss of appetite, insomnia
Antidepressant pharmacology: Affective disorders: depression and mania
Selective Serotonin Reuptake Inhibitors/SSRI’s – inhibits reuptake transport of 5-HT by the serotonin
transporter (SERT) thus increasing levels in the synapse without major effects on transport of
NA by the noradrenaline transporter (NET). Eg Sertraline Used for depression, anxiety
disorders, panic attacks and OCD. SE: nausea, anorexia, insomnia, loss of libido, failure of
orgasm, serotonin syndrome: tremor, hyperthermia, CVS collapse
Tricyclic Antidepressants – inhibits reuptake transport of 5-HT by the SERT and NA by the NET into
noradrenergic nerves thus increasing levels in the synapse. Eg Amitriptyline Used for
depression, antipsychotic. SE: sedation (H1 block), postural hypotension (α adrenoceptor
block), dry mouth, blurred vision, constipation (muscarinic block), mania and convulsions. OD:
confusion and mania and cardiac dysrhythmias
Monoamine Oxidase Inhibitors/MAOIs – irreversibly inhibits MAO which normally metabolises NA
and 5-HT thus increasing levels in the synapse. Eg Moclobemide. Used for depression. SE:
postural hypotension, atropine like effects, wt gain, CNS stimulation causing restlessness,
insomnia, liver damage. OD: CNS stimulation, convulsions CI: tyramine containing foods
(cheese reaction), TCA, SSRI’s, pethidine
Serotonin and noradrenaline reuptake inhibitors/SNaRIs. Eg Venlafaxine
Noradrenaline reuptake inhibitors/NRIs. Eg Reboxetine
Complementary medicines – active ingredient hyperforin inhibits both NET and SERT. Eg St Johns Wort
Lithium – Interferes with IP3 formation and blocks effects of receptor mediators and reduced cAMP
formation. Used for the mania part of bipolar and also for depression, mainly used as a prophalactic in
bipolar. SE: nausea, thirst, polyuria, hypothyroidism, tremor, weakness, mental confusion,
teratogenesis. OD: confusion, convulsions and cardiac dysrhythmia. Action enhanced by diuretics.
Alternative mood stabilizing drugs include carbamazepine and valproate.
Antipsychotic Drugs: Used for schizophrenia, affective disorders, organic psychoses
Schizophrenia: Positive sx: delusions (usually paranoid), hallucinations (voices, exhortatory), thought
disorder (wild trains, inserted thoughts or withdrawn by outside agency); Negative sx: withdrawal from
social contacts, flattening of emotional responses.
All anti-psychotic drugs are antagonists at dopamine D2-R but most also block other monoamine R esp
5-HT2 increasing midbrain dopaminergic neurons in substantia nigra and ventral tegmentum resulting in
the anti-psychotic effects. Also anti-emetic activity and anti-histamine effects important. Take several
weeks to take effect. Eg chlorpromazine, haloperidol, clozapine. SE: 2 main kinds of motor
disturbance called extra pyramidal effects: acute dystonias (involuntary movements (muscle spasms,
protruding tongue), Parkinson type syndrome (resting tremor, muscle rigidity, bradykinesia, shuffling
gait)) and tardive dyskinesia: disabling involuntary movements of face and tongue, trunk and limbs and
also endocrine effects due to increased prolactin from blocking D2R: breast swelling, pain and lactation
and other effects include sedation (anti-histamine effect, H1R), blurred vision, increased intraocular
pressure, dry mouth and eyes, constipation and urinary retention (from blocking muscarininc R),
orthostatic hypotension (blocking α adrenoceptors), wt gain (5-HT antagonism), jaundice, leukopenia,
agranulocytosis, urticarial skin eruption, neuroleptic malignant syndrome.
Schizophrenia drugs – block dopamine in the substantia nigra
Typical antipsychotic drugs – control positive symptoms of psychosis (Block D2 – more side
effects)
•
Phenothiazines: e.g. Chlorpromazine
•
Thioxanthines: e.g. Flupenthixol
•
Butyrophenones: e.g. Haloperidol
Aypical antipsychotic drugs – control negative symptoms of psychosis (Block D1 – behaviour
effects)
•
Risperidone, Clozapine
Opioid Pharmacology – all agonists and antagonists with morphine like activity
Types of opioids
1. Endorphin – endogenous opioid peptides (enkephalins, dynorphins and endorphins)
2. Morphine – phenanthrene derivatives. SE: sedation, resp depression, constipation, N&V,
ithching, euphoria and tolerance and dependence.
Agonists such as morphine, heroin, and codeine
Antagonists such as naloxone and naltrexone
Mixed compounds such as buprenorphine
3. Synthetic – produced compounds (pethidine, fentanyl and methadone)
Types of opioid receptors
1. µ-receptors – analgesic effects and major side effects, centrally acting (bendorphin agonist)
2. δ- receptors – analgesia, peripherally acting (enkephalin agonist)
3. κ- receptors – sedative and dysphoric effects, spinal (dynorphin agonist)
Mechanism of inhibitory effect
1. Suppression of adenylate cyclase, causing a decrease in intracellular cAMP
2. Open K+ channels causing hyperpolarisation and decreased neuronal excitability and
closing Ca2+ channels causing decreased neurotransmitter release
Pethidine – causes restlessness instead of sedation, more antimuscarinic action SE: as morphine,
anticholinergic effects, excitement and convulsion
Fentanyl – is a very potent pethidine analogue, with a shorter duration of action. SE: as morphine
Methadone – another pethidine analogue, with long duration of action. SE: as morphine but little
euphoric effects
Heroin – is diacetylmorphine. More lipid soluble so penetrates BBB more rapidly. SE: as morphine
Codeine – analgesic effect is due to partial conversion to morphine. SE: constipation
Naloxone and Naltrexone – both are antagonists at the three major opioid receptors.
Buprenorphine – is a partial agonist at µ-receptors with a long duration of action. SE: as morphine but
less resp depression not reversed by naloxone
NSAIDs Pharmacology
3 actions due to inhibition of COX conversion of AA to prostaglandin and thromboxane
1. Anti-inflammatory effect – decreased prostaglandins lessens vasodilatation and oedema
2. Analgesic effect – decreased prostaglandins lessens sensitivity of nerve endings to bradykinin
3. Antipyretic effect – decreased prostaglandins lessens hypothalamic set-point for temp control
Salicylates – all effects. Eg Aspirin
Paracetamol – no anti-inflammatory effects. Eg Panadol SE: rare, allergic skin reactions. OD:
hepatotoxicity, renal toxicity, N&V initially
Selective COX-2 inhibitors – no cardioprotectant effects. Eg Celecoxib
Gastro-oesophageal reflux pharmacology
Drugs that inhibit gastric acid secretion:
•
H2 receptor antagonists – blocks H2 receptor on parietal cell base to decrease gastric acid
secretion. Eg Ranitidine, cimetidine SE: rare, diarrhoea, dizziness, muscle pains,
rashes, hypergastrinaemia. Cimetidine decreases sexual function and causes
gynaecomastia and reduce renal tubular secretion and potentiate action of oral
anticoagulants, phenytoin, carbamazepine, quinidine, TCA and theophylline.
•
Proton pump inhibitors – inactivates proton pump on parietal cell apex to decrease gastric
acid secretion. Eg Omeprazole SE: uncommon, headache, diarrhoea, rashes, dizziness,
mental confusion, impotence, gynaecomastia
Prokinetic drugs to increase gastric emptying and improve oesophageal sphincter function:
•
Domperidone – dopamine antagonist, antinauseant, antiemetic, used in gastroparesis
•
Metoclopramide – dopamine antagonist, antinauseant, antiemetic, used in GORD (maxalon)
•
Cisapride – releases ACh at myenteric plexus which causes oesophageal peristalsis, gastric
emptying and intestinal motility
Agents to protect the oesophageal mucosa:
•
Sucralfate – HSO4 aluminium complex that provides protective coat to allow ulcer healing
•
Prostaglandin analogues – increases secretion of mucous in the stomach, and stimulates
bicarbonate secretion in the duodenum. Eg Misoprostol
Others
•
Anti-muscarinics – blocks action of AcH and decreases motility. Eg Atropine/Belladonna
•
Antispasmodics – relax smooth muscle and decreases motility. Eg Peppermint oil
•
Antidepressants – help symptoms of IBS. Eg SSRI's
Antibiotic drugs
Inhibition of cell membrane synthesis – Amphotericin B
Fungi
Inhibition of cell wall synthesis –
Gram +ve cocci (S. aureus)
Penicillin (Ampicillin)
Cephalosporin (Cephalexin) Gram –ve bacilli (E.coli)
Inhibition of protein synthesis – Aminoglycosides (Gentamycin) Aerobic gram –ve bacilli (P.aerugin)
Macrolides (Erythromycin)
Gram +ve cocci (for penicil resist)
Chloramphenicol
Broad spectrum (Typhoid)
Tetracycline (Doxycycline)
Intracellular bacteria (Chlamydia)
Inhibition of nucleic acid metabolism – Quinolones (Norfloxacin)
Gram +ve cocci (UTI’s)
Metronidazole (Flagyl)
Anaerobes and protozoa (Trichomo)
Rifampicin
Mycobacterium (TB)
Inhibit metabolic pathways – Sulfonamides (Sulfamethoxazole) Used synergistically (rashes)
Trimethoprim
Used synergistically (UTI’s)
Inflammatory bowel disease drugs
Corticosteroids – anti-inflammatory SE: suppression of response to infection and injury, suppressionof
pts capacity to synthesize corticosteroids, metabolic effects – Cushing’s, osteoporosis, hyperglycaemia
5-Aminosalicylic acid – anti-inflammatory by inhibiting prostaglandin production and scavenging
free radicals (aspirin)
Immunosuppressants
1. Azathioprine – help reduce the dose of corticosteroids and side effects ‘steroid sparing’. SE:
bone marrow depression, N&V, skin eruptions, mild hepatotoxicity
2. Methotrexate – help reduce the dose of corticosteroids and side effects ‘steroid sparing’. SE:
see above
3. Cyclosporin – immunosuppressant produced by a fungus normally used in transplant rejection
SE: nephrotoxicity, hepatotoxicity, HT, anorexia, lethargy, hirsutism, tremor, paraesthesia, gum
hypertrophy, GIT disturbances
TNF-α Blockers (Etanercept/Infliximab) – block the inflammatory cytokine TNF-α
Antibiotics – ampicillin and metronidazole inhibit leucocyte adhesion to vascular endothelium
Other investigational agents
1. Aloe vera derivative Acemannan – prevent inflammatory effects of IL-1, IL-6 and TNF-a
2. Unfractionated heparin – anticoagulant activity and immunomodulatory properties
3. Nicotine – transdermal or rectal nicotine may benefit Rx of ulcerative colitis
Supportive Drug Therapy in IBD – to reduce symptoms
o Analgesics
o Antidiarrhoeal agents
o Mineral and vitamin supplements – iron, folate and vitamin B12
o Bile acid sequestrants – cholestyramine to prevent colonic secretions induced by bile salts
after an ileo-colonic resection.
Treatment of diarrhoea
o Maintenance of fluid and electrolyte balance – oral rehydration with isotonic glucose
o Antibacterial agents – Campylobacter treated with erythromycin
o Antidiarrhoeal agents
Intraluminal agents – adsorbents (chalk, activated charcoal), bulk forming (psyllium)
Anti-inflammatory agents – salicylates
Antimotility and antisecretory agents
1. Muscarinic receptor antagonists – decrease gastrointestinal motility (Belladonna)
2. Opioids – mu and delta receptors increase anal sphincter tone (Loperamide)
3. A2-adrenoceptor agonists – inhibit fluid and electrolyte secretion (clonidine)
4. Somatostatin analogues – inhibits GIT hormone release (Octreotide)
Impotence drugs
Sexual stimulation causes NO release from penile non-adrenergic, non-cholinergic nerves which
activates endothelium guanylate cyclase to convert GTP to cGMP. This decreases intracellular Ca2+
thus decreasing smooth muscle contractility and increasing arterial blood flow.
Sildenafil – selective Phosphodiesterase 5 (PDE V) inhibitor thus preventing breakdown of cGMP SE:
blindness
Intracavernous Therapy
Papaverine – non-selective phosphodiesterase inhibitor preventing breakdown of cGMP
Phentolamine – non-selective α-adrenoceptor antagonist causing increased arterial flow
PGE1 – direct injection of prostaglandin causing penile smooth muscle relaxation
Topical Therapy:
Glyceryl trinitrate – dilates veins and relaxes smooth muscle but gives partner headache
Papaverine and PGE1 (alprostadil) – creams, gels or transurethral applications
Mood altering drugs
Alcohol – CNS mixed depressant/stimulant (Tolerance)
GABA mediated inhibition at GABAA receptors, activates Cl- channels, dec neural activity
Marijuana – CNS mixed depressant/psychomimetic
Binds to G-protein coupled cannabinoid receptors, blocks Ca2+ channels, dec neural activity
Phenobarbital (Barbituate) – CNS depressant (Tolerance, Dependance, Withdrawal)
GABA mediated inhibition at GABAA receptors, activates Cl- channels, dec neural activity
Temazepam (Benzodiazepam) – CNS depressant (Dependance, Withdrawal)
GABA mediated inhibition at GABAA receptors, activates Cl- channels, dec neural activity
Heroin (Opioid) – CNS depressant (Tolerance, Dependance, Withdrawal)
Binds to opioid receptor, blocks Ca2+ channels, dec neural activity
Caffeine – CNS stimulant (Withdrawal)
Inhibits phosphodiesterase breaking down cAMP so increases catecholamine (NA) NT release
Nicotine – CNS stimulant (Tolerance, Dependance, Withdrawal)
Stimulates sympathetic nicotinic receptors resulting in dopamine release and reward
Cocaine – CNS stimulant (Tolerance, Dependance, Withdrawal)
Potent inhibitor of catecholamine uptake by noradrenergic nerve terminals, enhances SNS
Ecstasy (MDMA, Methyledioxymethamphetamine) – CNS stimulant (Tolerance, Dependance)
Release NA, 5-HT and dopamine monoamines from pre-synaptic brain nerve terminals
Speed (Methamphetamine) – CNS stimulant
Release NA, 5-HT and dopamine monoamines from pre-synaptic brain nerve terminals
Acid (LSD) – CNS psychotomimetic
Inhibits the firing of 5-HT containing neurons in the raphe nuclei
Inhalants (toluene glue, kerosene, petrol, carbon tetrachloride, nitrous oxide) – CNS depressant
Obesity drugs
Fenfluramine – Serotonin agonist and sympathomimetic which decreases gastrointestinal motility SE:
pulm HT, heart valve defects so not used
Sibutramine – Serotonin agonist and sympathomimetic which decreases gastrointestinal motility
Orlistat – Peripherally acting pancreatic lipase inhibitor that reduces lipid breakdown in the
intestine allowing a proportion of ingested fat to be excreted, therefore reducing fat absorption.
Future drugs
•
Leptin and neuropeptide Y inhibitors – to influence the intake/expenditure pathway
•
Cholecystokinin promoters – reduces appetite
•
Troglitazone – increases lipolysis, decreases glycolysis
•
β 3 Adrenoceptor Agonists – direct effect on fat cells
Rheumatoid Arthritis drugs
‘Inverted pyramid’ uses steroids, methotrexate, sulfasalazine and hydroxychloroquine
Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) - Ibuprofen
Disease-Modifying Anti-Rheumatic Drugs (DMARDs) - Methotrexate
Inhibit cytokines and reduce inflammation, joint swelling, plasma acute phase reactants and
slow development of joint erosions and irreversible damage.
o Sulfasalazine – scavenges toxic oxygen metabolites produced by neutrophils. SE: GIT
disturbances, malaise, headache, skin reaction, leukopenia
o Methotrexate – folic acid antagonist with cytotoxic and immunosuppressant action
o Gold Compounds – inhibit lymphocyte proliferation, reduce activity of lysosomal
enzymes and decrease production of toxic oxygen metabolites SE: skin rash,
mouth ulcer, proteinuria, blood dyscrasias, encephalopathy, peripheral
neuropathy, hepatitis
o Penicillamine – Acts by reduction of IL-1 generation SE: anorexia, N&V, disturb taste,
rashes, stomatitis, bone marrow disorders, autoimmune conditions
o Chloroquine – inhibit lymphocyte proliferation, reduce activity of lysosomal
enzymes and decrease production of toxic oxygen metabolites SE: few in
chemoprophylaxis, for malaria use N&V, dizziness, blurred vision, headache,
urticarial sx, hypotension, fatal dysrhythmia in high dose
o Corticosteroids – anti-inflammatory
o TNF-α Blockers (Etanercept/Infliximab) – block inflammatory cytokine TNF-α
The rarely used drugs include
Azathioprine – immunosuppressant used when DMARDs are ineffective
Cyclosporin – immunosuppressant used when extra-articular side effects are severe
Bacteriocidal TB drugs
Isoniazid – disrupts synthesis of mycolic acid in mycobacteria cell walls SE: allergic skin eruptions,
fever, hepatotoxicity – check liver function, haematological changes, arthritic sx and vasculitis and
pyridoxine def causing central and peripheral NS effects therefore give pyridoxine as well. CI: G-6-P
def, decreases metabolism of anti-epileptic drugs eg phenytoin, ethosuximide, carbamazepine
Rifampicin – affects RNA synthesis by binding to the b-subunit of DNA-dependent RNA polymerase.
SE: skin eruptions, fever, GIT disturbances, liver damage with jaundice – check liver function, flu like
sx, CNS disturbances (dizziness, tiredness and confusion), urticaria and haemolysis. CI: increases
degradation of warfarin, glucocorticoids, narcotic analgesias, oral anti-diabetic drugs, dapsone,
oestrogens (failure of OCP)
Ethambutol – only has effects on mycobacteria and inhibits their growth SE: optic neuritis resulting in
visual disturbances initially red/green colour blindness followed by a decrease in visual acuity, GIT
disturbances, arthralgia, headache, giddiness, mental disturbances
Pyrazinamide – inactive at neutral pH but tuberculostatic at acid pH so effective against intracellular
organisms in macrophages. SE: gout, GIT upsets, malaise, fever, liver damage
Parkinson’s drugs
1. Dopamine precursors – Levodopa
First line Rx, dopamine can’t cross BBB but levodopa can. Used in combination with carbidopa
to create dopamine in brain not periphery. SE: vomiting, then long term wearing off or ‘end of
dose’ effect with writhing dyskinesias or ‘on-off’ effect with sudden hypokinesia then normality,
acute SE which wear off: nausea and anorexia, hypotension, delusions and hallucinations
2. Dopa decarboxylase inhibitors – Carbidopa (Sinemet)
Inhibits enzyme dopa decarboxylase which converts dopamine precursor to dopamine. Doesn’t
cross BBB therefore inhibits DD in periphery not brain thus preventing peripheral SE’s
3. Dopamine agonists – Bromocriptine, pergolide, lisuride
Dopamine receptor agonist derived from ergot alkaloids and is a strong agonist at D2 receptors
Use may decrease long term side effects of levodopa SE: similar to levo-dopa
4. Dopamine releasers – Amantadine
Antiviral drug used in early disease that increases dopamine release, improving all symptoms
5. MAO-B Inhibitors – Selegiline
Inhibit centrally-acting enzyme MAO-B thus dec breakdown of NA & SE catecholamines
6. Anticholinergic (muscarinic antagonists) drugs – Benztropine
Act as AcH antagonists on muscarinic receptors to decrease PNS tremor more than rigidity or
bradykinesia. Used in patients treated for psychosis as antipsychotics are dopamine antagonists
and therefore nullify L-dopa). SE: drowsiness, confusion
7. COMT inhibitors – Entacapone
Inhibit COMT thus decreasing metabolism of levodopa to 3-0-methyldopa and causing more
sustained plasma levels and more constant dopaminergic brain stimulation
Headache Drugs
Amitriptyline TCA – 5-HT receptor antagonist preventing perivascular inflammation caused by 5-HT,
SE: see above
Methysergide (ergot derivative) – last line 5-HT2 receptor antagonist, SE: N&V, retroperitoneal and
mediastinal fibrosis, CI: PVD
Pizotifen – 5-HT2 receptor antagonist preventing perivascular inflammation caused by serotonin
Ergotamine – a-adrenoreceptors partial agonist/antagonist causing vasoconstriction, SE: as
methysergide, vasoconstriction, CI: PVD
Sumatriptan – 5-HT1D receptor agonist causing vasoconstriction, CI: IHD
Epilepsy Drugs
Phenytoin (Dilantin) - Not effective in absence seizures. Limits repetitive firing of AP’s by slowing
the rate of recovery of voltage-activated sodium channels from inactivation, SE: ataxia, vertigo,
headache, gum hyperplasia, hirsutism and coarsening of facial features, megaloblastic anaemia,
hypersensitivity reactions (rash), and foetal malformation (cleft palate). CI: increases rate of
metabolism of other drugs by inducing the hepatic mixed function oxidase system eg OCP
Carbamazepine (Tegretol) - Effective in complex partial seizures and Trigeminal neuralgia. Limits
repetitive firing of AP’s by slowing the rate of recovery of voltage-activated sodium channels from
inactivation. SE: sedation, ataxia, blurred vision, drowsiness, water retention, bone marrow depression
causing neutropenia, rash, interacts with other drugs eg phenytoin, OCP, warfarin, corticosteroids
Phenobarbitone - Potentiates synaptic inhibition by GABAA receptor. SE: sedation, megaloblastic
anaemia, hypersensitivity reactions, depression. May increase rate of metabolism of other drugs by
inducing the hepatic mixed function oxidase system eg OCP
Sodiuim valproate (Epilim) - Effective in infantile epilepsy due to low toxicity and lack of sedative
action. Increases GABA content of brain by inhibiting the two enzyme systems that inactivate GABA.
SE: hair thinning and curling and teratogenesis eg spina bifida, nausea, wt gain, hepatotoxicity
Benzodiazepines (Clonazepam) - Clonazepam is effective in absence and myoclonic seizures in
children for long term therapy. Diazepam is used as sedative-antianxiety drug for status epilepticus as it
is too sedating for maintenance therapy. Acts more rapidly than other anti-epileptics. SE: sedation
Ethosuximide - First line drug for absence seizures. Inhibits Ca2+ channel function. SE: nausea,
anorexia, mood changes, headache
Meningitis Drugs
•
Meningococcal – Penicillin G or Ampicillin (for 5-7 days)
•
Pneumococcal – Cefotaxime or Ceftriaxone (for 10-14 days)
•
Haemophilus influenzae – produce β-lactamase so are resistant to Ampicillin (for 7-10 days)
•
Listeria meningitis – Ampicillin and Gentamycin
•
Staphylococcus epidermidis (CSF shunt infections) – Vancomycin and Rifampicin
Chemoprophylaxis for meningococcal
•
Rifampicin 2 days – turns tears orange
•
Cephtriaxone – useful in pregnancy
•
Ciprofloxacin – doesn’t interact with OCP
Chemoprophylaxis of rifampicin eradicates nasopharyngeal carriage, recommended for all primary
contacts (household and daycare) of kids with HI and NM not SP
Dexamethasone – is a glucocorticoid steroid anti-inflammatory agent that decreases permeability of
the BBB, decreases cerebral oedema and thus decreases ICP. It doesn’t change mortality but
does reduce initial inflammatory response, fever and incidence of hearing loss
Anaphylaxis Drugs
Adrenaline (epipen) – Nonselective adrenergic agonist
•
Beta-1 receptor – positive inotrope (force) and chronotrope (rate)
•
Beta-2 receptor – bronchial SM relaxant and vasodilator at low dose
•
Alpha receptor – vasoconstrictor at high dose
•
Stabilises mast cells
SE: (IM) – anxiety, tremor, sweating, tachycardia, (IV) – arhythmias, severe hypotension
Antihistamine (doxepin, piperidine)– H1 receptor antagonist
•
Histamine is stored in basophils in blood and mast cells in skin, bronchial and intestinal mucosa
•
Antihistamines decrease histamine-mediated contraction of the smooth muscle of the bronchi,
the intestine and uterus and reduce the increased vascular permeability
SE: antimuscarinic (dry eyes and mouth, constipation), tinnitus
Eczema Drugs
Topical Therapy
Coal Tar preparations – inhibits DNA synthesis but smells and is messy
Dithranol – anti-mitotic effect and forms free oxygen radicals, but stains skin and towels
Topical Corticosteroids – antiinflammatory SE: dermal atrophy and adrenal suppression
Calcipotriol – vitamin D analogue that inhibits cell proliferation and stimulates keratinocyte
differentiation, doesn’t smell or stain SE: hypercalcaemia
Systemic Therapy
Methotrexate – folate antagonist that is anti-inflammatory and immune-modulatory, is a teratogen
Retinoids – vitamin A derivative (isotretin) SE: dry mucous membranes, hyperostosis, teratogen
Cyclosporin – fungal peptide immunosuppressant that inhibits T-lymphocyte activation and IL2
Production. Can cause nephrotoxicity or cancer
Goeckerman regimen – Coal tar preparations with UV
Ingram regimen – dithranol, tar and UVB
Skin cancer drugs
5-flourouracil cream (Efudix) – pyrimidine analogue that inhibits DNA synthesis and decreases solar
keratoses (actinic keratoses)
Pituitary tumours
Treatment of prolactinomas – Cabergoline or Bromocriptine (dopamine agonist) D inhibits lactotrophs
Treatment of GH tumours – Octeotride (somatostatin agonist) SS inhibits growth hormone
Hyperthyroidism drugs
Carbimazole (brand Neomercazole) -­‐ Inhibit the peroxidase enzyme that iodinates tyrosine and thus
effectively decreases the production of thyroid hormones. SE: granulocytopenia, rash, headaches,
nausea, jaundice and joint pain Propylthiouracil -­‐ Similar MOA to Carbimazole but also reduces the peripheral de-iodination of
thyroxine (T4) to the more active triiodothyronine (T3). Used in lactating mothers as doesn’t cross into
breast milk SE: as above
Ionic transport inhibitors (perchlorate) -­‐ Competes with iodide for uptake but is of historical interest only High dose iodine (Lugol’s iodine) -­‐ Paradoxically, high dose iodine given to hyperthyroid patients decreases thyroid hormone production and reduces the vascularity of the gland. Useful in thyroid storm or preparation for surgery Radioactive iodine (131I) -­‐ This b-­‐particle emitter is taken up as iodide and exerts a cytotoxic action in the thyroid. Hypothyroidism will usually occur and is treated with daily replacement thyroxine. No evidence of causing cancer. Avoid in children and pregnancy Propranolol or metoprolol -­‐ b-­‐Adrenoceptor antagonists are used to control the sympathetic-­‐
like symptoms of hyperthyroidism such as tachycardia, dysrhythmias, tremor and agitation. SE: as above CI: asthma Surgery:
Sub-total (risk of severing recurrent laryngeal nerve)
Safe-total thyroidectomy (requires lifelong thyroxine replacement)
Hypothyroidism
Thyroxine (T4) for life. SE: bone resorption causing osteoporosis
Anxiety pharmacology
Benzodiazepines – endorse GABA-mediated inhibition of the CNS. SE of sedation and memory loss
Buspirone – 5-HT1A partial agonist that mimics serotonins action
SSRIs – inhibits uptake of 5-HT by the SERT, thus increasing levels in the synapse
β-blockers – treat symptoms of tachycardia, sweating and tremor. Don’t control central symptoms
Oral Hypoglycaemics
Sulfonylureas (chlorpropamide) - Promotes insulin secretion in response to glucose by closing ATP
sensitive K+ channels on β cell membrane causing depolarisation, Ca+ influx and insulin release. SE:
hypoglycaemia and weight gain therefore not first line in obese patients
Biguanides (Metformin) - Unknown MOA but it decreases gluconeogenesis, thus suppressing hepatic
glucose output and increasing insulin sensitivity. SE: anorexia, epigastric discomfort, diarrhoea
Alpha-glucosidase Inhibitors: (acarbose) - Inhibits intestinal alpha-glucosidase so delays CHO
absorption reducing the postprandial increase in blood glucose. Reduces intestinal glucose absorption.
SE: flatulence, loose stools or diarrhoea, bloating
Post-prandial glucose regulators (PPGRs): (repaglinide) - Stimulates insulin release from beta cells.
Short duration of action makes hypoglycaemia less common than sulphons. SE: Hepatic dysfunction
Thiazolidinediones: (rosiglitazone, pioglitazone) - Insulin sensitising agents which activate the
peroxisome proliferator activated receptor (PPAR-gamma) in adipose cells which stimulate transcription
of the glucose transporter molecule glut 1 and also decreases the transcription of resistin and reduce
resistance. SE: hepatotoxicity
Insulin:
Mimics natural insulin. Fast and short acting soluble insulin, peak action after s.c dose 2-4hrs, duration
6-8hrs and can be given IV, intermediate acting eg isophane insulin or long-acting eg insulin zinc
suspension and crystalline insulin zinc suspension. Insulin lispro is a new insulin analogue which acts
more rapidly but for a shorter time than natural insulin so pts can inject soon before they start a meal.
SE: hypoglycaemia, rebound hyperglycaemia can follow excessive insulin admin, allergy, weight gain
and lipohypertrophy at injection site.
Anaemia Pharmacology:
Iron: (ferrous sulphate) - Oral tablets. SE: nausea, abdo cramps, diarrhoea, iron toxicity
Folic Acid - Oral form. Used to treat folate def anaemia from poor diet, malabsorption or drugs
(phenytoin), to prevent toxicity from methotrexate and prophylactically in pregnancy, premature infants
and severe haemolytic anaemias and haemoglobinopathies (sickle cell). There is active uptake into cells
and reduction to tetrahydrofolate (FH4) by dihydrofolate reductase, extra glutamates are then added.
Folate polyglutamate is a cofactor in the synthesis of purines and pyrimidines esp thymidylate. SE:
none but if there is B12 def giving folate can improve the blood picture and cause neurological lesions
of B12 def to get worse so in a megaloblastic anaemia must determine if it due to a folate or B12 def.
Vitamin B12: (hydroxocobalamin) - Given by IM injection. Used to treat pernicious anaemia and
other B12 def and prophylactically after total gastrectomy. It is required for conversion of methyl-FH4
to active form formyl-FH4 which after polyglutamation is a co-factor in the synthesis of purines and
pyrimidines and for isomerization of methylmalonyl-CoA to succinyl-CoA. SE: none.
Erythropoietin: (epoietin) - Given IV, SC or IP. Mimics human erythropoietin and regulates red cell
production. Main use for anaemia of CRF where there is a decrease in erythrocytes due to reduced
erythropoietin by diseased kidney, also in blood loss assoc with dialysis and future uses in other chronic
inflammatory diseases eg cancer, RA etc. SE: transient flu-like symptoms, hypertension, iron def and
increased blood viscosity.
Myeloma:
Bisphosphonates: (disodium etidronate, alendronate) - Enzyme-resistant analogues of pyrophosphate
– which normally inhibits mineralization in bone. They reduce the turnover of bone by inhibiting
recruitment and promoting apoptosis of osteoclasts. They also indirectly stimulate osteoblast activity.
SE: GI upsets and bone pain.
Chemotherapy:
Melphalan - Alkylating agent - Nitrogen mustard – each 2-chloroethyl side chain undergoes an
intramolecular cyclisation with the release of a chloride ion. The highly reactive ethylene immonium
derivative so formed can interact with DNA. Can cross-link two nucleophilic sites in DNA causing
defective replication via substitution and chain breakage.
The DNA damage triggers apoptosis.
Cyclophosphamide - Also an alkylating agent affecting particularly the lymphocytes.
SE of alkylating agents: myelosuppression, sterility and risk of non-lymphocytic leukaemia.
Radiotherapy – for relieving bone pain
Bone Marrow Transplantation
Thalidomide - Prolongs remission. Mechanism unknown. Causes teratogenesis.