DRUG ACE inhibitors

EXAMPLES Ramipril, Lisinopril

USES Hypertension Heart Failure Post MI

MECHANISM Block ATIATII by binding to the site on the en yme that normally accommodates the terminal leucine o! ATI" Inhibits vasoconstriction.

B ta!B"oc# rs

Atenolol, Propanolol

Hypertension Angina Arrhythmias 'table heart !ailure

SIDE EFFECTS Hypotension #ry cough $increased bradykinin% Renal !ailure in pts &ith bilateral renal stenosis block (adrenergic receptors inhibiting Pro+ocation o! the asthma, heart e!!ects o! adrenaline and nonadrenaline" !ailure" ) $heart% blockage $ cr as s HR ,old hands an$ Bradycardia ( contracti"it%, * $bronchial and !atigue +ascular smooth muscle% blockage causes vaso$i"ation" *aso$i"ation block cellular entry o! ,a/ by pre+enting opening o! +oltage(gated L(type and T( type calcium channels increase &ater e1cretion by decreasing reabsorption o! 2a/ and ,l( in the distal tubule by binding to the ,l( site o! the electroneutral 2a/3,l( co(transport system and inhibiting its action causing a decrease in blood +olume, +enous return and ,4 Block 2a/ resorption in ascending loop o! Henle diuretic e!!ect" Flushing, headache, P"oedema Phenyalkylamines can &orsen heart !ailure 0ynaecomastia Impotence Hypokalaemia Hyponatraemia Hypotension 0out Type II #M

Ca"ci&' Chann " B"oc# rs

Thia)i$ Di&r tics

Dih%$ro(in s Amlodipine, Ph n%a"#%"a'in s( .erapamil, B n)thia) (in s( #iltia em Bendro!lua ide, hydrochlorothia i de

Hypertension Angina 'upra+entricular arrhythmia $Phenylalkylamines only% Hypertension ,ombined &ith loop !or Heart Failure

Loo( Di&r tics

Frusemide, Bumetanide

Potassi&'! s(arin+ $i&r tics

'pironolactone, Amiloride

Hypertension $but less e!!ecti+e than thia ides - used &hen renal impairment or resistant to multiple drug T1% Heart Failure 'econdary Hypertension 'e+ere heart Failure

Hypokalaemia Hyponatraemia Hypotension 0out

Blocks action o! aldosterone in distal con+oluted tubule diuretic e!!ect

Hypokalaemia Hyponatraemia Abdominal discom!ort

An+iot nsin II r c (tor anta+onists A"(ha! a$r nor c (to r anta+onists

Losarten, .alsarten

#o1a osin, Pra osin

Hypertension Alternati+e to A,5 inhibitor in heart !ailure Hypertension $in addition to other hypertensi+es%

*aso$i"ation - by inhibition at the angiotensin II receptor

6sually mild 2o cough like in A,5 inhibitors Postural Hypotension #i iness

Reduces peripheral resistance by inhibiting )( adrenoreceptor(mediated +asoconstriction"

Fibrino"%tics

'treptokinase

Thrombolysis Acute MI, stroke, P5

Forms a comple1 &ith, and acti+ates, plasminogen into plasmin" Irre+ersibly inhibits ,47 and so stops synthesis o! Thrombo1ane A* !rom Arachidonic Acid &hich leads to platelet aggregation" Inhibits acti+ation o! the glycoprotein IIb3IIIa receptor on the sur!ace o! platelets &hich is re8uired !or aggregation to occur" Blocks reduction o! .it" 9 epo1ide necessary !or synthesis o! !actors II, .II, I7 and 7"

2ausea3+omiting Bleeding

Anti("at " t a+ nts As(rin

Pre+ention and treatment o! MI and stroke" Pre+ention and treatment o! MI and stroke"

Haemorrhage

C"o(i$o+r "

Haemorrhage

Anticoa+&"ants ,ar-arin

Prophyla1is/treatme nt #.T, P5 Prophyla1is o! emboli ation in AF, Rheumatic disease / prosthetic +al+es" Treatment o! #.T, P5" Prophyla1is o! #.T3P5 post op" MI" Pre+ention o! cardio+ascular disease

Haemorrhage

H (arin

Statins

Ator+astatin, 'im+astatin, Pra+astatin

Nitrat s

0lyceral trinitrate $0T2%, Isosorbide mononitrate

Prophyla1is and Treatment o! angina" L.F

Potassi&' chann " activators

2icorandil $only licensed one%

Prophyla1is o! angina

Acti+ates antithrombin III, &hich limits blood clotting by inacti+ating thrombin and !actor 7" Re+ersibly inhibit en yme HM0 ,oA reductase &hich catalyses the rate(limiting step in the synthesis o! cholesterol: HM0 ,oAme+alonic acidcholesterol" This in synthesis L#L receptors so L#L le+els" Prodrugs - they decompose to !orm 24 &hich acti+ates guanylyl cyclase, thereby cyclic guanosine monophosphate $c0MP%" Protein kinase 0 is acti+ated and contractile proteins are phosphorylated" This all leads to #ilation o! +essels" Rela1ation o! smooth muscle and +asodilation" Acti+ates 9/ channels o! +ascular smooth muscle

Haemorrhage

Myopathy $muscle ache% #isturbed LFTs Abdominal pain

Postural hypotension Tachycardia Headache Flushing #i iness

Headache

causing 9/ to !lo& out o! cells causing hyperpolari ation" This there!ore inhibits in!lu1 o! ,a*/ and so inhibits contraction" Antiarr%th'ics C"ass Ia ;uinidine, #isopyramide, Procainamide Lignocaine, Me1iletine, Phenytoin .T <P< Block 2a*/ channels &hich increases re!ractory period and in addition there is a blockade o! 9/ channels &hich delays repolarisation" Block 2a*/ channels but little e!!ect on re!ractory period as 9/ channels not blocked" duration o! the action potential" Marked 2a*/ channel blockage re!ractory period, no e!!ect on the duration o! the action potential" 0I disturbances Hypotension

C"ass Ib

.entricular arrythmi, especially .T

C"ass Ic

Flecainide

Pre(e1citation AF cardio+ersion o! paro1sms,A.2RT ,A.RT, <P<, AF , AT , 2'.T $non( sustained .T% =unctional tachyarrhythmias, Paro1ysmal e+ents,AF, Flutter, 2'.T, '.T>s" AF, AT, A.RT, A.2RT, <P<, 2'.T

2ausea and .omiting ,2' to1icity Hypotension Bradycardia ,2' to1icity Hypotension Proarrythmogenic a!ter recent MI may increase mortality Pro+ocation o! asthma, heart !ailure" ,old hands Amiodarone : 0I disturbances" ,orneal microdeposits, throto1icosis, photosensiti+ity Flushing, headache P"oedema Phenyalkylamines can &orsen heart !ailure 0ynaecomastia Impotence Intracellular ,a*/ o+erload ?unctional escape beats, ?unctional

C"ass II

Beta blockers $see abo+e also%

rate o! spontaneous depolarisation o! 'A and A. nodal tissue conduction through A. node Block 9/ channels so prolong the duration o! the action potential"

C"ass III

Amiodarone, Bretylium, 'otalol $Beta blocker &ith class III properties% ,alcium channel blockers $see abo+e also%

C"ass I*

A.RT, A.2RT, Paro1ysms

Block ,a*/ channels - acts predominantly on the A.2 and a!!ect the plateau phase o! the action potential"

Di+o.in

AF Atrial Flutter

2ot strictly antiarrythmic indirect actions on the Action potential through stimulation o! the +agus ner+e:

 automaticity o! the 'A node &hich slo&s sinus rate re!ractory period o! the A.2 &hich A. conduction

A$ nosin Potent e!!ect on 'A node producing sinus bradycardia" 'lo&s impulse conduction through the A.2 but has no e!!ect on conduction in the +entricles" Inhibits e!!ect o! the +agus ner+e on the heart &hich rate o! !iring o! 'A node conduction through the A.2 +ia blockade o! muscarinic M* receptors"

'upra+entricular arrythmias

tachycardia, +entricular ectopic beats, .T" Increased +agal acti+ity can cause AT &ith *:) A.2 block 0I disturbances 2eurological disturbances 0ynaecomastia Bradycardia and A. block Malaise, !lushing, headache chest pain, bronchospasm Rhythm disturbances ,onstipation Reduced Bronchial secretions

Atro(in

'inus bradycardia A. block ,ardiopulmonary resuscitation

En$ocrino"o+%!Diab t s Ins&"in/ Is a polypeptide containing @) amino acids arranged in t&o chains $A and B% linked by #isulphide bridges" A precursor called proinsulin, is hyrdolysed inside storage granules to !orm insulin and a residual ,(peptide" The granules store insulin as crystals containing inc and insulin" Ins&"in R " as / 0lucose is the most potent stimulus !or insulin &ith surges at meal times" The B cells possess 9/ channels that are regulated by intra cellular adenosine triphosphate $ATP% $9atp channels%" <hen the blood glucose increases, more glucose enters the B(cells and its metabolism results in an increase in intracellular ATP, &hich closes the 9atp channels" The resulting depolori ation o! the B(cell initiates an in!lu1 o! ,a*/ ions through you +oltage sensiti+e ,a/ channels and this triggers insulin release" Ins&"in is destroyed the 0I tract so must be gi+en subcutaneously and I. or IM in some circumstances" In?ections should be rotated &ithin the same region to a+oid lipid hypertrophy" Absorption is !astest !rom the abdomen and slo&er !rom the thigh" Ins&"in R +i' s 1) 'hort acting insulin mi1ed &ith intermediate acting insulin in?ected subcutaneous t&ice daily, be!ore break!ast and be!ore the e+ening meal3 *% In?ection o! intermediate acting insulin to pro+ide background le+el o! insulin and soluble insulin three times a day" Short Actin+ Ins&"in So"&b" Ins&"in Actrapid 'imple solution o! insulin I. !or $onset AB mins, peak hyperglycaemic acti+ities *(Chrs, subsides by emergencies" Dhrs% 'ubcutaneous I! I. e!!ects only last AB in?ection minutes" Ins&"in "is(ro Humalog and Insulin analogues ha+e a Blood glucose Hypoglycaemia an$ Ins&"in 2o+orapid !aster onset and shorter control

as(art 0Ra(i$ Actin+1

action than soluble insulin" This is because they do not sel! associate to !orm dimmers" 4nset *B(AB minutes Peak action )(* hrs #uration A(C hrs 'uspension o! amorphous insulin inc" Mi1ture o! amorphous insulin inc $ABF% and insulin inc crystals $GBF%, the latter prolonging the duration o! the preparation 4nset o! action $*(C hours%" Peak action $E()*hrs% $#uration *B hrs% A comple1 o! protamine and insulin" The mi1ture is such that no !ree binding sites remain on the proatmine" A!ter in?ection, proteolytic en ymes degrade the protamine and the insulin is absorbed" The duration o! 2PH is similar to that o! Lente 4nset o! action 023!43 'ins% Peak action 05!6 hrs1 #uration action 07!86 hrs1 ,ontain +arious proportions o! soluble isophane insulin $e"g" ABF soluble and GBF isophane% The soluble component gi+es rapid onset and the isophane insulin prolongs the action" A pre(mi1ed short and intermediate(acting insulin &ill start to &ork hal! an hour a!ter being in?ected, peak at )()* hours and last !or )E(*C hours" The ultra(short acting insulins lispro and aspart are also a+ailable in a biphasic

Insulin auto antibodies Lipohypertrophy

Int r' $iat an$ Lon+ Actin+ Ins&"in $duration o! action bet&een )E(A@ hours% 'emilente $amorphous insulin inc% L nt Humulin L or Monotard

Blood glucose control Blood glucose conrol

Hypoglycaemia Hypoglycaemia

Iso(han Ins&"in 0NPH1

Insulatard

Hypoglycaemia

Bi(hasic -i. $ 'i.t&r s

Human mi1ed $short! an$ int r' $iat ! actin+% insulins: These include Humulin *B3DB, Humulin AB3GB, Humulin @B3@B, Mi1tard *B3DB, Mi1tard AB3GB, and Mi1tard @B3@B" Human mi1ed insulin analogues $9ith &"tra!

Hypglycaemia

short an$ int r' $iat ! actin+ (ro( rti s%: These include Humalog Mi1*@ $insulin lispro% and 2o+oMi1 AB $insulin aspart%"

!orm &hich retains the rapid onset o! action $about )@ minutes% but has a duration o! action similar to that o! intermediate(acting isophane insulins"

U"tra" nt

Humulin 6L 6ltratard

Ins&"in +"ar+in

Lantus

A suspension o! poorly soluble insulin inc crystals that has a duration o! up to A@ hours" The long duration o! ultra lente can lead to insulin accumulation and dangerous hypoglycaemia" 4nset o! action 0:!5 hrs1 Peak 06!:2 ho&rs% Is soluble at acid pH" It has a long peakless acti+ity $))()* hrs% and is gi+en once a day"

Hypoglycaemia

Hyoglycaemia

;ra" Anti Diab tic Dr&+s Tablets are introduced &hen metabolic control cannot be obtained by diet and li!estyle changes alone" ,hoice depends on indi+iduals characteristics" Patients &ith baseline Hb)A)c HF are les likely to achie+e target HbA)c &ith monotherapy" #rug o! choice started at lo& dose, dose is increased, additional drugs are introduces in combination therapy to ma1imum o! *(A drugs" Insulin is usually introduced in combination &ith met!ormin" Bi+&ni$ s Met!ormin The e1act mechanism o! Type * diabetes Lactic acidosis rare 4nly diabetic action o! met!ormin is and limited to those P,4' drug that reduces uncertain" It appears to act &ith impaired li+er 2on Alcoholic !atty cardio+ascular mainly by reducing hepatic o! kidney !unction" li+er disease risks" gluconeogenesis, it also 0I upset diarrhoea, It reduces &eight" decreases absorption o! +omiting cramps" glucose !rom the gastrointestinal tract and increases insulin sensiti+ity by increasing peripheral utili ation o! glucose"I 5+idence suggests that increased peripheral utili ation o! glucose may be due to impro+ed insulin binding to insulin receptors since met!ormin is not e!!ecti+e in patients &ho no longer ha+e any residual insulin production"The

Ja+erageJ person &ith type * diabetes has three times the normal rate o! gluconeogenesisK met!ormin treatment reduces this by o+er one third" Met!ormin stimulates the hepatic en yme AMP( acti+ated protein kinase $AMP9%, &hich plays an important role in the metabolism o! !ats and glucose" ,ausing &eight loss" The molecular targets &ith &hich met!ormin directly interacts remain elusi+e" Met!ormin is not metaboli ed, rather it is primarily e1creted in the urine &ith an elimination hal!(li!e o! E"* hours S&"(hon%r as 0lipi ide $short hal! li!e% 0lica ide $short hal! li!e% 0libenclamide $longer duration o! action% Tolbutamide" Type II diabetes $people &ith ideal &eight% These drugs are indicated in patients $especially those near their ideal &eight% in &hom diet !ails to control the hyperglycaemia" In about ABF control is not achie+ed by these drugs" They stimulate insulin release !rom the pancreatic islets and so patient must ha+e partially !unctional B(cells !or these drugs to be o! use" 'lo& onset ma1imum e!!ect )(* months o! treatment" Reduce hepatic glucose output and increase absorption into the peripheral tissues" Triglycerides decline and L#L is also reduced" #rugs increase sensiti+ity to insulin by binding to the nuclear pero1isome proli!erator acti+ated receptor gamma $PPAR(y% and by derepression, increase transcription o! 0I disturbance Rashes Hypoglycaemia Hypoglycaemic coma ,ontraindicated in se+ere hyperglycaemia, surgery and ma?or illness <eight gain Fluid retention ,ontraindicated in pregnancy

G"ita)on s

Rosiglita one and Pioglita one

Type II diabetes gi+en alone or in combination &ith meto!rmin or sulphonyreas in patients &ho cannot tolerate met!ormin or sulphonyreas combinations"

insulin sensiti+e genes" a! G"&cosi$as inhibitors Inhibits intestinal a( Flautlence glycosidases, delaying the #iarrhoea digestion o! starch and Abdominal Pain sucrose" It is taken &ith meals and lo&ers the post prandial increase o! blood gluocose" Pro"actino'as! oligomenorrhoea, ameno!!hoea, galactorrhea, in!ertility, loss o! libido, erectile dys!unction, osteoporosis" TRH stimulates prolactin, #opamine inhibits it" Do(a'in Bromocriptine 'timulates dopamine Prolactinoma 2ausea a+onist $r&+s $ergot deri+ati+e% receptors in the brain" Acromegaly Psyhchiatric ,abergoline 'ymptoms Hypogandism Postural 0alactorrhea Hypotension Fibrotic changes &hich can lead to +al+ular heart disease" Acro' +a"% 4+er secretion o! 0H Lgigantism be!ore puberty, acromegaly a!ter puberty" $gro&th o! hands !eet, tightening o! rings% So'atostatin 'omatuline 'omatostatin analogue" Acromegaly 0allstones ana"o+& s Autogel Inhibits the production o! 0H" ,onratindicated in 'andostatin LAR li+er and kidney 4creotide !ailure, diabetes mellitus, Insulinoma" Diab t s Insi(i$&s $no A#H produced so leads to e1cretion o! large +olumes o! isotonic &ater% ADH ana"o+& #esmopressin #esmopressin is pre!erred to #iabetes Insipidus <ater retention $nasal spray, +asopressin because it is a Hyponatremia tablets, or longer acting analogue" Make ,ontraindicated in subcutaneous sure to reduce !luid intake" heart !ailure, people in?ection% using diuretics !or other conditions" Alcoholics H%(oth%roi$is' tiredness and lethargy are the most common symptoms" #epression o! basal metabolic rate, appetite and cardiac output" Lo& output heart !ailure might occur" 'kin is dry" Thyroid depri+ation in early li!e leads to d&ar!ism and cretinism" Th%ro.in Le+othyro1ine Administered orally is the Hypothyroidism ,oncomitant treatment o! choice" conditions 'ynthetic TC is the sodium &orsened by salt o! le+othyro1ine $L( thyro1ine therapy" thryo1ine%" Its e!!ects are Heart disease, heart delayed until the plasma !ailure, in!arction, protein and tissue binding angina, chronic lung sites are occupied" disease, Treatment is assessed by breathlessness, Type II diabetes Acarbose

monitoring T'H le+els, &hich adrenal disease" !all to normal &hen optimum #ue to increase in dose is achie+ed" #aily dose o1ygen demand o! )BB and )@Bug best take on most tissues as &ell &aking" as myocardium Liothyronine Is the sodium salt o! TA and Hypothyrioidism 'ee abo+e because it is less protein bound, it acts more 8uickly than TC" The main use o! TA is in hypothyroid coma, &hen it is gi+en &ith hydrocortisone by I. in?ection" H%( rth%roi$is' basal metabolic rate is increased, causing heat intolerance, arrthymias and increased appetite &ith &eight loss" 'kin is &arm and moist" Tachycardia s&eating and tremor" Angina and high output !ailure may occure" 6pper eyelids are retracted" Treatment also includeds beta blockers discussed abo+e $Propranalol or atenolol% Antith%roi$s ,arbima ole Rapidly con+erted to Hyperthyroidism Rashes methima ole in +i+o Agranulocytosis 4nce daily doses, CBmg !or ) Patients should month, then ABmg !or ) report a sore month, *Bmg !or ) month throatM and then )B mg daily until reassessed"" 4nset o! action A(C &eeks Thionamides Possess a thiocarbamide Hyperthyroidism N group that is essential !or immunosuppressi+e their acti+ity" They pre+ent the synthesis o! thyroid hormones by competiti+ely inhibiting the pero1idise catalysed reactions necessary !or iodine organi!ication" They also block the coupling o! iodotyrosine especially diiodothyronine !ormation" 4nset o! action A(C &eeks Propylthiouracil Reser+ed !or patients Hyperthyroidism Nimmunosupressi+e intolerant o! carbima ole" Also inhibits the peripheral deiodination o! tC Iodides Ha+e poorly understood Hyperthyroidism 'kin rashes actions on the thyroid" They 2ausea inhibit organi!ication and and .omiting hormone release" In addition Allergic reaction" iodide decreases the si e and +ascularity o! the hyperplastic gland, e!!ects &hich are use!ul in

preparation o! patients !or thyroidectomy" They inhibit hormone release 8uickly $*(G days% is a +aluabe treatment !or thyroto1ic crisis" ,annot be used in long term because its antithyroid action tends to diminish" Pri'ar% H%(oa$r na"is'/ A$$isons disease Nor'a""%< 0lucocorticoids mainly cortisol are produced in the cells o! the ona !asiculata and ona reticularis" The release o! cortisol is controlled by negati+e !eedback mechanism in+ol+ing the hypothalamus and anterior pituitary" Lo& plasma cortisol le+els results in the release o! A,TH" <hich stimulates coritsol synthesis and release by acti+iating adenlyl cyclise" ,yclic adenosine monophosphate $cAMP% then acti+ates protein kinase A, &hich phoshoporylates and increases the acti+ity o! cholesterylester hydrolase, the rate limiting step in steroid synthesis" A"o$ost ron r " as is e!!ected by A,TH, but Renin release is more important in!luence" The steroids are e1amples o! gene acti+e hormones" The steroid di!!uses into the cells" In the absence o! cortisol the receptor is inacti+ated by a heat shot protein $hsp HB%" ,ortisol triggers the release o! hspHB and the acti+ated receptor 'R enters the nucleus &here it stimulates or inhibits the production or proteins, &hich then produce the characteristic actions o! the hormone" ,oritcothrophin releasing hormone $,RH% is a C) amino acid polypeptide &hose action is enhanced b% ar+inin avaso(r ssin 0ADH1. It is produced in the hypothalamus and reaches the adenopophysis in the hypothalamus(hypophsyial portal system &here it stimulates the production o! corticotrophin" A,TH is process !rom large molecular &eight precursor, pro(opiomelanocortin $P4M,% present in corticotroph cells o! the adenohypophosis, its main action is to stimulate the synthesis and release o! cortisol" Cortiso" Hydrocortisone I'' $iat 'ana+ ' nt. Addisons Moon !ace I- ac&t "% sic#< 'triae Take blood cortisol glucose Fat redistribution urea and electrolytes" 0i+e Hirsutsim hydrocortisone )BBmg as I. In!ection bolus" 0i+e saline in!usion Pro1imal muscle litre initially o+er C(E hours" &asting ,orrect hypoglycaemia i&th Bruising I. bolus o! *BF glucose" ,ontinue &ith &ith IM hydrocortisone )BBmg E hourly" Lon+ t r' H%$rocortison orally )Bmg on &aking, @mg at lunch and e+ening $dose +aries% F"&$rocortison B")(B"*mg per day" 'ynthetic mineralcorticoid deri+ati+e o! aldosterone" Plasme rennin aciti+ity should be measured * hours a!ter the !lurdrocortisone dose and maintained in the normal range"

S%nth tic A"$ost ron

Fludrocortisone

Addisons

Hypertension 4edema Peptic ulcers Mood changes 0I upset 0laucoma

C&shin+s S%n$ro'

E.c ss (ro$&ction o- cortiso"

= tocona)o"

<ell absorbed orally, &ide spectrum anti !ungal drug &hich has adrenal suppression e!!ects M tira(on Metyrapone blocks cortisol ,ushings synthesis by inhibiting steroid ))O(hydro1ylase" Mitotan 6nkno&n mechanism o! ,ushings action but inhibits adrenal Adrenal adenoma steroidal action H%( r(arath%roi$is' an$ Ma"i+nanc% acco&nt -or 43> o- H%( rca"ca 'ia R h%$ration I. 'aline Hydration must be Hypercalcaemia maintained &ith I. intrav no&s sa"in " This &ill pre+ent se+ere hypercalcaemia" 4nce +olume status is normal use bis(hos(honat s Bis(hos(hona Alendronate Bind to hyrdo1yapatite Hypercalcaemia t s 5tidronate crystals and reduce bone resorption" H%(oca"a 'ia Co''on st ca&s is *it D $ -ici nc% Ca"ci&' ,alcica Hypocalaemia S&((" ' nts 4steocare ,ushings Anti !ungal *ita'in D ana"o+& 5rgocalci!erol .it #* ,holecalci!erol .it #A Al!acalcidol )( hydro1y+itamin # ,alcitriol ),*@ #ihydro1y # Teriparatide Hypocalcaemia .it # de!iciency .itamin # analogues allo& absorption o! calcium !rom the gut"

Hepatic necrosis Adrenal suppression 2ausea +omiting, abdominal cramping pain" #i yness, dro&syness nausea and +omiting" Hypernaetremia

0I upset, 5rosion o! 4esophagus Hypercalcaemia 'tomach pain #iarrhoea Hypercalcaemia

R co'binant PTH ana"o+&

'timulates bones resorption, 9indey to re absorb calcium, stimulates production o! )"*@ #ehydro1y+it # at kidney" Pha ochro'oc%to'a 2eoplasm o! the adrenal medulla" )BF are malignant, )BF are e1tra(adrenal, )BF are !amilial" Blockage o! adreno receptors must be started !irst" a! Pheno1yben ami An irre+ersible antagonist is Tumours o! adrenal a$r nor c (to ne used to block the a(e!!ects o! medulla r anta+onist Labetalol the large amounts o! catecholamines !rom Doxazosin Phentolamine tumours o! the adrenal Prazosin medulla" Tamsulosin Terazosin Hypocalcaemia Hypoparathyriodism

#i yness Leg ,ramps 2ausea are bilateral, )BF Re!le1 tachycardia

b!b"oc# rs

Atenolol $see abo+e% Conns .c ss (ro$&ction o- a"$ st ron A"$ost ron 'pironolactone r c (tor $see abo+e% b"oc# rs 5plernone

,onns Li+er disease &ith ascites Blocks the binding o! aldosterone to its receptor and increases the e1cretion o! 2a/ and decreases the electrically coupled 9/ secretion" #ecrease the luminal membrane 2a/ permeability in the distal nephron by combining &ith 2a/ channels and blocking them ):) basis" This increases 2a/ $,l( and H*4% e1cretion and decreases 9/ e1cretion" 'e+ere Hyperkaleamia Pain!ul 0yanocamastia 'e+ere Hyperkalaemia

Postassi&' S(arin+ Di&r tic

Amiloride Triamterene

Potassium sparing diuretic ,onns

? ro ;r$ r =in tics

,ommon drugs Phenytoin, Aspirin, 5thanol, Theophylline, Thiopentone Anti!E(i" (tics @ 5pilepsy is a chronic disease in &hich sei ures result !rom abnormal discharge o! cerebral neurones" 5pilepsy is de!ined as a tendency to recurrent sei ures i"e" t&o or more sei ures" Partia" s i)&r s $sei ures begin !ocally% Si'(" $consciousness not impaired% Co'(" . $&ith impairment o! consciousness% Beginning as a simple partial sei ure and progressing to a comple1 partial sei ure" Impairment o! consciousness at onset" Partia" s i)&r b co'in+ s con$ar% + n ra"is $. G n ra"is $ S i)&r s Abs nc 'ei ure Typical $petit mal% Atypical. ;th rs Myoclonic sei ure, ,lonic sei ure, Tonic sei ure, Tonic(clonic sei ure $grand mal% Atonic sei ure" Treatment should be considered &hen t&o or more unpro+oked sei ures ha+e occurred &ithin a short period" <hene+er possible, treatment should in+ol+e only one drug" G n ra"is $ Lamatrogine La'atro+in and Lamatrogine E(i" (s% 'odium .alproate *a"(raot ha+e similar Blurred +ision mech o! action as di iness and Ph n%toins discussed dro&syness" 'erious belo&" *a"(roat also skin reactions can seems to in increase occur especially in 0ABAergi central inhibition children" mechanisms that may .alproate ( 2ausea, in+ol+e stimulation o! &eight gain, glutamic acid decarbo1ylase bleeding tendencies acti+ity and3 or inhibition o! and transient hair 0ABA(T acti+ity" loss%" The main disad+antage is that occasional idiosyncractic reactions cause se+er or !atal hepatic !ailiure"

Foca" E(i" (s%

,arbama epine Phenytoin

Ph n%toins anticon+ulsant action is probably a result o! its ability to pre+ent high !re8uency repetiti+e acti+ity" Phenytoin binds prerentially to inacti+ated $closed% 2a/ channels stabili ing them in the inacti+ated state and pre+enting them !rom returning to the resting closed state &hich they must do be!ore they can open again" High !reu8uency repetiti+e depolarisation increases the proportion o! 2a/ channels in the inacti+ated state and, because these are susceptible to blockade by phenytoin, the 2a/ is progressi+ely reduced until it is e+entually insu!!icient to e+oke and action potential" 2eruonal transmission at normal !re8uencies is relati+ely una!!ected by phenytoin because a smaller portion o! the 2a/ channels are in the inacti+ated state" ,arbama epine, lamotrigine, +alproate, and topiramate" Ha+e similar actions on neuronal 2a/ channels"

,arbama epine is metabolised in the li+er to carbam epine( )B,))( epo1ide, an acti+e metabolite that partly contributes to both its anti(con+ulsant action and neuroto1icity" In contrast to phenytion there is a linear increase in serum concentration &ith dosage" Mild neuroto1ic e!!ects are common $nausea di iness dro&syness, blurred +ision and ata1ia% Agranulocytosis is a rarer idyiosyncratic reaction" Phenytoin is hyro1ylated in the li+er by a saturable en yme system" The rate o! metabolism +aries greatly in patients" And up to *B days maybe re8uired !or the serum le+el to stabili e a!ter changing the dose" #ose is increased gradually until !its are pre+ented , or until signs o! cerebellar disturbance occur $nystagmus, ata1ia, in+oluntary mo+ements% 4ne the metaboli ing en1ymes are saturated , a small

Abs nc E(i" (s% in Chi"$r n

Absence sei ures in+ol+e oscillatory neuronal acti+ity bet&een the thalamus and the cerebral corte1" This oscillation in+ol+es $T(type% ,a*/ channels in the thalamic neurones, &hich produce lo& threshold spikes and allo& the cells to !ie in bursts" #rugs $5thosu1imide and .alproate% that control absences reduced this ,a*/ current dampening the thalmacortical osciallations that are critical in the generation o! absece sei ures" Par#insons @ Main (atho"o+% is th .t nsiv degeneration o! the dopiminergic nigrostriatal tract, but the cause o! the degeneration is usually unkno&n" Replacement therapy alone is not possible in parkinsons because the dopamine does not pass the blood brain barrier" Ho&e+er its precursor le+odopa $L(dopa%, does penetrate the brain &here it is decarbo1ylated to dopamine" 4rally administered, le+odopa is largely metaboli ed outside the brain and so it is gi+en &ith a selecti+e e1tracerebral decarbo1ylase inhibitor $carbidopa or bensera ide%" 'ome o! the peripheral side e!!ects o! dopaminergic drugs can be reduced &ith domperidone, a dopamine antagonist that does not penetrate the brain" Inhibition o! the drug monoamine o1idase B $MA4b% &ith selegilene potentiates the actions o! le+odopa" Anti(muscarincs are used !or the tremor that occurs &ith parkinsons" L vo$o(a Sin 'at Le+odopa is the immediate Parkinsons 2ausea and Ma$o(ar precursos o! dopamine and is +omiting caused by Both these drugs able to penetrate the brain stimulation o! the come &ith &here it is con+erted to ,TP" e1tracerebral dopamine" The site o! the Psych e!!ects +i+id decarbo1ylase decarboy1lation is uncertain, dreams, inhibitors% but as dopa decarbo1ylase is hallucinations, no rate limiting there maybe psychotic states su!!icient en yme in the and con!usion" remaining dopaminergic Postural ner+e terminals" Another hypotension is possibility is that the common" con+ersion occurs in nor #yskinesias $?erky adrenergic or seratonergic

5thosu1imide 'odium .alproate

increase in dose may produce to1ic side blood le+els o! the drug" 4ther e!!ects 0um hypertrophy, acne, greasy skin, coarsening o! the !acial !eatures and hirsutism" 5thosu1imide( 2ausea +omiting"

terminals" Because the de( carbo1ylase acti+ity in these neurones is not speci!ic"

Do(a'in R c (tor A+onists

Bromocriptine $ergot deri+ati+e% Ropinirole $non ergot deri+ati+e% Apomorphine $+ery po&er!ul gi+en by parenteral administration%

Parkinsons Prolactinomas

Pr S%na(tic R !U(ta# inhibitor

Amantadine

Parkinsons

#opamine agonists ha+e no ad+antage o+er le+opdopa and the ad+erse e!!ects are similar" 6sed &ith young patients, in particular &ho are gi+en a dopamine agonist as initial therapy $sometimes together &ith selegeline%" This strategy may slo& the de+elopment o! dyskinesias but only @BF o! patients sho& any bene!icial response to monotherapy &ith dopamine agonists" <hen patients on le+odopa therapy start to sho& deterioiration dopamine agonists are o!ten added to try and reduce the o!! periods" Potentiates dopamine by pre+enting re(uptake in the pre(synaptic terminals" Moderate e!!ect but toleranc

or dance like mo+ement% are an important ad+erse e!!ect" Long term a!ter !i+e years treatment about @BF o! patients &ill ha+e lost ground" In some there is a gradual recurrence o! parkinsionian akinesia" A second !orm o! deterioration is the shortening o! duration o! action o! each dose" .arious dyskinesias may appear and, &ith time rapid oscillations in mobility and dyskinesias" 2ausea, psychiatric symptoms, postural hypotension" Pulmonary !ibrosis and retroperitoneal !ibrosis" Apomorphine $highly emetogenic% domperidone should be gi+en be!ore treatment started"

#i yness, Loss o! co(ordindation, inability to sleep, nausea,

soon de+elops ner+ousness Inhibits monoamine o1idase 2ausea type B $MA4(B% there by Heartburn increasing dopamine" This is #ry mouth done by reducing the metabolism o! the dopamine in the brain potentiating the le+dopa &hich can be reduced by up to one )3A" It is used to reduce end o! dose akinesia" C;MT 5ntacapone Inhibbits catechol(4( Parkinsons #ro&syness inhibitors Ben ara ide methltrans!erase $,4MT% and #i yness pre+ents peripheral 'tomach upset con+ersion o! Le+odopa to #iarrhoea $inacti+e% A(4(methyldopa" It increases the plasma hal! li!e o! le+odopa and increases its action" Anti'&scarini Ben etropine Produce a modest Parkinsons #ry mouth cs Procyclidine iimpro+ement in the early 6rinary retention 4rphenadrine stages o! parkison>s disease, and constipation" Ben he1ol but the akinesia responsible 5!!ect memory and !or most o! the !unctional concentration" disability responds least &ell" M%a sth nia Gravis An ac8uired organ speci!ic autoimmune disorder in &hich antibodies are directed at the post synaptic acetycholine receptor" This results in &eakness and !atiguability o! skeletal muscle groups" The most commonly e!!ected muscles are the pro1imal limbs and the ocular an bulbar muscles" ;ra" Prydostigmine Most &idely used drugK it has Myaesthenia gra+is 4+erdose causes a ac t%cho"in st a duration o! about A(@ cholinergic crisis ras hours" Patients response &ill &ith se+ere determine the dose re8uired" &eakness" ,olic and 0reat symptomatic drug but diarrhoea may does not alter the natural occur" history o! the disease" Motor n &ron $is as Ri"&)o" Rilutek 6sed to treat amyoptrophic M2# 2ausea lateral sclerosis" #elays the Fatigue onset o! +entilator Hepatitis dependence or tracheostomy by * months" G&i""ain! Barr s s%n$ro' $post(in!ecti+e polyneuropathy% In!lammtory demyelinating polyradiculoneuropathy" 4!ten !ollo&s one to t&o &eeks a!ter in!ection or diarrhoea, &hich may ha+e been mild" ,ampylobacter ?e?uni has been particularly implicated as a cause o! the diarrhoea and is associated &ith the most se+ere !orm" ,lassic presentation distal paraesthesie, o!ten &ith little sensory loss, and &eakness can occure pro1imally, distally spreading or generalised" The symptoms ascend up lo&er limbs and body o+er days to &eeks" Facial &eakness present in @BF cases" In se+re cases respiratory and bulbar in+ol+ement occurs" IF ., drops to ) litre o! belo&: arti!icial +entilation is needed" Hi+h $os $I.Ig% 5ither high(dose intra+enous 0uillen Barres Hepatitis Mona'in o.i$as inhibitor t%( B 0MA;!B1 'elegiline Parkinsons

i''&no+"ob&" ins

immunoglobulins $I.Ig% at Renal !ailure CBBmg3kg !or @ days or plasmapheresis can be administered, as they are e8ually e!!ecti+e and a combination o! the t&o is not signi!icantly better than either alone" Therapy is no longer e!!ecti+e a!ter * &eeks a!ter the !irst motor symptoms appear, so treatment should be instituted as soon as possible" I.Ig is usually used !irst because o! its ease o! administration and sa!ety pro!ile, &ith a total o! !i+e daily in!usions !or a total dose o! * g3kg body &eight $"Ckg each day%" G"a&co'as! Mi1ed group o! disorders that ha+e some common !eatures: 4ptic disc cupping, +isual !ield loss and usually, raised intraocular pressure $I4P%" B ta!B"oc# rs Timolol, carteolol, Reduce a8ueous secretion by 0laucoma 4cular irritation beta1olol, inhibitory action on beta Bronchospasm le+obunolol adrenoreceptors in the Bradycardia cilliary body" 2ightmares 51acerbation o! hear !ailure M&scarinic Pilocarpine $also Increase a8ueous out!lo& +ia 0laucoma 4cular: Misosis 0(aras%'(ath a di!!erential !or trabecular mesh&ork by $reduced +ision in tic1 bilateral ciliary muscle contraction the presence o! a si'&"at s . constricted cataract% spasm o! pupilsM% accommodation, bro& ache 'ystemic: '&aeting, bradycardia, 0I disturbance A"(ha:! Brimonidine, Reduces a8ueos secretion by 0laucoma 4cular: Iris sti'&"ants Apraclonidine selecti+e stimulation o! darkening, To(ica" alpha* and adrenocrecptors con?uncti+al in the ciliary body increase hyperaemia, out!lo& by the u+eoscleral eyelash gro&th" route 'ystemic: bitter taste, asthma" Carbonic Aceta olamide Reduce a8ueous secretion by 0laucoma 4cular route: Anh%$ras $systemic% the cilliary body irritation and allergy Inhibitors #or olamide, 'ystemic route: Brin olamide Malaise,

paraesthesia, urea and electrolye disturbance, aplastic anaemia Mydriatics and cycloplegics - $ 6sed !or retinal e1amination and ob?ecti+e re!raction $retinoscopy% Anti'&scarini Tropicanamide, 5ye dilation !or e1am Inhibit muscarinic receptors cs cyclopentolate, o! parasympathetic ner+ous atropine" system to paralyse papillary sphincter and ciliary muscle" 4cular: Blurred +ision, glare, angle closure glaucoma" 'ystemic: Tachycardia, dry mouth, con!usion, tremor" 4cular: Blurred +ision, glare, angle closure, glaucoma, con?uncti+al blanching" 'ystemic hypertension 4cular: Allergy, blurred +ision

A"(ha! sti'&"ant

Phenylephrine

5ye dilation !or e1am

'timulates dilator muscle o! the pupil no cycloplegic e!!ect"

L&bricants @ Th r ar a 9i$ ran+ ,arbomers, hyrpmellose, poly+inyl alcohol, li8uid para!!in Ant!In-"a''ator% A+ nts. Most important immnosuppressants Corticost roi$ Prednisolone, s betamethasone, de1amethasone #ry eye 51act mechanism depends on the agent

drugs are corticosteroids, a .ariety o! other drugs are a+ailable including systemic 'uppress In!lammation 'uppresion o! broad spectrum o! in!lammatory processes $see corticosteroids% 4cular: 0laucoma $especially &ith local administration%, cataract $especially prolonged systemic use% e1acerbation o! some in!ections MMM e"g" herpes simple1" 'ystemic: 2egligible &ith topical use, common and +aried &ith systemic administration" 4ccular: Irritation 4ccular route: Irritation 'ytemic route: #ro&siness

Mast c "" stabi"is rs Anti! hista'in s

,romoglicate, nedocromil, lodo1amide" Topical: Anta oline, a elastine, le+ocabastine"

Allergy Allergy

'tabilise mast cells Block histamine receptor

'ystemic $chlorphenamine, ter!endaine, cetirisine% NSAIDS Topical: 5ye in!lammation $ketorolac, diclo!enac, !luribipro!en% Anti!In- ctiv a+ nts/ Topically applied antibacterial and anti+iral and antiparastic agents is much less !re8uent" Antibact ria"s Topical: Bacterial In!ection ,hloramphenicol, gentamicin, cipro!lo1acin, 2eomycin, !usidic acid" 4ccassionally intra(ocular, systemic Antivira"s Aciclo+ir, topical Herpes simple1, or systemic oster

Modulate prostaglandin production"

'ystemic: Peptic ulceration, asthma"

drugs are +ery commonly prescribed" The use o! anti!ungal Range o! acti+ities and speci!icities .ary &ith agent 4cular: allergyK corneal to1icity common &ith intensi+e use" 'ystemic: generally only &ith systemic use"

4cular: blurred +ision, corneal to1icity 'ystemic: Rashes: kidney, li+er and other e!!ects may occur &ith systemic use" Loca" Ana sth tics/ Ma?or uses are to relie+e pain and thereby assist &ith clinical e1amination and the !acilitation o! surgical anaesthesia Loca" Topical or peri( Block conduction along the ,linical e1am 4cular: Irritation, ana sth sia ocular in?ection" ner+e !ibres corneal to1icicty" 41yburprocaine, 'ystemic: generally pro1ymetacaine" accidental Tetracaine, intra+ascular or lidocaine" intrathecal $cerebrospinal !luid% in?ection" #uring surgical anaesthesia, cardiac arrythmmias, respiratory depression Bot&"in&' to.in/ 6sed in the management o! certain ocular motility disorders amd blepharospasm, and to induce ptosis !or corneal protection Bot&"in&' In?ection at site o! Pre+ents release o! the Motility disorder #ependant on

Inhibits herpes +irus #2A synthesis

to.in Mi+rain Pi)oti- n S&'atri(tan Ac&t Mi+rain M th%s r+i$ Lon+ t r' 'i+rain Urinar% Tract In- ction Tri' tho(ri'

action

neuro(transmitter acetycholine at neuromuscular ?unctions Migraine Migraine Migraine

treatment sitee"e"g un&anted ptosis or double +ision

'erotonin Antagonist @HT 'erotonin Antagonist @HT 'erotonin Antagonist @HT 5"coli, proteus, saprophiticus"

6TI

24T used in pregnancy 6se nitro!urentoin instead or amo1icillin 6sed in pregnancy

A'o.ici""in

6TI

Dia)o.i$ Blocks insulin release Insulinoma T ri(arati$ PTH analogue Hypocalaemia Corticost roi$s Release o! cortisol is controlled by negati+e !eedback mechanism in+ol+ing the hypothalamus and anterior pitruitary" Lo& plasms cortisol le+els result in release o! A,TH &hich stimulates cortisol synthesis and release by acti+ating Adenylate cyclise" cAMP then acti+ates protein kinase A &hich phosphorylates and inceases the acti+ity o! cholesterylester hydrolase, the rate limiting step in steroid synthesis" Aldosterone release is a!!ected by A,TH but other !actors $renin angiotensin are more important" 'teroids are e1amples o! gene acti+e hormones" 'teroid di!!uses into cells &here it binds to cytoplasmic glucocorticoid receptors" I2 the absence o! cortisol the receptor is inacti+ated by a heat shock protein" ,ortisol triggers the release o! hspHB and the acti+ated receptor enteres the nucleus &here it stimulates the synthesis o! proteins, &hich then produce the characteristic actions o! the hormone" ,orticotrophin is prcessed !rom a large molecular &eight precursor pro opiomelanocortin $P4M,% precent in the corticotroph cells o! the adenohypophysisK its main action is tto stimulate the synthesis an release o! cortisol" P4M, also contains the se8uences !or B lipoprotein $B(LPH% and B(endorphin, &hich are co comittantly release into the blood" ,orticotrophin is also belie+ed to sensiti e the one glomerulosa to other stimuli &hich cause aldosterone release" G"&cocorticoi$s/! M chanis' o- action! ,ortisol and synthetic glucocorticoids di!!use into target cells and binds to a cytoplasmic glucocorticoid receptor that belongs to the super!amily o! steroid thyroid and retinoid receptors" The acti+ated receptor(glucocorticoid comple1 enters the nucleus and binds to the steroid respsones elements on target #2A molecules" This either induces the synthesis o! mR2A or represses the genes inhibiting transcription !actors e,g, 2FkB !or most clinical purposes, synthetic glucocoritcoids are used because they ha+e a higher a!!inity !or the receptor are less rapidly inacti+ated and ha+e little or no salt retaining properties" E-- cts 0lucorticosteroids are essential !or li!e their most important !unction being !acilitating the con+ersion o! protein to glycogen" They inhibit protein synthesis and stimulate protein catabolism to amino acids" 0luconeogenesis glycogen deposition and glucose release !rom the li+er are stimulated, but peripheral glucose uptake is inhibited" #uring !asting they are essential

!or keeping blood sugars le+el" Anti In-"a''tor% E-- cts an$ I''&nos&((r siv -- cts" ,otricosteroids ha+e pro!ound anti(in!lamm e!!ects" They suppress all phases o! in!lammatory response, include the early s&elling , redness pain and the later proli!erati+e changes seen in chronic in!lammtation" In!lammation is suppressed by se+eral mechanisms ,irculating immunocompetent cells and macrophages are reduced and the !ormation o! pro in!lammatory mediators, as prostaglandins leukatrienes and platelet acti+ating !actor is inhibited" #one by stimulating the synthesis in leucocytes o! a protein $lipocortin% that inhibits phospholipase A*" This en yme in cell membrane is acti+ated in damaged cells adn is responsible !or the !ormation o! arachdonic acid" The precursor o! many in!lammatory mediators" ,orticosteroids suppress the genes coding !or phospholipase A*, $,47*% and the interleukin(* $IL(*% receptor" These genes are normally s&itched on by 2FkB but steroids induce the synthesis o! IkB that binds to the 2FkB and inhibits it by pre+enting its entry into the nucleus" They also depress monocytemacrophages !intion and decrease T(,ells, IL) and IL* is inhibited" H%$rocortison ,oritcosteroid $iI%s used orally !or Anti In!lamm Moon !ace, !at to replacement $ii% intra trunk and !ace, +enously in shock and status purple striae, asthmaticus and $iii% topically hirsutism,acne, $e"g" ointments in ec ema in!ections enemas in ulcerati+e colitis 4steoporosis, bruise skin, diabetes, hypercalaemia, Fluid retention, hypokalaemia" Pr $niso"on ,orticosteroid Is the most &idely used drug Anti In!lamm A s abo+e dri+en orally in in!lammatory and allergic diseases" B ta' thason ,orticosteroid Are +ery potent and ha+e so Anti Im!lamm As abo+e an$ salt(retaining actions" This D .a' thaso makes them especially n use!ul !or high dose therapy in conditions, such as cerebral oedema &here &ater retention &ould be a disad+antage" B c"o' tason ,orticosteroid Pass membranes poorly and Anti In!lamm As abo+e an$ are more acti+e topically B&$ soni$ than &hen gi+en orally" They are used in asthma and topically in se+er ec ema to pro+ide a local anti in!lammatory action &ith minimal systemic e!!ects" Tria'cino"on ,orticosteroid 6sed in se+er asthma and by Anti In!lamm As abo+e intra articular in?ection !or local in!lammation o! the ?oints" NSAIDS inhibit ,47 and inihibit prostaglandin synthesis" ,47 e1ists in tissue as constitiuti+e iso!orm $,47()% but at sites o! in!lammation cytokines stimulate the induction o! a second iso!orm $,47(*% Inhibition o! o! ,47(* is thought to be responsible

!or the anti(!lamm e!!ects o! 2'IA#'" Inhibition o! ,47 ) is responsible !or 0I problems" Most current 2'AI#' are ,47 ) inhibitors, but selecti+e ,47 * are on the market $,eleco1ib, eteroco1ib, +aldeco1ib% are selecti+e ,47 * inhibitors incidence o! gastric per!oration obstruction and bleeding is reduced by at least @BF" As(irin is long standing 2'AI# and anti analgesic Parac ta'o" is ?ust analgesic