IMMUNOLOGY# MICROBIOLOGICAL#DRUGS - Nigel …...M2##PHARMACOLOGYSUMMARY# IMMUNOLOGY#&#MICROBIOLOGICAL#DRUGS# 1.1#|#Corticosteroids# 2! 1.2#|#Immunosuppressants# 4! 2#|#AntiEMicrobials#

M2 PHARMACOLOGY SUMMARY

IMMUNOLOGY & MICROBIOLOGICAL DRUGS

1.1 | Corticosteroids 2 1.2 | Immunosuppressants 4 2 | Anti-‐Microbials 6

CARDIOVASCULAR 3.1 | Lipid Lowering Agents 26 3.2 | Diuretics 28 3.3 | Anti-‐Hypertensives; Vascular Drugs 31 3.4 | Drugs For Ischemic Heart Dx & CHF 35 3.5 | Anti-‐Thrombotic Agents 39

RESPIRATORY DRUGS

4.1 | Drugs For Cough & Cold 41 4.2 | Anti-‐Asthmatics 42

GASTROINTESTINAL DRUGS 5.1 | Anti-‐Emetic Agents 44 5.2 | Anti-‐Diarrhoeals 46 5.3 | Laxatives 47 5.4 | Drugs For Gastric Acid & Ulcers 48

ENDOCRINE DRUGS 6.1 | Anti-‐Diabetic Agents 50 6.2 | Drugs For Thyroid Disorders 54

RHEUMATOLOGICAL DRUGS 7.1 | NSAIDs 56 7.2 | Anti-‐Arthritic Drugs 58

PSYCHIATRIC DRUGS 8 | Central Nervous System Drugs 60

NIGEL FONG 2012/2013

M2 PHARMACOLOGY SUMMARY 1.1 | CORTICOSTEROIDS

NIGEL FONG 2012/2013 PAGE 2

1.1 | CORTICOSTEROIDS

MECHANISM & USES Steroids have extensive effects, activating 10-‐100 genes. Steroids bind to the steroid receptor, a nuclear receptor, and alter gene expression (transactivation or transrepression) Transrepression of:

Cyto/chemokines

Inflammatory enz Adhesion Receptor

TNFα Interleukins RANTES (attract T-‐cell) Eotaxin (attract eosinophil)

Inducible NO synthase, iNOS Cyclooxygenase-‐2 (prostaglandins) 5-‐lipooxygenase (leukotrienes) Phospholipase A2 (arachidonic acid)

iCAM, vCAM IL2-‐R TCR

Transactivation of:

• Annexin-‐1 / Lipocortin (PLA2 inhibitor) • β2 adrenoceptor • IL-‐1 receptor antagonist • Neutral endopeptidase (cleaves pro-‐inflammatory molecule e.g. substance P) • IκB-‐α (inhibitor of NF-‐κB)

Net effect is to suppress the inflammatory response,

• ↓ all immune cells except neutrophils (stay in circulation) • ↓ macrophage phagocytosis & cytokine production • ↓ Type 4 hypersensitivity • ↓ Antibody production • ↓ Capillary permeability, vasoconstriction (? Mast cell suppression)

Uses

• Anti-‐inflammatory agents, of use in almost all inflammatory diseases • Immunosuppressants • ↑ Platelets & RBC (use in thrombocytopenia) • ↑ surfactant production & prevent NRDS in pre-‐term baby. Inject into mother b/f delivery

DRUGS Nature Potency Duration of action Minerocorticoid actv Cortisone Prodrug Low Short

Yes Water retention

Hydrocortisone Active Prednisone Prodrug

Stronger 12-‐36 h Prednisolone Active Methylprednisolone Prodrug

None Triamcinolone Active Dexamethasone α-‐isomer

Strongest 24-‐72 h Betamethasone β-‐isomer N.B. fludrocortisone & deoxycorticosterone are minerocorticoids, for hormone replacement in hypoaldosteronism

M2 PHARMACOLOGY SUMMARY 1.1 | CORTICOSTEROIDS


SIDE EFFECTS 1. Minerocorticoid activity (cortisone – prednisolone)

• Fluid / Na retention, Edema, hypertension, CHF 2. Metabolic effects:

• Hyperglycemia : anti-‐insulin effect (DM pt may need insulin instead of oral medication) • Fat deposition : Cushing’s syndrome (central obesity, moon face, weight gain)

: Hypertriglyceridemia : aseptic necrosis of femoral head (microemboli due to ↑ lipid)

• Prot/bone catab : Growth retardation in pediatrics, osteoporosis : Muscle wasting, myopathy

3. Immunosuppression

• Infection: esp TB, Herpes, CMV, Fungi, Toxoplasma • GI bleeding (esp in combination with NSAID), can lead to peptic ulcer • Delayed wound healing

4. Endocrine effects

• Hypothalamic-‐Pituitary-‐Adrenal axis suppression; withdrawal symptoms (lethargy, headache, fever, joint pain) – must taper dose slowly

• Androgenic effect: Acne, hersutism, menstrual disturbance in females 5. CNS effects: euphoria, depression, psychosis 6. Local effects

• Cataract / glaucoma • Skin thinning

PRINCIPLES OF STEROID THERAPY

• Use only when host response is the cause of symptoms. Avoid in infection • Start with the lowest possible dose of short-‐acting steroids with little water retention (prednisolone is a

good choice) • Alternate day therapy if possible to maintain H-‐P-‐A axis • Do not stop abruptly • In prolonged therapy, check CXR, TB, DM, peptic ulcer, osteoporosis, mental disorder before prescribing

as these can be side effects • Local preparations of steroids reduce systemic side effects.

M2 PHARMACOLOGY SUMMARY 1.2 | IMMUNOSUPPRESSANTS


1.2 | IMMUNOSUPPRESSANTS

MECHANISM & USES Drug Mechanism Uses

Calcineurin inhibitor -‐ Cyclosporin A -‐ Tacrolimus Forms: PO / IV /

Opthalmic (C) / topical (S)

Bind cyclophillin (C) / immunophilin (T) Inhibit calcineurin (a phosphatase) Inhibit NF-‐AT translocation into nucleus Inhibit cytokine gene transcription Inhibit T-‐cell proliferation (specifically T cell)

Transplant Uveitis RA Psoraisis, Asthma

mTOR inhibitor -‐ Sirolimus

Bind immunophilin (FKBP) Inhibit mTOR Inhibit p70 S6 kinase & 4E-‐BP1 Inhibit cytokine-‐med prolif of B/T cells

Anti-‐proliferative Stents, prevent re-‐stenosis

Cytotoxics -‐ Azathioprine -‐ Mycophenolate

Conv to 6-‐mercaptopurine then 6-‐thioguanine -‐ Structural analogue of guanine: inhibit DNA syn -‐ Form thioinosinic acid: inhibit purine syn ↓ Lymphocyte proliferation

Used before T-‐cell specific drugs.

Conv to mycophenolic acid Inhibits IMPDH (inducible > constitutive) Inhibit purine syn ↓ Lymphocyte proliferation, antibody formation, chemotaxis to graft site

Polyclonal antibody -‐ Lymphocyte Ig -‐ Anti-‐thymocyte Ig

Horse/rabbit antibody recognizing multiple antigens on human lymphocyte/T-‐cell Ag-‐Ab binding: delete T-‐cells

Pre-‐transplant

Monoclonal Ab -‐ OKT3 (murumonab-‐CD3)

-‐ Anti-‐IL2, Anti-‐TNFα

Murine Ab against CD3-‐TCR. Deplete T-‐cells

Pre-‐transplant

IG IV Normalize immune sys autoimmune disorders, AIDS, bone marrow transp

Rhesus (D) Ig Human IgG against rhesus antigen. -‐ Inject into Rh – mother 24-‐72h before birth of Rh + infant -‐ Block primary immune response to Rh antigen -‐ Prevent erythroblastosis fetalis affecting next newborn

N.B. Triple therapy in transplant patients: calcineurin inhibitor + steroid + azathioprine -‐ Each drug at lower dose to minimize side effects

M2 PHARMACOLOGY SUMMARY 1.2 | IMMUNOSUPPRESSANTS


SIDE EFFECTS

Cyclospo

rin

Tacrolim

us

Sirolim

us

Azathiop

rine

Mycop

heno

late

Anti-‐lym/T m

AB

OKT

3

Effect

Notes

Y Y Y Y Y Y Y ↑ Infection, ↓ healing ↑ Cancer risk

Anti-‐lym/thy, OKT3: histiocytic lymphoma at injection site

Y Y Y

Y Bone marrow depression: thrombocytopenia, leukopenia etc

Y Y Y Nephrotoxicity Avoid CsA + sirolimus

Y Neurotoxicity

Y Y First dose: cytokine release syn. -‐ Fever, chill, hypotension

Y Y Serum sickness (Ag-‐Ab cplx) Anaphylaxis

Y Y Development of anti-‐foreign IgG

Y Y Hyperglycemia

Y Y Y Hyperlipidemia

Y Hypertension

Y Y GIT toxicity

Interactions:

• Sirolimus + Cyclosporin A: nephrotoxicity, cannot use together in long term • Azathioprine + allopurinol (for gout): allopurinol inhibits xanthine oxidase which metabolizes 6-‐

mercaptopurine. Combination use ↑ 6-‐mercaptopurine levels, causing toxicity

M2 PHARMACOLOGY SUMMARY 2 | ANTI-‐MICROBIALS


2 | ANTI-‐MICROBIALS

2.1 | MECHANISMS OF ACTION ANTI-‐BACTERIALS (a) Cell wall agents

Penicillins Cephalosporins Carbapenems Monobactams

The beta-‐lactams include the penicillins, cephalosporins, carbapenems, and monobactams. The penicillins have a common 5C thiazolidine and 4C beta-‐lactam ring. Cephalosporins have a 6C dihydrothiazine ring instead of the 5C ring. Oxapenems have a very closely related structure. Vancomycin is a stable chloride-‐ion containing glycopeptide (MW 1500) Beta lactams

1. Bind covalently to trans-‐peptidase (penicillin-‐binding protein), preventing cross linking of parallel peptidoglycan chains.

2. Activate murein hydrolase, which hydrolyses peptidoglycan As a result, bacterial cell walls lose structural strength and cannot resist osmotic pressure. Furthermore they can no longer play their role in binary fission. Beta lactams hence have a bactericidal effect on actively growing bacteria that are synthesizing cell wall. Resistance to beta-‐lactams occur due to

1. Beta-‐lactamase production 2. Transpeptidase mutation, preventing beta-‐lactam binding 3. Reduced permeability of cell wall / outer membrane, due to alteration of porins 4. Efflux pump

Oxapenems have weak antibacterial activity and high affinity for beta-‐lactamases. They complex bacterial beta-‐lactamase, allowing a co-‐administered beta-‐lactam antibiotic to act without getting destroyed by beta-‐lactamase. Vancomycin is an indirect cell wall agent. It binds to the peptide components of aminosugars to prevent interaction with transpeptidase. Resistance can arise due to binding site mutation (Ala to Lactate), reducing binding affinity of vancomycin.



(b) Protein synthesis inhibitors The aminoglycosides are small, highly water-‐soluble molecules. Tetracyclins are larger molecules. The macrolides have 14C (erythromycin, clarithromycin) or 15C (azithromycin) lactone rings (azithromycin with extra N) Inhibition of protein synthesis occurs by

• Aminoglycosides: irreversible inhibition of 30S subunit • Tetracyclins: reversible binding to 30S [bacteriostatic only] • Macrolides: binding to 50S ribosomal subunit • Clindamycin: binding to 50S ribosomal subunit • Linezolid: inhibit 23S subunit of 50S

Further notes on aminoglycosides

• Entry into bacterial cytosol via oxygen-‐dependent active transport is enhanced by cell-‐wall active drugs. Hence there is synergy if administered with a beta-‐lactam or vancomycin

• Once-‐daily dosing recommended in many scenarios due to concentration-‐dependent killing and significant post-‐antibiotic effect (avoid if renally impaired)

(c) DNA synthesis inhibitors Fluoroquinolones inhibit DNA synthesis and are bactericidal. Mechanism:

1. Block DNA gyrase (topoisomerase II) which promotes relaxation of supercoiled DNA [esp. in G-‐ bact] 2. Block Topoisomerase IV which promotes separation of chromosomal DNA into daughter cells during

meiosis [esp. in G+ bact] Folic acid inhibitors The folic acid inhibitors competitively inhibit (via structural similarity to the natural substrate) sequential steps in the folic acid biosynthesis pathway

• Sulphonamides inhibit dihydropteroate synthetase • Benzylpyrimidines (trimethoprim) inhibits dihydrofolate

reductase If used together, they are bactericidal. Bacteria, but not humans, synthesize their own folic acid and this is important for DNA, RNA, and protein synthesis. However, humans have dihydrofolate reductase for reducing dietary dihydrofolic acid to the active form, and this will also be inhibited. Hence there is a need for supplementation with active folinic acid (tetrahydrofolic acid) and not folic acid. (d) Others Polymyxins are cyclic peptides with a hydrophobic tail (amphoteric). They have affinity for and disrupt the lipopolysaccharide phospholipids in gram negative bacteria. This causes damage to cell membranes and increases cell wall permeability to other antibiotics. Resistance to polymixins develops through structural modifications of lipopolysaccharide to inhibit binding. Nitrofurantoin is reduced by bacterial nitrofuran reductase to reactive intemediates which damage bacterial DNA, ribosomal proteins, and respiration. It has a bactericidal effect.



ANTI-‐TB DRUGS The 1st-‐line anti-‐TB drugs: H and Z resemble nicotinic acid

• Isoniazid (H) inhibits mycolic acid synthesis for the Mycobacterial cell wall. H is a prodrug; its activated form inhibits acyl carrier protein reductase & keto-‐acyl synthetase. Bactericidal in rapidly multiplying bacteria, but bacteriostatic in dormant bacteria.

• Rifampicin (R) inhibits DNA-‐dependant RNA polymerase. Bactericidal. • Pyrazinamide (Z) is converted by TB pyrazinamidase to pyrazinoic acid, which inhibits TB growth. This

occurs in macrophage lysosomes. Bacteriostatic. • Ethambutol (E) inhibits arabinoglycan synthesis for the Mycobacterial cell wall, by inhibiting TB

arabinosyl transferases. This also facilitates the entry of antibiotics through the TB cell wall. Bacteriostatic.

2nd-‐line anti-‐TB drugs include streptomycin/amikacin, fluroquinolones (e.g. levofloxacin), and cycloserine. Cycloserine, resembling alanine, competitively inhibits alanine racemase & ligase, inhibiting incorporation of alanine into peptidoglycan. Bacteriostatic. Multiple-‐drug therapy is always used in TB due to development of resistance. This may occur through

• Rifampicin: mutated rpoβ leads to altered enzyme • Pyrazinamide: pncA mutation • Ethambutol R: mutated embB gene (arabinosyl transferase) or over-‐expression • There is no cross-‐resistance between isoniazid and pyrazinamide, despite their structural similarity.

ANTIFUNGALS The polyenes: Amphotericin B is an amphoteric polyene macrolide, nearly insoluble in water and therefore prepared as a colloidal suspension or as liposomes. It binds to ergosterol in the fungal cell membrane, creating pores and killing the fungi. Nystatin is similar. The Imidazoles & triazoles inhibit ergosterol synthesis by inhibiting the demethylation of lanosterol to ergosterol. The echinocandins (caspofungin) inhibits synthesis of 1,3-‐D-‐glucan, disrupting the fungal cell wall. Flucytosine (5-‐fluorocytosine) is a water-‐soluble pyrimidine analogue. It is converted by fungal cytosine deaminase to 5-‐fluorouracil (mammals lack this enzyme), and in turn to

• F-‐dUMP, which binds thymidylate synthetase and inhibits thymidylate synthesis, inhibiting DNA synthesis, plus

• 5-‐UTP, which inhibits RNA processing and mRNA translation. Terbinafine (lamisil) is a lipophilic allyl-‐amine compound inhibiting squalene epoxidase, which synthesizes ergosterol from squalene. Squalene accumulates and is fungicidal.

METRONIDAZOLE Metronidazole is a nitro-‐imidazole compound. Its nitro group is reduced by nitro-‐reductase (specific to protozoa and anaerobes) to cytotoxic metabolites which damage DNA, interfering with DNA synthesis.



ANTIVIRALS (a) HIV Antivirals Highly active anti-‐retroviral therapy (HAART) is prescribed to many HIV+ people to minimize viral load. HAART involves (1) one nRTI (2) one PI (3) a second nRTI or an nnRTI. Antiretroviral therapy is for life and should never be stopped once initiated, or drug resistance may be bred. Nucleoside Reverse Transcriptase Inhibitors (nRTI): Zidovudine (thymidine analogue) and Lamivudine (cytidine analogue) are phosphorylated by host enzymes to form 5’ triphosphates, which inhibit reverse transcriptase by

• stopping strand elongation once incorporated into the viral DNA • competing with natural nucleotides.

As resistance to lamivudine (M184V) develops rapidly, Combidir (combination of both) is used. Lamivudine resistant strains are still zidovudine sensitive. Non-‐nucleoside reverse transcriptase inhibitors (nnRTI): Efavirenz and Nevirapine bind non-‐competitively to the catalytic site of reverse transcriptase, inhibiting DNA strand formation. Protease inhibitors (PIs): Saquinavir and Indinavir bind the active site of HIV protease, blocking polypeptide cleavage. These are the most effective anti-‐HIV drugs available PIs are always used with 2 RTIs to prevent resistance. Due to high pill burden, patient compliance may be poor. Boosting with ritonavir is sometimes used. (b) Other viruses: Viral DNA polymerase inhibitors Acyclovir (acyclic guanosine derivative) and ganciclovir (acyclic guanosine analogue) are monophosphorylated by viral thymidine kinase and then triphosphorylated by host kinases. The triphosphate terminates DNA synthesis by

• Inhibiting DNA polymerase • Incorporation into viral DNA strand and causing chain termination

Resistance results from mutations in thymidine kinase or DNA polymerase; HSV resistant to acyclovir are also resistant to ganciclovir. CMV is resistance to acyclovir. Valacyclovir and Valganciclovir are their L-‐valine ester prodrugs. These are hydrolyzed to the active drug in the intestinal wall and then absorbed. These have better bioavailability than acyclovir and ganciclovir.



2.2 | DRUG LISTS ANTI-‐BACTERIALS DRUG FORM / A Β-‐LACTAMASE D M/E INDICATIONS & SPECTRUM NOTES

Penicillins (+

Oxapenems) Benzylpenicillin:

Penicillin G Benzathine / procaine pen G

IV

IV (ER) S

Cross BBB if meninges inflammed

Renal E (tubular)

G+: Strep (Pneumococci, Enterococci), Staph, Clostridium G-‐ cocci (Neisseria) Others: T. pallidium

Check for drug allergies.

Phenoxymethylpenicillin: Pen V PO (Poor abs) S Only minor infections, narrower spectrum

Isoxazolylpenicillin: Cloxacillin, Flucloxacillin PO (Good abs) R Narrow spectrum: Staph, Step [methicillin S sp only]

Aminopenicillin: Amoxicillin PO (Good abs)

S Extended spectrum: coverage of Penicillin G, plus -‐ G+: V gd for S. pneumonia. Also, Listeria -‐ G-‐: H. influenzae, E. coli. Proteus [but many HAI ‘R’]

+ Clavulanic acid = Augmentin (co-‐amoxyclav)

Ampicillin PO / IV + Sulbactam = Unasyn (Sultamicillin)

Ureidopenicillin: Piperacillin IV S Above, plus Pseudomonas, Klebsiella, Enterobacter. + Tazobactam = Tazocin

Ceph

alospo

rins 1G: Cefazolin

Cephalexin IM, IV, eye, sy PO, syrup Low R

Poor D to CSF

G+: Wide – Staph, Strep G-‐: Few – some enterobacteriae

2G Cefuroxime, Cefaclor, Cefoxitin

PO, syrup IV Mod R G+: As per 1G

Extended G-‐ cover: Klebsiella, B. fragilis, H. influenzae

3G Ceftazidime, Cefotaxime

IM, IV High R Good D, inc CSF

As above, plus • Especially penicillin-‐R S. pneumoniae • Also: Neisseria, B. pseudomallei • Anti-‐pseudomonal: ceftzidime, cefepime

Ceftriaxone Hepatic E Don’t give w Ca dilutent/soln: pot fatal ppt in lungs/kidneys

4G Cefepime Renal E (t)



DRUG FORM / A Β-‐LACTAMASE D M/E INDICATIONS & SPECTRUM NOTES

Carbap

en

Meropenem IV Used to be R

But now sometimes S

Good D, inc CSF

Renal E Drug of last resort • Most effective beta-‐lactam against anaerobes

• Able to penetrate G-‐ cell envelope

Esp Pseudomonas & Enterobacter

Imipenem +Cilastatin (Tienam) IV Renal M dehydro-‐peptidase

Meningitis in infants Intra-‐abdominal sepsis Skin infections

Cilastatin inhibits renal dehydropeptidase, extending imipenem half life

Misc cell wall agents Monobactams:

Aztreonam (Azactam) IV R to most Cross BBB if meninges inflammed

Renal E + some liver

G-‐ aerobes only: Neisseria, H. influenzae, Legionella, Campylobacter, Shigella, Salmonella, E coli.

High therapeutic index: Low potential for toxicity

Vancomycin PO

-‐

Not a beta-‐lactam

For C. diff assoc diarrhoea & pseudomembraneous colitis Metronidazole now 1st line due to VRE development

IV

Good D to CSF, pleural, pericardial, ascitic fluid

Renal E (glomerul)

G+ bact: e.g. Staph, MRSA, C. diff. • Combine w ceftriaxone: N meningitidis, H influenzae • Prophylaxis for endocarditis in penicillin-‐allergic pt • Prophylaxis for prostheses implantation op (if MRSA rate is high)

• Empiric antibiotic for MRSA while awaiting culture

Tetracyclin

es

Tetracycline PO, topical PO (abs best bf food inhib by Ca Mg Al)

-‐

Not a beta-‐lactam

Poor D to CSF

Liver conj & E in bile

Broad spectrum: G+ & G-‐ • Esp Rickettsiae, Mycoplasma, Chlamydiae, • Also Vibro, Corynebacterium

Avoid in • 2nd trimester pregnancy (impairs teeth devt)

• Nursing mothers (drug secreted in breast milk)

• Children up to 8y (affect teeth)



DRUG FORM / A D M/E INDICATIONS & SPECTRUM NOTES

Aminoglycoside

s Systemic use:

Gentamycin Tobramycin Amikacin

IM, IV, syrup IM, IV IM, IV, syrup

Poor D into CSF

Renal E (glomerul)

Both G+ & G-‐ but not anaerobes (low O2, poor uptake) • Esp severe inf: Enteric bact, E. coli, Klebsiella, Proteus, Enterococcus

• MDR: Acinetobacter, Pseudomonas • S. pneumoniae in neonate (combine with beta-‐lactam) [Amikacin can work for gentamycin-‐R bacteria]

• Caution in pt with renal impairment, hearing defect, myasthenia gravis

• Reduce dose in elderly • Avoid use with other nephrotoxic drugs

• Avoid use w NMJ blocker • Pre-‐tx audiometry • Monitor PDC for toxicity

Streptomycin IM, IV As above, and for TB.

Neomycin PO Sterilize gut before pre-‐operative intestinal surgery

Topical: Genta, Tobramycin Eye drops, ointment Eye infection Skin infection

Gentamycin Ear drops Ear infection

Macrolid

es

Erythromycin IV

PO: stearate (food intef w abs), or as ethylsuccinate. Less acid stable,

poorer abs Poor D into CSF

Accum in WBC & tpt to site of inf

E in bile

(partially M in liver)

G + bacteria, some G-‐ • CAI pneumonia: S. pneumonia, Mycoplasma, Legionella • Chlamydia, Camphylobacter, Vibros • Alternative to penicillin in allergic patients

Clarithromycin PO Active

metabolite Renal E

• As above, including H. influenzae • Triple therapy for H. pylori

Azithromycin IV PO, syrup Slowly rel fr tissues, t1/2 3d, renal E

• As above, slighter better for H. influenzae, slightly worse for Strep compared to Erythromycin

• Salmonella, Shigela, Listeria • With ceftriaxone for resistent N gonorrhoea

Given once a day and shorter total duration than other 2 macrolides



DRUG FORM / A D M/E INDICATIONS & SPECTRUM NOTES

Misc prot inhib

Lincosamide: Clindamycin PO, IV, topical Poor D to

CSF Liver M

G+ aerobes and anaerobes • Staph & Strep; skin & soft tissue inf (e.g. necrotising fasciitis) • Anaerobes: Clostridium perfringens, bacteriodes. • Prophylaxis for endocarditis in valvular dx pt, prior to dental ops

Oxazolidinone: Linezolid

PO (100% F) IV

Liver M (1 active

metabolite)

G+ microbes • Staph, Strep, Listeria, Corynebacteria, Nocardia • Useful for MRSA, VRE: unique binding site (23S) means no cross-‐resistance with other drugs

Fluo

roqu

inolon

es

Ciprofloxacin IV

PO (divalent cations, antacids affect abs)

Good D, inc CSF

Accum in neut + mphage

Partial liver M

Both G+ & G-‐: • Intracellular organisms: Chlamydia, Legionella – accumulates in neutrophils & macrophage, so good for intracellular org

• E coli, Shigella, Salmonella… : travel diarrhea, food poisoning • Bacillus: Anthrax • Strep, Staph: Necrotising fasciitis [but MRSA often R] • Also: Haemophilus, Pseudomonas, Neisseria, Mycoplasma

Avoid in pregnant / breast-‐feeding pt Caution in pt on anti-‐arrhythmic drugs

Ofloxacin

Renal E

Levofloxacin IV

Above. Also: • Most effective in CAI S. pneumonia • E coli prostatitis • TB (accum in macrophage & neutrophils, good for intracellular bact)

Gatifloxacin Eye drop As per Ciprofloxacin

Folic acid inhib

Sulphonamides: Sulphamethoxazole (SMZ) Sulphadiazine

PO Good D to CSF

Renal E (glomerular)

Usually combined as Cotrimoxazole (Bactrim, Septrin) • G+: MRSA, Staph saprophyticus, Listeria, Nocardia, Anthrax • G-‐: Enterobacteriae -‐ E coli, Shigella, bacterial diarrhea • Others: pneumocystis jaroveci in HIV pt • Poor against anerobes, Pseudomonas, Rickettsiae Trimethoprim can be used singly for vaginal & prostatic inf: weak base, secreted in acidic fluids

Give w folinic acid (converts to active tetrohydrofolic acid). Not dihydrofolic acid (inactive form)



DRUG FORM / A D M/E INDICATIONS & SPECTRUM NOTES Misc

Nitrofurantoin PO (macrocrystaline) Renal E (glomerular

& tubular)

Excreted quickly, no systemic antibacterial effect Use: Urinary antiseptic: lower UTI / prophylaxis. • G+: Staph, Strep • G-‐: E coli, Neisseria, Bacteriodes • Minimal R. R: P aeruginosa, Klebsiella, Proteus

• Use in pt w norm renal func: in renal impaired pt, will not be adeqately excreted to treat UTI

• Cause brown discoloration in urine • Avoid in pregnant & elderly patients

Polymyxin B

IV, ear / eye

Poor A: PO not for systemic inf

G-‐ bact • Pseudomonas aeruginosa, Enterobacter, Acinetobacter baumanni, E coli, Klebsiella

• Proteus mirabilis is R

TB drugs

Isoniazid (H)

PO

(A inhib by food, Al, antacids)

Good D to CSF

M: inactivation by acetylation &

hydrolysis, then E TB, first line and prophylaxis

Give pyridoxine supplementation. Indians slow acetylators, Chinese fast. Bi-‐weekly /weekly less effective in fast.

Rifampicin (R) (best abs on

empty stomach

inc abscess, phagocytes

M: deacetylated to active metabolite. Entero-‐hepatic circ E by feces/urine

TB, first line and prophylaxis • Also for M. leprae (give with sulphone) Potent against other bacteria, but don’t abuse • Prophylaxis for meningococcus carriers • Combination therapy for serious Staph inf

Orange discolouration in urine, sweat, saliva, tears

Pyrazinamide (Z)

M to inactivate, then E TB

Ethambutol (M) In higher dose E unchanged. TB Decrease dose in renally impaired.

Avoid in child who cannot do eye test

Cycloserine 50% M, 50% E TB. Broad-‐spectrum but reserved for TB Periodic therapeudic drug monitoring. Peak PDC < 25-‐35 µg/ml

Streptomycin/amikacin and levofloxacin is also used as 2nd /3rd line drugs for TB; see relevant sections.



ANTI-‐FUNGALS DRUG FORM / A D M/E INDICATIONS & SPECTRUM NOTES

Polyen

es

Amphotericin B

IV (liposomes) Eye drop

Intra-‐articular PO (poor A)

Poor D to CSF

Liver M Long t1/2 due to tissue binding

Broad anti-‐fungal spectrum • Invasive aspergillosis • Systemic candidiasis • Histoplasmosis, etc.

Infusion rx: ‘shake and bake’. Give small test dose, slow infusion of final dose. Intrathecal use – experts only.

Nystatin PO, pessary Oral / vaginal candidiasis

Triazoles Itraconazole PO (A ↓ by antacid, proton

pump inhib, H2 antagonist) Poor D to CSF Liver M Blastomyces, Histoplasma, Trichophyton

Fluconazole IV, PO Good D to CSF

Renal E. Long t1/2

Cryptococcal (inc meningitis) Candida

Voriconazole IV, PO (A>90%) ? Liver M Candida Invasive aspergillosis (alternative to amp B) Histoplasma, Blastomyces

• On infusion: chest tightness, dyspnea, faintness, flushing may occur – stop if occurs

• Foetal toxicity: avoid in pregnancy

Others

Echinocandins: Caspofungin IV (poor oral A) -‐ Liver M

Narrow: Candida, Aspergillus • Salvage therapy in pt w invasive aspergillosis, unresponsive to amp B

• Candidaemia, mucocutaneous candidasis

• Avoid in pregnancy • High cost • Rifampicin, carbamazepine reduce plasma levels of caspofungin, requiring higher dose.

Flucytosine PO Good D to CSF Renal E Narrow: Combi therapy w amphotericin B for

systemic candidiasis & cryptococcal meningitis • Monitor leukocytes, platelets, liver enz weekly. • Renal toxicity from Amp B can lead to retention

Topical Imidazoles:

Clotrimazole Micoconazole

Topical Skin / vulvovaginal infections Tineal infections, vulvovaginal candidiasis, thrush

Terbinafine Topical cream Dermatophyte infection of skin & nails Shd not exceed 4 wks. Causes dry skin.



METRONIDAZOLE DRUG FORM / A D M/E INDICATIONS & SPECTRUM NOTES

Metronidazole IV (diluted form) Oral (good A)

Good D to CSF

50% Liver M to active metabolite Gut flora M to inactive metabolite All renal E

Protozoa & Anaerobes • Amoebiasis, Trichomonas, Giardiasis • Anaerobes, inc. C. diff • H. pylori triple therapy

Bitter metallic taste, dry mouth, nausea, headache Take with meals to reduce GIT effects Avoid in pregnant pt.

ANTI-‐VIRALS DRUG FORM / A D M/E INDICATIONS & SPECTRUM NOTES

nRTI Zidovudine PO, IV Enters CSF Mainly liver M Newborn: daily until 1 wk old

Use in combination to prevent resistance: Combidir

Lamivudine PO (gd A) Poor D to CSF Mainly renal E

nnRT

I Efavirenz PO (empty stomach, w high fat meal) Poor D to CSF Avoid efavirenz in pregant pts Monitor AST/ALT (stop when >3x) Dose escalation over 14d to minimise rash. Nevirapine PO Enters CSF mod

Cross placenta, sec in breast milk Newborn: 1 dose aft delivery

PI Saquinavir PO (with food) Poor D to CSF Liver M

Indinavir PO (empty stomach) Enters CSF Liver M

Ritonavir Ritonavir boosting: Combine nnRTI with low dose ritonavir (subclinical, no activity). Ritonavir inhibits CYP450, increasing nnRTI effectiveness and allowing use of lower dose nnRTI, hence dreasing toxicity.



DRUG FORM / A D M/E INDICATIONS & SPECTRUM NOTES Vir D

NA po

l inh

ib Acyclovir IV, PO (poor A), topical

Enters CSF Renal E, 50% tubular & 50% glomerular

HSV > VZV > EBV > CMV (CMV ‘R’) • IV in immunocompromized VZV patients to reduce dissemination • Prophalytic use in pt at risk of reactivation (eg immunosuppression/RT), or in pt with frequent genital HSV recurrence

IV acyclovir: Give slowly (1h) and ensure adequate hydration to prevent renal deposition Valacyclovir PO (better A)

Ganciclovir IV mainly (PO poor A) Enters CSF Renal E

CMV > HSV > VZV > EBV • 100x better for CMV than acyclovir • IV in life or sight threatening CMV infections in immunocompromized • Valganciclovir shown to reduce genital HSV transmission

Not in pregnant women



2.3 | PHARMACOKINETICS: GENERALIZATIONS Caution: not all pharmacokinetic details are important!

METABOLISM All antibacterial drugs are mainly renally excreted except

• Ceftriaxone (bile excretion) • Imipenem • Tetracycline, Doxycycline, Minocycline • Erythromycin (excreted in bile), Clarithromycin (active metabolite) • Clindamycin • Linezolid • Ciprofloxacin (partly)

All TB drugs are metabolized except

• Ethambutol • 50% of cycloserine are excreted.

All antifungal drugs are metabolized except

• Fluconazole • Flucytosine

All antivirals are metabolized except

• Lamivudine • Acyclovir & Ganciclovir

Azithromycin, Amphotericin B, and Fluconazole have long plasma t1/2 DISTRIBUTION The following drugs suffer poor delivery into CSF

• 1st & 2nd generation cephalosporins • All bacterial protein synthesis inhibitors. • All antifungals, except fluconazole and flucytosine • Lamivudine, Efavirenz, Saquinavir.

ABSORPTION Absorption is inhibited by antacids (Mg, Al salts):

• Tetracyclines (also inhibited by divalent cations) • Fluoroquinolones (also inhibited by divalent cations) • Isoniazid • Itraconazole (absorption also decreased by proton pump inhibitors, H2 antagonists)

Absorption of azithromycin is delayed but bioavailability does not change.



2.4 | DRUG INTERACTIONS CYP450 INHIBITORS

• Macrolides: Erythromycin, Clarithromycin (not azithromycin) • Ciprofloxacin • Isoniazid (esp in slow acetylators, i.e. Indians in SG, and in those also receiving R or Z. Risk increases

with alcohol intake) • Antifungals: Itraconazole, fluconazole, voriconazole, ketoconazole, flucytosine • All protease inhibitors • Cimetidine, SSRIs • Grapefruit juice

Effects

• Warfarin toxicity: erratic bleeding, increased PTT • Theophylline toxicity: insomnia, tremors, nervousness, seizures, heart dysrhythmias • Cyclosporin toxicity: CNS, hepatorenal toxicity • Increase oral bioavailability & elevate serum levels of digoxin • Phenytoin: ataxia, nystagmus, gum hyperplasia • Sulphonyluria toxicity • Digoxin toxicity • Increased levels of zidovudine, nevirapine.

Administering ciprofloxacin + another CYP450 inhibitor can result in increased fluoroquinolone levels. Avoid concomittant use of voriconazole and other powerful CYP450 inhibitors/inducers. Protease inhibitors slow metabolism of drugs that are CYP450 substrates to cause serious toxicity from elevated levels. In particular lovastatin & simvastatin levels are increased; these should not be used.

CYP450 INDUCERS

• St John’s wort • Anti-‐epileptics: Phenytoin, carbamazepine, phenobarbitone • Rifampicin • nnRTIs: Efavirenz & Nevirapine

Inhibitors induce metabolism of

• themselves • Doxycycline: shorten half life by 50%. • Warfarin • HIV protease inhibitors and non-‐nucleoside reverse transcriptase inhibitors (nNRTIs) • Oral contraceptives: important to warn patient; it’s troublesome if a TB patient gets pregnant.



OTHERS Cotrimoxazole competes for metabolism & binding

• Warfarin: increases antithrombotic effect • Phenytoin: reduce metabolism • Methotrexate (anti-‐cancer / immunosuppressant): increase levels by displacing binding to plasma

albumin. • Elevates lamivudine levels when coadministered

Rifampicin increases urinary excretion of methadone, leading to methadone withdrawal signs. Probencid (for gout) decreases clearance of zidovudine



2.5| SIDE EFFECTS (BY SYSTEM) For a list of side effects by individual drug classes, refer to lecture notes

HYPERSENSITIVITY Hypersensitivity occurs with

• Penicillins (0.4% -‐ 7% of users): due to degradation products [haptens] which are immunogenic when combined with host proteins

• Cephalosporins: 1% of patients allergic to penicillins cross-‐allergic to cephalosporins. Do not give in patients with history of anaphylaxis with penicillin.

Hypersensitivity can be immediate (2-‐30min), accelerated (1-‐72h), or late (days to weeks), and take the form of

• Anaphylactic shock • Skin reactions, including toxic epidermal necrolysis and Stevens-‐Johnson syndrome.

Milder hypersensitivity & rashes also occur with most other antibiotics. Of note:

• Vancomycin gives a peculiar “Red-‐neck” / “Red-‐man syndrome”: rash above nipple line due to histamine release, when infused too rapidly. Infusing over 1-‐2h

• Erythromycin: fever, rash, and eosinophilia. • Cotrimoxazole: rash common, can be severe in elderly, Stevens Johnson possible • Nitrofurantoin: occasional rash, pneumonitis, chills, fever • Fluconazole, and voriconazole to a lesser extent, can cause Stevens Johnson syndrome. • Caspofungin: fever, histamine-‐like facial flushing, rash, puruitus. (but generally well tolerated) • nnRTIs can cause rash, from mild to severe (e.g. S-‐J syndrome). Escalate dose gradually over 14d to

minimise rash.

NEPHROTOXICITY & OTOTOXICITY Aminoglycosides cause nephrotoxicity by inhibiting renal protein synthesis in the proximal tubule, causing acute tubular necrosis and acute renal failure (reversible if drug is stopped). Ototoxicity can occur affect either the vestibular division (esp streptomycin & gentamicin), or the cochlear division (esp amikacin, affects higher frequencies more). This is especially so if dose is high, duration of treatment is long (>5 days), other nephrotoxic drugs are used, patient is elderly or genetically predisposed, or renal function is already compromised. For this reason, aminoglycosides are normally given < 5-‐7 days if possible. Renal function (U/E/Cr) and drug concentrations are monitored (beware if troughs are rising). Clinical monitoring through bedside hearing acuity and vestibular function assessments, as well as audiometer and nystagmometer tests are used. Vancomycin can also give nephrotoxicity and ototoxicity, if used with another nephrotoxic / ototoxic agent (e.g. aminoglycoside). Reduce the dose in renal-‐impaired patients. Vancomycin accumulates in renal impairment and cannot be removed by hemodialysis Other nephrotoxicity Nephrotoxicity may occur with

• Polymyxin (generally low toxicity) • Amphotericin B. Avoid use with other nephrotoxic agents (e.g. aminoglycosides, NSAIDs, cyclosporin). • Tetracyclins (ex doxycycline) in patients with pre-‐existing renal disease. • Acyclovir IV: due to deposition in tubules. Give slowly & ensure adequate hydration.



NEURO / CNS EFFECTS Major

• Aminoglycosides can cause NMJ block and should be avoided in patients with myaesthenia gravis. • Isoniazid causes peripheral neuritis, especially in slow acetylators (Indians in SG). Presents as

parasthesia in distal distribution, some distal motor weakness. CNS effects (including seizures) possible in susceptible patients. Somewhat preventable with pyridoxine supplementation.

• Fluoroquinolones can cause headache, insomnia, diazziness. If used with NSAID, incidence of seizures rises.

• Cycloserine: 10% of patients face CNS disturbances, inc acute psychosis with suicidal tendency, headache, tremor, confusion, seizures. Peripheral neurotoxicity also possiblePyridoxine can help.

Optic

• Ethambutol causes optic neuritis (retrobulbar neuritis) with visual abnomality, red/green colour blindness, loss of peripheral vision with central scotomata

• Voriconazole can cause visual disturbances: colour perception defect, reduced visual acuity, photophobia.

Minor

• There is a slight risk of neurotoxicity due to penicillin use, especially in renal failure patients who face elevated plasma drug concentrations.

• Seizures occur rarely with carbapenem use. • Linezolid can cause optic neuritis and peripheral neuropathy when used >28days • Neurotoxicity may occur with polymyxin B (generally low toxicity) • Metronidazole can commonly cause insomnia, vertigo, and less commonly, ataxia, convulsions,

peripheral neuropathy. • HIV antivirals: Efavirenz (in 50% of patients), nRTIs (zidovudine > lamivudine), and acyclovir can cause

headache, insomnia, anxiety, confusion/agitation. These tend to resolve with continued therapy (2-‐4 wks)

HAEMATOGENIC Linezolid: Duration-‐dependent bone marrow suppression, thrombocytopaenia. Cotrimoxazole: Pancytopenia (anemia, leucopena, thrombocytopenia), megaloblastic anemia due to

inhibiton of RBC cell maturation. Hemolysis esp in G6PD deficiency. AIDS patients treated for P jaroveci more likely to develop side effects than others.

Nitrofurantoin: Can cause neutropenia, hemolysis in infants and G6PD deficient subjects. Rifampicin: Thrombocytopaenia, possible spontaneous intracerebral haemorrhage. Mediated by IgM, IgG

against platelets. Check platelet count. Flucytosine: Serious bone marrow suppression (perhaps due to some metabolism to the cytotoxic 5-‐FU by

gut flora). Zidovudine: Myelosuppression is common, can cause severe anaemia and neutropaenia. Acyclovir: Bone marrow suppression, esp neutropaenia.

Acyclovir may cause thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome

Protease inhib: Increased risk of bleeding in hemophiliacs. May need more coagulants to counter.



HEPATOTOXICITY Liver abnormalities (presents drug-‐induced hepatitis, transaminasemia, hyperbilirubinaemia, jaundice) can occur with

• Aztreonam • Doxycycline & tigecycline (monitor in patients with severe liver impairment) • Fluoroquinolones • TB drugs except ethambutol. Fulminant hepatic failure possible with isoniazid. Monitor liver enzymes &

check for clinical hepatitis monthly, stop if transaminase levels 3-‐5x basal level. Tends to occur 4-‐8wks after drug initiation, esp in older patients, pt with daily alcohol intake.

• Itraconazole • Flucytosine (mild and reversible damage common) • Caspofungin, if combined with cyclosporin. • nnRTIs (esp. nevirapine which can cause liver failure in 12 mths). Risk is higher in patients with a history

of chronic HBV/HCV infection. Monitor liver enzymes and stop when levels elevated 3x. • Protease inhibitors, esp in pts with HBV/HCV.

CARDIAC Erythromycin can cause QT prolongation. Fluoroquinolones (levofloxacin) can cause QT prolongation and torsades de points. Caution in patients on anti-‐arrhythmic drugs, many of which work via QT prolongation Itraconazole can cause cardiac suppression due to negative ionotropic action. Flucytosine may interact with anti-‐arrhythmic drugs (quinidine) to cause dysrhythmia

BIOCHEMICAL Tetracyclines deposit in bones and teeth and chelate calcium. In teeth buds this leads to discolouration and enamel dysplasia, in growing bones this leads to growth inhibition and deformity. Hence it is avoided in pregnancy or in young children <89. Linezolid can cause lactic acidosis and serotonin syndrome when co-‐administered with SSRIs (selective serotonin re-‐uptake inhibitors). Isoniazid promotes pyridoxine excretion, leading to deficiency. This also reduces availability of pyridoxal phosphate for formation of nicotinic acid from tryptophan, predisposing vegans and malnourished patients to pellagra (dementia, diarrhoea, dermatitis). Supplement with pyridoxine and give nicotinic acid supplements if necessary. Pyrazinamide’s metabolite interferes with tubular secretion of uric acid. This can cause gouty arthritis. (Occasionally possible with ethambutol) nRTIs cause lactic acidosis (due to mitochondrial damage), with hepatic statosis. Especially when taken with another nRTI in pregnancy. Protease inhibitors have multiple metabolic effects

• Hyperglycaemia • Pseudo-‐cushing syndrome (maldistribution of fat) • Hyperlipidaemia (elevated cholesterol & triglycerides), which may lead to coronary artery disease and

pancreatitis. Do not use lovastatin & simvastatin as their levels are elevated



MUSCULOSKELETAL Fluoroquinolones can reversibly damage growing cartilage, or lead to tendinitis and rupture (esp archilles & patella tendon), especially in older patients, patients on steroids, or with kidney, heart, and lung disease. Protease inhibitors can cause osteomalacia (reduced density). Give Vitamin D & calcium supplement.

LUNG Nitrofurantoin can cause pulmonary interstitial fibrosis (presents as exertional dyspnea) with chronic use, esp in the elderly

GIT EFFECTS Almost any PO drug can cause GIT upset (nausea, vomiting, diarrhoea). Some IV medications like Meropenem but can also cause GIT symptoms. Especially tetracyclins, erythromicin, cotrimoxazole (nausea, diarrhea, glossitis, stomatitis -‐ inflammation of corners of mouth). Penicillins & vancomycin usually well tolerated. Of the HIV drugs, only zidovudine is notable for GIT disturbances.

DISRUPTION TO NORMAL FLORA Disruption to normal flora from broad antibiotic cover can result in clostridium difficile associated diarrhorea (CDAD) or pseudomembraneous colitis (PMC). This is possible with ampicillin, cephalosporins, tetracycline, and clindamycin (generalization: broad spectrum antibiotics, especially those with activity against anaerobes which form majority of gut bacteria) Superinfections occur in patients given powerful broad-‐spectrum antibiotics (e.g. carbapenems). Tetracycline use can cause enterocolitis from Enterobacteria overgrowth, or oral/vaginal thrust from Candida overgrowth.

TERATOGENICITY Drugs to avoid in pregnancy: tetracyclins, fluoroquinolones, voriconazole, nitrofurantoin, metronidazole, caspofungin, efavirenz, ganciclovir. Ganciclovir can cause irreversible aspermatogenesis at high doses; avoid pregnancy for at leat 90d after end of treatment.



INFUSION REACTIONS Amphotericin B causes a ‘shake and bake’ infusion reaction, with fevers, chills, and rigors. Give a small test dose first, and infuse the final dose slowly over 2-‐4h. Thrombophlebitis occurs with cephalosporins, tigecycline, amphotericin B, and caspofungin. Its pathogenesis involves a chemical reaction to introduced IV drug, and/or introduced skin microbes. The risk is of thromboemboli formation, which could lead to a dead in bed patient. Minimise the risk by giving these drugs slowly and in diluted form, and by rotation of the infusion site Voriconazole infusion may be associated with chest tightness, dyspnea, faintness, and flushing. Stop if this occurs.

OTHERS Low doses of intermittant rifampicin can cause a flu-‐like syndrome, possibly with acute tubular necrosis. This is immune-‐mediated.

M2 PHARMACOLOGY SUMMARY 3.1 | LIPID LOWERING AGENTS


3.1 | LIPID LOWERING AGENTS

MECHANISM OF ACTION Class Mech Uses

Statins* HMG-‐CoA reductase inhibitors Competitively inhibit cholesterol syn ↑ LDL receptor (cholesterol depletion)

↓ Cholesterol -‐ all hyperlipidemias ↓ coronary events in IHD pt

Niacin (Vit B3)

↓ Hepatic lipase, ↓ VLDL prod ↓ Adipocyte lipolysis, ↑ lipoprot lipase ↓ TG, ↓ LDL, ↑ HDL Rev thrombosis: ↓ fibrinogen, ↑ tPA

Widely used, esp -‐ IIb: familial mixed hyperlipidemia (overprod VLDL) -‐ IV: familial hyperTGnemia (overprod VLDL)

Fibrates Ligands for PPAR-‐α (peroxisome proliferator activated receptor) ↑ lipoprotein lipase, ↓ VLDL, ↓ TG ↑ apo-‐I & -‐II, ↑ HDL

In ↑VLDL, esp -‐ III: Familial dysβlipoproteinemia (overprod IDL) Can use for TGnemia even when cholesterol norm.

Bile acid sequestrants

Cationic resins: bind bile acids/salts in GIT, ↓ reabs. ↓ LDL to ↑ prod BA/BS HDL no change.

Useful for isolated ↑LDL only. Not v effective alone, stim syn of cholesterol to replace lost BS. -‐ IIa: Hypercholesterolemia ( ↓ LDL recep) -‐ With niacin in IIb

Contraindication *

HMG-‐CoA reductase is an important developmental enzyme synthesizing isoprenoids. Inhibition results in morphological defects. Hence avoid statins in

• Pregnant or lactating mothers • Children / teenagers (except homozygous familiar hypercholesterolemia)

DRUGS Class Drugs PK

Statins Simvastatin (Zocor) Lovastatin (Mevacor)

PO in evening (cholest syn at night) Inactive lactones: hydrolyse in GIT M by CYP3A4, 10-‐20% E in urine

Rosuvastatin (Crestor), Atorvastatin (Lipitor)

Niacin Niacin PO, Conv in body to nicotinamide

Fibrates Gemfibrozil (Lopid), Fenofibrate (Tricor) PO

Sequestrant Cholestyramine (Questran) Colestipol (Colestid) PO, non absorbed.

M2 PHARMACOLOGY SUMMARY 3.1 | LIPID LOWERING AGENTS


Interactions • Fibrates displace warfarin from plasma protein binding • CYP3A4 inhibitors (macrolides, HIV protease inhibitors, cyclosporin, grapefruit juice) elevate simvastatin

& lovastatin levels

TOXICITY Statin Niacin Fibrate Resins Effect Notes

Y Y Ex ER

(niaspan) Y

Gemfibrozil Hepatotoxicity

(esp: statin + fibrate) Caution in liver dx pt, monitor enz Stop when AST/ALT 3x > norm

Y If w statins

Myotoxicity, ↑ CK enz Acute muscle pain Rhabdomyolysis, death (esp rosuvastatin) Stop when CK 10x > norm

Y Cataract

Y Cutaneous flush Prostaglandin mediated, pre-‐treat with aspirin 30min before dose or use ER

Y Hyperglycemia

Y Hyperuricemia, gout

Y Gallstones

Y ↓ abs of fat-‐soluble vitamins – A, D, E, K, folate

Y Y Y GIT: N/V, diarrhoea Resins: Constipation, nausea, flatulence due to malabsorption of fat

Y Rash

M2 PHARMACOLOGY SUMMARY 3.2 | DIURETICS


3.2 | DIURETICS MECHANISM OF ACTION

PCT Loop of Henle DCT

Cortical collecting tubule Distal collecting tubule Drug Excretion of:

Class Mech Na+ H2O

HCO3-‐ K+ H+ Mg2+ Ca2+ Uric

acid

CAI PCT: Block HCO3-‐ reabsorption + +++ –

Loop TAL: Inhibit NKCC2. ↓ Lumen +ve, ↓ paracellular cation reabs ++++ + + + (+) * –

Thiazide DCT: Block NCC, block NaCl reabs ↑ Ca reabs -‐ hypovolemia -‐ ↓ Cell Na, ↑ Na/Ca exchange

++ + + – # –

K-‐sparing Steroids – aldosterone antagonist Others – Na channel inhibitors + – –

ADH ant Blockade of V2 receptors H2O + Na+ 0

* Ca excretion is under PTH control, usually unaffected. However Ca excretion can + in hypercalcemia. # Hypercalcemia rare. May unmask hypercalcemia due to other pathology (e.g. hyper PTH, CA) Caffeine is also a diuretic, acting via weak antagonism of adenosine receptors.



DRUGS Class Drugs PK

Carbonic anhydrase inhibitors Acetazolamide

Loop diuretics (Sulphonamides) Furosemide Bumetanide, Torsemide PO, rapid A

E: filtered + secreted T1/2 depends on renal function (Others) Ethacrynic acid

Thiazide (Sulphonamides) Hydrochlorothiazide All PO

K-‐sparing (Steroid) Spironolactone Eplerenone

Slow onset More selective on aldos recep

(ENaC inhibitor) Amiloride Triamterene

Not metab M + E: Shorter T1/2

ADH antagonists Vaptans (e.g. conivaptan)

Interactions with NSAIDs

• Proximal straight tubule secretes organic acids into the lumen. NSAIDs and probencid compete with secretion of diuretics, blunting their effect

• Loop diuretics, Thiazide diuretics, and K sparing diuretics induce COX2 production of PGE2, which inhibits NaCl transport. NSAIDs interfere (esp in pt w nephrotic syn, hepatic cirrhosis)

TOXICITY

Loop Thiazide K-‐spare Effect Notes

Y Y Hypokalemia + Metabolic alkalosis

↑ NaCl delivery to macula densa, ↑ K & H secretion

Y Hyperkalemia + Metabolic acidosis

Esp in -‐ renal dx -‐ renin inhibitor (NSAID, β blocker) -‐ Ant II inhib (ACE-‐I, AT1 antag)

Y Y Hyperuricaemia, gout Hypovolemia -‐ ↑ uric acid reabs

Y (less) Y Hyponatremia Hypovolemia -‐ ↑ ADH, thirst

Y Hypomagnesemia Give oral Mg

Y Ototoxicity Esp with ↓ renal func, w sim ototoxic drug (aminoglycoside) use

Y ↓ carb tolerance ↑ hyperlipidemia

↓ Insulin release, tissue uptake Goes back to baseline in long term

Spirono Androgenic effect Gynaecomastia, impotence, BPH

Sulphonamides Allergic rxn Not ethacrynic acid

Triamter Renal failure w indomethacin Kidney stones due to ppt

ADH inhibitors – can cause nephrogenic diabetes insipidus, hypernatremia, SIADH with hyponatremia.



CLINICAL USE Heart failure, pulmonary edema

• Loop diuretics most efficacious; thiazides also used • However excessive diuretic use can diminish venous return and impair cardiac output • To correct induced alkalosis, replace K, use IV saline, or acetazolamide • To correct induced hypokalemia, reduce Na intake, replace K, add K-‐sparing diuretics

Hepatic cirrhosis (↓ plasma vol, edema, ↓ renal perfusion, ↑ aldosterone)

• Often R to loop diuretics: (1) decreased secretion into tubular fluid. (2) Loop diuretics ↑ NaCl delivery to colecting duct and are negated by aldosterone

• S to spironolactone & eplerenone • Excessive diuretic use can cause hepatorenal syndrome, hepatic encephalopathy

Hypertension

• Sodium restriction • Thiazides: mild to moderate hypertension + norm renal & cardiac func. Better than ACE-‐I • Loop diuretics: severe hypertension • MOA: initially ↓ BP via ↓ vol & ↓ CO, 6-‐8 wk later CO normalizes and ↓ TPR due to increased vessel

stiffness • K depletion hazardous in pt taking digitalis, w chronic arrhythmia, AMI or LV dysfunction. Dietary

sodium restriction also helps to reduce K loss Renal obstruction

• Kidney stones: Thiazides enhance Ca reabsorption, ↓ urinary Ca. Do ↑ fluid intake. • ARF due to pigment overload: Loop diuretics to flush intratubular casts

Other electrolyte imbalances

• Hypercalcemia: loop diuretics + saline • Hyperkalemia (mild): loop diuretics + saline [severe: correct K, IV vol, aldosterone] • Anion overdose (Br, F, I): loop diuretics

Other uses

• Nephrogenic diabetes insipidus (e.g. due to lithium): thiazide diuretics (paradoxical!) • Hyperaldosteronism (Conn’s syn, ectopic ACTH, secondary hyperaldosteronism etc). Use K-‐sparing

diuretics Carbonic anhydrase inhibitors No longer used as diuretics; their efficacy decreases over several days as bicarbonate depletion leads to enhanced NaCl reabsorption. Indications:

• Glaucoma: Topical CAI (dorzolamide, brinzolamide) to reduce intraocular pressure • Acute mountain sickness: Act on choroid plexus, ↓ CSF prod. Corrects pulmonary / cerebral edema,

lowers cerebral pH leading to correct ventilation. • Metabolic alkalosis: due to correction of resp acidosis, or in heart failure pt where IV fluid cannot be

used • Urinary alkalinzation: to increase excretion of weak acids, e.g. uric acid, cysteine. Supplement HCO3

-‐

M2 PHARMACOLOGY SUMMARY 3.3 | ANTI-‐HYPERTENSIVES; VASCULAR DRUGS


3.3 | ANTI-‐HYPERTENSIVES; VASCULAR DRUGS

1) RAAS INHIBITORS Class Drugs PK

ACE inhibitor Captopril (and other – pril) Renal E: ↓ dose in renal insufficiency

Other –pril Prodrugs, hydrolyzed in liver.

AT1 recep antag Losartan ( -‐ sartan)

Renin inhibitor Aliskiren

Mechanism RAAS inhibitors ↓ systemic resistance and ↓ BP.

• Reflex sympathetic activation is not seen, unlike vasodilators. • Hence they can be used in IHD.

Class Mech Uses

ACE inhibitor Inhibit angiotensin converting enzyme 1) ↓ conversion of angiotensin I to II. -‐ ↓ sympathetic actv, vasoconstriction -‐ ↓ aldosterone & ADH secretion 2) ↓ bradykinin breakdown – vasodilation

Hypt, HF, MI

Chronic renal failure: ↓ efferent art vasocon ↓ glomerular pressure ↓ proteinuria, ↑ func

Useful in DM

AT1 recep antag Antagonize angiotensin II (type 1) receptors More selective: No effect on bradykinin More complete: non-‐ACE enz generate ATII LT: ↑ renin, ↑ AII, ↑ ATII recep (vasodilation)

Renin inhibitor Prevents rise in renin activity with ACE inhibitor, AT1 receptor antagonists

Interactions: NSAIDs impair hypotensive effect of ACE inhibitors -‐ Bradykinin acts via prostaglandins, the synthesis of which NSAIDs inhibit. Toxicity

1. Contraindidicated in pregnancy: teratogenicity in 1st trimester, fetal hypotension, anuria, and death later

2. Severe hypotension with initial doses in hypovolemic patients

3. Acute renal failure if bilateral renal art stenosis

4. Hyperkalemia esp in pt with renal insufficiency, DM, or taking K-‐sparing diuretics

5. Dry cough, wheeze. (due to Bradykinin, Substance P)



2) CA CHANNEL BLOCKER Class Drugs PK

Non-‐dihydropyridines Verapamil Diltiazem PO, high first pass, extensive M

Verapamil & Nifedipine also IV Dihydropyridines Nifedipine (other – dipine)

Mechanism Bind L-‐type calcium channels, inhibit calcium influx, hence… Action on Effect Uses

Cardiac muscle -‐ Reduce contractility -‐ Reduce SA/AV conduction -‐ ↓ myocardial O2 reqt

↓ BP

Anti-‐angina Anti-‐arrhythmia (tachycardia)

Smooth muscle ↓ formation of Ca-‐calmodulin cplx ↓ myosin light chain kinase activation Vasodilation (arterioles > veins, so orthostatic hypt uncommon)

Dihydropyridines are more selective for vascular beds, while non dihydropyridines are more selective for cardiac muscle (verapamil more so than diltiazem). Skeletal muscle is not affected by Ca channel blocker as skeletal myocytes have an intracellular Ca pool. Minor notes

• Short acting nifedipine ? raises risk of MI – use dihydropyridines other than nifedipine. • Nimodipine ? selective for cerebral BV

Toxicity

1. Cardiac depression (rare): Arrest, bradycardia, AV block, heart failure [esp w β-‐blocker]

2. Relaxation of smooth muscle: flushing, dizziness, nausea, constipation, peripheral edema.



3) CLINICAL APPROACH TO HYPERTENSION Clnical diagnosis: Measure BP on at least 3 different visits or using ambulatory monitoring. Rule out causes of secondary hypertension – treat the root cause if any. Therapy is based on: diuretics, β-‐blockers, ACE inhibitors, angiotensin receptor blockers, and calcium channel blockers. In mild to moderate hypertension, thiazide diuretics alone suffice. Control of sodium intake is important In more severe hypertension, combination therapy with multiple drugs from different classes may be necessary. Most drugs evoke compensatory regulatory mechanisms for maintaining blood pressure, e.g. vasodilators evoke compensatory tachycardia and salt/water retention that almost reverses the effect. Vascular responsiveness is diminished by sympathoplegic and vasodilator drugs, so blood pressure becomes very sensitive to blood volume, hence they are most effective when used together with a diuretic.

The presence of concomittant disease should influence selection of antihypertensive drugs

• RAAS inhibitors useful in patients with DM, proteinuria etc. • β-‐blockers and Ca channel blockers useful in pts with angina • α1 blockers in men who also have benign prostatic hyperplasia

Contraindications

• RAAS inhibitors contraindicated in pregnancy • Ca channel blockers may worsen heart failure due to –ve ionotropic effect. • β-‐blockers contraindicated in asthma and DM.



4) OTHER VASODILATORS *MCQ only Class Drugs Mech PK

α1 blocker Prazocin Dilate arterioles (resistance) & veins (capacitance)

M

Hydralazine Dilate arteriole: ↑ cGMP, ↓ Ca release M: rapid acetylators ↓ effect

Minoxidil Dilate arteriole: Open K+ channels, =↓ contraction

Clinical use Vasodilators result in salt/water retention if administered without diuretic. More effective when used with diuretic or β-‐blocker (controls renin release). Specific subgroups

• Prazosin -‐ men with hypertension & prostatic hyperplasia. Helps BPH as urinary sphincter under α1

receptor control • Hydralazine: with nitrates in African-‐Americans with hypt + heart failure

Toxicity

1. First dose effect: marked postural hypotension. Give small first dose at bedtime.

2. Vasodilation effects: dizziness, palpitations, headache

3. Reflex sympathetic effect (Minoxidil): Tachycardia, palpitations, angina, edema, when diuretic or β-‐blocker inadequate

4. Minoxidil: sweating, hypertrichosis (hair growth). Now use topically for male baldness.

5) SILDENAFIL (VIAGRA) Mech: ↑ cGMP, ↓ breakdown by PDE5 (in arterial wall of lungs & penis). Vasodilation

• Erectile dysfunction (↑ blood flow to corpus cavernosum) • Pulmonary hypertension (relax pulmonary art, ↓ RV workload)

Contraindication:

• Nitrates, hypotension • Hepatic impairment, renal dysfunction

Side effects: Headache, flushing, nasal congestion

M2 PHARMACOLOGY SUMMARY 3.4 | DRUGS FOR ISCHEMIC HEART DX & CHF


3.4 | DRUGS FOR ISCHEMIC HEART DX & CHF

1) NITRATES

Class Drugs PK

Nitrates Nitroglycerin (GTN) High M, low oral bioavailability, short T1/2 (metabolites active). Give sublingual for immediate effect, transdermal / ER for ext. Renally excreted

Mechanism

Releases NO in smooth muscle. Increases cGMP, dephosphorylate (inactivate) myosin light chain kinase, resulting in smooth muscle relaxation

• ↑ Venous capacitance, ↓ Preload (usually CO↓ but may ↑ in CHF with high preload) • Vasodilate coronary art: ↑ coronary flow (normal person) or redistribute flow to ischemic regions (in

CAD) • ↓ Myocardial oxygen consumption via ↓ preload & ↓ afterload (arteriolar dilation)

Applications

• Angina – whether effort, vasospastic, or unstable • Tolerance develops so most effective in short term; Systemic compensation (sympathetic or salt &

water retention) plays role in tolerance Toxicity

1. Tachycardia due to baroreflex

2. Hypotension due to venodilation. Orthostatic hypotension, syncope

3. Headache due to meningeal artery vasodilation. Contraindicated in ↑ ICP



2) BETA-‐BLOCKERS Class Drugs PK

Nonselective Propanolol, timolol, nadolol, carteolol Propanolol: Extensive M by CYP2D6 (saturable), low bioavailability Rest: E in urine, prolonged in renal failure. T1/2 3-‐10h

β1 selective Atenolol, metoprolol, acebutolol, esmolol

α + β blocker Labetalol

Partial agonist Pindolol, acebutolol

Mechanism Competitive antagonist (or partial agonist) of catechoamines at β adrenoceptor

• Heart: -‐ve ionotropic, -‐ve chronotropic effect. Slow AV conduction, ↑ PR interval • ↓ BP due to suppression of renin release (however may ↑ BP in short term as β2 receptor is

vasodilatory) • LA effect: blockade of Na channels (but not achieved due to insufficient conc)

ADRENOCEPTORS α: Vasoconstriction, sphincter contraction, intestinal relaxation β1: Cardioacceleration β2: Vasodilation, bronchodilation

Applications

• Hypertension. Labetolol additionally vasodilates due to α receptor effect • Ischemic heart disease (Angina, post MI): ↓ work & oxygen demand • Chronic heart failure: inhibit myocardial remodelling, improve survival • Arrythmias: treat supraventricular, ventricular arrythmias due to –I effect • Glaucoma: topical (betaxolol, carteolol, levobunolol, metipranolol) beta blocker to reduce aqueous

humour production. Do not use any with LA effect • Hyperthyroidism

Toxicity

1. Bradycardia, coolness of extremities

2. CNS effects: sedation, depression etc

3. Withdrawal symptoms: do not stop suddenly to avoid marked BP / IHD rebound

4. Contraindicated in insulin-‐dependant DM (↑ risk of hypoglycemia with insulin excess. The sympathetic response is an impt mechanism in hypoglycemia; adrenaline also promotes gluconeogenesis)

5. Contraindicated in asthma (catecholamines bronchodilate)

6. Contraindicated in AV blockade & severe LV failure. Caution in pt with compensated heart failure, myocardial output may depend on sympathetic stimulation



3) PHARMACOLOGICAL APPROACH TO ANGINA

Effort angina

• Address underlying causes with antiplatelet agents, statins, hypertension control. • Hypertensive pt: β-‐blocker, Ca-‐channel antagonist • Normotensive pt: Long-‐acting nitrate • Combination therapy if single drug inadequate • Surgery

Vasospastic angina Nitrates and calcium channel blockers, surgery not indicated. Unstable angina Aggressive antiplatelet therapy, stenting. Relief with GTN, β-‐blocker, Ca-‐channel antagonist.

4) CARDIAC GLYCOSIDES

Class Drugs PK

Digitalis Digoxin Good A, wide D, renal E

Mechanism Inhibits Na/K ATPase. Increased Na leads to less Ca efflux.

• Mechanical effect: ↑ cardiac contraction (in both normal & failing heart), ↑ CO ↓ sympathetic activity & ↓ RAAS volume retention -‐-‐> ↓ preload & ↓ afterload

• Electrical effect: ↓ HR, ↑ PR interval, ↓ QT (due to ↓ SA firing, ↓ conduction) Applications

• Systolic heart failure (not diastolic) [usu aft refractory to diuretics, ACEI] • AF • No net effect on mortality. ↓ progressive heart failure but ↑ sudden death.

Toxicity

1. Dysrhythmia: AV junctional rhythm, automaticity, extrasystole (premature ventricular depolarization, bigeminal rhythm), AV block, AF, VF

2. GIT: anorexia, nausea, vomiting

3. CNS: blur vision, headache -‐-‐ Early warning signs, stop if any!

4. Gynaecomastia (rare)



Interactions Digitalis toxicity ↑ in

1. Hypokalemia enhances digoxin (hyperkalemia inhibits): K and digitalis compete for binding to Na/K ATPase.

-‐ Also implies intx w corticosteroids (minerocorticoid activity), K-‐depleting diuretics

2. Hypercalcemia (increase intracellular Ca), hypomagnesemia

3. Verapamil, quinidine – PK interactions.

Treatment of toxicity • Reduce dose or stop if there are early warning signs, i.e. GIT / CNS • Correct K / Mg deficiency • Temporary pacemaker • Neutralization with digoxin Fab fragments (digibind) • Antiarrythmic drugs are dangerous when automaticity is depressed – may lead to arrest. • Cardioversion only if VF (digitalis-‐induced arrythmias made worse by cardioversion

5) Pharmacological approach to heart failure Note – systolic failure and diastolic failure imply different management! Chronic heart failure

• Patients at high risk (AHA stage A, B): control HT, HL, DM. Active treatment only once signs/symptoms of failure (stage C)

• ACE inhibitor is first drug in non-‐edematous pt (+/-‐ diuretics) ↓ preload, ↓ afterload, ↓ progressive dilatation.

-‐ Not to replace digoxin in patients already on digoxin. -‐ Angiotensin II receptor inhibitors for pt who cannot tolerate ACE inhibitors

• Diuretics (esp in edematous pt): thiazide in mild, furosemide if more severe. Manage hypokalemia: K supplementation, ACE inhibitor, K-‐sparing diuretic

• Pt with dyspnea (due to high filling pressures) – Long acting nitrates (venous dilator)

• Low LV output, fatigue – Hydralazine (arteriolar dilator)

• β-‐blocker can worsen heart failure in short term, but may be useful in long term.

• ACEI and β-‐blockers reduce long-‐term remodelling of heart (hypertrophy)\

• Digoxin when diuretics and ACE inhibitors fail to control symptoms. Only 50% of pt will have relief.

Acute heart failure

• AMI: emergency revascularization.

• Vasodilators: nitrates, nitroprusside, hydralazine

M2 PHARMACOLOGY SUMMARY 3.5 | ANTI-‐THROMBOTIC AGENTS


3.5 | ANTI-‐THROMBOTIC AGENTS ANTI-‐COAGULANTS Drug Mech Notes PK

Heparin (IV/SC) 1. Bind antithrombin III Inactivate factor IIa, VIIa, IXa, Xa

2. Stimulate endothelial release of tissue factor pathway inhibitor

From animals

Immediate onset

Heparin low MW (SC only)

Fractionated; simpler dosing

Warfarin (PO) Inhibit Vit K epoxide reductase, deplete Vit K Factor II, VII, IX, X, prot C cannot conv to active form

Slow onset: 8-‐12h Long t1/2: 36h

Use

• Prophylaxis of vascular events (DVT, pulmonary embolism, MI etc) -‐ Venous thrombosis (clotting more significant) > Arterial thrombosis

• Use heparin to induce anticoagulation and warfarin to maintain • Pregnant women: use heparin NOT warfarin

Side effects HEPARIN WARFARIN

Both have narrow TI and can cause bleeding; monitor the INR

• Allergy (esp high MW): -‐ heparin induced thrombocytopenia (HIT) -‐ paradoxical thromboembolism Monitor platelet counts!

• Long term: osteoporosis, spontaneous fractures

(low MW form has less SE)

• Teratogen; crosses placenta (Fetal warfarin syndrome). DO NOT USE IN PREGNANCY

• Cutaneous necrosis, infarction of breast, buttock, intestine, extremities

• Multiple drug interactions -‐ PK interaction -‐ PD (CYP450 inhibitor/inducers

Antidotes In overdose, neutralize Heparin with Protamine sulfate (basic – complexes heparin) Warfarin with Vitamin K1 (phytonadione)

M2 PHARMACOLOGY SUMMARY 3.5 | ANTI-‐THROMBOTIC AGENTS


ANTI-‐PLATELETS • Prevent further clotting but not lyse existing clots. • Use: prophylaxis of vascular events (MI, stroke)

-‐ Arterial thrombosis (platelet aggregation more significant) > Venous thrombosis Type Drug Mech SE

NSAID Aspirin (low dose)

Irreversibly acetylate COX1 & COX2 (hence long duration of action) Inhibit thromboxane A2 syn

Bleeding Peptic ulcer Allergy

Thienopyridine Clopidogrel Inhibit ADP-‐induced platelet aggreg Inhibit platelet lifespan

Bleeding Minor: N/D, rash…

GPIIb/IIIa antagonist

Abciximab mAb against GPIIb/IIIa receptor (normally binds fibrinogen) High risk angioplasty pt: -‐-‐ aspirin + heparin + abciximab.

Bleeding Thrombocytopenia Human anti-‐mouse Ab

FIBRINOLYTICS Drugs: Streptokinase | Urokinase | t-‐PA (tissue plasminogen activator) Source: Streptococci | Human kidney | Recombinant Fibrinolytics (all IV) lyse clots immediately by converting plasminogen to plasmin; plasmin then degrades fibrinogen & fibrin. All fibrinolytics are comparable (but it is claimed that t-‐PA is better). Fibrinolysis is useful in MI, peripheral arterial thromboembolism, pulmonary emboli, and DVT. Heparin may be used to initiate anti-‐coagulation in less serious clots, but in life threatening situations, fibrinolytics are needed. Side effects: Hemorrhage Streptokinase – due to its source, it can cause allergy and may be neutralized by anti-‐streptococal antibodies

M2 PHARMACOLOGY SUMMARY 4.1 | DRUGS FOR COUGH & COLD


4.1 | DRUGS FOR COUGH & COLD

APPROACH These drugs are not curative, merely symptomatic treatment. Decision whether to use should be made on the balance of benefits vs adverse effects. Don’t use in cough induced by drugs (e.g. ACE inhibitor), tumor, etc.

DRUGS Class Drugs Mech & Use Adverse effects

Suppressant (antitussive)

Codeine Dextromethorphan

Suppress cough ctr Constipation (↓ GIT motility) Urinary retention esp in BPH Sedation Death in overdose Addiction (esp codeine)

Expectorants Guaiphenesin Loosen mucus Try to avoid

Mucolytics Carbocysteine (Rhinothiol) Ambroxol (Mucosolvan)

Thin mucus, easier removal by coughing

Antihistamine 1st gen: Diphenhydramine Chlorpheniramine Triprolidine Promethazine Hydroxyzine

H1 receptor competitive antagonists Decrease secretion, decrease vasodilation

Dry mouth Crosses BBB: sedation

2nd gen: Cetrizine Loratadine

Dry mouth Do not cross BBB: no sedation

Decongestant Pseudoephedrine (PO) Phenylephrine (PO/nasal) Oxymetazoline (nasal)

Vasoconstriction Relief congestion

Epinephrine effect -‐ ↑ HR : Caution in arrythmias -‐ Feel high : Addictive

Combinations: Actifed = Pseudoephedrine + Triprolidine Dhasedyl = Promethazine + Codeine Polaramine expectorant = Chlorpheniramine + Pseudoephedrine + Guaiphenesin

N.B. do not take preparations that contain the same type of medicine at the same time.

M2 PHARMACOLOGY SUMMARY 4.2 | ANTI-‐ASTHMATICS


4.2 | ANTI-‐ASTHMATICS

APPROACH Two drugs are necessary:

• An anti-‐inflammatory agent (controller) to prevent attacks • A bronchodilator (reliever) to manage acute attacks

There is synergism between inhaled steroids and beta agonists; inhaled steroids upregulate β2 receptors and hence potentiate the effect of beta agonists. Combined preparations (steroid + beta-‐agonist) may be used to improve compliance

ANTI-‐INFLAMMATORY DRUGS Class Drug Mechanism of action Notes

Inhaled steroid Fluticasone (inhale)

↓ Airway hyperresponsiveness ↓ mucus secretion ↓ exacerbations ↓ airway remodelling

Nuclear receptor; transactivation/repression • ↓ Immune cells, ↓ epithelial shedding • ↓ COX II, 5-‐LOX, NOS, PLA2 • ↑ Annexin (lipocortin), ↑β2 receptors

Most effective

Leukotriene recep antagonist

Monteleukast (PO)

Inhibit leukotriene-‐mediated effects. Steroid sparing.

Aspirin, exercised induced asthma

Mast cell stabilizer Cromolyn (inhale)

Inhibit mast cell degranulation due to IgE cross-‐linking, alter delayed Cl channel & inflamm mediator release.

Cold, dry air, exercise induced bronchospasm

Anti-‐IgE Mab Omalizumab (SC Q2-‐4wk)

mAb against IgE Fc, deplete IgE Decrease IgE receptor on mast cells

Allergic asthma, allergic rhinitis

Precaution: Using leukotriene receptor antagonists to reduce steroid dose can cause rebound eosinophilia as leukotriene receptor antagonists are less effective. Side effects of inhaled steroids:

• Much less than systemic steroids; high first-‐pass to reduce systemic side effects • Mainly oropharyngeal candidiasis (mitigate with good oral hygiene), dysphona, and cough / throat

irritation • Some minor systemic absorption can cause easy bruising of skin, adrenal suppression, posterior

subcapsular cataracts, and osteoporosis.

M2 PHARMACOLOGY SUMMARY 4.2 | ANTI-‐ASTHMATICS


BRONCHODILATORS Beta agonists are the most effective, the other drugs are used as adjuncts (add-‐on)

Class Prototypical drug Mechanism of action Notes

Beta2 agonists (inhaled) ↑ Adenyl cyclase, ↑ cAMP ↓ [Ca2+], ↓ MLCK, ↑ K conductance

Short-‐acting (SABA) Salbutamol Bronchiole smooth muscle relaxation 3-‐6h, rapid acting

Long-‐acting (LABA) Salmeterol Maintenance / prevention 12h

Ultra long acting Indacaterol COPD only 24h

Methylxanthines Theophylline (PO)

Inhibit PDE: cAMP accumulation Block adenosine receptor: relaxation ↑ Epinephrine release fr adrenals ↑ Contractility -‐ fatigued diaphragm

Weak diuretic (caffeine sim str)

Anti-‐muscarinics Ipratropium bromide

(inhale)

Inhibit M3 receptor bronchoconstrict Reves vagal-‐stim mucus secretion COPD

Quartenary amine, does not cross BBB

Side effects: Beta agonists

• β2 effects: skeletal muscle tremor, cramps, peripheral vasodilatation, hyperglycemia • Cross rxn with β1: palpitations & tachycardia • Stimulation of renin release: hypokalemia • Warning: LABA can cause tolerance via downregulation of receptors. Can cause asthma-‐related death. If

an acute attack develops in a tolerant patient, salbutamol will not work. Other bronchodilators need to be used

Side effects: Theophylline • Has a narrow therapeutic range (5-‐20 mg/L) • Liver metabolism: *Drug interaction alert • GIT effects: N/V, anorexia, abdo discomfort • CNS: Nervousness, tremor, anxiety, headache, seizures • CV: Arrhythmias

M2 PHARMACOLOGY SUMMARY 5.1 | ANTI-‐EMETIC AGENTS


5.1 | ANTI-‐EMETIC AGENTS

SUMMARY OF TARGETS

N.B. the chemoreceptor trigger zone (CTZ) lacks blood-‐brain barrier; so PK considerations are not important

CHEMOTHERAPY-‐INDUCED VOMITING

• Often used in combination: 5-‐HT antagonist + corticosteroids +/-‐ neurokinin receptor antagonists • 5-‐HT antagonists are not effective for delayed nausea/vomiting (>24h after chemotherapy) but the

other 2 drugs help. • Use benzodiazepines for anxiety-‐induced vomiting.

Drug Mech PK Side effects

5-‐HT3 antagonists -‐ Ondansetron

Antag. 5-‐HT3 (serotonin) receptors in GIT For acute chemo-‐induced n/v (not effectv for delayed n/v)

T1/2 4-‐9h. IV 30min / PO 1h bf chemo P450 M + renal E. -‐ Other drugs may ∆ M -‐ ↓ dose in liver dx.

• Headache, dizziness, constipation

• QT prolongation (small risk)

Corticosteroids Unknown See corticosteroids notes

Neurokinin receptor (substance P) antagonists -‐ Aprepitant (PO) -‐ Fosaprepitant (IV)

Inhibit NK1 recep in area postrema (chemoreceptor trigger zone)

M: CYP3A4 -‐ Intx w chemo agents -‐ P450 Inhibitors / inducers may ∆ M

Fatigue, dizziness, diarrhoea.

M2 PHARMACOLOGY SUMMARY 5.1 | ANTI-‐EMETIC AGENTS


DOPAMINE, MUSCARINIC, AND HISTAMINE RECEPTOR ANTAGONISTS

Class

Drug Antagonizes receptor

Dopamine M1 (muscarinic) H1 (histamine)

Site of action: CTZ* Vestibular system & vomiting ctr

Substituted benzamides Metoclopramide Y

Anticholinergics Hyosine (scopolamine) Y

Diphenhydramine Y Y

Phenothiazines

Prochlorperazine Promethazone Y Y Y

Butyrophenones Droperidol Y (weakly)

CTZ = chemoreceptor trigger zone

Notes: • Motion sickness – use hyosine, diphenhydramine

(As they act on the vestibular system, these H1 and M1 receptor antagonists are useful) • Phenothiazines & butyrophenones are also antipsychotics. • Metoclopramide is also a prokinetic

Side effects Dopamine antagonism: 1. Extrapyramidal side effects (especially in the elderly)

• Restlessness, dystonia, parkinsonian symptoms • In long term use -‐ irreversible tardive dyskinesia

2. ↑ Prolactin (dopamine is a hypothalamic hormone that ↓ pituitary PRL release)

• In females – menstrual disorders, galactorrhoea • In males – gynaecomastia, impotence

Muscarinic antagonism: Anticholinergic (parasympatholytic) activity

• Dry mouth, blur vision, constipation (transdermal hyosine ↓ SE) Histamine antagonism: Sedative (ref drugs used in cough & cold) Others: Droperidol can cause QT prolongation; the antipsychotics may cause hypotension

BENZODIAZEPINES Drug: Lorazepam & diazepam

Mech: Binds to the allosteric site on GABAA receptors, increasing chloride conductance Anxiolytic, hence reducing anticipatory vomiting (due to anxiety – e.g. before chemo) Side effects

• Sedative / hypnotic, especially in combi with other sedatives (antidepressants, alcohol, opoids) -‐ Respiratory depression on overdose

• Avoid during pregnancy (esp 1st trimester) due to risk of cleft palate

M2 PHARMACOLOGY SUMMARY 5.2 | ANTI-‐DIARRHOEALS


5.2 | ANTI-‐DIARRHOEALS GENERAL CASES

Note: in diarrhoea, first maintain hydration

Drug Use / Mech Side effects

Opoid agonists -‐ Loperamide -‐ Diphenoxylate

Act on enteric nerv sys Loperamide: does not cross BBB, Diphenoxylate: CNS effect, addiction, abuse

(tab often include atropine, a muscarinic antagonist to discourage abuse)

Bismuth subsalicylate (cf. bismuth subcitrate for H. pylori)

Traveller’s / infective diarrhoea -‐ Bind enterotoxins -‐ Antimicrobial -‐ Salicylate: inhibit prostaglandin prod & Cl secretion

• Blacken stool, darken tongue • LT use: Bi toxicity, encephalopathy

Avoid in pt with renal insufficiency • Avoid in children with viral infection:

Reye’s syn risk if salicylate + Influenza B

Kaolin, pectin Absorb bact toxin, fluid Seldom used chronically

• Constipation • ↓ Abs of other meds (space 2h apart)

Lysophilizate of killed Lactobacillus acidophilus -‐ Lacteol forte

Traveller’s / bact diarrhoea: Competive exclusion of pathogenic bact

Contraindicated in pt with lactose intolerance (contains lactose)

SPECIAL CASES Drug Use / Mech Side effects

Bile salt binding resins -‐ Cholestyramine -‐ Cholestipol -‐ Colesevelam

Diarrhoea caused by excess fecal bile salts: bind bile salt

• Bloating, flatuence • Constipation, fecal impaction • Fat malabsorption (if underlying def) • ↓ Abs of other meds (space 2h apart)

Somatostatin-‐like peptides -‐ Octreotide

Secretory diarrhoea caused by -‐ carcinoid tumors, VIPoma -‐ Vagotomy -‐ Gastric dumping syn -‐ Short bowel syn -‐ AIDS Somatostatin inhibits various hormones (gastrin, 5-‐HT, VIP) ↓ secretions & ↓ motility

• Steatorrhoea (due to ↓ pancreas sec) -‐-‐> fat soluble vit deficiency

• Gallstones (50% of pt), cholecystitis • Hypothyroidism • Bradycardia • Nausea, abdo pain, flatuence,

paradoxical diarrhoea

M2 PHARMACOLOGY SUMMARY 5.3 | LAXATIVES


5.3 | LAXATIVES Drug Use / Mech Side effects

Bulk forming agents -‐ Psyllium, Agar, Bran -‐ Methylcellulose -‐ Polycarbophil

Indigestable, hydrophillic ↑ stool mass ↑ peristalsis

Flatus, bloating, pain – Avoid if IO ↓ abs of other drugs; give separately

Softeners (stool surfactants) -‐ Docusate (PO / enema) -‐ Glycerin (supp) -‐ Mineral oil (oral)

↓ surf tension, so water can penetrate Mineral oil lubricates

Mineral oil -‐ lipid pneumonitis if aspirated -‐ impair abs of Vitamins A, D, E, K

Osmotic laxatives -‐ Sorbitol, lactulose -‐ Mg(OH)2, Mg citrate, Na3PO4 -‐ Balanced polyethylene glycol (PEG)

Water osmosis into stool ↑ Stool liquidity, volume ↑ Peristalsis, purgation PEG (or + Bisacodyl): Colon cleansing prior to colonoscopy

Flatus, cramps (action of colon bact) Need to maintain hydration Na3PO4: ↑ PO4 ↑ Na, ↓ Ca ↓ K : arrhythmia, renal ppt & ARF : Avoid if frail, on diuretics, renal dx, cardiac dx Balanced PEG is safer, no cramps

Stimulant laxatives (cathartics) -‐ Anthraquinone: Aloe, Senna, Cascara -‐ Diphenylmethane: Bisacodyl (all PO or PR)

Produce migrating colonic contractions

Anthraquinones: melanosis coli (brown pigmentation of colon) [Phenolpthalein withdrawn – cardiac toxicity]

Cl channel activators -‐ Lubiprostone

Stim type 2 Cl channel (ClC-‐2), ↑ fluid secretion ↑ Motility

Rebound constipation after d/c Avoid in pregnancy (unknown) Nausea (delayed gastric emptying)

Opioid antagonists -‐ Methylnaltrexone bromide -‐ Alvimopan

X cross BBB, X CNS effect -‐-‐> Undo constipation due to opioids -‐-‐> Post-‐operative ileus

-‐-‐> <7d use only as ? CVS toxicity

5-‐HT4 receptor agonist -‐ Tegaserod (withdrawn) -‐ Cisapride -‐ Prucalopride

Stim presyn 5HT4 recep on submucosal intrinsic 1º afferent neurons ↑ neurotransmitters (eg calcitonin gene-‐rld peptide) ↑ Peristalsis

Adverse CVS effects due to -‐ Tegaserod: 5-‐HT1B receptor -‐ Cisapride : hERG K+ channel Prucalopride ↑ affinity for 5HT4 only, CVS events less likely.

M2 PHARMACOLOGY SUMMARY 5.4 | DRUGS FOR GASTRIC ACID & ULCERS


5.4 | DRUGS FOR GASTRIC ACID & ULCERS

DRUGS TO REDUCE GASTRIC ACIDITY Drug Mech PK Side effects

Antacids -‐ NaHCO3 -‐ CaCO3 -‐ Mg(OH)2 + Al(OH)3 (Maalox, Mylanta)

Chemical neutralization; does not prevent acid production.

Liquid dissolves faster Rate of neut: HCO3 > CO3 > OH

• Na: fluid retention, CHF, hypt • Ca: Hypercalcemia, rebound acid • HCO3, CO3 : distention, belching

: metabolic alkalosis • Give Mg (osmotic diarrhea) and Al

(constipation) together to minimize SE • Renal insuff pt shd not take long term • Affect absorption of other drugs; do

not give within 2h of other drugs.

H2 blockers -‐ Cimetidine (old) -‐ Ranitidine -‐ Famotidine

Competitive inhibitor of Histamine2 receptor Suppress acid secretion -‐ Nocturnal +++ -‐ Meal induced +

Ranitidine v safe Cimetidine has many side effects and is not used anymore.

Proton pump inhibitor (PPI) -‐ Omeprazole

Pro-‐drugs activated by +H in parietal cell. Covalently bind & inhibit H+/K+ ATPase Suppress acid secretion (meal & nocturnal)

Food affects abs: OM/ON on empty stomach (1h bf meal). 3-‐4d to max effect

Very safe Minor: headache, nausea, constipation, flatulence, diarrhoea

MUCOSAL PROTECTING AGENTS Drug Mech PK Uses Side effect

Sucralfate Sucrose + sulfated Al breaks down into sucrose sulfate. Binds +ve proteins at ulcer crater -‐-‐ gives protective gel.

Not absorbed QID on empty stomach (hence uses limited)

Prevent stress-‐related bleeding in critically ill pt

No systemic effect Constipation Impair drug abs

Bismuth subcitrate potassium

1. Bi form protective layer coating ulcer beds. 2. Stim prostaglandin, mucus, HCO3 secretion 3. Antimicrobial vs H. pylori

H. pylori quad therapy. (See bismuth subsalicylate)

Safe Blacken stool Darken tongue

Misoprostol Synthetic PGE1 analogue, Bind PGE2 GPCR recep 1. Promote HCO3 & mucus sec 2. Inhibit gastric acid sec

Short t1/2, QID dosing Prevent NSAID-‐induced ulcers. Limited use now.

Abortion Abdo pain, diarr, bone pain, hyperostosis

M2 PHARMACOLOGY SUMMARY 5.4 | DRUGS FOR GASTRIC ACID & ULCERS


TREATMENT OF H. PYLORI It is now known that most gastric & duodenal ulcers are infected with H. pylori. Treatment of the ulcer itself (e.g. with anti-‐secretory therapy) is insufficient (recurrence rate 60-‐100%); an effort to eradicate H. pylori is necessary. H. pylori is inherently R to vancomycin, nalidixic acid, cotrimoxazole. Double antibiotic therapy is required as it rapidly develops R to metronidazole and clarithromycin if given alone.

(first line) Triple therapy : 2 antibiotics + PPI (second line) Quadruple therapy : 2 antibiotics + PPI + bismuth

Antibiotics used include clarithromycin, metronidazole, and amoxicillin (each comes with its own SE). By raising intra-‐gastric pH, the PPI also lowers MIC of antibiotics against H. pylori.

M2 PHARMACOLOGY SUMMARY 6.1 | ANTI-‐DIABETIC AGENTS


6.1 | ANTI-‐DIABETIC AGENTS

PHYSIOLOGY OF INSULIN Structure -‐ Human insulin contains an A chain and a B-‐chain, linked by 2 disulfide bonds. -‐ Synthetically, modifications to amino acid seq -‐-‐> different insulin preparations Production -‐ Physiological cleavage of C-‐chain from pro-‐insulin yields insulin -‐ Only endogenous insulin has C-‐chain. C-‐chain levels indicate beta-‐cell function Metabolism -‐ Reductive disulfide bond cleavage (by insulinase), then proteolysis. Stimuli -‐ Glucose -‐-‐> Increase ATP levels -‐ Amino acids Closure of ATP-‐dependent K+ channels -‐ Vagal Cell membrane depolarization -‐ Sulphonylurea Ca2+ influx -‐ Incretins. Insulin release Insulin receptors & downstream effects Mechanism -‐ Bind to insulin receptors (extracellular recognition unit + tyrosine kinase) -‐ Phosphorylate tyrosines, first of insulin receptor substrate (IRS-‐1) -‐ Activate phosphatidyl-‐inositol-‐3 kinase (PI3K), downstream signalling Affects affinity -‐ Corticosteroids: lower -‐ Salicylates: potentiate insulin release -‐ Elevated insulin downregulates insulin receptors. Effects -‐ Promote glucose uptake by upregulating GLUT4 -‐ Glycogen: ↑ synthesis ↓ glycogenolysis -‐ Protein: ↑ synthesis ↓ catabolism -‐ Fat: ↑ TG syn

INSULIN PREPARATIONS Drug Duration Onset Route Notes Lispro

Short Rapid SC Administer 15min before meal Aspart

Glulisine

Regular insulin Short Slower SC/IV/IM

Neutral protamine hagedorn (NPH) Intem

SC

Protamine (from trout semen) slowly releases insulin from binding

Detemir Fatty acid side chain: binds albumin

Glargine Long (1/day) Forms microcrystals &slowly dissoc Notes: All are clear except NPH which is cloudy. All contain Zn to stabilize insulin protein

Combinations: Mixtard = Regular + NPH.



Delivery of insulin In T1DM, there is often a need to prescribe both a long-‐acting insulin to replace basal insulin secretion, in combination with a short-‐acting insulin to handle post-‐prandial glucose peaks. Syringe in a pen is convenient for accurately delivering a specific amount of s/c insulin to periumbilical region. There is no need to carry a vial of insulin or refrigerate (stable at RT); the tiny needle allows less pain from injection. Only regular insulin can be used IM/IV, all other preparations are SC. Abdomen is preferable for SC injections because it provides consistent absorption

-‐ Short duration rapid-‐acting insulins more rapidly absorbed -‐ Deeper injection results in faster absorption.

Side effects

1. Hypoglycemia due to accidental overdose -‐ Or factitious hypoglycemia when used by non-‐diabetics for attempted suicide

2. Lipodystrophy at injection site -‐ Bovine/porcine insulin -‐-‐> Crater (lipoatrophy) Due to antigenic rxn -‐ Human insulin -‐-‐> Bump (lipohypertrophy) As insulin is lipogenic -‐ Rotate injection site to prevent lipodystrophy

3. Redness at injection site

ORAL HYPOGLYCEMIC AGENTS Class Drug Mechanism Use/Notes

Insulin

secretago

gues Sulphonylureas Tolbutamide Simulates action of glucose:

Trigger insulin release Closes ATP-‐sensitive K channel on pancreatic islet cells, depo-‐larizing the cell, causing calcium influx and insulin release.

Glibenclamide

Glipizide Fast onset, short duration

Gliclazide

Meglitinide Repaglinide Same as sulphonylureas but adjacent target site.

Prandial glucose regulator: One meal, one dose.

DPP-‐4 inhibitors Sitagliptin Inhibit dipeptidyl peptidase-‐4 ↓ Incretin breakdown ↑ glucagon-‐like peptide ↑ gastrointestinal peptide ↑ insulin, ↓ glucagon

Sensitisers Biguanides Metformin ↑ Density of insulin receptors Only works if there is

circulating insulin. Thiazolidinediones Rosiglitazone Pioglitazone

Bind peroxisome proliferator activated receptor (PPAR-‐γ) ↑ Exp insulin response gene May take several weeks.

Sparers Alpha-‐glucosidase

inhibitors Acarbose Bind glucosidases of small

intestine villi (except lactase) Slow polysaccharide digestion Blund post-‐prandial ↑ glu

Take with first bite of meal Lower HbA1c by 1% only Not as monotherapy



Other effects

Other beneficial effect: Metformin also ↓ TG levels; rosiglitazone ↑ HDL Synergism

Since the insulin sensitizers only increase the effect of insulin, and require insulin to be effective, they are often used in combination with a secretagogue (or insulin) for maximum effectiveness. Metformin with Repaglinide or Sitagliptin Rosiglitazone with Sulphonylureas or Sitagliptin or Insulin Metformin and rosiglitazone are also used in combination Acarbose is not used as monotherapy, but combined with sulphonylurea or insulin. -‐ Acarbose not with metformin: both cause GIT discomfort & acarbose interferes with metformin abs Pharmacokinetics

Class Drug Liver Renal Prot binding Notes

Insulin

secretagog

ues

Sulphonylureas Tolbutamide M Y

Glibenclamide M* * Y *Active metabolites accum in renal failure

Glipizide M

Gliclazide M

Meglitinide Repaglinide M E Caution on liver/renal dx

DPP-‐4 inhibitors Sitagliptin E ↓ dose in renal pt

Sensitis

ers

Biguanides Metformin E

Thiazolidinediones Rosiglitazone Pioglitazone M then E

Spar

ers

Alpha-‐glucosidase inhibitors

Acarbose In gut <2% E

renal Not absorbed



ORAL HYPOGLYCEMIC AGENTS: SIDE EFFECTS General

1. Hypoglycemia -‐ Esp glibenclamide. Rarer with tolbutamide, sitagliptin etc.

2. Liver damage (↑ AST/ALT) -‐ Tolbutamide, Gliclazide (rare), Rosiglitazone, Acarbose (if high dose). -‐ Avoid rosiglitazone in liver impaired pt

3. Allergy: sulphonylureas, sitagliptin.

Particular

Metformin -‐ GIT (common) -‐ Metallic taste

-‐ Lactic acidosis (serious): esp with liver dx, ↑ alcohol, shock/hypoxaemia -‐ Megaloblastic anemia & neuropathy, due malabsorption and def of folate /B12 Rosiglitazone -‐ Contraindicated in cardiac failure (esp with insulin) -‐ Fluid retention: apparent ↓ Hb, hematocrit, WBC Tolbutamide -‐ Hypothyroidism, nephrotic syndrome, weight gain -‐ Teratogenicity (avoid in women of child-‐bearing age) Acarbose -‐ Contraindicated in chronic inflammatory dx of intestine Gliclazide -‐ Hematological Sitagliptin -‐ Upp resp infection, headache

ORAL HYPOGLYCEMIC AGENTS: INTERACTIONS

Sulphonylureas ↑ Effect Acute alcohol intake, Isoniazid -‐ Inhibit metabolism Sulphonamides -‐ Compete for metabolism NSAID, phenylbutazone -‐ Displace plasma prot binding ↓ Effect Chronic alcohol, rifampicin, phenobarbitone -‐ Induce metabolism Glucocorticoids -‐ Enhance glycogenolysis, gluconeogenesis Oral contraceptive -‐ Insulin resistance Phenothazines, thiazides, diazoxide -‐ ? interfere with insulin release ↑ Effect ↓ Effect

? Effect Propanolol -‐ ↓ Adrenaline ↓ glycogenolysis -‐ ↓ Glucose-‐induc insulin rel ↓ glycogen release . Thyroid hormones -‐ ↑ use of glucose -‐ ↑ Glucose abs Thiazolidinediones: -‐ Gemfibrozil inhiits metabolism and increases levels.

M2 PHARMACOLOGY SUMMARY 6.2 | DRUGS FOR THYROID DISORDERS


6.2 | DRUGS FOR THYROID DISORDERS

THYROID REPLACEMENT DRUGS

Class Drug PK A

Synthetic hormone

L-‐thyroxine (T4) Long t1/2 (7d) PO 1/d (or IV) Higher dose in child

A 80%. ↓ if on -‐ Al antacids -‐ Sucralfate -‐ Fe supplements -‐ Cholestyramine

Liothyronine (T3) Shorter t1/2 (1-‐2d) Multiple daily dose

Almost 100%

Uses

L-‐thyroxine preferred 1. Replacement therapy for hypothyroidism

2. Suppress TSH release in TSH-‐dependant thyroid cancers.

Liothyronine for 3. Myxoedemic coma

Side Effects

1. CHD, MI: Increase myocardial O2 DD, potentiate effects of catecholamines -‐ Increase dose stepwise in at-‐risk (older pt, long-‐standing hypothyroid, CVS dx) -‐ Monitor for arrhythmias, angina pectoris

2. Toxicity if overdose -‐ Thyrotoxic state (nervous, heat intolerance, tachy/palpitations, wt loss) -‐ Accelerated growth and early bone maturation in children

ANTI-‐THYROID DRUGS

Class Drug PK

Ionic inhibitor Perchlorate (ClO4)

Thiocyanate (SCN-‐)

Pertechnetate (TcO4)

Thioamide Propylthiouracil (PTU) T1/2 = 1-‐2h Protein bound: Does not cross placenta

Carbimazole T1/2 = 3-‐6h Actv metabolite T1/2 = 3-‐6h

Less protein binding: Cross placenta, sec in milk

Iodides Lugol’s iodine (5% I2 + 10% KI)

I2 reduced before abs Crosses placenta

Radioactive iodine 131I

M2 PHARMACOLOGY SUMMARY 6.2 | DRUGS FOR THYROID DISORDERS


Class Uses & Mech SE & Disadvantages

Ionic inhibitor Compete with I-‐, block iodide trapping

Bone marrow toxicity: fever, anemia Rash, kidney/liver toxicity No longer used

Thioamides Block T3, T4 synthesis (slow onset) -‐ Oxidation I-‐ -‐-‐> I2 -‐ Binding of I to tyrosine -‐ Coupling of MIT, DIT to T3, T4 Uses -‐ Thyrotoxicosis (avoid surgery) -‐ Waiting for operation or 131I * Give PTU in pregnant women

A rthralgia B one marrow suppression C holestatic jaundice D rug rash E nlarged LN F ever H ypothyroidism -‐ overtreatment -‐ fetal (Carbimazole) Slow onset

Iodides 1. Prophylaxis vs endemic goiter

2. Tx thyroid storm (immediate) -‐ Inhibit T3 & T4 release -‐ ↓ I2 uptake, organification, coupling

3. Pre-‐op: ↓thyroid vascularity (1-‐2wk) -‐ Easier surg, protect rec laryngeal n

1. Iodism fr chronic overuse: -‐ Fever, rash -‐ Bleeding -‐ Rhinorrhoea, conjunctivitis, sialadenitis, mucous mem ulcer -‐ Metallic taste

2. Fetal goiter

3. Exacerbatations of thyrotoxicosis following withdrawal

4. Delay onset of thioamides Prevent use of 131I for wks

Radioactive iodine

Emit beta & gamma radiation -‐ Beta: localized rad, lim penetration -‐ Convenient & inexpensive -‐ Slow onset (1-‐2m to start, 4m to peak)

1. Hypothyroidism in later life

2. Contraindicated in -‐ Child (DNA damage, carcinogen) -‐ Pregnancy / nursing (fetal thyroid)

CLINICAL NOTES

Thyrotoxicosis

While waiting for diagnosis, thioamide response, or operation. adjunct beta-‐blocker (e.g. propranolol) can be used to quickly relieve sympathetic over-‐reactivity

Thyroid storm (thyrotoxic crisis)

• IV iodides : quickly block release of thyroid hormone • Propanolol : block sympathetic activity • Hydrocortisone : protect from shock, block T3 to T4 conversion • Initiate antithyroid drugs (e.g. PTU) to reduce hormone synthesis & T3 to T4 conversion • Supportive management: fluids, oxygen, anitpyretics, digitalization.

M2 PHARMACOLOGY SUMMARY 7.1 | NSAIDS


7.1 | NSAIDS NON-‐SELECTIVE NSAIDS Aspirin:

An irreversible COX (cyclo-‐oxygenase) inhibitor which blocks prostaglandin synthesis

Effect Mechanism: ↓ prostaglandin causes…

1. Anti-‐inflammatory : ↓ vasodilation, ↓ increase in vascular permeability

2. Analgesic : ↓ sensitization of nociceptive fibres to stim by inflammatory mediators -‐ Also via CNS effect -‐ Has analgesic ceiling as it does not block direct nociceptive activation

3. Antipyretic : Act on hypothalamus & reset thermostat (but do not alter a normal temp)

4. Antiplatelet : Block TXA2 (platelet aggregation) > Block PGI2 (inhibition) -‐ Blocks both PGI2 is restored faster by synthesis of new COX TXA2 is restored only by formation of new platelets -‐ Low dose aspirin useful as a blood thinner for CVS dx (main use now)

Other NSAIDs PK Notes

Naproxen Long T1/2 (12-‐24h) More effective in women: dysmenorrhea

Indomethacin Strong anti-‐inflamm, steroid-‐like ↓ PLA2 CNS SE: confusion, depression, psychosis

Diclofenac Short T1/2 (<2h) Less GI risk due to short T1/2 But longer T1/2 in synovial fluid

SIDE EFFECTS OF NSAIDS Effects are dose dependant and may be stronger for aspirin as it is an irreversible inhibitor SE Presentation Mech

GIT Dyspepsia, n/v, ulcer Prostaglandins have a protective func to ↓ acid, ↑ bicarbonate & mucus

Renal Edema, hypertension ↓ PGE2 (inhibits reabs), ↑ Na+ & H2O reabs at TAL

Hyperkalemia, ARF ↓ PGI2 (stim RAAS), ↓ renin & aldosterone . Does not offset ↑ Na+ & H2O reabsn due to PGE2 as the effect of ↓ PGE2 causes little Na

+ would reach the DCT on which aldosterone acts.

Pseudo-‐allergic Rash, itch, nasal congestion, anaphylaxis

Inhibition of arachidonic acid -‐-‐> prostaglandins Shunt arachidonic acid to produce leukotrienes

Asthma Bronchospasm in susceptible

Bleeding Bruising, bleeding etc Due to antiplatelet activity.

M2 PHARMACOLOGY SUMMARY 7.1 | NSAIDS


Reye’s syndrome

Aspirin is not to be prescribed to children with viral infections as it may cause Reye’s syndrome. Symptoms: encephalitis, liver swelling, vomiting, delirium, convulsions, loss of consciousness. Pregnancy

Avoid NSAIDs in third trimester of pregnancy. May cause premature closure of ductus arteriosus.

COX-‐2 INHIBITORS

Coxibs, e.g. celecoxib

Mechanism

Selective inhibition of COX-‐2 (inducible) reduces GIT side effects. Mainly as an anti-‐inflammatory and analgesic, anti-‐pyretic effect not marked.

Side effects

It was later found that there is also constitutive COX-‐2 at various sites, leading to these SEs:

1. Renal toxicity : due to COX-‐2 in kidney

2. Effects on ovulation : inc delayed follicular rupture

3. Contra in pregnancy : premature closure of ductus arteriosus

4. GIT sparing incomplete : due to impairment of wound healing

5. Increase risk of thrombosis : ↑ CVS death -‐ COX2 produces PGI2 (inhibit) but not TXA2 (clot) -‐ Block COX2 disrupts balance btw TXA2 & PGI2 production -‐ Shunts more arachidonic acid to COX1, prod TXA2 > PGI2

PARACETAMOL (ACETAMINOPHEN) Thought to be a CNS-‐selective COX inhibitor.

• May also involve serotonin relays or receptors. • Metabolite AM404 may modulate pain transmission by inhibiting cannabinoid reuptake, activating

transient receptor potential vanilloid 1 (TRPV1) receptor, or inhibiting COX. It is a good analgesic and potent antipyretic, safe for children with few side effects. Not potent as an anti-‐inflammatory. Side effects

• Liver damage (exacerbated by chronic alcoholism, or due to overdose) • Allergy • Nausea / vomiting.

Similar to the

non-‐coxibs

M2 PHARMACOLOGY SUMMARY 7.2 | ANTI-‐ARTHRITIC DRUGS


7.2 | ANTI-‐ARTHRITIC DRUGS OSTEOARTHRITIS 1. Pain relief : NSAIDs (or paracetamol, coxib)

: Corticosteroids

2. Viscosupplementation : intra-‐articular hyaluronic acid -‐ Shock absorption, lubrication, induce hyaluronic acid syn.

3. Symptomatic slow-‐acting drugs : Chrondroitin : Glucosamine

GOUT Approach:

• Acute tx with an anti-‐inflammatory: NSAIDs, steroids, or colchicine • Prevent further episodes with anti-‐hyperuricemic agents (allopurinol, probenecid) • Avoid drugs that induce hyperuricemia (thiazide, aspirin, cyclosporine A)

Drug Mech SE

Anti-‐infla

mmatory

NSAIDs

Corticosteroids

Colchicine Relieves pain in 12-‐24h -‐ Bind tubulin, -‐ ↓ polymerization to microtubules -‐ ↓ leukocyte migration, phagocytosis -‐ ↓ leukotriene prod

-‐ Diarrhoea, N/v -‐ Hepatotoxicity

Anti-‐hype

ruric

emic

Xanthine Oxidase Inhib -‐ Allopurinol -‐ (Febuxostat)

↓ Uric acid prod from purines Useful in gout & urate nephrolithiasis

-‐ Stevens-‐Johnsons esp if renal impairmt or on thiazides.

-‐ GIT -‐ Peripheral neuritis

Uricosuric agents -‐ Probenecid -‐ (Sulfinpyrazone)

↑ uric acid excretion -‐ Org acid, compete for anion tpt -‐ Hence ↓ uric acid reabsorption

-‐ Maintain large urine vol to minimize calculi formation

-‐ Keep urine pH > 6 (give alkali) -‐ GIT, rash -‐ Nephrotic syn.

M2 PHARMACOLOGY SUMMARY 7.2 | ANTI-‐ARTHRITIC DRUGS


RHEUMATOID ARTHRITIS Anti-‐inflammatory

• NSAIDs for immediate relief • Glucocorticoids to halt progression

Non-‐biologic DMARDs

• Methotrexate is the first line drug • Often used in combination (Methotrexate + another drug)

Drug Mech SE

Methotrexate

1. Inhibit AICAR transformylase. -‐ Adenosine accumulation -‐ Activate adenosine recep, anti-‐inflam

SE -‐ Myelosuppression, ulcers -‐ Teratogenic -‐ Hepatic fibrosis, pneumonitis Precautions: -‐ Monitor albumin, ALT, CBC, creatinine

-‐ Give concomitant folic / folinic acid

2. Folic acid analogue, ↓ folic acid syn -‐ thymidylate synthetase -‐ dihydrofolate reductase ↓ DNA syn, ↓ T cell proliferation

Downregulate immune response

Hydroxychloroquine Anti-‐malarial drug Best tolerated DMARD

Biologic DMARDs Drugs : Anti TNF-‐alpha : Anti IL1 : Anti IL6 Indication : RA patients who do not respond well to conventional DMARDs : Use in combination with methotrexate. Side effect : Infection (avoid in Hep B pt, screen for TB, avoid live vaccines) : Malignancy

M2 PHARMACOLOGY SUMMARY 8 | CENTRAL NERVOUS SYSTEM DRUGS


8 | CENTRAL NERVOUS SYSTEM DRUGS Only bolded drug names are need to know

1. BENZODIAZEPINES: ANXIOLYTICS & HYPNOTICS

Use: Anxiolytic Hypnotic i.e. sleeping pill (↑ dose) -‐ Relax pt for surgery, colonoscope -‐ Stop febrile fit in child (midazolam)

[However drug-‐induced sleep has less REM and deep (stage 4) sleep] Mechanism: Bind to BZD sites of the GABA receptor – Cl ion channel cplx (in the CNS) Potentiate GABA action, ↑ frequency of Cl channel opening GABA dependent (does not open channels in absence of GABA)

• Higher TI: overdose with BZD alone does not kill (but may be lethal if BZD interact with alcohol and other CNS drugs)

• Cf. barbiturates: non-‐GABA dependent and lethal in overdose due to permanent opening of Cl channels

Drugs

Drug Mode PK

Short acting (2-‐4h) Midazolam

PO: Fast o

nset (0

.5-‐1h)

IV Rapid clearance: may evade forensic detection in urine if used criminally

Intemediate (10h) Lorazepam IV

Alprazolam

Long acting (24h) Diazepam IV Long acting active metabolites

Can accumulate Furazepam

Side effects 1. CNS: Drowsiness, ↑ reaction time, ↓ motor skills (dose dependant)

-‐ May precipitate falls; caution against driving

2. CNS: Anterograde amnesia (esp after IV)

3. CVS: ↓ BP, ↓ Respiration in susceptible patients

4. Paradoxical: Excitement, garrulousness, irritability, hallucination, rage, violence -‐ Due to disinhibition by benzodiazepines

5. Neonatal toxicity: Floppy child syndrome when given to expectant mothers before delivery

6. Tolerance, dependence, and withdrawal. Need larger dose to have the same effect with time.

Non-‐benzodiazepine hypnotics Zolpidem, zopiclone

Act on BZD sites, having the same hypnotic effect and adverse effects



2. ANTI-‐DEPRESSANTS

Theory: Monoamine deficiency is responsible for depression. Hence correcting this deficiency treats depression

SSRI (Selective serotonin reuptake inhibitor)

TCA (Tricyclics)

Drugs Fluoxetine (Prozac) Escitalopram, Sertraline, Paroxetine

Amitriptyline Imipramine

Mech Inhibit serotonin transporter Inhibit norepinephrine & serotonin tptr

↓ re-‐uptake: neurotransmitter accum in synapse, correcting monoamine deficiency Has trophic action, ↑ BDNF, neuronal survival

Advantage No fatality in overdose Gold standard; most effective

SE Anxiety Weight loss, gain Headache, nausea Sexual dysfunction SSRIs are liver enzyme inhibitors: beware of drug interactions

Mech: norepinephrine (parasymathetic) block

-‐ CVS: Tachycardia, Arrhythmia, Postural hypotension

-‐ Anti-‐ACh: Glaucoma, blurred vision, Dry mouth, constipation, Urinary retention

-‐ CNS: Sedation, fatigue

3. ANTI-‐PSYCHOTICS

Theory: Psychosis arises due to § Excessive dopamine in mesocortico-‐limbic system § Abnormality in 5-‐HT, glutamate, and other pathways

Schizophrenia is a subgroup of psychosis with delusion, hallucination, avolition etc Mech: Antipsychotics treat symptoms (not underlying cause) of psychoses

§ Block dopamine receptors § But not specific to dopamine receptors or mesocortico-‐limbic system (‘dirty drug’),

causing many side effects

N.B. It is not possible to directly downregulate dopamine as that causes Parkinsons’

Typical antipsychotics (1st gen) Atypical antipsychotics (2nd gen)

Drugs High potency: Haloperidol Low potency: Chlorpromazine, Trifluoperazine

Clozapine, Olanzapine, Risperidone, Quetiapine

Diff Block D2 > 5-‐HT2 receptors Block 5-‐HT2 > D2 receptors

ADR More: also block other receptors (cholinergic, histaminic, alpha adrenergic)

May also block other receptors But no / less extrapyramidal SEs



SEs: typical antipsychotics 1. Extrapyramidal: Due to block of dopamine receptors in basal ganglia (EPS effects)

-‐ Acute dystonia : Muscle spasm, easily confused w meningitis -‐ Parkinsonism: : Bradykinesia, rigidity, tremor etc -‐ Akathisia : Urge to move abt -‐ Malignant syn : Catatonia, fever, unstable BP, can be fatal -‐ Tardive dyskinesia

2. Antiadrenergic: Postural hypotension, sedation

3. Anticholinergic: Dry mouth, etc

4. Metabolic: Weight gain

5. Allergy [Low potency antipsychotics are more toxic and hence infrequently prescribed]

SEs: atypical antipsychotics

Clozap

ine

Olanzap

ine

Risperidon

e

Quietap

ine

Effect Notes

Y Agranulocytosis In 2% of pts. Pt may hv infection but no fever Warn pt to go to A&E if they have any sore throat etc

Y Extrapyramidal SE Dose-‐dependant

Y Y Y Y Weight gain More severe in clozapine, olanzapine

Y Y Sedation

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