AUTACOID & ANTI-INFLAM DRUGS Autacoids : subs that initiate & sustain inflam & immune response activate the repair process localy acting hormones examples : amino acids derivatives histamine 5-ht

Morphine Tubocurarine Certain radiocontrast media Trimetaphan Deferoxamine

H2 Receptors Distribution: gastric mucosa, cardiac ms Effect: Inc gastric HCl & Pepsin secr Inc cardiac contractility & HR H3 Receptors Distributon: CNS Action: wakefulness, modulation of other transmitter release H4 Receptros Distribution: various inflam cells Action: regulation of inflam response

vasoactive peptides angiotensin kinin endothelins eicosanoids

Fatty acid derivatives

Family of cytokinesInterleukins TNF Interferones Growth fc

Histamine Formed from amino acid histidine. Stored mainly in mast cells Non-mast cell histamine found in several tissue brain : neurotransmitter Synthesis/metab : not affected by any clinically useful drug Certain drugs cause the release from mast cell Pharmacological Actions of Histamine Acts on at least 4 ,types of receptors H1 Receptors Distribution: neuronal tissue, bl vs, sm ms Effects: Intense VD e increased cap. Permeability, flare & swelling Pain & itching Constriction of airway & GIT sm ms Inc bronchial/intestinal secr. Dec of systolic/diastolic bl pressure Histamine Releasers

Histamine Antagonist Physiological antagonist: Adrenaline Sm ms actions opposite to histamine Act at diff rec Histamine rec. antagonist: H1-blockers - Diphenhydramine - Loratidine H2-blockers - Cimetidine - Ranitidine - Famotidine H3 & H4-blockers (not available) Histamine Release Inhibitors: Inhibit Ca2+ influx into mast cell prevent degranulation Ketotifen Cromoglycate Immunotherapy Process allergic patient can become desensitized to pollens/inhalants that trigger allergic patient response H1-Rec Antagonist (AntiHistamine) 1st Generations Ethanolamines

Clemastine Diphenhydramine Dimenhydrinate Ethylenediamines antazoline Piperazines Cyclizine meclizine Alkylamines Chlorpheniramine Phenothiazines Promethazine Others Cyproheptadine

Dec bronchoconstriction & bronchial secr.

Not Related to H1-rec Blockage (1st-Gen. only) Sedation (marked excitation, convulsions in some cases) Antiemetic Action: prevent motion sickness Antiparkinsonian Action: ability to block central muscarinic rec. in extrapyramidal syst.[Diphenhydramine] Anticholinergic Action: most can block peripheral muscarinic rec urine retention & blurred vision Alpha-rec Blocking Action: cause orthostatic hypotension [Promethazine]

2nd-Generations Loratidine Azelastine Fexofenadine Cetirizine Pharmacokinetics Absorption: rapidly after oral admin.

5-HT rec Blocking Action: useful drug to treat Carnicoid syndrome & as appetite stimulant Local Anesthetic Action: block sodium channels in excitable membranes

Clinical Uses of H1-BlockersType equation here. Allergic condition: In which histamine is 1 mediator [allergic rhinitis/urticaria] effective In bronchial asthma largely ineffective Motion Sickness & Vestibular Disturbance: Scopolamine & 1st-Gen : efficacy I Meniers syndrome is not established Carcinoid Syndrome: Caused by serotonin-secreting neoplasm of enterochromaffin cells When tumor not operable, use of cyproheptadine & other 5-HT blockers is useful. Side Effect of H1 Blockers

Distribution: widely throughout the body 1st-Gen. drugs enter CNS readily Metabolism: most by hepatic microsomal enzyme several 2nd-Gen by CYP3A4 syst. [important interactions when given with other drugs (ketoconazole) that inhibit this subtype of P450 enzymes]

Pharmacological Effects Related to H1-rec Blockage (antiallergic react) Alleviation of itching, pain & allergic resp. Dec cap permeability & inflam. edema

1st-Gen: Sedation Anticholinergic Act Orthostatis Hypotention Drug Allergy (common aftr topical use) 2nd-Gen: Dangerous arrhythmia (torsade de pointes) due to prolongation of QT-interval Drug Interactions: 1. Several 1st-Gen: potentiate Central Depressant Action sedatives, hypnotics, alcohol 2. Several 2nd-Gen: metabolized by CYP3A4 syst. Dangerous Arrhythmia when given e other drugs that inhibit this subtypes of P450 enz. H2-rec Antagonist Dec HCl in acid-peptic disease

sumatriptan zolmitriptan naratriptan

activate 5-HT(1B/1D) rec. cause VC of dilated cerebral vs inhibit release of VD peptides alleviation of acute attacks of migraine headache Side Effect: coronary VC C/I = ischemic Heart Disease

5-HT Antagonist Cyproheptadine Block 5-HT, H1 & muscarinic rec. ttt: symtoms of carcinoid tumor allergic Side Effect: Atropine-like action (dry mouth/ urine retention)

Serotonin (5-hydroxytrypyamine; 5-HT) Formed from amino acid tryptophane Stored mainly in chromaffin tissue Synthesis/metab : not affected by any clinically useful drug Many drugs act on 5-HT as agonist/antag. Pharmacological Action: Act on at least 7 types of receptors During inflam, 5-HT can affect bl vs tone via activation of 5-HT receptors 5-HT Agonists: Buspirone Activate central 5-HT(1A) rec. Selective & non-addictive anxiolytic ttt: anxiety (esp-in elderly patients)

Ketanserin Block 5-HT(2) rec in platelet Inhibit 5-HT promoted platelet aggregation Block vascular alpha-1 adrenoceptor -> VD ttt: hypertension, vasospastic conition Side Effect: mild dizziness, fatigue Ritanserine Similar to Ketanserin but has little/no alpha-1 blocking action Ondansetron Selectively block central/peripheral 5HT(3) rec (CTZ/GIT) ttt: nausea, vomiting associated e surgery, cancer chemotherapy Alosetron block 5-HT(3) ttt: severe irritable bowel syndrome e diarrhea Renin-Angiotensin-Aldosterone System

Triptan

plays an important role in regulating bl volume & systemic vascular resistance influence cardiac output & arterial pressure

Inhibitors: Drugs which inhibit Renin release - Beta blockers - Clonidine - Alpha methyl dopa - Prostaglandin inhibitors (indomethacin) Drugs which inhibit Renin - enalakrine - pepstatin Drugs which inhibit conversion of Ang I Ang II - Angiotensin Converting Enz Inhibitors (ACEIs) > Sulph-hydryl containing ACEIs > ACEIs without sulph-hydryl group > ACEIs inhibitor which contain phosphinate group - Fosinopril Angiotensin II rec blockers - Saralasin - Losartan - Valsartan

Pharmacological Effect of Angiotensin II Acts on at least 2 subtypes of rec.: AT1 rec; Distribution: vascular/renal tissue, cardiac ms, CNS Effects: VC Inc aldosterone/vasopressin secr Inc peripheral noradrenergic act Modulation of central symp actvty Central osmocontrol Cardiac hypertrophy Vascular sm ms cells proliferation Extracellular matrix formation AT1 rec; Distribution: fetus/ neonate Effects: Inhibition of cell growth Fetal tissue development Modulation of extracellular matrix Apoptosis Cellular differentiation VD (maybe) DRUGS ACTING ON R-ANGIOTENSIN SYST.

KININ Potent VD peptides Formed from Kininogen by effect of kallikrein enz Pharmacological Action of Kinins: Acts on at least 2 subtypes of rec.: B1, B2 VD of arterioles & VC of venules inc cap permeability & breaf fall of bl pressure Contraction of sm ms (BC, GIT colic) Stimulation on sensory nerves pain

Kinin rec Antaginist: Kinin B2 rec blockers under trials ttt inflam. & neurogenic pain Synthesis of kinins inhibited by kallikrein inhibitor : aprotinin

ENDHOTHELINS VC peptide Produced by endothelium 3 isoforms Endothelin 1 = strongest VC

Derived from arachidonic acid [by action of cyclooxygenase enz-has 3 isoforms] 1. COX-1 (physiological/constitutive) Synth. of protective PGs: PGE2, PGI2 > protection of stomach fr HCl > reg of RBF > inhibition of platelet aggregation 1. COX-2 (pathological/inducible) Synth. of undesirable PGs: PGF2, PGD2 > inflam reaction > BC 1. COX-3 (central) Only found in brain Synthesis PGs responsible for fever & pain sensation Selectively inhibited by analgesic/ antipyretic drugs : acetaminophena & dipyrone

Pharmacological Effect Act at least 2 subtypes of rec: ET(A), ET(B) ET(A) rec Distribution: sm ms of vascular/other tissue Effects: Potent VC Vascular sm ms proliferation Cardiac hypertrophy Sodium retention Prolong elevation of bl pressure

ET(B) rec Distribution: vascular endothelial cells Effects: Diuresis Natriuresis Transient dec of bl pressure

Therapeutic Uses of PGs PGE1 ttt: erectile dysfunction (men) Alprostadil peptic ulcer [dec HCl, inc gastric mucus secr] Mesoprostol during surgery of cong great vs transposition in infants (i.v) Alprostadil : maintain VD patency of ductus arteriosus pulmonary vascular bed prevent hypoxia PGE2 Induction of Abortion/facilitation of labor [stimulate uterine contr] Dinoprostone ttt: peripheral vascular disease

Endothelin rec Antagonist: Non-selective: Selective [ET(A)]: Uses: Bosentan Sitaxentan

ttt essential/pulm. Hypertension Ischemic Heart Disease Cardiac hypertrophy Heart Failure

PROSTAGLANDINS

:TXs & LTs no clinical uses: PGI2 Prevent platelet aggregation Prostacycline : Thrombotic disorders Cardiopulmonary bypass surgery Hemodialysis Retinal artery occlusion ttt: pulm.hypertension peripheral vascular disease Leucotriene Inhibitor: Zafirlukast & Montelukast Block leukotriene rec Absorbed orally Zafirlukast : twice daily Montelukast : once daily

Uses: ttt - bronchial asthma & other inflam cond. Zileuton Inhibit 5-lipooxygenase enz dec LTs synth. Uses: ttt - bronchial asthma & other inflam cond.

PGF2 Induction of Abortion/facilitation of labor Enzaprost ttt: open-angle glaucoma [enhance uveoscleral outflow of aqueous humor] Latanoprost

THROMBOXANES (TXs) Products of cyclooxygenase enz Synthetized in high concentration in platelets 2 forms : TXA2 (active), TXB2 (inactive) TXA2 most potent endogenous stimulator of platelet aggregation

Inhibitors Of Eicosanoid Synthesis Corticosteroid Inhibit phospholipase A2 enz consequently all eicosanoids family Non-Steroidal anti-inflam (NSAIDs) Inhibit cyclooxygenase enz

&

drugs

LEUKOTRIENES (LTs) Derived from arachidonic acid by the action of lipooxygenase enz 4 main types : LTB4, LTC4, LTD4, LTE4 Mixture of LTC4, LTD4, LTE4 = released during inflam response [termed > SRS-A (slow-reacting subs of anaphylaxis)] LTB4 powerful BC & chemotactic for leucocytes

Classical NSAIDs : inhibit both COX-1 & COX-2 non selectively i. Aspirin ii. Ibuprofen Newer NSAIDs : inhibit COX-2 selectively (induced during inflam) i. Celecoxib

Leukotriene Inhibitor : see B4 Pharmacological Action of Eicosanoids

Act on cell surface seven-transmembrane rec (G-protein coupled rec) NSAIDs 1. Non selective COX inhibitors Salicylic acid derivatives Aspirin Aloxiprine Aminosalicylic acid Diflunisal Methyl salicyliate Acetic acid derivatives Carboxylic acetic acid i. Indomethacin ii. Sulindac iii. Etodolac Phenyl acetic acid i. Diclofenac

Chemistry: White crystalline subs Stable in dry air Hydrolyses in moist air -> salicylic & acetic acid Pharmacokinetics: Absorption Oral absorption complete & rapid (peak level after 2 hrs Most absorption stomach & upper GIT Rectal absorption slow & regular Distribution Widely to all tissue including CNS Plasma prot binding high Metabolism/Excretion Metabolism by hepatic microsomal enz Elimination : Low doses - 1st order process Elimination : High doses Zero order pro. Excretion inc by alkalinization of urine (pH8)

Propionic acid derivatives Iboprufen Ketoprufen Fenoprufen Naproxen Fenamic acid derivatives Mefenamic acid Fulfenamic acid Pyrazolone derivatives Phenylbutazone Azapropazone Oxicams Piroxicam Tinoxicam

Mech of Action Non selective COX inhibitor inh. of PGs/TXs Pharcological Effects Analgesic effect: Mild/med intensity pain (not severe) Mech dec PGS synth i. Peripheral in peripheral inflamed tis ii. Central in thalamus/hypothalamus Antipyretic effect: Not hypothermic agent (can lower elevated body temp, not normal temp) Mech i. Dec PGE2 synth in hypothalamus ii. Dec hypothalamic response to IL-1 iii. Cutaneous VD/inc sweating

1. Selective COX-2 inhibitors Celecoxib Valdecoxib Meloxicam Aspirin/acetylcsalicylic acid

Anti-inflam, rheumatic

anti-immunological,

anti-

Mech i. ii.

iii. iv. v. vi. vii.

Dec PGs synth & other inflam med. Decreased Leucocytes Margination, Emigration, Migration (fr blood -> site of inflam) Stabilize lysosomal membrane Dec cap permeability Dec synth of mucopolysaccharides (form ground subs) Dec hyaluronidase enz & spread of inflam Analgesic/Antipyretic effects

Hypersensitivity Bronchospasm, urticaria, skin rash, shock More in bronchial asthma GIT Epigastric pain, nausea, vomiting Acute/Chr gastric ulcers Hepatic Mild hepatic injury Severe hepatic injury (child) Reyes syndrome Kidney Analgesic nephropathy Salt/Water retention Dec diuretic effect of loop diuretic Dec anti-hypertensive effect of blocker Precipitation of acute gout (low D) in hyperuricemic patient

Therapeutic Uses Salicylates a. Anelgesic Headache Arthritis Rheumatic pain a. Antipyretic Not used routinely a. Anti-inflam/anti-rheumatic Rheumatic fever Rheumatoid arthritis Osteoarthritis a. Antithrombotic Ischemis heart dis Deep vein thrombosis AF a. Cancer colon & Alzheimers dis Thru COX inhibition a. Keratolytic ttt warts (salicylic acid) counter irritant local rheumatic pain (metylsalicylic acid) Side Effect

Blood Inc bleeding tendency Displacement of other plasma prot drugs fr

Male/Female reprod. Fc Prolonge pregnancy delay labor Reversible infertility male Drug interactions 1. Antagonizes uricosuric effect of probenecid 2. Antagonizes diuretic effect of loop diuretic 3. Antagonizes anti-hypertensive effect of blocker/ACEIs 4. Inc plasma conc of anticoagulants (heparin/warfarin), phenytoin, thyroxin & others inc effect/toxicity 5. Antacids dec aspirin absorption Salicylate toxicity

Acute toxicity Cause: ingestion of large D of salicylates Manifestatons: i. Nausea, vomiting, hematemesis ii. Acidosis, dehydration iii. Pulm. Edema, CVS collapse iv. Hyperpyrexia, hyperventilation, coma Treatment: i. Repeated gastric lavage e activated charcoal ii. Cold fomentations hyperpyrexia iii. Vit K -> control he iv. i.v fluid -> dehydration v. i.v sodium bicar. -> acidosis vi. Alkalinization of urine -> enhance salicylate excretion vii. Hemodialysis (severe case)

1. 2. 3. 4. 5. 6. 7. 8. 9.

GIT : peptic ulcer, gastritis He : Hemophilia, thrombocytopenia Ch. Renal dis : Renal Art stenosis, RF Ch. Liver dis : Bleeding tendency CVS dis : CHF, sev. HTN Gout Pregnancy B4 surgery Child (< 12 yrs) -> Reyes Syndrome

Selective COX-2 inhibitors Reduces risk of peptic ulcer Inc risk of CVS accidents (inc in TXA2 & platelet aggr.) i. Myocardial infarct. ii. Thrombosis iii. Stroke

Chr. Toxicity Cause: prolonged admin. Manifestations: i. Headache ii. Tinnitus iii. Tachypnea iv. Resp. alkalosis Treatment: i. Stop salicylates (cond. is reversible)

Acute Rheumatic Fever Goal of therapy 1. Suppression of the acute inflam. response 2. Prevention of complication 3. Eradication of streptococcal inf. 4. Prevention of recurrence Non Drug-therapy Absolute bed rest Aim : avoid cardiac complication Duration : 2 weeks : in absence of carditis 4 weeks : in presence of carditis 8 weeks : in presence of Heart Failure/cardiomegally Salt & Fluid restriction In presence of carditis/HF avoid volume overload & cardiac strain Drug Therapy

Precautions & C/I

1. Eradication of streptococcal inf 1st choice : penicillin-G nd 2 choice : Co-trimoxazole Erythromycin 1. Suppression of acute inflam Salicylates (aspirin/Na salicylamide) Indication: acute rheumatic fever wo carditis Mech : Analgesic action Antipyretic action Anti-inflam/rheumatic Corticosteroid Indication: acute rheumatic fever e carditis Mech : Anti-inflam/rheumatic

1st-line Drugs (background therapy) 1. NSAIDs Symptomatic relief Not prevent joint destruction Large D required

1. Corticosteroid Bridging therapy (during DMARDs not take effect yet) By direct injection in affected joint 2nd-line Drugs (dis-modifying drugs-DMARDs) antirheumatic

Prevent progressing of dis Slow down joint destruction Effect takes 6w 6m to be evident Combination 2/more more effective

1. Prevention of recurrence (prophylaxis) Long-acting penicillin : Benzathine penicillin When stop? Severe carditis/recurrent ARF : life Mod. Carditis: till 21 yrs Mild/No Carditis: 3 yrs fr last episode

Methotrexate 1st choice used >60% of RA cases Used in much lower D needed in cancer chemo. Mech: inh multiple intracellular enz (for activation of PMLs, T cells & macrophage) Hydroxychloroquine (AntiMalarial Drug) Dec synth of DNA & RNA in inflam cell Dec response of T cells to antigen Stabilizes lysosomal membranes Sulfasalazine Metab sulfapyridine & 5-aminosalicylic acid Leads to inh IgA & IgM rheumatoid fc production Causes suppression of T cells & B cells response & proliferation

Rheumatoid Arthritis

Anti-Gout Drugs Immunosuppressant Drugs Cyclophosphamide : cause DNA alkylation prevent cell replication, suppresses T/B cells func. Cyclosporine-A : inh IL-1&2 rec prod. Inh T cells func. Hyperuricemic Drugs (for chr) Inc uric acid excretion i. Probenecid ii. Sulfinpyrazone iii. Benzobromarone Gold Salt i.m/orally alter morphology/func human macrophage inh release many inflam. cytokines & GF fr inflam. cells Inc uric acid metab i. Uricase enz Dec uric acid synth i. Allopurinol ii. Thiopurinol

Anti-Inflam Drugs (for acute) i. Colchicine ii. Corticosteroid iii. NSAIDs

Probenecid Chemistry : organic acid TNF--Blocking Drugs Have central role in patho of RA Mabs : i. Adalimumab ii. Infliximab iii. Rituximab Monoclonal ab complex e suitable TNF- Inh its interaction e T cells & macrop. Etanercept : Recombinant prot Interferes e soluble TNF- Prevent it fr binding to its cell sf rec. Pharmacokinetics Absorption : good oral Metabolism : hepatic active metabolite Excretion : via kidney Mech of Action Low D : dec tubular secr of uric.A by Renal PCT Ther D: inc uric.A excr by 50% (inh reabs. Fr Renal PCT) Therapeutic Uses 1. Uricosuric agent chr gout 2. Prolong half-life of some acidic drugs by inh renal tubular secr. : i. Penicillins ii. Rifampicin Side Effect 1. GIT disturbance

Leflunamide Suppresses pyrimidine synth arrest stimulated cell growth Suppresses T/B cells func. Inh bone damage, radiographic change

2. 3. 4. 5.

Skin Rash Fever Nephritic syndrome (rare) Aplastic anemia (rare)

3. Precipitation of acute attack of gout Precaution 1. Do not give during acute attack 2. Give NSAIDs/Colchicine e Allop. prevent initial hyperuricemic & acute gout Uricase Enz Enz of bact origin Convert uric.A allantoin Parentally admin Indicated in: Gout e renal failure ttt of hematologic mg (prevent massive uricosuria & renal calculi)

Sulfinpyrazone Similar to Probenecid Has antithrombotic action (dec TXA2) Benzobromarone Potent uricosuric Low D : No hyperuricemic effect

Allopurinol Chemistry : structural analogue of Purine Pharmakinetics Absorption : good oral admin Long duration of action (converted to active metabolite) Excretion : kidney Mech of action Inh xanthine oxidase enz inh uric.A synth Allopurinol : competitive inhibitor Its Metabolite : non-compet. Inh. Therapeutic Uses Chr gout Adjuvant therapy ttt of hematologic mg (prevent massive uricosuria & renal calculi)

Colchicine Chemistry : natural plant alkaloid Pharmacokinetics Absorption : good after oral admin Excretion : thru bile Mech of Action 1. Inh intracellular microtubular syst. inh leucocyte motility & phagocytosis 2. Inh mitotic spindle & cell division 3. Inh release of LTB4 by leucocytes Therapeutic Uses 1. Accute attack of gout (fatal D: 8mg-24h) 2. Familial Mediterranean fever Side Effect 1. Nausea, vomiting, diarrhea (most common) 2. Allopecia, myopathy (most rare) 3. Aplastic anemia, agranulocytosis (serious) NSAIDs Indomethacin & Naproxen Provide symptomatic relief

Side Effect 1. GIT disturbance 2. Hypersensitivity react. (skin rash)

D must be reduced if taken e precenebid (precenebid inh their renal excr)

a. -methyl dopa b. clonidine c. guanfacine 1. Ganglion blockers - trimetaphan 2. Adrenergic neuron blockers a. reserpine b. -methyl dopa 3. 4. 5. 6. 7. -adrenergic blockers - prazocin Concurrent & blockers - labetalol Serotonin antagonist - ketanserine Direct VD - hydralazine Dopamine rec agonist fenoldopam

Corticosteroid As anti-inflam agent (when other 2 not sufficient or C/I)

HYPERTENSION Non-Drug Therapy Dec Na intake Weight reduce (obese) Stop smoking, coffee, alcohol Exercise program Control DM & hyperlipideamia

DIURETICS Thiazides Initial therapy most cases Part of most combined antihypertensive regimen Loop Diuretics Hypertensive crises Ch renal failure Resistant htn (marked Na retention) Spironolactone 1ry hyperaldosteronism Correct hypokalemia (caused by T & LD) -BLOCKERS 1. e stable angina, supraventricular/ventri. arrhythmia 2. e Inc adrenergic activity 3. Hyperrenenimic htn 4. Part of combine therapy CALCIUM CHANNEL BLOCKERs (CCBs)

Drug Therapy (antihypertensives) Common : 1. ACEIs/ARBs 2. -Blockers 3. Calcium-channel Blockers 4. Diuretics

Other : 1. Agent interfering (centrally acting)

adrenergic

func

Block slow ca2+ influx (during terminal phase depolarization / plateau phase act potential)

Classification: 1. More selective on heart Verapamil Diltiazem 1. More selective on bl vs Nifedipine Nimodipine Almodipine 1. e tissue protection Flunarizine Nifedipine

MoA : Dec art bl pressure, contractility, HR dec myocardial O2 demand Dec coronary vascular resistance Dilation of epicardial coronary artery Dec Ca load improve myocardial relaxation & dec myocardial cell necrosis 1. Cardiac arrhythmias Prolong intranodal conduction time Slow AV conduction Lengthen ERP of AV node

Pharmacokinetics Absorption: nearly complete after oral admin 1st past hepatic metabolism dec bioavailability Effects evident within 30-60min (oral) Peak effect verapamil 15min (i.v) Some have metabolite [verapamil, diltiazem VD] In patient e hepatic cirrhosis bioavailability & half-life inc [D should be dec] Half-lfe longer in older patient Pharmacological Effect Relaxation of vascular sm ms, bronchiolar, GIT, uterine Dec cardiac contractility (in D-dependent) Protect against damaging effect of Ca2+ Block tachy in Ca dependent cells Dec platelet aggregability Inhibit insulin release (verapamil) Inh Ca influx across CNS limit seizure activity Therapeutic Indication Cardio-selective 1. Ischemic heart dis (angina/myocardial infarction)

1. Hypertrophic obstructive cardiomegally Dec contr force during systole dec O2 consumption & inc exercise tolerance Inc relax during diastole improve coronary flow 1. Arterial htn d2 VD of bl vs, dec of HR & contr.

Vascular-selective 1. 2. 3. 4. Arterial htn Cerebral vasospasm Peripheral vascular dis Ch renal failure

5. Re-perfusin injury in myocardium 6. Migraine Side Effect i. ii. iii. iv. v. Aggravation of CHF AV block-in-patient e pre-existing dis or when combined e -blockers Nausea, vomiting, constipation, hepatotoxicity (reversible) Worsen diabetes Hypotension, flushing, tinnitus, nasal congestion, occasional aggravation of angina Ankle edema

Prevent inactivation of kinins inc conc of bradykinins (potent VD)

vi.

Pharmacological Effects Dec peripheral resistance Not modify cardiovascular response to autonomic reflex. Not cause tachy despite of hypotension Inc RBF Maintain cerebral/coronary BF (systemic bl pressure is reduced) In CHF inc COP, cardiac index Dec HR Dec Lt ventricular mass/wall thickness (prevent ventri. enlargement after myocardial infarction)

C/I & precaution 1. Verapamil HF, unstable AV block, sick sinus symdrome, low bl pressure states 2. Verapamil & Diltiazem C/I in WolfParkinson-White symdrome complicated e AF & A flutter 3. Nifedipine C/I in Idiopathic hypertrophic subaortic stenosis & unstable angina 4. Verapamil C/I in non-insulin dependent DM Drug Interaction 1. Verapamil e digitalis/-blocker AV block (d2 additional effect on conducting syst) Nifedipine : DoC 2. CCBs & Direct VD profound hypotnsion ACEIs Mech of Action Interrurt R-A-A pathway thru inh of peptidyl dipeptidase enz (convert ang I -> ang II) [prevent ang-II form]

Clinical Uses 1. HTN 2. HF 3. Postinfarction ventricular remodeling 4. Renal dis (microalbuminuria, ch renal dis) 5. Insulin resistance 6. Arteriosclerosis 7. RA Side Effect 1. 1st D hypotension 2. Cough & bronchospasm 3. Angiedema resp arrest & death 4. Proteinuria (patient e compromised renal func) 5. Skin rashes 6. Temporary lost of taste 7. Headache, dizziness, fatigue 8. Teratogenic 9. Hyperkalemia 10. Neutropenia C/I

Hypotension Severe renal failure Hyperkalemia Severe anemia Immune problem

Neutropenia/thrombocytopenia Pregnancy/breast-feeding Bilateral renal artery stenosis/stenosis in solitary kidney

Arterio-dilators Hydralazine Nifedipine Minoxidil Venodilators Nitrates Mixed arterio-venodilaters Na nitroprusside Prazocin ACEIs Trimetaphan

Precaution Initial low D Diuretic use e caution Electrolyte assay (potassium) Measure bl urea/creatine (b4, 1w after, every 3 months)

ARBs Pharmacological Action/Effects Block ang-II type 1 rec No effect on bradykinin metabolism (more selective blockers of ang) More complete inh of ang action

HYDRALAZINE Absorbed from GIT Acetylated in liver Directly relaxes small arteries/arterioles Dec art bl pressure Uses 1. Ocombination therapy HTN 2. 1ry pulm. HTN Side Effect 1. Systemic Lupus-like syndrome 2. Nasal congestion 3. Flushing 4. Drug fever 5. Skin rash 6. Headache 7. Palpitation 8. Tachycardia 9. Angina pain 10. Anorexia, nausea, dizziness MINOXIDIL Absorbed from GIT Metab by conjugation e glucorinic A in liver Excrete in urine

Side Effect 1. Similar as ACEIs 2. Havard during pregnancy 3. Cough/angioedema less common

VASODILATORS include oral agent used for long-termed outpatient therapy used to treat HTN emergencies

Arteriolar VD activation of K channel hyperpolarization of cell memb relax of vasc sm ms

Rapidly metab in red cells cyanide metab thiocyanate prior to renal excr.

Uses 1. Severe HTN in comb. Therapy 2. Azotemic hypertensive patient 3. Topical Minoxidil : ind hair growth Side Effect 1. Palpitation 2. Tachycardia 3. Angina pain 4. Headache 5. Edema 6. Hypertrichosis

Uses 1. HTN encephalopathy 2. Refractory cases of CHF Side Effect 1. Nausea, vomiting, restlessness 2. Headache 3. Palpitation 4. Substernal pain 5. Prolonged therapy metabolic acidosis, arrhythmias & death (accumulaton of cyanide) / delirium & psychosis (acc. of thiocyanate)

DIAZOXIDE Related to chlorothiazide Produce Na retntion rather than dieresis 90% bound to plasma albumin Direct VD action on arterioles (activate K channel) Uses 1. HTN emergency (HTN encephalopathy, toxaemia of pregnancy) 2. Hypoglycemia (d2 hyperinsulinism dec insulin secr from pancreatic cells Side Effect 1. Tachycardia precipitate angina 2. Hyperglycemia 3. Na/Water retention 4. Hyperuricaemia 5. Nausia, vomiting, constipation

Precaution 1. Infusion must not stop abruptly avoid rebound HTN 2. In liver dis : cyanide not thiocyanate & hence more toxic 3. Higher rates of infusion acc of cyanide 4. Avoid exposure to light

SODIUM NITROPRUSSIDE VD effect on sm ms of venoarteriolar beds (activate guanylate cyclase inc cGMP)

CENTRALLY ACTING ANTIHYPERTENSIVES

CLONIDINE Pharmacological Action/Effects

Suppressing symp outflow & dec bl pres. (agonist to central postsynaptic 2 adrenoceptors & imidazoline rec) Dec synth of NE (dec dopamine hydroxylase & N-methyl tranferase enz) Act on peripheral postsynaptic 2 adrenoceptors inh NE release Dec plasma rennin activity, dec renal vascular resistance, maintain RBF Dec HR Dec COP

Stimulate 2 rec Dec periph resistance lower bl press. (not affect COP) Dec plasma rennin activity Has rapid onset as antiHTN Used for emerg. control of sev HTN e pheochromocytoma

Uses 1. Mod. & severe HTN 2. Prophylaxis in Migraine 3. In opiate withdrawal (dec signs of symp. overactivity) 4. Sedation/Dec anxiety (preanaesthetic medication)

KETANSERIN Lower the BP eout postural hypotention / reflex tachy Not affect gromerular filteratn rate/RBF Uses 1. Orally : HTN, periph vasc dis 2. i.v : asthmatic attack, thrombophlebitis, pulm emboli

Side Effect 1. Dry mouth 2. Sedation 3. Salt/Water retention 4. Withdrawal syndrome HTN crisis 5. Pressor effect of clonidine not observed 6. Overdose induce severe HTN Drug Interaction 1. Tricyclic antidepressant (TCA) may block antiHTN effect of clonidine 2. -blockers may aggravate HTN crises following sudden clonidine withdrawal 3. CNS depressant cause excessive drowsiness e clonidine GUANFACINE MoA similar to clonidine HypoTN effect associated e reduction in peripheral resistance, HR & COP Side Effect Dry Mouth - Dizziness Somnolence - AstheniaCONCURRENT & ADRENOCEPTOR BLOCKER

DOPAMINE (D1) REC AGONIST Pharmacokinetics cont. i.v admin metab in liver by conjugation Pharmacological Effects stimulate D1 rec (periph arteriodilatation & natriuresis Uses 1. ttt HTN emengency 2. ttt post operative HTN Side Effect 1. Reflex Tachy 2. Headache 3. Flushing 4. Inc Intraocular glaucoma)

art)

Pressure

(avoid

in

LABETALOL Block both (selective ,non selective )

HYPERTENSIVE EMERGENCIES HTN encephalopathy Cerebral stroke Acute Lt ventricular failure

Aortic dissection Epistaxis Severe renal failure

i. ii.

Nitrates : nitric acid (ester) Nitrites : nitrous acid (ester)

Management Hospitalized Reduction of BP (in hours) Sublingual therapy : nifedipine/captopril Parenteral therapy : Diuretics frusemide/bumetanide (i.v) Diazoxid (i.v) Na Nitroprusside (infusion) Hydralazine (i.v) Propanolol (i.v) Methyl Dopa (i.v diluted) Nifedipine (i.v diluted) Nitroglycerin (i.v)

Pharmacokinetics Absorption : readily by buccal mucous memb, GIT, skin, tracheobronchial tree (inhalation) Sublingual admin rapid onset, short duration Oral more prolonged prophylaxis Metabolism : rapidly by liver (1st pass metab) Excretion : kidney

THERAPY OF ANGINA PECTORIS General Measures 1. Alteration of life style Avoid stress, heavy meal, smoking Daily dynamic exercise 1. Correct obesity & reduce fat intake 2. ttt predisposing fc : hyperlipidaemia, HF, HTN, DM Drugs A. Acute Attack 1. Short acting nitrites & nitrates 2. Sedative, analgesics A. Between Attack 1. Long acting nitrates 2. -Blockers 3. CCBs 4. Cytoprotective drugs 5. Antiplatelet drugs: Aspirin Dipyridamo l Surgical : Myocardial Revascularization NITRITES & NITRATES Chemistry Mech of Action Involve formation of nitric oxide (NO) NO stimulate guanylate cyclase inh Ca entry / promote Ca exit produce cGMP coronary VD cGMP dephosphorylation of myosin light chain prevent interaction myosin e actin prod. PGE, PGI2 Pharmacological Effects (Side Effect*) Blood Vessels dec RV/LV end diastolic pressure inc coronary BF arteriolar dilatation (face -> flushing) VD (meningeal art throbbing headache) Heart Dec VR dec cardiac work Blood Pressure

Rapid admin high D dec systolic & diastolic BP & COP palpitation, weakness, dizziness & tachy Inc systemic venous capacity Smooth Ms Relax biliary, GIT, bronchial, uterine Respiration Inc RR Sm ms relax in bronchospastic disorder Therapeutic Uses Angina Pectoris CHF Acute myocardial infarction Biliary colic Constriction ring of uterus ttt of cyanide poisoning

Useful in stable/unstable angina May worsen variant angina (coronary spasm Sudden cessation may worsen angina (up-regulation) Beneficial effect : Slow HR i. Red myocardial O2 consumpt. ii. Inc diastolic perfusion time Redistribution of coronary BF to ischaemic area Exert cytoprotective effect ttt typical angina (combine e nitrates)

How nitrates relief angina pain [a] Reduction myocardial O2 demand Venodilatation dec VR/ R&L ventri end diastolic volume dec systolic ejection time Arteriodilatation dec periph resistance [b] Enhancement myocardial perfusion Dilatation large epicodial vs redistribution coronary flow to ischaemic subendocardium Coronary collateral VD inc BF to ischaemic area Precaution 1. Start e smallest possible D (minimize SE) 2. Nitrate shouldnt abruptly stopped avoid withdrawal symptoms 3. > 3 tablets sublingually over 15 min e,out improvement doctor fear MI 4. Nitroglycerine not in sunlight/ e cotton 5. Burning taste check expired date -BLOCKERs-ANGINA

CYTOPROTECTIVE AGENTS provide emough energy to maintain efficient myocardial contraction during ischaemia trimetazidine : prod metabolic switch (inh fatty acid oxidation toward activation of glucose oxidation during ischaemia limits intracellular acidosis & Na/Ca accumulation preserves contractile func & limi cytolysis limits membrane damage induced by O2 free radical

THERAPY of ACUTE MYOCARDIAL INFARCT.

CARDIAC GLYCOSIDES (DIGITALIS) 1. Admitted to coronary care unit 2. Take Vital Sign freq. RR, BP, pulse 1. Daily recording of ECG 2. Oxygen : inc PO2, inc diffusion of O2 to ischemic myocardial 3. Morphine Sulfate : relief pain 4. Mepridine : relief pain (e inferior MI, bradycardia, Av conduction delay) 5. Diazepam : sedation 6. -blockers, NG, CCBs : limit size infarct 7. Fibrinolytic therapy 8. Anticaogulant : patient obese, history of prev MI/transient ischemic attack 9. ttt of arrhythmias,HF, cardiogenic shock 10. Control of risk factor : smoking, physical activity, obesity, HTN, DM Chemistry : combination of aglycone & genin Pharmacodynamics I) +ve inotropic action Inc free Ca concentration during systole inc contractile force of cardic cells : Inh membr bound Na/K ATPase inc intracellular Na inc in free intracellular Ca i. Diminution of exchange ii. Displacement of Ca fr its binding site Directly facilitates entry of Ca to cardiac cells Inc release of Ca from sarcoplasmic reticulum

HEART FAILURE 1. General measures : rest, sedatives, freq small meals e salt restriction 2. ttt of cause : hyperthyroidism, cong H dis 3. Diuretics 4. +ve inotropic agents Cardiac glycosides Dopamine Dobutamine Prenalterol PDE inhibitors 1. ACEIs 2. VDs 3. Nitrates 4. -Blockers : Carvedilol

I)

Autonomic action of digitalis Vagal action : Sensitization of barorec in aortic arch/carotid sinus Stim. Of central vagal nuclei & nodose gang. Sensitization of cholinergic rec in heart Symp action : Dec sensitivity of SAN & AVN to stim. Toxic D : inc cardiac symp activity

POSITIVE INOTROPIC DRUGS

Therapeutic Uses 1. Ch congestive HF (asso. e atr fibrillation)

2. HF failing to response to other drugs 3. AF : Red ventr rate Elimination of pulse deficit Improve ventr func 1. Atrial flutter 2. Paroxysmal atrial tachy C/I 1. 2. 3. 4. 5. 6. 7. 8.

2. Lean person red binding digoxin to sk ms 3. Ch pulm dis, hyspoxia, acid base imbalance: arrhythmia (inc occurance) 4. Myxedema heart more sensitive to digit. 5. Hepatic dis inc bl conc of digit 6. Acute mMI inc sensitivity of cardiac ms to arrhythmogenic effect of digit. DIGITALIS TOXICITY

Heart block Hypertrophic obstructive cardiomyopathy Wolf-Parkinsonism-White Syndrome Paroxysmal ventr. Tachy VF Cardiopulm dis : ch lung dis e hypoxia Renal/hepatic insufficiency Hypertensive HF Sick sinus syndrome

Stop digit admin Stop drugs cause hypoK Slow i.v K correct hypoK Antiarrhythmic drugs Lignocaine Phenytoin -Blockers Atropine 1. Fab fragment of digit 1. 2. 3. 4.

Side Effect 1. Coronary constriction (toxic D) 2. Nausea, vomiting 3. Diarrhea, anorexia 4. Excitability, convulsion 5. Yellow vision 6. VF & ventr tachy 7. Skin rash

DOPAMINE Small D : Useful in starting dieresis in resistant HF Mod D : enhance myocardial contr Stim 1 Large D : adverse -adrenergic VC Uses

Precaution 1. Patient in other drugs w inh AV conduction (-blockers) 2. Patient likely to require cardioversion 3. Patient e hypersensitive carotid sinus 4. Never give i.v b4 sure patient not received digoxin during prev 14 days avoid digitalis toxicity 5. Make sure K level normal 6. In elderly patient changes in kinetics in elderly Fc Modifying Response to Digitalis 1. Renal failure red excr of digoxin

Correct haemodynamic imbalance in shock syndrome d2 AMI, trauma, open-heart surg & chr cardiac decomposition (CHF)

DOBUTAMINE Cause D-related inc in COP (1 stim) Used in short-term myocardial support CHF & MI) PRENALTEROL Similar to Dobutamine Longer duration & can given orally

PHOSPHODIESTERASE INHIBITORSCARDIOACTIVE BIPYRIDINES

[Inamrinone, Milrinone more potent]

MoA

+ve inotropic e VD properties Inc myocar contr & dec periph resistance No effect on HR / BP Orally/parenterally

1. 2. 3. 4.

Ablation tech Implantable cardiovector defibrillator Artificial pacemaker Electric shock therapy

ANTIARRHYTHMIC DRUGS

Uses

PDE-3 inhibitors inc cAMP (cardiac tissue & sm ms) Inc inward Ca (act potential)

Acute Heart Failure Acute exacerbation of Ch HF Side Effect 1. Thrombocytopenia 2. Nausea, vomiting 3. Hepatotoxic 4. Cardiac arrhythmias (less than digit)

Class

I (Sodium Channel Blockers) Red max rate of depolarization Depress excitability Dec cond velocity Block fast Na & K channels Ia : Quinidine Disopyramide Procainamide Ib : Lidocaine Mexilitene Aprinidine Tocainide

CARDIAD ASTHMA & PULM EDEMA [Acute Lt Ventr Failure]1. 2. 3. 4.

Hospitalization Semisitting/sitting position dec VR ttt of causes (AF, rapid rise BP) Morphine Pain relief Arteriolar dilatation Venodilatation Sedation dec anxiety 1. Oxygen (mask/tent) Inc intra-alveolar press Dec transudation & pulm cap pressure 1. Diuretics - Relief pulm edema 2. VD Na nitroprusside/Nitroglucerin (i.v) Nifedipine/Captopril (subling) 1. Rapid digitalization 2. Aminophylline diminish bronchospasm Inc renal plasma flow Inc Na excr & has diuretic effect Inc myocardial contr ARRHYTHMIA Non-Pharmacological tech

Ic

: Flecainide Lorcainide Encainide

Class

II (-Blockers) Depression of phase-4 depolarization Slow conducton thru AVN Esmolol, Metoprolol, Propanolol

Class III (K Channel Blockers) Homogenous prolongation of act potential duration (delay repolarization) Amiodarone, Bretylium, Ibulilide, Sotalol Class IV Ca Channel Blockers: Diltiazem K Channel Openers : Adenosine Cromakalim Pinacidil Therapeutic classification

Verapamil,

1. Supraventricular arrhythmias

Adenosine Verapamil Digoxin -blockers 1. Ventricular arrhythmias Lidocaine Mexiletine Disopyramide Sotalol 1. Supraventricular & Ventricular arrhythm. Amiodarone Quinidine -blockers

4. Atrial/Ventricular extrasystoles 5. Ventricular tachy 6. Maintenance of sinus rhythm (after successful direct current cardioversion) Side Effect 1. Cinchonism : ear ring, blurred vision 2. Embolism : d2 dislodgment mural thrmbus 3. Quinidine syncope : recurrent light headedness, episode of painting, Torsade de pointes 4. Paradoxical tachy : (atropine-like effect) 5. Idiosyncrasy : fever, skin rash, diarrhea 6. Hypotension : (if i.v)

QUINIDINE Chemistry : alkaloid of Cinchona bark Phamacokinetics Absorption : 70% fr gut Peak plasma conc. : 1-3hrs Half-life : 7-9hrs (inc in renal/liver dis) Protein binding : 80-90% Metabolism : liver Plasma level arrhythmic affect : 2-5ug/ml Pharmacodynamics Block Na channel antiarrhythmic action Atropine-like action blocking properties VD, activate symp efferent Antimalarial Antipyretic Analgesic Oxytoxic Sk ms relaxant Therapeutic Indication 1. AF (less than 6 month duration) 2. Atrial flutter 3. Paroxysmal atrial tachy

C/I 1. 2. 3. 4. 5. 6. 7.

Complete AV block Old standing AF Prolongation QT interval Congestive HF Hypotension Hypersensitivity Myasthenia gravis

PROCAINAMIDE Differ fr procaine (contain amide str) Pharmacological Action/Effects Cardiac effect : as Quinidine Autonomic : weaker anticholinergic, not cause blockage, has ganglion blocking ef. Therapeutic Uses 1. Ventr Arrhythm. (2nd line after Lidocaine) 2. Supraventr Arrhythm. (as effective as Quinidine higher D) DISOPYRAMIDE Pharmacokinetics Absorption : well after oral admin

Excretion : 50% in the urine unchanged

Inactivated by microsomal enz in liver 90% bound to plasma protein

Pharmacological Action/Effects Marked anticholinergic & ve inotropic Therapeutic Uses 1. Ventr Arrhythm. 2. Supravent Arrhythm in WPWS eout CHF 3. Hypertrophic cardiomyopathy Side Effect 1. Anticholinergic sympt.: dry mouth, consti. 2. Nausea, vomit, abd pain 3. Congestive HF C/I : HF, hypoT, glaucoma, bg hypertrophy prostate

Pharmacological Action/Effects Heart : as Lidocaine ANS : depressant effect Therapeutic Uses 1. Digitalis induced cardiac arrhythmias 2. Ventr arrhythmias (after surg - cong heart dis/cong prolonged QT syndrome) 3. Epileptic seizures (antiepileptic drug) Side Effect 1. Nystagmus, vertigo, dysarthria, confusion 2. Hepatotoxicity, hirsutism, megalob anemia, hypoT, gingival hyperplasia

LIDOCAINE Kinetics Amide local anaesthetic Oral admin very low plasma conc (1st pass metb) Pharmacological Action/Effects Dec slope of phase 4 depolarization & pacemaker activity of Purkinjie fibers No effect on SAN Dec memb excitability of Purkinjie fibers Inc threshold for ventr fibrillation Red APD in PF & vent ms (K chan Opener) Therapeutic Uses 1. Ventr arrhythmias (during/after cardiac surg, e AMI) 2. Digitalis induced arrhythmias Side Effects 1. Least cardiotoxic of antiarrhythmias 2. Perioral parasthsia, tremors, dizziness PHENYTOIN (Diphenylhydantoin,DPH) Pharmacokinetics Absorption : slow after oral admin PROPAFENONE Some blocking Class III & IV activity Uses : Vent/supravent arrhythmias & WPWS Side Effect : AV block Visual disturbance Metallic taste -BLOCKERs Substantial inc in effective refractory period of AVN & SAN Dec conduction velocity thru AVN Propanolol : class I & IV Sotalol : class III Therapeutic Uses 1. Supravent arrhythm. (exercise-induced) 2. Digitalis induced vent arrhythm. 3. Chest pain & arrhythmias of mitral valve prolapsed (DoC) AMIODARONE Pharmacokinetics

Absorption : well orally Extensively bound to tissue Metabolism : slowly in liver

Prod controlled hypoT (in surg & diag. coronary art dis) DIGOXIN Shorten refractory period in artial cells Prolong effective refractory period & diminish conducting velocity in AVN & PF Uses : control ventr response rate in AF & A fluter MG SULFATE Admin i.v Suppress drug-induced torsade d pointes Treat digitalis-induced ventr arrhythmias ttt : supravent arrhythm e mg deficiency

Pharmacological effects Prod prolongation act potential ( block K chan) Block Na chan. (class I) Block & rec (class II) Weak Ca chan. blocker (class III) Potent sm ms relaxant Prod marked coronary/periph VD

Therapeutic Uses 1. Supravent/vent arrhythmias 2. Arrhythmias e WPWS 3. Control recurrent vent tachy/fibrllation Side Effect 1. Corneal micro-deposits 2. Alteration of thyroid func 3. Photosensitivity 4. Pulm infiltration 5. Myopathy 6. Periph neuropathy 7. Hepatotoxicity 8. Sleeplessness 9. AV block 10. Sinus bradycardia VERAPAMIL prevent supravent tachy, red ventr rate in AF & A flutter MoA : delay impulse transmission thru AVN ADENOSINE K chan. opener Uses : AV tachy in WPWS

NEUROGENIC SHOCK (1ry)

resting a recumbent / head down position Narcotic analgesic (morphine) Sympathomimetics elevate BP

HYPOVOLAEMIC/OLIGAEMIC SHOCK (2ry)

Blood transfusion (in blood loss) Transfusion human plasma / plasma substitute (blood compatible not available) Plasma transfusion (plasma loss) Saline (severe vomit) Saline & Na lactate (severe diarrhea) Phenoxybenzamine (only after full replacement of iv fluid volume e blood or other appropriate fluids Dopamine Cortisone

CARDIOGENIC SHOCK

Dopamine/Dobutamine iv fluid correct hypovolaemia

VD ( Na (noradren)

nitroprusside)

/

VC

Cadioversion (show sign of CHF / angina) Vagotonic maneuvers inc vagal tone Verapamil, Esmolol, Adenosine iv (DoC) Class Ia/Ic Class Ia/III/IV avoid recurrence

JUNCTIONAL TACHYCARDIAS SEPTIC SHOCK

Antibiotics Corticosteroid (high D) Dopamine/Dobutamine (CVS support) Initial fluid balanced salt solution Maintain ventilation Recumbent position Adrenaline (DoC) Glucocorticoid Antihistamine (H1 antagonist) Aminophylline (iv slowly) severe bronchospasm Plasma transfusion (severe case)

VENTRICULAR TACHYCARDIAS

ANAPHYLACTIC SHOCK

Emergency Lidocaine (1st choice haemodynamically stable) Amiodarone iv Cardioversion (VT persist after lidocaine) Propholyxis Lidocaine iv cont at least 2-3days after return of SR Quinidine oral cont at least 3 months (AMI)

ATRIAL FIBRILLATION

Emergency Digitalis iv (DoC) dec AVN conduction Cardioversion (cause : hyperthyroidism) Non-emergency Digitalis orally Quinidine (convert AF sinus rhythm[SR])ATRIAL FLUTTER

TORSADE DE POINTES

Emergency Digitalis iv Cardioversion Non-emergency Digitalis orally convert rhythm to AF & slow vent rate. stop digitalis SR not reappear within 48hrs : maintain digitalis & oral QuinidineWPWS

Mg sulfate, cardiac pacing, isoproterenol (iv) patient e arrhythmia shorten QT

VENTRICULAR FIBRILLATION

Amiodarone Sotalol/Propanolol procainamide/quinid

+

Adjunct ttt admin b4 & () attempts at electricaldefibrillation : Lidocaine Procainamide Bretylium Amiodarone Implantable cardioverter-defibrillator long-termed preventive therapy

BRADYARRHYTHMIAS & HEART BLOCK

Cardiac pacemaker (ttt of choice) Atropine iv/isoprenaline Hydrocortisone iv acute case HB DIURETICS WATER DIURESIS Water dilute irritant subs in urine dec crystalluria & renal lithiasis Mech of Action Inc plasma volume stim vol rec (Lt atrium) dec ADH secr Dec plasma osmotic pressure dec ADH secr Inh ADH secr dec water reabs (coll ducts) inc volume voided urine (by):

Duration : short (4 hrs) Mech of Action [A] Renal : - inh Na/K/2cl co-trnsport dec Na & Cl reabs - inh NaCl reabs in PCT - stim cyclooxygenase activity inc synth of PGE2, PGI2 inc glom filtration, promote water & Na excr [B] Extra-renal: - venodilator action RBF & dec LV filling pres. Uses 1. 2. 3. 4. 5. 6. 7. 8. 9.

Acute pulm edema Na & water retention (all types) Hypertensive emergengies (iv) HyperCalcemia Oliguria d2 acute renal failure HyperKalemia Anion overdose Drug poisoning Uricosuric agent hyperuricaemic

LOOP DIURETICS (high ceiling) Furosemide Bumetanide Torsemide Ethacrynic Acid Indacrinone Pharmacokinetics Absorption : rapidly fr GIT & can be given iv Strongly bound to plasma prot. Reach site of action : actively secreted by prox convulated tubules by orgnc acid transport syst. Genaral Charecteristic Site of Action : thick part ascend limb of Loop of Henle Efficacy : high (at the segment), effective at low GFR Onset : rapid (oral = -1hr, iv = 5-10min)

Side Effect 1. HypoK metabolic alkalosis 2. HypoMagnesaemia 3. HypoVolaemia & HypoNatraemia 4. Hyperuricaemic (dec uric A excr) 5. Ototoxicity (D related hearing loss) 6. Glucose intolerance (inh insulin release) 7. Hypersensitivity & idiosyncrasy 8. Hyperlipidemia (inc LDL & TG, dec HDL) 9. Interaction Diuretic-induced K defi inc sens of

myocardium to digitalis Furosemide/Ethacrynic A high plasma prot binding capacity compete e other (warfarin) Ethacrynic potentiate ototoxicity of aminoglycoside Furosemide potentiate ephrotoxicity of cephalosporins

NSAIDs potent inh of PG synth dec furosemide diuretic effect

THIAZIDES Chlorothiazide Hydrochlorothiazide Bendroflumethazide Indapamide Pharmacokinetics Absorption : well fr GIT Distribution : widely can cross placenta Excretion : renal orgnc acid secr syst (PCT) General Characteristic Site of Action : prox part of DCT Efficacy : moderate (avoid in renal impairment) Onset : 1hr after oral admin Duration : vary (chloroT/hydroCT: 8-12hrs bendroflumeT : 24hrs)

More potent Cause Na excr in advanced renal failure Side Effect 1. HypoK metabolic alkalosis 2. HypoVolaemia & HypoNatraemia 3. Hypotension 4. Hyperuricaemia 5. Hyperglycemia 6. Hyperlipidemia-d2 dec insulin act/release 7. Hypersensitivity 8. Deterioration (patient e hepatic/renal F) 9. Parathesia (D related) 10. Drowsiness (D related) 11. Fatigability (D related) 12. Impotence (D related) INDAPAMIDE Not thiazide (qualitatively similar) Sulfonamide diuretic Useful in patient e renal insufficiency Alter Ca flux in vasc wall dec BP 1ry use HTN, not edema Less side effect than thiazide

Mech of Action Inh NaCl co-transport (prox part of DCT) Na & Cl reabs Uses 1. Essential HTN (initial monotherapy-alone, combined antiHTN regimen) 2. Idiopathic hypercalcuria e recurrent urinary calculi (dec Ca excr dec tubular fluid Ca conc dec renal Ca stone form) 3. DI (nephrogenic type) 4. HyperK 5. Edema & ascites (all types Na/water ret) d2 mild/mod congestive HF & hepatic dis 6. Toxemia of pregnancy 7. Premenstrual tension d2 pelvi congestion METOLAZONE Thiazide-like analogue

K-SPARING DIURETICS Aldosterone antagonist : Spironolactone Eplerenone Direct Na-chan inhibitors : Triamterene Amiloride Phamacokinetics Metabolism : largely in liver Excretion : Kidney Amiloride)

(Triamterene,

General Characteristic Site :Distal part of DCT/cortical - CD Efficacy : weak Onset : slow (Spironolactone) Duration : Amiloride < Triamterene

Mech of Action Block aldosterone rec dec Na reabs & inc K & H secr Inh Na transport thru spec epith Na chan Uses 1. Balance excess K loss (e Loop/Thiazide) 2. Hyperaldosteronism (1ry Conns Synd, 2ry CHF, hepatic cirrhosis, nephritic synd) 3. Refractory edema 4. Hirsutism in female (spironolactone) antiandrogenic effect Side Effect 1. HyperK (dec K secr) 2. Hyperchloraemic metabolic acidosis (dec H secr) 3. Nausea, abd pain, drowsiness, confusion 4. Gynecomastia, impotence, menstrual disorder

OSMOTIC DIURETICS Mannitol Concenterated glucose Glycerol Relatively inert & largely excreted eout metabolic changes Filtered freely thru glom Undergo limited reabs by renal tubules

Mech of Action Inc osmolarity of plasma inc osmolarity of glom filtrate & tubular fluid dec water reabs. marked inc urine volume & smaller inc Na secr

C/I 1. HyperK 2. Combination e other K sparing drug/ K supplement 3. Chr renal insufficiency 4. Liver dis red D (metabolized in liver) Interaction 1. Admin e ACEIs, other agent causing hyperK & K supplement hyperK 2. Spironolactone not e carbenoxolone (antagonist to each other) Spironolactone dec ulcer healing effect Carbenoxolone aldosterone-like action

Uses 1. 1. 1.

Maintain high urine vol Acute renal failure (prophylaxis/ttt) Drug intoxication (ttt) Acute congetive glaucoma dec intraoccular pressure Inc intracranial tension

Side Effect 1. Headache, nausea, vomiting 2. Dehydration/hypernatraemia 3. Hypersensitivity (mannitol) 4. Hyperglycemia/glucosuria (glycerol) C/I 1. Severely impaired renal function

2. Marked pulm edema 3. Congestive HF 4. Active intracranial bleeding PEPTIC ULCER Genaral lines 1. Rest & sedation 2. Stop smoking 3. Diet ; small freq reg meals 4. Avoid ulcerogenic agent: caffeine, alcohol

Drug Treatment 1. Medication dec acid secr proton pump (H/K ATPase) inhibitors H2 rec antagonist Anticholinergic drug 1. Drug enhance mucosal defense mech Antacids Sucralfate Colloidal Bismuth compounds PGs analogues

Pharmacokinetics Unstable in acid formulated in gelatin capsule Metabolism : liver Excretion : bile & urine Uses 1. Gastric/Duod ulcer 2. Stress ulcer 3. Severe gastro-esophageal reflux dis (GERD) 4. Patho. Hypersecretory synd. Zollinger Ellison Syndrome Side Effect 1. Diarrhea, abd colic, headache, dizziness, skin rash (low incidence) 2. D-dependent dec in Vit-B12 absorption 3. Alter bioavailability oral admin drugs 4. Inh hepatic P450 isoenz (dec elimination of phenytoin, diazepam, warfarin. 5. Gastric carcinoid tumor (rat)

1. Antimicrobials Amoxicillin Tetracycline Bismuth subsalicylate Metronidazole Clarithromycin

H2-RECEPTOR ANTAGONISTS Cimetidine Ranitidine Famotidine Pharmacokinetics

PROTON PUMP INHIBITORS (PPIs) Omeprazole Lansoprazole Pantoprazole Rabeprazole Mech of Action Diffuse across gastric paretal cell convert into active metabolite bind (irrev) to parietal cell in H/K ATPase enz D-dependent inh gastric acid secr (basal/stimulated)

Absorption : rapidly fr GIT Metabolism : liver Excretion : kidney

Pharmacological Action

Competitive block of H2 rec Endocrine action (Cimetidine) Enz inhibition (Cimetidine)

Uses

1. 2. 3. 4.

Gastric/Duod ulcers Zollinger Ellison Syndrome Reflux oesophagitis Gastritis

5. Prophylaxis injury of gastric mucosa 6. Prophylaxis gastric ulcer/bleeding in stress

Side Effect 1. Nausea, vomiting, diarrhea, constipation 2. Antiandrogenic side effect (high D) 3. Hyperprolactinaemia gynecomastia (male) & galactorrhea (female) 4. Metabolic enz inhibition 5. Myalgia, arthralgia & fatigue 6. Headache, slurred speech, delirium, confusion, occasionally coma 7. Granulocytopenia, aplastic anemia 8. Rev. hepatitis, cholestasis Precaution Cross placenta/pass e milk avoid during pregnancy & lactation Rebound ulcer d2 sudden withdrawal

ANTICHOLINERGIC DRUGS Pirenzepine (gastrozepin) Telenzepine Mech of Action Selective blocker of periph M1 muscarinic rec (intramural ganglia/ECL cell) suppress basal gastric acid secr Less effect on secr stimulated by food Uses

Adjuvant to H2 rec antagonist

Side Effect Untoward effect of cholinergic blockage Dry mouth Mydriasis Glaucoma Constipation Tachy Urine retention

Interaction Cimetidine inh cytochrome oxidase P450 dec metab/inc effect many drugs (blockers, CCBs, warfarin) Cimetidine/Ranitidine dec glucouronation of acetaminophen(paracetamol) inc its effect RANITIDINE More potent than cimetidine Doesnt affect cutochrome oxidase P450 Minimal risk of untoward antiandrogenic effects & hyperprolactinaemia FAMOTIDINE Most potent Longer half-life No antiandrogenic / enz inhibitory effect

ANTACIDS Mech of Action Weak bases neutralize gastric acidity (inc pH) dec total acid delivery to duod & inh pepsin act dec pain (ulcer), promote healing Uses 1. Symptomatic ttt gastric/duod ulcer & oesophagitis 2. Duod ulcer (high D) Classification 1. Na bicarbonate (NaHCO3) 2. Ca carbonate 3. Mg salts Mg hydroxide Mg oxide & mg trisilicate

1. Aluminium hydroxide 2. Antacid combination NaHCO3 Absorbable antacid Rapid onset Inc pH 5-7 Short duration Induce systemic alkalosis, Na retention, release of CO2 rebound hyperacidity & perforation Can combine e alginic acid (as in gaviscon) Ca carbonate Non absorbable Relative rapid onset Ca stim secr & release gastrin acid rebound e Na intake milk-alkali-syndrome (hypercalcemia, constipation, alkalosis, renal failure)

Gaviscon Side Effect 1. Change bowel habits Constipation Diarrhea 1. Cation absorption Ca hypercalcmia e calculi formation & milk-alkali-synd (in renal impairment) Mg ms weakness & fatigue Na systemic alkalosis 1. Hypophosphatemia e ms weakness & bone resorption 2. Rebound hypersecretion of HCl 3. Dec absorption of tetracycline (Ca,Al,Mg) 4. Dec absorption of digoxin, isoniazid, warfarin, anticholinergic drug & iron (Al) 5. Inc excr of quinidine

SUCRALFATE Mg hydroxide Non-absorbable Rapid onset Inc pH 8-9 Mg oxide/Mg trisilicate Slow onset Long duration Coats base of ulcer by Sico2 (physically) Inc gut motility & prod diarrhea Aluminium hydroxide Non-systemic Binds bile, pepsin & phosphate Dec hyperphosphatemia in Ch RF Has direct cytoprotective action (bind bile, pepsin) Induces constipation Antacid combination Mech of Action Protect gastric/duod mucosa fr acid pepsin : Formation complex e prot at ulcer site form protective layer Dec back diffusion of H Inc secr of endogenous PGs Pharmacokinetics Absorption : slightly fr GIT Excretion : stool & urine Uses

Duod/gastric ulcer heal & dec recur.

Side Effects 1. Constipation 2. Dec bioavailability digoxin & phenytoin

of

tetracycline,

COLLOIDAL BISMUTH COMPOUNDS Tripotassium Dicitrato Bismuthate (TDB) Bismuth Subcitrate Mech of Action Act locally Selective binding e exudates, mucus & prot (in base of ulcer) Coat & protect fr acid & pepsin Inhibit pepsin activity Inc mucus & PGs synth Antimicrobial activity (gastric H.pylori) Uses

PGs ANALOGUES Synthetic PGE1 (misoprostol)

analogue

Mech of Action Inh histamine stimulated cAMP production inh gastric acid secr Cytoprotective effect e inc mucus & biocarbonate secr Maintain gastric mucosal bl flow & stim mucosal cellular reg

PharmacokineticsAbsorption : rapid

Excretion : urine

Duod/gastric ulcer

Uses

Side Effects 1. Stool & teeth discoloration 2. Encephalopathy (in renal failure)

1. Peptic ulcer 2. Prevention/ttt mucosal damage by NSAIDs

Side Effect1.

Diarrhea 2. Uterine contraction (delivery/pregnancy) bleeding/abortion

CARBENOXOLONE (biogastrone) Mech of Action Inc prod, secr & viscosity of mucus inc mucosal resistance & dec back diffusion of H into mucosa Slow down gastric epith turn over Affect metab of PGE, PGF Dec pepsin activity Uses 1. Gastric ulcer 2. Oesophagitis 3. Duod ulcer Side Effect 1. Na retention 2. HypoK (aldosterone-like effect) 3. Edema 4. HTN 5. HF BLEEDING PEPTIC ULCER Hospitalization & keep in bed Blood transfusion Gastric lavage (after suction of blood) Cimetidine/Ranitidine/Omeprazole (iv high D) Antacids (best Mg hydroxide, avoid Al hydroxide) Human thrombin, fibrin, vit K / coagulin After bleeding stop oral regimen as peptic ulcer Surgical (if fails)

Prophylactic therapy 1. Maintain pH in neutral range (aim) 2. PPIs (DoC) sucralfate/H2 rec antag

Prokinetic Drugs & Stimulant of GI Contractility

Cholinomimetics 5-HT4 agonist Chloride chan. activator (lubiprostone) Cholecystokinin 1 eceptor antagonist (dexloxiglumide) Octreotide (somatostatin analogue) GABA agonists (baclofen) Nitric oxide synth inhibitors Prokinetic drugs ; Metoclopramide Domperidone Erythromycin

6. Improve analgesics absorption (migraine) 7. Vomiting d2 anaesthesia, uremia, drugs Side effect 1. Sedation 2. Diarrhea 3. Extrapyramidal effect 4. Hyperprolactinemia Drug interactions Give e dopamine antag precipitate acute dystonic reaction (ms contr) Corticosteroid synergetic effect in its antiemetic activity DOMPERIDONE (motilium) Mech of Action Dopamine antag (D2 rec) Less antiemetic effect than metoclopramide Inc GI motility (block adrenoceptor)

METOCLOPRAMIDE (primperan) Mech of Action Cholinergic effect release ACh fr GIT cholinergic neurons Sensitizes intestine sm ms cells to action of ACh Block inhibitory action of dopamine on GIT tone & motility Act as an agonist on 5-HT4 rec Uses 1. GIT investigation 2. Gastro-esophageal reflux & peptic oesophagitis 3. Patient e gastric motor failure (diebetic gastro paresis) 4. Disorder of gastric emptying (postoperative & idiopathic gastric emptying) 5. Rapid emptying of stomach into intestine (b4 emegency surg/labor) Pharmacokinetics Absorption : rapidly after oral admin Excretion : feces Half-time : 7-8hrs Cross BBB Uses 1. Disorder of gastric emptying (accelerate) 2. Gastroparetic condition 3. Long-termed therapy ch & debilitating nausea & gastric retention 4. Counteract GIT effect of levadopa & bromocriptine in Parkinsons dis 5. Chr gastric reflux (inc low esoph spinc pres) 6. Vomiting d2 cancer chemo. Side Effect 1. Headaches

2. Hyperprolactinemia (d2 antag of D2 rec) ERYTHROMYCIN Macrolide antibiotic Prokinetic activity in stomach Used for diabetic gastroparesis Other agents that suppress GIT motility Organic nitrates CC antagonists Botulinum toxin

Drug inc LESP antacids, cholinergic, prokinetics Drug dec LESP anticholinergic, nitratesPORTAL SYSTEMIC (HEPATIC) ENCEPHALOPATHY

A) Treat precipitating fc e.g : drug, infection, GI bleeding A) Treat hyperammonemia Dietary restriction of prot Lactulose Metronidazole Neomycin Flumazenil Branched chain amino (BCAA)

GASTRO-ESOPHAGEAL REFLUX DIS (GERD)

Non-Drug measure 1. Sleeping in high pillow 2. Avoid : Large meal & eat b4 sleep Alcohol, smoking, spicy & coffe Aspirin, NSAIDs Tight clothes aroung abd. 1. Weight reduction

acids

A) Treat metablic complication Hypoglycemia by 10% glucose solution Hypokalemia by K chloride (iv)

Drug Therapy 1. Prokinetic drugs 2. Antacids & Antacid Anginic Acid Products Neutralize gastric fluid Inc lower esoph spinc pressure Gaviscon : i. Alginic acid + Mg trisilicate + Al hydroxide gel + NaHCO3 ii. Form highly viscous foamy solution of Na-alginate iii. Prevent gastric reflux 1. H2 antagonist 2. PPIs Provide symptomatic relief Provide esoph. Healing in severe GERD & severe erosive esophagitis 1. Surgical

LACTULOSE Non-absorbable disaccharide Metabolized in colon by intest. Bacteria Have osmotic laxative action Used for long-termed therapy for PSE Improve prot tolerance in patient e advanced hepatic cirrhosis Admin as retention enema for patient in impending coma, or coma stage of encephalopathy (slow onset) Side effect : abd distention, flatulence, nausea, vomiting, diarrhea METRONIDAZOLE Dec ammonia prod fr GI bact Side Effect : i. renal impairment

ii.

ototoxicity

ii. Long duration iii. Inc pulm & mean BP dec systemic VC effect (combined e nitroglycerine) Vasopressin i. Act as glypressin ii. Side effect : cardiac VC, skin art VC iii. Used as combined e nitroglycerine

NEOMYCIN Non absorbable aminoglycoside antibiotic Dec elevated blood ammonia level in patient e PSE by destroy some intest. bact In acute exacerbation : rapid > lactulose, toxic > lactulose Side effect : diarrhea, rev malabsorption, super infection, inflammatory bowel dis, ototoxicity, nephrotoxicity FLUMAZENIL Alternative conventional ttt failed Antagonizes benzodiazepines-like mediators produced during PSE Parenteral route Short duration

A) Sclerotherapy By injection of varices by spec sclerosant liquid (ethamolin, Na morrhuate) A) Drugs prevent re-bleeding fr varices Propanolol Venodilators : isosorbide dinitrate H2 blockers : ranitidine / famotidine Surgical

BCAA Dec false transmitter form (GABA-like) Improve some measure in ch PSE liver function test & nutritional measure

VOMITING TTT (ANTIEMETIC DRUGS) H1 rec antagonist Meclizine Promethazine Muscarinic rec antagonist Hyoscine/scopolamine Dopamine antagonist (D2) Phenothiazine Butyrophenones Metoclopramide Domperodone 5-HT3 antagonist Granisetron Ondansetron

ACUTE VARICEAL BLEEDING (d2 portal HTN)

A) Fresh blood transfusion/fresh frozen plasma B) Drugs dec intravariceal bleeding (constriction of splanchnic BF & hence dec portal pressure) Somatostatin & octreotide Glypressin i. Analogue of vasopressin

Miscellaneous agents Benzodiazepines High D steroids Vit B6 Nabilone

Uses

Vomiting d2 : Cancer chemo Radiation therapy Post operative Migraine

H1 REC ANTAGONISTS Mech of Action Inh cholinergic pathway of vestibular apparatus Uses

Side Effect Anticholinergic effect Drowsiness, dry mouth, blurred vision Extrapyramidal effect dystonia 5-HT3 ANTAGONISTS

Nausea, vomiting (ass e motion sickness) True vertigo Vomiting d2 drugs

Mech of Action Block 5-HT3 rec in CTZ Uses

Side Effect (atropine-like action) Dry mouth Blurred vision

Prevent chemo-induced vomiting Post-operative nausea & vomiting

Side Effect : Constipatin & headache

CHOLINERGIC ANTAGONISTS Mech of Action Block muscarinic receptor Uses

NABILONE Mech of Action Block opiate rec Uses

Prevention & ttt of motion sickness

Control chemo-induced vomiting

Side Effect Drowsiness Dry mouth Blurred vision DOPAMINE ANTAGONISTS (Phenothiazines, butyrophenones) Mech of Action Block D2 in CTZ Inh periph transmission to vomit center

Side Effect Sedation Psychoactive effect Dry mouth VIT B6 Mech of Action Related to GABA & glutamate balance Uses

Vomiting of pregnancy

3. Relief of period pain PAPAVERINE EMETICS 1. SYRUP IPECAC MoA : stim CTZ & induce GI irritation Use : remove unabsorbed toxin fr stomch 1. APOMORPHINE MoA : dopaminergic agonist stim CTZ Parenterally admin (SC) Not toxic Can cause CNS, RC depression ANTISPASMODICS Anticholinergic drugs Propantheline Dicyclomine Oxphencyclimine Oxyphenonium Buscopan MoA : inh phosphodiesterase enz elevation of cAMP Alter mitochondrial resp. Uses 1. Spasm GIT, Bile duct, Ureter 2. VD (cerebral, coronary) in subarachnoid he & coronary art bypass surg 3. Sm ms relexant microsurgery 4. Erectile dysfunction (male) Side 1. 2. 3. 4. 5. 6. Effect Polymorphic ventri tachy Constipation Inc transaminase level Inc alkaline phosphatase level Somnolence Vertigo

Direct Sm Ms relexants Papaverine Mebeverine Alverine Camylofin (avafortan) Pinaverium Drotaverine Mixtures Librax (clinidium + chlordiazipoxide) Donnatal (hyoscyamine + atropine + scopolamine + phenobarbital) MEBEVERINE &

LIBRAX MoA : 1. Relax digestive syst 2. Reduce stomach acid 3. CNS depressant Uses 1. Stomach/intestinal prob ulcer, colitis 2. Abd/stomach spasm/cramps Side Effect 1. Constipation 2. Eye pain 3. Mental depression 4. Skin rash 5. Confusion 6. Drowsiness 7. Dry mouth, nose, throat 8. Tachycardia

ALVERINE CITRATE, DROTAVERINE

MoA : Direct sm ms relaxant Uses 1. GIT spasm 2. Irritable bowel syndrome

9. Skin flushing CONSTIPATION Drugs cause constipation 1. Antacid 2. CCBs 3. Ms relaxant Baclofen Dantrolene 1. Opioids Codeine Dextropropoxyphene Fentanyl Loperamide Morphine 1. Anticholinergic (atropine)

Castor oil Anthraquinone derivatives Diphenylmethane derivatives Phenolphthalein & bisacodyl 1. Surfactant laxatives (stool softeners) Docusate salt Na, K, Ca of dioctyl sulfosuccinate Liquid paraffin Glycerin suppositories 1. 5-HT4 rec antagonist

Uses 1. Constipation 2. Hepatocellular failure 3. Prepare & clean bowel xray, proctoscopic, colonoscopic 4. Hasten excretion of poisonous subs 5. Postoperative after hemorrhoids

Non-drug treatment 1. 2. 3. 4. Fluid intake Reduce strong/excess tea/coffee Fiber intake (fruit, vegetable) Exercise BULK LAXATIVES MoA retain water in gut lumen gels distending LI & stim peristalsis Use constipation e diverticulosis, irritable BS & ulcerative colitis Side Effects 1. Flatulence 2. Bind digoxin, salicylate 3. Form masses in gut int obstruction

Drug treatment (LAXATIVES) 1. Bulk laxatives Agar Psyllium seeds Dietary fiber 1. Osmotic laxatives Lactulose Mg sulphate Na sulphate Na-K tartrate

1. Stimulant/irritant laxatives

OSMOTIC LAXATIVES

1. Saline Laxatives MoA Retain water in lumen (osmosis) distention & reflex in in peristalsis Side Effects Congestive HF Precipitate dehydration hypoK RF

MoA

Induce inflam in SI & LI accumulation of water/electrolytes & stim int motility

1. CASTOR OIL Use Not for common constipation Prepare radiological exam Side Effect Bad taste Morphologic change alter mucosal permeability, colic, dehydration 1. ANTHRAQUINONE GLYCOSIDE Cascara Senna Danthron Aloes

1. Polyethylene Glycol MoA Retain in lumen by its osmotic nature effective laxative effect Side Effect Electrolyte imbalance Bowel dependent

1. Lactulose MoA Transformed by bact lactic A + acetic A (have osmotic laxative activity) inc fluid accumulation in colon Other Use Hepatic encephalopathy Side effect Abd discomfort Bad taste

Side Effect Red discoloration - urine Cathartic effect in babies (milk) Bg pigmentation of colon Cathartic colon Inc menstrual blood flow 1. PHENOLPHTHALEIN MoA Stim sensory nerves reflex stim peristalsis alter active electrolyte transport Side Effect Cumulation Mucosal & liver damage Dermatitis Itching Colored urine 1. BISACODYL

IRRITANT/STIMULANT LAXATIVES

MoA : as Phenolphthalein Side Effect Atonic colon (used > 10 days) Mucosal damage Fluid/electrolyte disturbance STOOL SOFTENER 1. DIOCTYL MoA Facilitate incorporation of water into fatty intestinal material Uses Replace mineral oil reduce strain of defecation

MoA Promoting stool evacuation tissue dehydration soften inspissated faecal material Use Re-establish proper (temporary use) Side Effect Local discomfort Burning Hyperaemia Irritation

bowel

habit

1. LIQUID PARAFFIN MoA Coats intestine dec water absorption soften stool Uses Ch constipation Side Effect Malabsorption of fat soluble Infiltration in liver Granulomatous reaction mg

DIARRHEA A) Maintenance - Fluid/Electrolytes Balance B) Non-Specific Antidiarrheal Therapy 1. Adsorbents Kaolin Pectin Dietary fibers Active charcoal 1. Bismuth Subsalicylate 2. Anti-cholinergic agents (atropine) 3. Opiates/opioid containing preparation Diphenoxylate Loperamide (Imodium) 1. Cholestyramine

1. GLYCERIN SUPPOSITORIES

A) Specific Anti-Infective Agents B) Anti-Inflam Drugs 1. Glucocorticoid 2. Sulfasalazine 3. Immunosuppressive agents ADSORBENTS

MoA Adsorption of microorga./toxic compounds Coat mucosa Protectants BISMUTH SUBSALICYLATE MoA Provide protective coat for mucosa Subsalicylate hydrolyzed by coliform salicylic A inh synth of PG (int inflam, hypermotility, secr) Uses ttt & prophylaxis of travelers diarrhea

Cross BBB poorly Therapeutic D no CNS effect Give e atropine dec motility more

LOPERAMIDE (IMODIUM) Synth morphine derivative Cant cross BBB Inactivation calmodium dec int secr Uses : irritable bowel synd Side Effect Anti-cholinergic Narcotic effect Precipitate toxic megacolon in ulcerative colitis CHOLESTYRAMINE Uses : diarrhea caused by bile salt malabs pseudomembranous colitis (e vancomycin)

SPECIFIC ANTI-INFECTIVE AGENTS ANTICHOLINERGIC AGENTS MoA Block response of int sm ms to cholinergic stim inh colonic peristalsis Uses Diarrhea e cramps OPIATES/OPIOID CONT. PREPARATION MoA Act on opiate Mu rec in submucous plexus inc int segmenting contraction & inc resistance to flow thru lumen Dec fluid/electrolyte secr into lumen Inc viscosity of luminal content & stool form. Act on presynaptic opioid rec dec ACh release DIPHENOXYLATE Synth morphine derivative Amoebic dysentery : Giardiasis : GLUCOCORTICOID MoA : stim. Na-absorption fr intestine Uses 1. refractory diarr. unresponsible to other 2. control acute episode SULFASALAZINE E coli Salmonellosis : : Tetracycline Chloramphenicol Co-timoxazole Erythromycin Ampicillin : Ciproflaxacine Norfloxacin Co-trimoxazole Diloxanide furoate + Metronidazole Metronidazole

Campylabacter : Shigella : Most cases bact diarrhea

MoA Inh of PG & Leukotreines prod Alter cytokine func Free radical scavenger Prod cytoprotective & immunosuppressive act Uses 1. Active ulcerative clitis 2. Rheumatoid arthritis Side Effect 1. Allergy 2. Nause 3. Vomiting 4. Headache 5. Fever 6. Bone marrow depression 7. Megaloblastic anaemia 8. Serum sickness

Choleretics Bile acids Bile salt

:

inc bile prod

Hydrocholeretics : inc bile volume Dehydrocholic acid Cholagogue : Mg sulphate Cholecystokinin Fat/olive oil stim GB evacuation

CHENODEOXYCHOLIC ACID (CDCA) MoA

Dec hepatic cholesterol synth/secr Dec cholesterol saturation of bile Inc bile acid pool & phospholipid output

IMMUNOSUPRESSIVE AGENTS ACTH Hydrocortisone Prednisone Cytotoxic drug Azathioprine Mercaptopurine Effective to patient e ulcerative colitis, crohns dis More effective as prophylaxis in crohns dis Cyclosporine : limited use toxicity on ch use DRUG THERAPY TRAVELERS DIARRHEA Prophylaxis : ciprofloxacin Treatment : replace fluid/electrolytes Ciprofloxacin Co-trimoxazole Bismuth subsalicylate BILE FLOW & CHOLELITHIASIS

URSODEOXYCHOLIC ACID (UDCA) Metabolite of CDCA More potent in dec hepatic cholesterol synth UDCA & CDCA interconvertible during enterohepatic cycling in man Given orally Side effect : diarrhea (CDCA - common, UDCA unusual)

PARASYMPATHOMIMETICS (cholinomimetics)

Classification 1. Directly acting Choline esters Acetylcholine Bethanechol Methacholine Carbachol Cavimilline Alkaloids Pilocarpine Muscarine Nicotine Lobeline

Poorly absorbed iv short duration (d2 rapid metabolized) resynth pseudocholinesterase (few weeks), true cholinesterase (months)

Pharmacological Action stim muscarinic rec stim nicotinic rec Therapeutic uses limited (d2 short dur & non-selectivity) Side Effect all except thoese needed therapeutically

Phamacalogical Effect 1. Indirectly acting (choline esterase inh) Reversible Physostigmine Neostigmine & substitutes Tacrine Donepezil Irreversible Organophosphorous compound CVS GIT Lung

Dec all cardiac properties exc conduction in atria VD Dec BP (small D)

1. Augment ACh action Sildenefil

Inc peristalsis (gastric/intestinal) Relax sphincter Stim salivary/gastric sect

BC Inc bronchial secr

ACETYLCHOLINE (ACh) Pharmacokinetics Inactive orally

Urinary T Contract detruser ms Relax sphincter Inc peristaltic waves ureters Eye Miosis Dilate central retinal artery

Sk Ms Stim motor end plate

Pharmacokinetics Long duration not hydrolyzed by CE Effective orally Pharmacological Action Stim muscarinic rec (alimentary tract & urinary bladder) Pharmacological Effect Inc motility Relaxes sphincters Inc secr Uses

Post-operative retention of urine Paralytic ileus Acute dilatation of stomach

METHACHOLINE Pharmacokinetics not effective orally subcutaneous best iv/im abolish selectivity & inc toxicity not hydralized by psuedoCE & destroyed less rapidly by true CE longer duration Pharcological Action stim muscarinic rec (CVS) Uses

CARBACHOL Pharmacokinetics Effective orally Long duration Pharcological Action Stim musc/nicotinic rec Uses

Miotic glaucoma

Side Effect : as ACh paroxysmal atrial tachycardia CEVIMILLINE Direct muscarinic agonist Not hydrolyzed by CE Taken orally Uses : xerostomia

Side Effect Heart block Hypotension Bronchoconstriction BETHANECHOL

PILOCARPINE Pharmacokinetocs

Not inactivated by CE Longer duration

NEOSTIGMINE Pharmacokinetics Irreg absorbed fr GIT Cant sross BBB Phamacological Action Rev inh of CE Direct stimulant action on NMJ of Pharmacological Effect Muscarinic more on alimentary T Nicotinic more on NMJ No CNS effect

Phamacological action Stim M rec Pharmacological Effect : as ACh Uses

Glaucoma Counteract mydratic effect homatropine & eucatropine Xerostomia

PHYSOSTIGMINE (eserine) Phamacokinetics Diffuse readily thru mucous memb Caross BBB

Uses

Myasthenia gravis Antidote to D-tubocurarine Post-operative retention of urine Paralytic ileus

Pharmacological Action Bind to esteratic & anionic site of CE enz accumulation of ACh in effector organ

Phamacological Effects

Side Effect All muscarinic & nicotinic effect (exc needed therapeutically) NEOSTIGMINE SUBSTITUTES 1. PYRIDOSTIGMINE More selective on NMJ than neostigmine Longer duration Uses : Myasthenia gravis 1. AMBENONIUM : as pyridostigmine

Muscarinic/nicotinic effect CNS : headache, restlessness, nightmares, tremors & convulsions

insomnia,

Uses

Glaucoma Counteract mydriatic effect & cycloplegia by atropine Alternatively e mydriatics Atropine poisoning & tricyclic antidepressant toxicity Alzheimer dis

Side Effects All muscarinic/nicotinic/CNS effect

2. EDROPHONIUM More selective on NMJ than neostigmine very short acting

Uses : i. Myasthenia gravis (diag) ii. Myasthenic crisis iii. Diff () myasthenic crisis cholinergic crisis iv. Antidote for D-tubocurarine v. Paroxysmal atrial tachy

ii. Neostigmine + atropine 1. 2. 3. 4. 5. 6. 7. Ephedrine Immunosuppressives Corticosteroids ACTH Cyclosporine Thymectomy KCl & spironolactone

&

1. BENZYPYRINIUM More selective on GIT & urinary T Weak action on NMJ Uses : i. post-operative urine retention ii. paralytic ileus

DONEPEZIL TACRINE & RIVASTIGMINE centrally acting rev CE inhibitors readily cross BBB act inc conc of ACh at central cholinergic synapses uses : Alzheimers Dis MYASTHENIA GRAVIS Diagnosis : 1. Edrophonium Improve sk ms contr. 1. Neostigmine + atropine Atropine given b4 produce initial brady followed by tachy Initial brady by atropine potentiate brady by neostigmine cardia arrest

ORGANOPHOSPHOROUS COMPUNDS Nerve gases : Sarin & Soman Insect killer : Malathion, Parathion & TEPP Drug used clinically : DFP MoA

Bind covalently to CE ACh accumulate at effector site parasymp. Effect Takes about 1-12hrs looses alkyl & alkoxyl group (aging of enz)

Phamacological Effect Muscarinic, Nicotinic & CNS effect Side Effect Resp bronchospasm, resp distress CVS brady, hypoT, excessive cold sweat GIT excessive secr, abd colic, diarrhea CNS severe miosis, headache, sk ms fasciculation, convultion & coma Treatment of Side Effects

Treatment : 1. CE inhibitors i. Ambenonium/pyridostigmine

Protection 1. Wear gloves & masks 2. Thorough washing of vegetables 3. Kept away fr children Treatment 1. Stomach wash 2. Skin wash e Na bicarb. / ethyl alcohol 3. Maintain air passage 4. Atropine high D 5. Cholinesterase re-activator 6. Anticonvulsant (dialpezam) convulsion

Atropine Scopolamine A) Synthetic Esters 1. Use 4 ttt parkinsons dis i. Benzatropine ii. Trihexyphenidyl iii. Cycrimine iv. Biperiden 1. Use to prod mydriasis/cycloplegia i. Atropine ii. Homatropine iii. Eucatropine iv. Cyclopentolate v. Tropicamide 1. Use to prod BD i. Ipratropium ii. Tiotropium

SILDENAFIL Pharmacokinetics Rapidly absorbed after oral admin Oral bioavail. 40% Widely distrib. Metab. By cytochrome P450 enz Excreted 1rily in feces Uses

1. Use as antisecretory/antispasmodic i. Buscopan ii. Novatropine iii. Propanthelin iv. Pipenzolate v. Pirenzepine vi. Glucopyrrolate vii. Dicyclomine viii. Methscopolamine 1. Used i. ii. iii. iv. for genitourinary syst Oxybutynin Glucopyrrolate Dicyclomine Emepronium

Male erectile dysfunction

Side Effect Headache (mild, transient) Blurred vision Nasal congestion C/I

Dont take e organic nitrate profound hypoT, reflex tachy, worsen angina pectoris, death PARASYMPATHOLYTICS A) Naturral Alkaloids

ATROPINE Pharmacokinetics Readily cross membrane barrier Well distrib.

MoA

Metabolism in liver Renal excretion Half-life : 2 hrs Duration : 4-8hrs

Competitive pharmacologic antagonist Blocking effect can be overcome by inc conc of muscarinic agonist

Uses CVS 1. Bradycardias (by excessive blocker, by stimulant-noradrenaline) 2. Heart block

Toxicity 1. Hyperthermia/atropine fever child 2. Dryness of secr 3. Acute angle-closure glaucoma 4. Urinary retention 5. Constipation 6. Blurred vision 7. Lost light reflex 8. CNS : sedation, amnesia, delirium, halluci. 9. CVS : block intraventri. conduction Toxicity ttt 1. Control env. temp 2. Catheterization 3. Avoid over ttt of convulsion (barbiturate) 4. Physostigmine counteract CNS effect

CNS 1. Motion sickness 2. Parkinsons dis Eye 1. 2. 3. 4.

C/I & 1. 2. 3.

Precaution Used cautionly in infant - hyperthermia Glaucoma esp closed angle form Prostatic hypertrophy

Fundus exam Iritis & iridocyclitis Counteract effect of miotics Alternative e miotics

NEUROMUSCULAR BLOCKING AGENTS A) Competitive (non-depolarizing) D tubocurarine Gallamine A) Depolarizing Decamethonium Succinylcholine

Bronchi BC in asthma & c hobs. pulm dis GIT

GIT spasm Acid peptic dis

Bladder Cystitis Nocturnal enuresis Ureteric spasm in renal colics Side Effect Dry mouth Skin flushing Urine retention Acute attack of glaucoma

Competitive (non-depolarizing) Pharmacokinetics Long half-live Given parenterally

Prolonged action in patient e impaired renal function

4. Post-operative pain & acute hyperK (d2 severe ms contr) Interactions 1. Inhaled anesthetics strongly potentiate & prolong NM blockage 2. Aminoglycoside antibiotics & antiarrhythmic prolong & potentiate relaxant action of NMB to lesser degree C/I & 1. 2. 3. 4. 5. Precaution General anesthetic reduce D of curare Antibiotics curare-like action Quinidine & lidocaine curare-like action Glaucoma prevent by prior tubocurarine Myasthenia gravis sensitive to compet. Agents & resistant to depolarizing agents 6. Tetracyclines & CCBs inc NM blockage

MoA

Surmountable blockers Compete e ACh CE reverse their effect Act directly to plug ion channel operated by ACh rec (some)

Depolarizing Pharmacokinetics Metabolized by plasma CE Duration : few minutes (single D) Given by continuous infusion (prolong paralysis) Not rapidly hydrolyzed by true CE MoA

GANGLION BLOCKER AGENTS Trimetaphan Pentolinium Mecamilamine Pharmacological Action Competitive blockade ganglia GANGLION STIMULANT Nicotine Lobeline Phamacological Action Stim of ganglia Large D initial stim of ganglia followed by block Stim chemoreceptive & neuroeffector CNS stim

of

autonomic

Like nicotinic aginist Depolarize NM end plate Twitching & fasciculation accompany the initial depolarization Plug end plate channel

Uses 1. Induce muscular relaxation (during general anesthesia & to facilitate endotracheal intubation 2. Control convulsions during ECT Toxicity 1. Resp paralysis 2. Aiutonomic effect & histamine release 3. Mg hyperthermia

Uses

Neonatal asphyxia (lobeline as analeptic - intraumbilical)

Side Effect

1. 2. 3. 4. 5. 6. 7.

VC Tachy Elevated BP Nausea, vomiting, diarrhea Dryness of exocrine gland Tremors, convulsion Depression

Acute/ch cough

Side Effect Nausea, vomit, constipation, dizziness Dryness of mucosa, thickening-sputum Dependence Resp depression/excitement PHOLCODEINE Little/no analgesic effect Less addictive property than codeine

COUGH ANTITUSSIVES Reduce freq/intensy of coughing Classification 1. Peripheral i. Demulcent - linctuse ii. Steam inhalation menthol 1. Central Narcotic i. Codeine ii. Pholcodein Non-narcotic i. Dextromethorphan ii. Noscapine iii. Levopropoxyphen 1. Central/Peripheral i. Benzonatate ii. Carbetapentane CODEINE Weak analgesic effect Respiratory depressant Drug of abuse Uses

DEXTROMETHORPHAN Act centrally Selective depressant action on cough center No analgesic, resp depressant, dependence liability Not prod constipation Used as over the counter Overdose antagonist by naloxone NOSCAPINE Selective central antitussive No CNS effect Papaverine-like action Relax. Of bronchial ms LEVOPROPOXYPHEN Selective central antitussive No opioid effect

BENZONATATE/CARBETAPENTANE Depress pulm stretch rec Cough rec Inh transmission of afferent impulse to cough center Have central antitussive effect

EXPECTORANTS 1. Sedative i. Alkaline ii. Nauseant iii. Iodides iv. Guaifenesin 1. Stimulant/aromatic i. Creosote ii. Guaiacol

Inc secr of lanchrymala, nasal, saliv glands painful swelling of gland Gastric irritation (long used) Thyroid dysfunc Allergic manifestations C/I : Acute bronchitis Tuberculosis

GUAIFENESIN Inc rept tract secr Dec adhesiveness & surface tension of viscid sputum expectoration

ALKALINE Na/K citrate & acetate inc alkali reserve of blood Na/K stim bronchial gl secr protective mucus Dissolve mucus/sputum less sticky easily expectorated Uses early dry stage of acute bronchitis

CREOSOTE/GUAIACOL Dec sputum amount Deodorant action Mild antiseptic action Stim healing/repair of ch. Inflam. resp mucosa Uses : lung abscess, ch bronchitis, bronchiectasis MUCOLYTICS Reduce viscocity of resp tract secr liquefaction of viscid sputum Not inc secr amount a) Bromhexine (bisolvon) b) Ambroxol (mucopect) c) Acetyl cysteine & carbocysteine d) Iodides e) Enzymes f) Water vapour g) Cough mixture BROMHEXINE Reduce viscocity by fragmenting its glycoprot. Uses : 1. Ch bronchitis 2. Ch obstractive pulm dis 3. Ch sinusitis

NAUSEANT Stim sensory nerve ending (stomach) reflex copious bronchial secr Uses - early dry stage of acute bronchitis e.g : i. tincture ipecacuanha, ii. tincture senega, iii. ammonium chloride

IODIDES Rapidly reach bronchial mucus gland stim mucus secr (low viscosity watery) Have mucolytic action Uses cough e ch resp dis & ch BA Side effect : Metallic taste

4. Otitis media AMBROXOL Metabolite of bromhexine As bromhexine but less gastric irritant ACETYL CYSTEINE/CARBOCYSTEINE Have free sulphydryl groups that open disulfide bond in mucus reduce viscocity Used to dissolve inspissated mucus plug

Criteria : i. No more than 3 active ingredients ii. Each present in effective safe conc & contribute to ttt for w the product is used iii. Used only multiple symptoms present concurrently

Uses : 1. Ch

BRONCHIAL ASTHMA resp dis Bronchitis Emphysema Bronchiectasis Cystic fibrosis BRONCHODILATORS 1. -adrenergic agonist 2. Methyl Xanthines 3. Muscarinic rec antagonist -ADRENERGIC AGONIST a) Non-selective Adrenaline Isoprenaline Ephedrine pulm a) Selective Salbutamol [short acting] Terbutaline [short acting] Fenoterol [short acting] Salmeterol [long acting] Formeterol [long acting] MoA

1. Acute resp dis Bronchitis Pneumonia Asthma 1. Post-operative/post traumatic complication 2. Care of tracheostomies

IODIDES By potentiate effect of proteolytic enz ENZYMES Trypsin, chymotrypsin & streptokinase WATER VAPOUR Excellent expectorant/mucolytic Dilute/liquefies resp sect Act rapidly COUGH MIXTURE Symptomatic ttt Contain : expectorant, sympathomimetics, antihistamine

Adrenergic -agonist bind e rec activate adenyl cyclase convert ATP to cAMP i. Relax. of airways ms ii. Inh of release of BC subs fr mast cell iii. Enhance mucociliary func iv. Dec microvascular permeability

ADRENALINE Stim rec VC of submucus vs mucus memb decongestion (addition to BD)

1. Synthetic Aminophylline Pharmacokinetics Well absorbed fr GIT Eliminated mainly by hepatic metabolism Clearance reduce in Infant < 6 months Cirrhosis, HF, corpulmonale Erythromycin, quinolones, cimetidine Clearance inc in Smoking Rifampin, phenobarbitol, carbamazepin

SELECTIVE 2 AGONIST Least systemic effect can given to hypertensive patients Uses : acute episode BA, prophylactically prevent airway obstruc. Side Effect : Tremor sk ms, nervousness, weakness Tachy (2ry to hypoT by sk VD) hypoK tolerance loses its selectivity given large freq D

MoA

Block cell surface rec for adenosine Inh phosphodiestrase enz (PDE) inc intracellular cAMP relax of airway ms & inh BC subs fr mast cell Stim release of catecholamines fr adrenal medulla & inh COMT enz BD Improve diaphragmatic contr & reduce resp ms fatigue (theophylline) Exert anti-inflam & immunomodulating effect (theophylline)

Uses Side

XANTHINES CNS stimulants 1. Natural Caffeine Theophylline Theobromine

Symptomatic relief acute attack of BA CNS depressan