1 general pharmacology-1

GEN ERAL PH A RM A COLO G Y

Yzz/r/#zzc//yp to Pharmactjlogy)sphartnàcilogy:ls the sçience which deals with drugs.

*Drugs:*rfhese arc chcmical agents used for: tregtlnent (cure) ()17 diseases,prophvlakts (prevention) of diseases as l-tkkllnpicin in llrophylaxis againstmeningitis, aspirin in prophylaxis against throlnbo-enlbolism, andnitrates in prophylaxis against angina pectoris - diagnosis of diseases as

132 ' l id l'-tlnctions -- and forradioactiye iodine (1 ) in diagnosis ol t lyro' )

prevention of pregnancy (contraceptioq). .

*'Drugs ''modffy'' an existing cell function either by stilnulation

(activation) or inhibition (depression) but tlley do llot create a newftlnction. '

*'Names (Nomenclature) of drugs:1 - Chem ical nam e.2- Non-propietary = Generic name (may be referred to as scientifienamel.3- Propietary = Commercial nafne (may be f'efkrrett G as tradd name).

*lklost dfugs are purchased only accordillg to a ''prescription'' and areltnown as ''Prescrlvtion-onlv tnedication = PO54'' whereas few drugs arepurchased without a prescription as antipyretics (aspirin alld ,paracetafnol), drugs for common c01d, and laxatives tlsed in treatnzent ofconstipation. These drugs are known as ''O ver '/>t? (Llottnter tW'//g,j' =u

/3///-1/-$. to l/.çc..(flw about lr/g,î-.is.4'-' hemelz.'1- Sottrce. '11- C/vzzpj-s-//'y'.111- Pharmacokinetics./Pt Pharmacodynamics.IQ lndications = Therapeutic ttses.V1- yltA/e/w: effects.

. . *e *

Iz11- C''-tn/-?/rti/jzltF/jctr//jtvil.V111- D?-z/,g' Interactions.1X- Routes tl-/-x-rlt7///'/ïnj-s'//'l/j/n.

l

'It is more blessed to give than to receive.WhiteKnightLove

http://www.facebook.com/DoctorWhitey


1- sbt/rce-l 1of Drugs:

l-plant souices: e.g. Atropine is obtained t'rom Atropa belladùnna andother plants, M orphine is bbtained from Papaver somniferum , Ephedrineis obtained from Ephedra plant, etc. . .z-Animal' sources: e.g. animal lnsulin was prepared from pigs (known asporcine insulin) and from cattle (known as bovine insulin), Heparin(unfractipnated heparin = UFH) is obtained from the lungs and intestinesof cattle and pigs. These drtlgs are highly antigenic and are replaced ntlwby human insulin and low molecular weight heparins (I-MWHs);respectively.3-Microorganisms'. Antibiotics (as penicillin t'J') are prepared fromm icroorganism s as fungi and bacteria.p-Mineral sources'. e.g. iodine and magnesiutn sltlphate, and alsoi tive isotopes as 1131 (therapetltic) and 1132 diagnostic).rad oac (

s-svntheiic drugs'. most drugs are chenlically synthesized, e.g. Aspirtn,Propranolol, Sulphonamides: Benzodiazepines, Paracetamol, etc. . .ti-Biotechnology (genetic engineering): some drtlgs are prepared usingj ' .'recombinant DNA technology'' aj H uman jzb'///jz/, Growth hormone,recombintmt tissue Plasminogen Activator (1.- tPA '= Alteplase) .The mail't disadvantage of these drugs is their high cost (expensive).

11- Chem istty:* Some drtlgs -as Aspirin (Acetyl Salicylic Acid) and Barbiturates- al'eweak acids, whereas otllers- as Ephedrine and Amphetamine- are weak

bases.* M ost dtmgs are organic compounds bllt few drugs are inorganic

elements as Lithium and Iron.* Some dftlgs contain a specific chem ieal ring) e.g. Steroid hormones asCortisone contain a steroid ring, and catecholam illes as Adrenalinecontain a catechol ring.

JJ/- Pharmacokinetics..The term ''pharmacokinetics'' describes the movenlellt ofdrugs inside thebody, and is tlsually referred to as ''1p# tat #?e botlv (,/.4.7:,$. to the (-#w.e''.

. '''

'

''-'-----'----'''--- ''-'---''''- '-'-''''-'' '----'''

'

- -'- - - - --------' - '-''--- . '

Pharmacokindics include:

1 -àbsorption.l-oistribtttion.Lj-Metabolism = Biotransfortnation.n-ïxcretion.(N.B.: pharmacokinetics are sometimes l-etkrred to as ''absorption andfate'' and m etabolism and excretioll al'e called togetlzer ''elimination'' or

''clearance''). *

3

Freely you have received; freely give.WhiteKnightLove



lV- P//t7rzl/.tlwtlt/lv/.w pojccThe term pharmacodynam ics is referred to as ''kvhat the Jrl/g does to the

bodv'' and it incltldes:

A-avechanism of Ac. tip n: the most important lnechanism of action is onspecif-ic ''receptots'' btlt some drugs may aet on ejlzymes, cell lnembrane,

r 7

DNA, chenlically, physically, etc. (see later).

B-pharmacological Actionsk the actions of the drtlg may be:l-laoeal aetions (also known as topical actions) where tlle drug acts at thesite of application, e.g. skin ointments and eye drops.z-system ic actions: the drug reaclles tlle systenlic circulation and isdistribtlted to different systems as CNS, CVS, respiratory systemp etc.3-lletlex actions (also called remote actions): e.g. drugs that elevatearterial blood pressure as Noradrenaline lead to ''reflex bradycardia''through vagal stimulation.

VL Indications = Therapeutic ?/-$'d.$'.'The diseases for which the drug is prescribed to treat or prevent, exg.Aspirin is indicated 'in treatm ent of headache and tkver, and to preventthrom boembolism .

V1- Adverse etfects:This term describes the unwanted drtlg effects alld is solnetilues referred

to as ''side effects'' or ''toxic ellkcts'' (see Iater).

V1I- Contraindications:The diseases in which the drug shotlld not be prescribed, e.g. Aspirin is

contraindicated in peptic ulcer.

VlI1- llrsfyr Intqra-ctkon-y'l-Drug-brug interaetions: when 2 or more drugs are prescribed to thepatient, these interactions may be benefieial (favorable) or harrpful(unfavorable).z-Drug-lzood interactions, e.g. MA O inhibitors ustxl in treatm ent bfdepression interact with food containing tyram ine as cheese and yoghtlrtand lead to seriotls and m ay be fàtal elevatipll o12 blood pêessure.

1.Y- ./l(p2//t?,5' ofzqdministratip.q (see later).

3




1- '/JllrlApy/ct?k/pyr/k.î

A s previously m entioned; the term ''pharmacokinetics'' describes themovem ent of drugs inside the body, and is usually refen-ed to as''F hat thq bodv does to the drug''. Pharmacok-inetics include'.L-jbsomtion.2-1j.:/?'j/?2///taz?.à-xetabolhm = Biotransformation.4-fxcretion.

. )

l-A bsorption:

ww.p#fi.p--iti-9.-1.)-:. it is the passage (transfer) of the drug from the site ofadm inistration to the system ic circulation.

* It is obvious that absorption from any site (GI'r lung, skeletal muscles,skin, and inucous membranes) occurs by passage of the drug across thecell m em brane which is m ade of plzospholipid bi-layer and contains

minute water-filled channels (pores).1

wpassagq o.f drugs across cell ?z?c/a:?.w/?e,$'.' also ltnown as''transm em brane m ovement of drugs'' and it oceurs l)y one of thefollow ing m ethods'.l - Siluple diflksion (the most il-nportallt lnethod fklr drug absorption).2- Filtration (also fmportalzt for drtlg excretion by tlle kidney- see later).*simple difftlsion and filtration are als() known as ''passive tratlsfer''.

3- Active transport.4- Pacilitated diffusion.,.' x ./ *Active transport and 'facilitated dittksion are known as ''carrier-lnediated/ transport'',

*

5- Pinocytosis'. it is an active process (energy-dependent) in wllich thedrug is ''engulfed'' inside the cell, e.g. absorption ()f vital-nin Bi2/ intrinsic

tàctor com plex.*Active transport, f acilitated ditl-tlsiollp alld pinocytosis are known as

'' ialize'd transport''spec .




km

' , jl k.

.k j > ua : tw j Q. <' ) R ' . . x' l j :u.' -e!1 j ; 'NQ ' co' . wI j zg k . ; j y rg . y j uo, . y ! y kao j' 1 uw ' ='. e 'd t I Q) .w. I ..-..2 2c > fb i :2 rv ll

. . ... . >. ; Qt . . o1 <.... '' ) Qh k.t rk y 2

QL ; e.t

'

l61i j

tn 7x tx C = to - >- # = e* M N kn W W) C = to - - ï M M s tm .> tx '* e to '*w t.t kn 41 tr C e $a - t-I k 1 o - x = g .- o = > 4 l I o - . x = x 1 67 Ch ' I 1 : = x C x 4 a l o = Jk wm xm r7 x r r7 t< = r o o vn cp o z m t< ) > = > r = . 67 = r - > z o x. x.= = o o .-. = o = r ,- . .x :z. =-

= > o = = G = ) = o o & o = - = p' = o o o o ..- o q oe' N o (7 G > O - C) o ' r N fp a fk G > G i - = & G > G n= o = :ru > < .s .. . >. > o. .. ) o R CA c rp w' ; o. x o. y p g xto y ru o o.- - . z = 5 c. = > o a (m x o .y p J a o =.+ q > o .x a ex .+. .x o g. o .x ex >> G o q+ 6 ** 7 m = =

.-. VD ex &.< .x o r .- 1 c g = z q w q r s. r $z z .x m sx r ..+ r=. M .x m - IZ .- o > G: =. m ! px .x . y m w x sx . m m m (jp >. m& N' (m c: o DQ tm o m C7 > C) G' y' r. > (m VQ o = = o UQ o p o . o a> A.< ' r = *M x X > > o G x = != Q' r > t-t o g -.= r. - ''< o o H =z C) 1 o o v? > > r7 . m I . >e . . zt K > m . . . x x o m :y.

o o (> . :: > d = oe = > = o o o > z o v) i C) xq C) G y ' o ' = o .% m (7 M N o o m or7 o C :r ' 67 C) r7 o w q. xt qs I > > o < = (a > cp C < = m >Cm o < œ 1 y' r o o a. = r x = z. o o o o > r > o o o ur; = > m z o o x . p = > m a o ! o - o o o ., . rz a; o o x x a; ; rz or o o w m rz a v 1 r cp o = = v) œ i > m o o o o o o o o o a . - .> = o = N' uva r > y . yaM = = = ' % = l z z. . o r. o. w = .. o s o o. m .. . m- % o - aCr . c - . m X c . . . - . Q . . t . o m o a w m g m . r o o o z. Mo g V > j' o o z. o 4 j C) 1 x 67 = 'o > lo > a. c a o > a. m z . o 1.= > o' r o X * r > jg r 1 : w > yn . .= > uz x v, . . >. o g = ji

' M z - r j p g? o M ' *= = ! - y . ' o (za *. Z Q ' > > r X. ;l (r4 i = = (m $ = = - o (m = = (m rb !l I l =- = = z - .w = ï p o @& .x = g = 1 I i. - > = œ j: o = o x o p - m p a o I o o -l = = z o m z.

- = ca rz m = = I = . m.l 1 = =- . o'- ! 54r7 y rg . l j rk j o- l , zs j Y . .1 l m- . SN o- o- =- . o$ jx tre z tro1 '- x.c = . - o =. m , z - r. - = = =:I tr ' = = l < eo o. q = x. s. j q 0. q .-. q a . ji ,-. G ! a va .j .. .-. p o j m1 .-s = 1 = Mo eo - ' % (m ,.+ a: X -l =. o = 1 * - = q o ) m. o =1- :::::::::::;r'''--' '''-'5E?'''--

'

''' li :::::::::::::::;--

*

.-----------. -----:;:-.---

*

''' ,

'

1:::7::::::.)------

*

1,---5;7----.

*

'''

'

1 w ' j & 1 = '1 1 ; i. 1 !

l I e > k j ; e G) œ r * tc M s c c - r c G) W * 1 e ha * m = - ' '27 1 c x. j G) x Ms ' = X . = Q. q - ! = g l Rw L % =a m, a= = m =. li F) = z w rs :; K > 1 - a I = = o trro x z m- o o

. % o @ > r p a m é Q . .g '1 $1 m .-.= ! tv a . m o z z m w m g a w a r m m m ...1 r r > m = j ) = >. - gp o .- z m r .N m -. mI * . - x p I / = (m o o > o c m. -. x o s.$ = 1 (?4 un - : z p G o o = = > r. '-- o x m. = o o o = p v) j1 r > o cq l 2 m - n K . r r e. = w o ..G w.-- . q< c7 r o ..= o- '

. o -Q1 M . 'r-' ,.-. = . l E ' ( v (m vo s - xr-z = = o p 'g w p m a -x ' o = = . tg p. ui (m q u< I = o = o - . >-. . .-- C w % r . xz o -. i No 'I = ! - > = > c .- m r: (r > rv o o =' = r T . = ; o # - = x m u = > . mv 1 = = = o- ' o % = 'X'X! .- -. = ,- s r z . m = m .: .x w . z p .s; s . ,- .= x x -. 2o (fp = N = o . / . = p o z ... .. o uz a1 o ex > = . l =. ev cs - o o ... x. x w r. o > m x - -. yoxl ! oœ '-- -c x . I $ 'y =a o -= ' .. ' n. = 4 k<. . w o 7x ' 0.. Oo -'-0 wx =- o- q ,a &-l = = = *vz I l I l % c) = ox w x ..+ G. . *. m- -> 2. . n-o ' = -c , =- ' Rzul = = o = 4z - ; o = = rv o . . -. a.t v; (J = m l . z o o = = > =.. o =. -r . m . z .

> . a .s m. xo re - i = o ; o o 1 r o o w x - . - cc = ---i

> = = z > - (rq > = - N m w o y' = w / .-. j o c x - - o m o va x< m o ... a j g - > w o m x m m a m z p= . o z o o œ = o o 9 - = w a mc > '- xo ( o. - s s = m

az e- .z > wm =.0 s . s.j u ox >> w j

- a = w o u. m p . o o o < vn = - a o c:X 1 r E o -o or > j R % ->= ! r m =

I > rk oi c

'It is more blessed to give than to receive.

WhiteKnightLove



Drug llm ization:How mtlch of the drug is ionized (lipid illsoltlble-llydropllilic-polar) andhow much' is unionized (nonionized-lipid soluble-lipophilic) isdetermined according to the following rules:1- Most drujs are either wealt acids as aspirin (salieylates) andphenobarbitone (barbiturates), or weak bases as ephedrine andamphetaml,ne.2- Drtlgs are present either in an acidic 'mediufn (as the stomacl) which ishigllly acidic, or urine which is slightly acidie), or in an alkaline medium(as the intestine).3- The presence of an acidic drtlg-as aspirin- in an acidic m ediuln-as thet h- makes most of the drug unionized and lipid soltlble so it will beS Om aC ,

easily absorbed by simple difhlsion.4- The piesence of an acidic drug- as aspirin- in an alkaline m edium asthe small iptestine -makes m ost of the drug ionized and lipid insoluble

,

and accordingly it will be poorly absorbed ( * ion trapping).5- 'l-lte prejenee of a' basic drtlg in an acidic m ediufn renders m ost of thedrug ionized and poorly absorbed; whereas the presence ofa basic drug inan alkaline medium allows most of the drug to be in the ttnionized formand alm ost complete absorption occurs.

6- lonization Constant = pKaa' it is the p14 of the m edium in which 50t% 01:-the drtlg is ionized and 50% is unionized.lt is clear that pKa is ''constant'' for every drug, e.g. pKa of aspirin = 3,5.This m eans that at pl-l 3.5, 50% of aspirin is ionized alld 50% isunionized.7- Hendelrson-llasselbalch Equations' this eqtlation clarifies the relationbetween pKa, pl-l, and degree ofdrtlg iollization. lt states that:

pKa = pl-l + log. Unionized fbrmtj-.ol- acidic drugs)

lonized fbrm

pKa = pl'l + log. lonized tbrm. . . ( j7j.; j. t; jj jj j (; (j j. ( j g jj j

Unionized forl'n

8- The sam e rules are applied to renal excl-etion 01' drtlgs: allkalinization ofurine by Nal4C()? enhances (increases) renal excretion of acidic drugs asaspirin because aspirin will be mostly ionized so it will be hydrophilicand excreted not reabsorbed, but if urine is m ade more acidic by vitamin




C (ascorbic acid) or NH4CI, most of aspirin will be unionized and lipidsoluble jo it will be ''reabsorbed'' by rellal ttlbular cells.On the other hand, basic drugs as am phetam ine and ephedrine will bemore excreted by acidification tsf urine.

Factors qyecting (modifvinz) Jr/?.e abaorptiomThe tttctofs that intluence drtig absorption can be classified into factorsrelated to the drug and factors related to tlle patiellt.

i

A- Factors relat-ed to the drtlg:1- Lipid splubility and lipid-watet partition coefficiellt: the m ore the lipidsolubility, the better the absorption.2- Degree of ionization: the more the unionized tbrm of the drtlg, them ore the lipid solubilit'y and hence the bet-ter the absorption.3 Valency: fenous salts (Fe2+) are better absorbed than ferric salts (Fe3+)4- Chemical nature: inorganic drugs are better absorbed than organicdrugs. !5- Pharmatetltical form tllation:*Aqueous solutions are better absorbed than suspènsions.wDrugs that are rapidly disintegrated (dissolved) in tlïe stomaeh -asparacetamol-are better absorbed than slowly disilltegrated drugs asdigoxin.B- Factors related to the patient'.1- Route ofadministration'.*lntravenous injection (l.V.): 100% of the drug l'eaclles the systemiccirculatiön almost imm ediately.*lntzumujctllar injection (l.M .): most of the drtlg is rapidly absorbed dueto the high vascularity of skeletal m uscles.*subcutaneous injection (S.C..I: absorption is less than after I.M .injection because the S.C. tisstle is luuch less vasctllar than the skeletalmuscles.*lnhalation: lipid soluble drugs as inhalation general anaesthesia arerapidly and almost completely absorbed because tlle alveoli have a verywide sufface area and very rich blood supply.lsublingtial: drugs given as sublingual pellets -as nitroglycerin intreatpent of acute apginal attacks-are better and nlorö rapidly absorbedthan orally adm inistered drugs because they reach the system iccirctllation directly and avoid passage throtlgh (J11' alld the Iiver.woral absorption is usually variable dtle to the ef-fbct of GlT pnd the liveron the drtlg before reaching the systemic circulation', this is known as

'' 1St ass effect'' (see later).P(I.V. > lnhalation > I.M. > S.C. > lntact skin).




J ;z-surface area of the absorbing surface: the m ore the surface areaexposed to' the drug, the better the absorption; e.g. small intestine

( * about 1000 times the surface area oftlle stomach due to the presenceof microvitli) and lung alveoli.3-vasculafity (blood supply) of the absorbing stlrface: the richer theblood supply of the absorbing surface, the better the absorption', eag. the

11 intestine and the lung alveoli. 'Sn3a4-state of health of the absorbing surface: oral absorption is greatlydecreased in the prcsence efdiseases ofGlT as malabsorption andgastritis ('Uhich decreases alcohol absorption).

I x

s-state of general circtllation: in cases of shock,' sym pathetic stim ulationcauses vasöconstriction of subctltaneotls blood vessels and markedlyreduces blpod flow to S.C. tisstles. Drugs as morphine should be given. . '

I.V . in case of shock.6-speeific factors: oral vitam in Bl2 is absorbed only in the presence ofintrinsic faktor syntlzesized by the gastric parietal cells.

Factors J//-cc//pxr (modilving) tprtv/ drug J/?.Ntpz'/p/jtn/?.(A- Factors related to the dl-ug: see before.B- Factors related to the patient'.1- Surfacç area of the absorbing surface: see before.2- Vasctllarity (blood supply) of the absorbing surfaee: see befbre.3- State of health of the absorbing surface: see betbre.4- Specill' ç factors: see before.5- Gut m ofility: drugs that stimulategut lnotility and accelerate gast'ric

drugs'' as l'netoclopram ide-will increaseeluptyingzknown as ''prokineticoral absofption of rapidly disintegrated drtlgs as paracetamol but they willdecrease absorption of slowly disintegrated drugs as digoxin.Drugs that inhibit gut motility and slow gastric elnptying-as atropine-have opposite effects.6- Gut pl-I: acidic dnlgs as aspirin are better absorbed in aeidic m edium asthe stom gph, whereas basic drugs as ephedrine antl alnphetam ine are

better absorbed in alkaline medium as the intestine (.)$,'/?p?).7- Gut contents (food and other drugsl::!-9- . . . qs 'l- :1t ..i-lllood containing Ca , and antaeids contaillillg Al and M g deereaseabsorption of tetracyclines due to chelalion.''r tracyclines decrease absorptitln of Ca21' ajld ij-()j).* e*lk-ood decreases absorption of anlpicillill.*cholestyram ine and charcoal decrease absorptioïl ofmost drugs by

adsorption.*'l-annic acid in teaand coffee (lecreast)s absotptitln of ir()n.




!

i!

* * Grape' fruit inhibits P.glycoprotein-which is responsible for reversedl .transport pf drugs from gut m ucosa into gut lumen-and so it increases

drug absotp. tion.8- First pajs effect (first pass metabolisml'. orally-administered drugs maybe partiall/ or completely metabolized while passing in GlT (gut firstpass) or tlie liver (hepatic first pass) before reaching the systemic

;circulatiop.A-Gut firk; pass effect'.lsome pep' icillins are destroyed by gastric aeidity and ate known as''acid-sensktive penicillinsl', e.g. benzyl penicillin (penieillin G).*polypeplide hormones as insulin are destroyed by the digestiveenZym CS. l

*some drlgs are metabolized by the gtlt mtlcosa as chlorpromazine anda-methyl dopa.

l first pass effect (muclz more iluportant than gut first passl:B-l-lepatic

Lipophiljc drtlgs are metabolized by the liver (see later).**some of lthese dnzgs are largely m etabolized by first pass hepatic effect,e.g. proprynolol. Other drugs are extensively fnetabolized, asnitroglycefin, or almost com pletely metabolized as lidoeaine.

. û

'

How to avoid fir-s/ pass e. J/rec/ ?.'J the' dose of orally- administered drugs as propranolol andl-lncreas

nitroglycdin.z-changelthe route of administration'. the drug may be given I.V. as

benzyl peàicillin anb lidocaine, S.C. as insulin, or sublingual (S.I-.) as! înitroglycer n.

i1

Bioavailà ili ..#Definitiun: it is the fraction (proportion or percentage) Of tlle cllemicallyunchanged drug reaching the system ic circulation fbllowingadm inistration by any route.*Bioavailgbilit'y after I.V. injection = 1009$.*Bioavailbbility is very high followillg administration by inhalation

:(ïnhalatièn general anaesthetics).+B- ioavailàbility af-ter I.M . injection is Iligher than after S.C. injeetion.

i ility after S.L. adluinistration is higher tllan aher oral*Bioavailab

adm inistràtion.*oral bioitvailabilitycalctllated as follows:

is variable beeatlse of first pass ellkct, and is

AUCOfitlx ! UU

i AUCIVAUC: Area Under plasma concentration-time fus'ntltve.

j - .'K

'

:1.:

' :' j

1




?1, . Coa ceMt-ll'o.

&

W J * W *r -. y r pg(z o

- . (z) r.o a o ooM r c G= r %ci.ro' . '-' ' t ;2' . $2

. & < > .> R< 1 v:o %f7 (% -= %m rt Q ''Dok * @ -(p oe

= Y 17 Q .o '-x >wt c) m cq

o= = o =p M - .r = 0X = o mG = > <c o 1 =- > M =G G

e.+ x..> m:5 : =' o == ='o e ) q<J r =C) &= Cr =< = -* > r7=

- x= = -p= n= y)X.. : G'd = wY: G c- m -= > Q

>> = vn= @Q =O y) =w*)13 = ,*Q C) '-o= ; =.r7 >

=eeo o

c' 7%

- 1j''

M'p

XM

glos- Q ucx.t-fo:l. . . - %. . *

N

---)*A'

7




lis .

2- D isrtibution:Once the tlrug is absorbed from any site, i.e. it reaches the systemic

' ' iibuted to the body fluids and tissues as tbllows:circulation, it is dist,' j!A

- Compqrtment M odel:l'T'he bopiy fluids = 42 L. representing 60% of the total body weight(TBW) of, an average 70 Kg. person and include: plasma (4 L.),interstitia/ tluid (10 L.), and intracellular tluid (28 L.). The plasma isrefbrred ttl as ''intravascular compartment'' and it represents 6% ot--rBw ,

I

whereas $e plasma and the interstitial tluid together (14 la.) are referredto as ''ekttacellular compartment'' and it represents 20% of TBW .

i! 28 lwiters.qi

'

i

! 10 Litersi 4 Liters

li

!

.' lj

, a Ayvg g yjuy yPLASMA ?N7'W/?,$>F/? 1AL /AC RA(. -/?/-t7/f) >7-zt7/D

i(I x 7 .

ll3rugs are distributed according to one ot the lollowing7 f distribution.

..pa//é'/w-t f?

)/- Olw Cèl??/?/r///7en/ Model:Drugs thqt are extensively bound to plasma proteins and drugs that have avery high7

, molecular weight as high molectllar weight heparin (l'lMW l4)and dextràn (plasma expander) can not pass throtlgh the capillary

j 'endothelium and are distribtlted ill plasma only = intravasctllarcompartn!! ent = 4 L .

2- FJI?/ Cbmpartment M odel..Drugs that are hydrophilic and w ith Iow m olecular weight cqn passthrotlgh the capillary endothelium but can not pass the cell membranesbeing lipid insoltlble and ionized-as quaternary ammonium cùmpoundsand N acl-and accordingly are distribtllèed in 2 conlpartlnents: plasma and

!1 tluid =extracellular cofnpal-tm ent = 14 L.interstitiq .

I 1




3-khtlticl mpartment Model:Drugs thât are of 1ow molecular weight, non-ionized, and lipophilic are

ld in al1 compartlnents- both ext-racelltllar and intracellular-anddistributç

Iaccordingly are distributed in 42 L.I

l4- Special D istribution..Som e drpgs are concentrated in eertain tissues, e.g. tetracyclines are

bted in bone and teeth (Caz+-colltaillingl-iotlille is concentrated inconcentri .thyroid tijspe

-thiopentone in fatty tissues-heavy metals as lead andl hair and skin-digitalis in cardiac m tlscles

.arsenic iyi

B- Binding of Druzs to Plasma Plote*ytfter reaching the system ic eirculation

, any drug will be found in 2forms; thJ free (unbound) form and the bound fbrm.

l1l'bree Form /.101//7# Form

-Diffusiblte. -Non-diffuslble (confined to plasma).p

-jnactive.-Active. j-l-iable töl liver metabolism. -tk'ot liable to liver metabolism.-laiable toi, renal excretion (mostly -hlot liable to renal excretion.by glpmetular filtration). -Açts as a ''reservppi -''- - - .- - - . - L.-- -

i .*Drugs Ve bound mainly to albtlmin and to a lesser extent to globtllin

) .

and a-acid glycoprotein.I'

j ,*some drpgs as aspirin and sulphonamides have a highly affipity (arehighly boùnd) to plasma proteins and they displace other drugs withlower affitlity as digoxin, sulphonyltlreas (oral hypoglycemics), and

.s ' 1 x,

wartarin (pral anticoagulant) if adlninistered together, which results ini' ncrease in the free ''active'' forn'l of tlle latter drtlgs and this may lead tosevere adverse (toxic) effects:#Aspirin ànd sulphonam ides displace digoxin leading to digitalis toxicity.

i .

# Aspirin >nd sulphonam ides displace sulphonyltlreas leading tohypoglycem ia.# Aspirin iand stllphonam ides displaee warl-atin leading to bleeding.

:

lsulphoùam ides displace bilirubin frotn plasnaa proteins, which increasesthe tkee bilirtlbin causing hyperbilirubinelnia and may be kefnicterus ininfants.

*1n condisions catlsing ''hypoalbulninenlia'' as in old age, liver diseases,lnalnutritibn or starvation; the tkee fotn-l of drugs as phenytoin

12




!

- i: . 1.(antiepilejtic) is higher than in normal individuals and toxic effects mayitl)! therapeutic doses

.OCCX Wll - he drtlg, the longer its duration. This isl'I'he morr the bound form ot t

shown witlh some sulphonamides.I

'

. ' jC

- PIJSSYIW JJFOSS Svrriers:!l 'os

-q blood brain barrier (#.#. #.).'1 -#z7.ç.çt7gt?I acl..llwipid solùble unionized drugs can penetrate B.B.B. and exert C.N.S.

actions, wjereas hydrophilic ionized drugs can not pass across B.B.B.and have àlmost no C.N .S. actions in normal conditions.

k

'

*P. enicill ri s can not penetrate normal meninges but can pass acrossmeninges to C.S.F. in case of meningitis (due to increasedintlamed lt d so are useful in tteatment.permeabils y), ani

' j

'

z-passage, across placental barrier to /)/z/x.*M ost drulg s can pass across the placental barrier fiom the matemalcirculation! to the fetus.*lwipid soltlble unionized drugs pass mtlch more easily than hydrophilic

!ionizecl drugs.

*some drtpgs -as aspirin, cortisone, AC E inhibitors, benzodiazepines,i x

phenytoin, etc.. . cause fetal m altormations known as ''teratogenicity'' or; 1, . st''fetotoxicity if given in early pregnancy ( 1 trimester)

.

IN B. Thalidom ide -which was tlsed as axiolytic and llypnotic- caused. i . v .,% , ,amelia ory hocolnelia on a large ntlnlber ot newborn infants whieh was'i-rhalidom ide disaster''known as y

Recently; j rugs are classified into categories'. A, l3, (*-3., D, and Xaccording t,ô their possible teratogenic etlkct.

ithrough breast milk:l-passage .

lklost drur' s can pass throtlgh breast milk to the stlckling babies', some ofwhich ma# cause serious adverse effbcts as morplline, fluroquinolones,radioactivt iodine, etc..*llasic drtigs are ionized and ''trapped'' in breast milk' because its pl-l ismore acidic (= 7) compared to plasma pH (= 7.4.).*lwipophilic drugs are retained in breast m ilk because of its rich fàt

. :content.

D- Redistrlbution: '' !Highly lipophilic drugs as benzodiazepines alld barbiturates especially

thiopentone (used as I.V. anaesthetic) are concentrated in C.N .S. becatlse




of its high lipid conent and rich vasctllarity, then tlley are redistributedC Nlj to adipöse tissues, skeletal muscles, and other tisstles.from . .

Redistribtjtion terminates the action of the drug and accordingly theduration pf these drugs depends on redistribution and not on metabolism

i i n Thiopentone is described as ''ultrashort acting bàrbiturate''.or excret p .

I. ' j .

C- Apparqnt vta/l/zz,c ofdistribution (P',/-u- I* --1 he app lArent volume of distribution (Vu) is a rough measure of drugdistributiln; the largcr thc Vd, the more the drug distribution.

! I*'T'he apparent voltlme of distribution is ealculated in liters (or in litersI/Kg.) accqrding to the following equation:.

1 Amount ofdrug!

r), -toncentration tnplasmaIt a (in mg

.)lCI U W 'W't

'

C (in mg. //??f .)l d f the adlninistered drtlg.A : Amoupt or ose o

C.' Concelj' tration of the drug in plasma.r-

* Sign T/cli nce of rim.l-Tlàe terli ''apparent'' indieates that it may not be a true value as in the

* l . rcase of diyoxin which has a Vu ol 500 liters wlziell is much higher that tlletotal flqid ivolume (42 L. in an average 70 Kg. persoll).1z-llligh Vk indicates that the drug is distributed as a nmlticonapartm ent

imodel ot Las high tissue concentration.(

.3-Low Vu jndicates that the drug is retained in plaslna (intravascular, onecompartmknt model) mostly due tt) higll binding to plasma proteins.4-lonowing' the Vd allows the estimatioll ofthe ''loading dose'' which is

; . .the initial d, ose required to reach a specific drtlg concentration, and alsoallows m eàsurem ent of the total am ount of the drug in the body:

Lk xcA /7s-Drtlgs 11th low Vd as aspirin are highly botlnd to plasrna proteins

im eaning that they a have high plasma concentration, that is whyhemodialysis is useful in treatment of acute toxicity by these drtlgs.It is clear that hem odialysis is not benetieial in treatment of acute toxicityby drugs w' ith high Vd because they have low plasma concentration beiltghighly disfributed or highly concentrated in tisstles.

14




Ii.1I

Factors a ' ectin distribution..l-physicop,çhemical properties of the drtlg:-lsipid soltlbility.-Degree qf ionization.

l-M oleculgr weight.

l i binding (see before).z-plasma prote n3-passageljacross barriers (see before).

1I .l '

Il' j.I

I!Il)

'

!!I

1

*

-

i1l

. 1J

Iiil.!f

.1 !i!




i. q .1

3- M E TA B OLISM =BIO T M W ORM A TION!

* Thtse are chem ical reactions that occur mainly in the liver., l ,, jj opjjjjjc* rhç aim of biotransformation reactions is to convert p

li !id soluble) drugs into water-soltlble (hydrophilic, ionized,or(p(')lh.rl metabolites to be easily excreted in urine.P ;! clear that water-soluble drugs do not undergo metabolism and* It iy

arerexcreted ''unchanged'' in urine.1 ' li ophilic drugs-after t'iltration through the renal* Ontthe other hand, p

glo eruli-will undergo ''reabsorption'' by the renal tubular cells,

ma ing renal excretiofi of these drugs very slow. So, they arem eiabolized to be converted into water soluble form to promote

' â

'

thelr renal excretion.I

hasesl of Biotransformation Reactions:P1- Phaje 1 Reactions:* Thesè are ''Non-synthetic'' reactions.1* The drug undergoes either: oxidation, reduction, or hydrolysis.* Phast 1 reactions will result in one of the following:

1. I

jf . , ,1- Conyersion of an active drtlg into an ''inactive metabolite. l his isthe m oist comm on result, e.g..; .

HydrolysisAcetylçholine * eholine + acetic acid

2- Cohsyersion of an active drtlg into an ''active'' metabolite, e.g. :

ù Oxidation!

pjayyjajetjn jactive) .----. . , . F paracetamol = acetaminophen(3UtiVC) .

! ytay jjtljgjj)Chloral hydrate (active) --- -. .- ---'.--.----*' trichloroetllanol (aetive).

é

'

3- Conkersion of an ''inactive'' drug into an ''aetive'' metabolite alld inthis case the parent dnlg is known as a ''ptç)-p.(#lg'' e.g. cortisone--. --.>

I . . k ojjo (aotjvo and(inadiye) is changed into Coltisl3l=hydl-octllt S ,' (enalapriltinactive) is metabolized into ertalaprilate (active).; Oxidation

jjujpj-afnjne #. dcsiplXlllille.

4- Vely rarely; a .toxic metabolite is fbrmed, e.g. methyl alcohol

(methanol) is metabolized by oxidatioll into fbl'maldellyde which' ' blindness, being rdinotoxic.catlses lpelmanentJ * ' ..! ! Axt > - $ ) - j J 9Z11 t.? t..yot Q xt 4 s..w, 4?t- . aJ : dazs ...11 a x 1 - ...,.% f...i $ #J

1

16




1 ,i

i

ll-phase 11 Reactionsr-'' J ''s thetic'' reactions.These ar yn

I f) 7r hase I reaction is ''conjugated''*-f'he drug; or a m eta olite resulting t om pidogenous polar com potlnd as glucuronic acid, sulphate,withxan enj

glycine, aretate, glutathione or methyl grotlp.Aphase llrfeactions mostly result in drug inactivation, with some

1 hich is partially converted intpexceptionj as morphine (active) wmorphine q-glucuronide (active metabolite), and tninoxidil (inaetive) isconjugateb into minoxidil sulphate (aetive).B mostldrtlgs are metabolized by phase l reactions followed by phaseN. .

11 reaction/, undergo phase l reaction only, or phase 11 reactions only.l7ew drugk as isoniazid is metabolized by eonjugation (phase l1) followed1

f, w j- tjyo pjjases 1. .by oxidatijn (phase l), i.e. there is reversal ot order o. h!I

Types of Enzvm es Responsible fbr Biotransfopnation Reactions:i ''' .

M içrosom al Enzymes Non-M icrosom al Enzymesl

D X =l-Found ilil sm ooth endoplasmlc l-Found ln the cytoplasm and1 f liver cells

, that is why mitochondria of liver cells, skin,retictllum otlzey are rlferred to as ''hepatic'' Gl'1', lungs, and in plaslna.lmicrosomjl enzymes (l4ME).

lz-They catalyze the following z--rlley catalyze the followingbiotransfojmi ation reactions: biotransfornlatioll reactions:-oxidatiolt (by cytochrome P -oxidatioll.I450=CYPks() enzymes). -lteduction.

I-Redtlction. -l-lydrtllysis.I.lydrolyspks

. -t-a-olljugatitlll exce-pt Nvith

: j ju akyjd.-conjugatlon with glueuronie aicd g tlctlron/y lOn

. j)I

! ' r .j3--l-heir adivity varies with age, sex 3- * lheir activit.y varies with age

of the patik nts, starvation, liver and sex, but is not affeeted bydiseases, :nd by drtlgs: their starvation, liver diseasesn or dtugj.

activity is increased or decreasedby drugs known as HM E inducersand HM Etinhibitors; respectively(see later);

g '4-Act on lkpophilic drtlgsu *- - - - - .-- -

1-.--.-A...-ç/-:+llf1-r:l).l1il-ic drtlgs.- # --.

17




l!l' j

!l

Factors Affecting Hepltic M icrosomal Enzymx-actj-yjty:l-lhe fxec/ ofDrugs:j '

x* Some drngs increase the activity ol hepatic microsomal enzymesd! known as HM 'E indtlcers ()r activators

, whereas other(HME) an areIce or inhibit the activity Ot-l1ME and are thus called HMEdrugs redr

inhibitors; !* Examples of HM E inducers: phenytoin, phenobarbitone, rifam picin,icotine (tkbacco smoking), testosterone (androgens), carbamazepine

,n

x 1 xgriseotulv n, chronic alcohol ingestion, * coftke and tea.

* Exampl s of HM E inhibitors'. cimetidine, chloramphenicol,t

contracept/ve pills (containing estrogen and/or progesterone),ketoconaztj le, erythromycinn fltlroquinolones, allopurinol, grape fruit,

è * stllphonam ides, sodium valproate, M AO lnhibitors,om eprazo jl ,

isoniazid, jnd acute alcoholism.* lm ortartce of HM E induction:

* HME inqucers increase their own metabolisln, which may lead totolerance lind dependence, e.g. pllenobarbitone, nicotine and chronictalcoholism .* I'IME inpucers increase the metabolisln of otller drugs given at the same

. j . . . , , . . jrustim e leadipg to deereased aetivity of the otlker drugs. l-his lequ

increasing il he dose t)f the other drugs.. Some HM E inducers as phenytoin inerease the nzetabolism of vitamins1

' leading to megalobl/stic anemia,as folic acijl, vitam in K., and vitam in I3,hemorrhagh, and osteomalacia; respectively.* HME indltlcers as phenobarbitone are used in treatment of mildI

joyj ot-bilirubin.hyperbilirqbinemia in neonates as they induce conjugat*lmpoljant-t-of HM E inhipjtorî)'-- - !Adm inistr 'gtion of HM E inhibitors w ith some drugs - as warfarin,digitalis, oral hypoglycem ics, tlleopllylline- may lead to increased plasmalevels ofsuch drugs even with therapeutic. doses, which may lead to''toxicity'' i! hat is why we should reduce the dose of warfarin, digitalis,oral hypogtycemics, and theophylline ifgiven with IIME inhibitors.

II

2- Age: I:The aetivity of HME is lower in extremities of age; i.e. neonates(especiallyp if premature) and o1d age, so they sltcluld be treated withlow er doset than adults.

3- u%x Getlder .'M ale sex hbrmones (androcens) act as LIM E indtlcets whereas lkmale sex

l ''''' '''''''''''' '''' . .

hormones (estrogen and progesterone) aet as I-IME inhibitors. -I'l1is is an

18




ë 1.

important tause why fbmales receive lower doses than males (of-the same.!

age and wyight).

4-patholo ical conditions..

Liver dijejses as cirrhosis markedly reduce the activity of HME and thedose of àrtlgs metabolized by these enzymes should be adjusted

Ito liver function testsx * e.g. the effect of diazepam on CNS isaccordinglwhich may lead to coma if given in therapetltic doses toincreased,l

patients with hepatic im pairm ent.1.

5- starvaii'on:' I

.ln cases o starvation, there is marked depletion of glycine content which

inhibits gl cifle conjugation.

6- Geneti ' actors Pharmaco eneticsh'.There is arked variation (polymorphism) in thu enzyme activity amongthe populltion which intluences drug action and toxicity.In additio , genetic abnormalities may result in defective or abnorm alenzymes; .g. genetic defed in pseudocholinesterase enzyme greatlyreduces m -tabolism -and increases the action- of succinylcholine(skeletal pmscle relaxant) and may lead to ''apnea''. 'fhis abnormal drugresponse )ue to genetic defect is known as ''idiosyneracy''.

l(

'

' jJ

I ,

Ilii!

I

I

19




iiiI

j'4- EXc etion:Drugs an their metabolites are excreted by the follow ing routes:

l-Kidne Renal excretion ...'rhe m os important route of drtlg excretion is excretion in urine.

k.'l'he drtl tmdergoes one -or m ore-of the following processes In thenephrons:

l-Glomer 1ar Filtration (passive process): the free ('unbound) form of thedrug is fil ered, depending on the glomerular filtration rate.z--l-ubulat Reabsorption (passive processl: the unionized (lipophilic) formof the dru undergoes tubular reabsorption.

3-rfkbula Secretion (active processl: some drugs- as well as endogenoussubstance as uric acid-are actively transported illto the lumen of theroximal onvoluted tubules (PCT) of nephrons, e.g. penicillins',Pcephaloso, ins, probenicid, thiazide and loop diuretics, etc.. .

l 2 active transport systems (carriersl; one fbr secretion ot-*'l-here ar iorganic ajidic drugs as penicillin and probenicid, and the otller fbrsecretion jf organic basic drugs as ephedrine and amphetamine.

II

.penicilliy and probenicid compete for the same carrier are secreted bytransport system (carrierlk that is why probenicid increases thethe samei action of penicillin, as probenicid will decrease tubularduration jo

'etion ùfpenicillin leading to increase in its plasma concentration.secl1I ,

. . . jtjj.j o j. jjrtjgs -, j . e..R-lle H f tlrine chan es the rate t)f tlrillal v excl et'

x

alkaliniza ion of urine by NallCO3 increases tlrinary excretion ot acidicdrugs as a pirin and phenobarbitone, because most ol- tlle drug will be inthe ionize' hydrophilic form

, which is easily excretttd and not reabsorbed

(ion trajping).! ' idification of urine by ammonitlm chloride (NH4Cl)On the other hand, ac

i jon ot- basic drugs asor vitamip C (ascorbic acid) promotes excretamphetantine and ephedrine.

1IThese fac s are clinically useful in treg-pnent of açute drtlg toxicity. byincreasin their excretion in urine through changing the pl-l Of urine.

i1

;.- G1 7-7 ' i' r

'

Somc drugs may be excrded by:' drugs are excreted in bile in one oftwo forms; free drugA-Bile. som e

(active), à,s ampicillin and rifampicin, t)r conjugated drug (inactive), ashlineiand phenolphthalein (a chelnical Iaxative).luorp .

I!I 2()III

1I

. 2




i

1I

. II

I yj jjSome dru s excreted by bile m ay undergo entero-hepatic recycle whichprolongs le duration of action of such drugs.

B-saliva'. .g. morphine, iodine (which may cause a metallic taste andinflamma 'ion of the salivary glands), and rifampicin.

C-stomac : morphine is partially excreted in the stomach; that is whystomach ash is perform ed in case of acute morphine poisoning despitethe fact th t momhine is adm inistered intravenously.

D-lLar e ntestine Stools : drtlgs that are poorly absorbed orally asaminogly osides (e.g. streptomycin) and some tetracyclines are excretedin stools.

3-Respir tol ,$' stem .. inhaled general anaesthetics, whether gases asnitrous ox'de, or volatile liquids as lzalothane, are excreted by lungs.

vl-sweat.. ery few drugs are excreted in sweat qs rifampicin and 1312.

s-Breast ilk'. many drugs can be excreted in breast m ilk and can affectsuckling i fants, e.g. laxqtives (as phenolphthalçin), antihistamilzics (incommon old medications), oral anticoagulants (as warfarin), antibiotics(as chlor: phenicol, tetracyclines and tluroquinolones), morphine,antithyroi I drugs, etc..lt is well nown that basic drugs as amphetamine and morphine are''trapped'' nd excreted in breast milk (see before).

N.B... rifa zpicin is excreted in tlrine, sweat, saliva, and evell in tearscausing o nge-red discoloration ofall the fluids.è Sweat lands and mammary glands are'called ''skin glands''.

1

I

- i:

h

'

21




1

*Give Re jon Ex lain ..l-Aspirin is partially absorbed from the stom ach.2-NaHCO3 is essential in treatnwnt of acute salicylate toxicity.3-Acidifa tion of urine by NH4CI or ascorbic acid is helpful in treatmentof acute a phetam ine toxicity.4-salicyl- es are better absorbed from the upper part of the small intestinethan from its term inal part.5-In case f shock; m orphine should be given I.V . and not S.C.6-Drugs a e absorbed mainly from the sm all intestine not from thestomach.7-The dos of orally- administered nitroglycerin is m tlch higher than theS.L. dose.8-lt is not advisable to prescribe aspirin to patients treated with warfarin.9 -sulpho am ides are contraindicated in late pregnancy and neonates.lo-llem o ialysis is beneficial in acute salicylate toxicity.1 l-rrhe d se of drugs metabolized by l1M Es is higher in smokers than innon-smok rs.l l--l-he d se of warfarin should be reduced in patients treated withalloptlrin 1.l2-The d se ot-theophylline shotlld be increased i11 patients treated w ithphenobar itone.l3-l-lypo iycemic coma may occtlr iforal hypoglycemic drugs are givenwith cime idine.l4-severe hem orrhage may occur in patients treated with wartl-trin andconsum ip grape fruit.

*Enumer tq:l - Factors affecting drug absorption.

1I

2- Factors affecting oral absorption.

3- Factorj affecting bioavailability.

4-Factors affecting drug distTibution.

s-Factors Iaffecting hepatic mierosom al enzym e activity.

WDe-fme.. J

-Absorptitln.l

- K 2P a. !

-Bioavailability.I

-NJd. !:I!II

!I

i

73




'

j;

l ,I

Routes t?/'pr/zf AdministrationThere are m ain routes of drug adm inistration:1- Entera route: drugs are given through GIT. lt is either:

A- Oral ( .0.). B- Sublingual (S.L.). C- Rectal (P.R.).2- Parent ral route: includes injection and S.C. implantation.3- Inhala ion: either for local action (as treatment of bronchial asthmalaor for syst mic action (as inhalation general anaesthesia).4- To ica local .. on skin and mucous membranes as eye, nose, ear, andvagina.

U - --Rollt The drug A tlvttntttges Disadvantages

should bel-Enteral:A-oral l-stable. l-Easy. Not suitable for:

2-Not irritant. z-convenient. l-Emergencies (due to3-Absorbable. 3-Economic. delayed onset of action).

4-saf'e. z-unconscious patientss-suitable for most (for fear of aspirationdrugs. pnetlmonia).

3-lrritant drtlgs.4-unabsorbable drugs asl

jnoglycosides. am(streptomycin).s-ullcooperative patients(as children).6-111 presence of nausealand vom iting.7-flrugs with almostcomplete first pass effectI

jjdoeajne).I (as! 8-Absorption is affectedby the presence of food

B-sublinglhal l-stable. l-lkapid onset of and other drugs.I z-soluble in action.(S.L.I: e.g.I

nitroglyceltin saliva. z-Avoids first passpellets in j 3-palatable. effect.

' p i in 3-overdose ef-fects 'acute angiljal 4-cffect vel .

attacks. small doses. ean be avoided byswallowing ol'spitting of the

' ellç/.. - . . ----- -- - - ..--- - - - - ..- - - - -- - - - - - -

III 23




;

C-Rectal: ln the form of Can be used if oral l-inconvenlent tbr mostsuppository and route is ineffective patients.enema. Enem a is as in: z-may catlse rectal

either: l-retention Unconscious- intlammation (proctitis).enema (MgSO4, Vomiting-lrritant 3-variable absorptionIglucosersteroids) drugs- especially when thez-evacuant Uncooperative rectum if ftlll ofstools.enema (e.g. in patients-Drugs withconstipation). extensive first pass.

2-1n ectio : AlI drugs shouldbe sterile andpyrogen-free.

A- I.V .: l-most drugs l-Tlle most rapid l-Allergic reactions as(bolus or should be slowly route so useful in anaphylactic shock.infusion) injected. emergencies. z-ltapid injection of

2-On1y aqueous z-Achieves 100% am inophylline causessoltltions are bioavailability. severe hypotension andallowed. 3-useful for highly arrhythm ias=velocity

irritant dttlgs. reaction.4-useftll in 3-l3yrogenic reaction m aytlnconscions occtlr.patients. 4--l-hrombophlebitis.

I s-uselkl for drtlgs s-rl-ransm ission of diseasesnot absorbed orally. as hepatitis B and C.6-useftll in 6-Extravasation of thevomiting. drug may cause necrosis'/-l-arge volumes (see noradrenaline).can be yiven by '/-Avoid oily preparations1 V infusion. and stlspensions to avoid

em bolism .

B-I.M .. l-soltltions. Rapid onset and l-Avoid highly irritantzsuspensions. high bioavailability. drugs (to avoid3-Oily intlammation).reparations. z-lleparin should never beP4-M oderately given IM to avoid

1 irritant. hematoma.l 3-paina irritation.)

'

i . j jlockC-S.C.: l As 1M . Use Only Slower and lowel' WOt suitable in. '-S .

non-irritant bioavailabily than z-irritant drugs.drugs. IM (less vasculaf). 3-lar e volumes.

J

24

f

II




iI

3-lnhala ion Gases-volatile l-llseftll for * lrritation of bronchi byliquids-Aerosol system ic actions as some drugs-irregular(solution given genoral anaesthesia dosage.by inhaler or and local actions asnebulizerl-finely t'reatment ()fmicronized bronchial asthma.

powder (given z-very rapid onsetby spinhaler). and very high

bioavailability ifsystem ic action isdesired.

4-To ic l :A-skin: l-o intments

, Absorption of somecream s, and harmful drugs as steroidspowders are applied (cortisol) especially infbr Iocal actions. children

,

z--l-ransdermal organophosphorous

delively system compotmds (in the form of(TDS) as insecticides), and picotinetransdermal patches (in workers collectingwhich are applied tobacco leaves) may occurfor systemic actiolls causing systemic actions

.

l as nitroglycerill. ltavoids 1St pass andhas long dtlration.

l-used fbr ltx al Undesirable system icB-Nlucous actions, e.g. eye adions may occur

, e.g.membranps: drops in glatlcoma. timolol eye drops used inN ose. 2-M ay be tlsed for glaucom a may cause

-Ear. system ic actions as severe bronchospasm in-fîye. nasal vasopressin asthm atic patients.-Mouth. (AD1-l) in treatment

of diabetes1 insipipus.

-- - - -

l st (jj-ugsN .l1.: Drggs given orally al-e liable to 1 pass lnetabolism, w hereas

i i tion inhalation, and by 'I-DS avoid l St pass eftbct.jgiven S ,L., njec ,* Skin a 'sor tion can be increased b .l-lnuncti n (rubbing of oily drugs).z-lontopàoresis (galvanic current for water soltlble drtlgs).

'

y '.1 5

1

I1!




iI

*other outes o A dm inistratlon:

-other m thods o in 'ection:*lntra-d nhal: sensitivity tests and vaccines.

wlntra-a erial'. thrombolytics (fibrinolytics), angiography and in cancerchemoth rapy.

*lntra-c diac: adrenaline in cardiac arrest (cardiac resuscitation).*lntra-ar icular'. cortisol in treatment of arthritis.llntra-p ritoneal.. in peritoneal dialysis.llntra-th cal: in spinal anaesthesia and in treatm ent of m eningitis

.

* * lntra cameral: injection into aqtleous humor.* * Intra osseous'. injection through the shaft of long bones.

-subcttta ct?lz: im lantation: e.g. contraceptives as norgestrel which is inthç form f a solid capsule (pellet) implanted under tlle skin, from whichthe horm ne is released for a long period (up to 5 years).

' .

,*How t rolon the duration ofaction ofdrttgs..l-Delay bsorption by:-Add vas constrictors as adrenaline to local anaesthesia.-Add oil o the drug (as vasopressill).-use sus ensions as protam ine zinc insulin.-S.C. implants as contraceptives (norgestrel).-use 1on ' -acting preparations as sustained release (SR) preparations, alsoknown fis controlled release (CR) and timed-release (TR) preparations.

2-Use pr larations that are higllly boulld to plasnla proteills (long actingsulphona ides).

3-Decrea e m etabolism by HM E inhibitors.

4-Delay r nal exeretion e.g. by adding probenicid to penieillin.

11I '1I

26

t

I




2k' '

:

1 --ki!!::''' .--,--:!5111 --tb'bkètï?. .. .---,--qE111.. . - . $6613311/,'.. . .. .. . .,633332133,... . -- . .....

--.1!41(;11.-............

.è:IIi'''''. - -.- . .

--i!'''i'ih'-'. -..-.. - . ..

---,--1111..-.... .. -. - - -.... -... ---.-...

.--JI!'-------.'1t!:llè7''. ,-136b11'. ... . .

' '' hat the drug does to the''pharmacèdynamics is usually referred to as - w

tt g (,? î zv $7bo# . j .z p. y*lt includqs: A-M echanism of adion. B-pllarmacological actions.rx 'L

M echanistn of action of Jzw#x.'l ' 'r'' '-'ï ?'' d:': 7...1- ''' A t.-> '-'t J- '/-'krr' (; --.. -- . . .. -- .

. , jes 'z'y . y yM ecjanlsm of Actlon Exan'tp o,a , ..- . -...x : .., ,,, .,1 -pllyslcal Fk -,) , ---t'; , f ,'- t.w é.'Ly. ,k.j-,,......;r ---y L.-j-...uv.---,.-.-=-c...''s-'.ï.+',.. ,,,u .r r . :

* ' ' 'V '' '

A-Adso tlon. -lkaoll'n dsorbs toxins in case of diarrhea-t-'.#>' j ywv- a..,g j c. ) ( ji charcoal adsorbs other drugs. av-o'- t--.r t. .<-

...y;j . ------ . - - -. . .- ... --..... ., .. ,,...,. . . . . . gj z.jj .j. ., B-osjyjosjs. -osmotld dl llfetlçs aS n-lanl Tjroanu -osm.9-tlç ) yj yjy y

.

.M I .(. ). ! . zuxxyj,..o ezl.o ( uuyG, .....x..s!s.r..=.r' z---.ujlw..:=c xu.

.j ,y j . gp. sm. y m g ss ..y .y. . g .. s- . t.,-..r.z.'7.V.v- k't r>'' yx sg l Ij').e urga t I-V CS 11, (N1. S.. V* - b 4D ''-g.''..

'> 57 p ) . ( ;,;. .y . . ... . !. . y y y s ...... .s y .jyyym. . .... . ... -. -.-. -.. ...... --..j ..-. , .-.-..,,* l . q -. c.'r Vwv tqr? Y î,' y ... r .A '' sï

'-s'-l.w --- 4:1121 1(-1. (ë): lrll-l. 1t (:27 Iïlk 1L -. .r-..- v' -4:' ' r, .'L,: ''' ''tf. jq. . ... .?,-. ys , :.?e.<ynJ. ,! - -k-. ' 1- .,:#--- ..r -:.. ....r . ..;,. , :. ,r:., ç ;tt- ,-.' 2 ,,gj):?-, -J?tL.,(1ï.--3t--e .!;;. ' (.-:?,. (4gr.-', ',; -' ,-.' I ()'(-; . z' tb-'''' ' ! t' .1. . ''' '' ' -J ' ' ' ' ' ' ' :1/'- ' ' .

A-Neutrallzatlon. j ,, j -An.tac..l.d. s as NaHcoa are tlsed t() neutrallze ,p (::) . 'h(;' cz'k-t / (r- tf:t . . .! . ' ' .. . - -. -- v - .... ...'. - ....rl) ïtkiz' t'''7 :.7 . v..

f o,ak. v, 4,, ,.,..q, ,z. LICI ln cases ot hyperacldlty- protam lne t-,gr.. zs.,.,, .-, ,...c

l k7 ' ' --**'-X - ' ' - ' ' '! sulphate Is tlsed to neutrallze heparin (antidote)B-chelatlon.

.s fv k, , ! ,:, 1,., ,.,a . .-flesferr xalulne t() chelate lron- .d. .lmercaprol

l V . ' ' --'--'-''- ..- .-'-'' ' ' ' '' . '' '' A ' 't (BAlw) to chelate heavy metals as mercury,)..m .. .z x . t,x . '* 'j . . . . . , vs m, % 'k ., n . .,

Lw'' c,.') sxo''b .-. '; lead and antlmony. k e ro ;,- .' ,n.y ''p - ''ï3 z, 7,t t (>' , :r c. o .y.

s.- (y j -. ..... j . .. .. . ............ ..... ....!j.......... .... . . . ,, , , 4:,; ..... yzympsyy.. p- y.. o.. .. yyqugy y.tl> .. ytly . . . k . . . , jyzj y g.A pjy. y ,q rctriêf'f - 3-lnhlbltlqn of cell dlvlslon Cancer chelnotherapy. 'G :? . o'

s,

t'4 I' totoxic l'action). ! r'1, ; ,J', , :.:...-...-.-...-.--.-.-.....,--..-.-- ..-.--....--..- --./1Y '1, ) (p IC.Y. cy. . at.z-uju ....y.. z.s ..y ..t j ; v ..-- -..---...---t- - ----.-..-.---.. --z--

: ,/r7'7 , -',,, ., ''' 4-lnterferùnce with norm al S ulphpgka-o ides inhibit bacterial folic acid' êq '' r? ..- --.----..+--.-- '' '' ''? ï'* f- ' -- tabol ic pathway. sypthesis l)y conz etition with PABA.okf/ - . jue3p- l'?, h .,o flp-, f)-4 ,i-!l:' j - Ijaterfkrqncu with selective N.U channel blockers as lid %.a--l'lml,tused as: tyj ? .z zztLzvz,;;. .:ï. .. .. ..

,. ''' ) . f) '''.'' ,. .i ')c olw. y,sv -z:r .' ' passage of; lons througlz 1on local a

--p#mpjststul-.pçutytaqyyyoyad antlarrhythmlcs), and/?>. s , ,- c ; , ) y , ,; . .j sj (.! 2+ ' o. yyjoqkejs as verapamil (used as. l , ! ..;/ channels . â ( fsvu.z .-s,./ Nj c.s ,. . j:.;jv..-.-..j;c. .y...... ., s,.y#...,. Chanl'l .l r7 l,9 , .#7 .> ) o m ..-... . apysjx .w 4 xw j us g.,y j jy xo:-' ( ' /5 -. -.... -'gr..r ..- r - -- --r ) ..... . .... -.. .- . ... ,. . -LL-ï,. --. -ïr' k-kùr.p-.- .:' . - ' crk

j C.w.. . . tmtjmgjejgjj'jajsy gjpjtjtjjef/j/tlsllllcs ZRd S 4 y ) y yy.--m..''x. .w '''* /.W V .î =ïy .

. antih pertensives). ,-,..-,'-s'.-,-6-Action o'n Enzymes (mostly by -Aspl'rl'll irreversibly inhibits cyclooxygenase

i ' hlkh is either (CO X) enzymes.enzyme inbibition, w'' . /:/J '' r ''irreversible'') -tlrganophosphprous conapoullds in-eversiblyreYels O

.

$ - l 'b- holinesterase enzyme.; ln 11 It c.-A* '<t -:'' . . -- #2> . . . . .

'-Neos. .t..!gm...l.p-e alld physpstlglnlne lnhlblt..z< r= . r gsucn . . . . .......-...reversibly chollnesterase enzyme.Alloptlrintll inhibits reversibly xanthinep-y-idase enzym e.

- - -- - . . m -r .

7-Action o, n Receptors: -Aeetylcholine (agonist) and atroplne' x *

'

*

The tnost 'imnortant mecllanism of (antagonlst) act on muscarlnlc receptors.g ..* ' ''''v

'

'

drug action. -Adrenaline (agonist) and propranolol' (anta onistl act on -receptors.

. . !l




h :

o f %? ' 'Z ' '. . . . .

: .. J J' . .

RECEPTORS.. . ;,,. . ,, jp-.l ,.y,.,.. . , . ; ,- y,y/r) ;jjt. trl , jly..? -.rj, -:,; v, . -. . ( .: ,.,y,.,yj ,,:r j. ., -.-.jj - -f .

.,-'. /.-- :' :

-'za rjy (,,:.,a.:y. Jh-.; (:.,- .* Receptors are specific protein macromolecufes present on tht cellmembrane (e.g. (z- and p-adrznergic receptors, and muscarinic andnicotinic receptors), inside the cytoplasm (e.g. receptors for steroidhormones and vitamin D), and inside the nucleus (e.g. receptors forthyroid hormones).

* Any chem ioal substance that has the ability to bind to a receptor is

called a ''ligand''* Ligands m ay be: drugs, hormones, or chem ical transmitters

(neurotransmitters).The ability of the ligand to bind to the reeeptor is ealled ''aFinilv''.

. Affinity may be due to the fact that the shapes of the ligand and thereceptor are complementary (Kev and Lock theorv), whicll allows thedrtlg to ''fit'' onto the receptor.

* Drugs Acting on recçptors are classified into:

1-A GtlNfuîtF,.j'x'AAgopists are drugs that activate (stinlulate) tlle receptors.#'l-hey are characterized by having:A-Affinity.

4 .B- Etficacy (intrinsic activity = * 1A): agonists have the ability tochanye Ye pg--y...ti ity of the cell; either by stimulation or inhibition (e.g.'àtflYiplipç ac!j,.#...j an agonist on p-receptors in the heart catlsing- % . .v .'stlmulation o? cardiac properties as heart tate, and aets on j-receptorsin the smooth m tlscles of tlle intestine causing inhibition or

relaxation).id rate of association and dissociation:') t kV' ....jo C - Ra'' - A%soctalion ''w,''* '- ,*' 'zvF/z'v.

ruo -y . rj..Ka -''' = - ' '''kv,,/ ,.sk' .-c, zac o ,.e

,MX ' p *

Qr

()+.R. . DR com plex- --. ., . --'. 1 drug res))tlnse

Dissociation

. d 1t. receptor --K.a'.. rate ot: assoeiation- Ku.. rate of dissociation).(17

. rtlg- .1

MExam ples of agonists: Acetylclltlline-Adrenalille-Noradrellalille.

ATlle response (effect or action) of the agonist depends on:l--fhe num ber of receptors occupied by the agonist: the m ore tllenumber tlle more the response. 'l-llis is known as ''occupation theory ''.

.-2..2-22U72:2

28




h

-3333333L2;6'-,. . 4:.......,!,.-.'',''''. 4:::::::ë5). @t.,---.! ;ti,' .kr' (k..' f

y 'n*>' ' .''> l

,./ '. à,. ' z-ouantal Dose -Response Curyez..

' .?' u'-fhe dose or log. dose of a drug is plotled versus the number or

. . ;C

'), ... percentage of individuals or experim ental animals receiving the drug.VI:7 -...,

.. -M edian Effective Dose = EDs: it is the dose that achieves a. . '

'

partieular therapeutic effect in 50ty0 of individtlals or experimentalmzim als.-M edian Toxic Dose = TDsj: it is the dose that induces a specific toxiceffed in 50% of experim ental animals.-M edian Lethal Dose =LDX: it is the dose that catlses death of 50% ofexperim ental animals.-rrherapeutic lndex = IvD5e/ED5a. It is a measure of drug safety; thehigher the index the safer the drug.

Z-ANTAGONISTS = BLOCKERS:Antag6nists are drtlgs that block the receptors thus preventing theadion of the agopist, and are characterized by the follow ing:A- Affinity.B- efficacv (zero efficacyl: no chan e in tlle activity of the cell in

. . N = a ,

the absence o f an agonist, but tlley revent the action ()f the@gonist.

C- 5-1(.)W) rate of association.lmd dissocmi tion..... ... . . .----- j,.q '''' . . jfz --.#. --. . .. - y) ............jt?r L-. x/ztv-'a (r' c? sczd-o, . 'z-.@ 'G?i k-m /'' ' f..-..,.

. (.. ....ays j ,0 ) r?. .y3''S''.- .- -

-

Types of Pharm acological antagonists'. /.-w.-? )jy: (j.! .- >'' *

) .. ' :s,v ,'L:ï,;- ',' l-colnpetitive Antagonistsz.' there is competition between the agonist>x '. . ç ) . -' < -,' ' -- ' ' - - * . . .p-.o k I cv ào- m ' . tLv. alydtlguta onlstlon the same receptor, and exqjp-t;. ag-u-ol-lj-st can displace<'

/ jt/ ,x $s-- , 'v----- -z-- - .Qe '1'' ' tlle ahtagonlst. Examples'. Atl-opille-làl-öpralloltll-llrazosin-curare.Competitive antagonists catlse ''parallel sllil?t tt) the right with sameeffi' cacy'' of the log. dose/ response ctlrve of the agonist.

t/g. y '

,rr z-Non-competitive Antagonists'. the antagonist ittlltl--y-be dis laced byJ .'31-'lê tsw r-eovzgas-excess agonist. They cause ''non-parallel shitt to the rig--ht with red.

uce

efficacy'' of the agonist log. dose - response ctlrve..

- ' '

.':3/' .,1b'i.'>.: Non-competitive antagonists are ftlrther stlbdi vided into: ./ s' t.;: ),,.- . ,r--- 'i-peversible Antagonists: the enkct ot- the antagonist is ot- short 'tp.- 1- - -'-' t>.:*.. k-ê'J.'duration because it is rapidly nwtabolized, e.g. succinylcholine (non-compditive neuro-muscular blocker).

hsç .,' ' '

ii-lrreversible Antagonists: the etlkct of the alztagonist is plmlongedbecause it binds to the receptor by a ''coycltp-ts-éb Jl'ld'', and its effect is

tenuinated by syp- ptl-tqj&pf. .!1q receptors, e.g. phenoxybenzapzine(irreversible a-blocker). ,..'k'?.o

30' ) !

I /xf , y < : sj ,,4e'?.. ,c . ..f* .> ( r .>,-. x.as 4w' </' w.

... '. . 1J




t4Y*<

X

/wo .' ,V 6'? 1 S

. y. )s.-s't o .+9 ,' J cT , /J ... , , $ 4.-cfzg .:î '$? e. zry. t'-'y' .e'; . .s o.

, '

LJ

&a . t'L ..s .

* Parallel shiû to the light.*stzn'te çfticacy (Emax).

4% -MW ''' ',1. t trrà !q. . ç! ? ...v.4'

.l > z yjgonjst ayter('*- '.', Competitive Antagonist

'

j llel shift to tlae right.s xo-p para'-k-a. ,bà, .x'. ' '

*.-p.,-.:-1J1- efficacy (Euzx is reduced).

Agonist tz/crNon-competitive Ahtagonist

Graded Dose-Response tn..lfz-vewv-ftn//t)wj?kg dfferent fl?/ptw (tfWz?/yzxg'tqlz/j,s'/x

3-PAR TIAL ,4 GONISTS tDttttlist%l..Few drugs act as partial agonists having the

A- Affinity.

tbllowing characters: t pz.J. .yj .,y? , o.y.d ' .) ' 6

1 j. / ?<. ys . jk r g

..%.>t .' eix lmlqxk.- 9

J3- M oderate efficacv (less than the agonist and higher than tl4eantagonist).C- Slo' l

.

y or moderyte rate orassociation and d is>ociation (slower thantlle agonist).yzN. .' k=..-'1 artial àgonists are used clinically as antagonists. Exam ples: some

Is-blockers as..xpxprvnotol, pipdw.o. lolrand aeebutolol-Nicotine in largedose-succinylcholine. / .t

*1 1.-... ''uo/t.r ''z-'--''k'h/m ..- .:r- ;;; J-lnj''?- t ri,J toj;,y: :);; g.

/..')J..?'. 1




Tvpes of Receptors and Siznal-lkansduction1M echanism s,

Receptors have 2 m ain f'unctions; to bind ligands and to initiate a''response'' or effect in the cells by signal transduction.

,( ')st,.,'' There' are 4 types of receptors according to the signal transduction,.'-tL y ,.N jx.,.

. t, t ,,.. mechànism responsible for inducing the response of agonists:

, jgn . . ... kq ; . .. ,.17' ,..... t ......''

i- ,.... :.qr'' ' (' v.u jr//-''ljllllyly.- .,:: ; 2 ( ' ' t v-vrbL' ./' h j jjyked yzcgpjpyx= Lkayd.paktj ytlyj chgyyvjs:'î ' s o *J. - 0n-C J/l/ldy

- >

,f A- They are located in the cell membrane on the gates of ion channels.s. 'V 7 w9 Activation of this type ot receptors by specific agonists leads toz, d;r. W'

,1* change in the shape of the receptor (coflformational change) followedtç. ï''''''' h. ' ' '' ' '.r.t'' .,..by opening of the gates of specitic ion channels. Examples include'.

tspsfî

They are formed of 5 subunits'. 2 a, 1 j3, 1 y, and l ô. Activation of this$ receptor by gç

.stylqh....o..-lxine (which binds to both g. subunits) induces' + fk é1s --> Na* influx and depolarization.' opening of Na -c ann1@'ê '' GABA receptors: there are 2 types of GABA receptors ip CNS'/vj *

. .

t GABA receptors which opçpywçl- çllp.!!!lt!s leading to Cl- influx and.j .. .$r .- .h

yperpolarization, and GxbAy-receptors wllieh open K--channels't -,-. ... . . . . . - ..' .. ...- -.. - -.-t also leading to K efflux and hyperpolarization and may also lblo-ék-

) 2+t Ca -èhannels.t,it$

.4,2.7 Gm kotein-linked receptors.

-Nicotinic reççptors (N)'.

* 'Fhry are serpentine in sllape, m ade up of 7 polypeptide loops thatspan the cell membrane (7 (y helical segments).

Type of G- Receptors &plf# trtinsdudionProtein

Gs -Al1 Vr'receptors. Actlvation of adenyl' 'n'T?&%Lq=5U=

-lda-receptors. cyclase and increase in-D l-rece torja JI-AM P

Gi , -gzrreceptors. lnhlblt adenyl cyclase:'''>$j --

..rreceptofs. and decl-ease C- P,..>= D:-Gz ,a .jj-5-1-1'1 l-receptors. and may open K j--th-receptors. :llAlll-lçls. . .-.. 4 ..

i ation o? lGq -ly-receptors. Act v .-&ta.and Mu (except on llos holi 1se C andi E.;. '''' wblood vessels). increased DAG, 111), ,

, 2., , c ,,,,-4. , ,-.,, , -.'-l-ll-receptors (except f)n and C

..y.. .. , j---2...> fq :blood vessels). t''t? t- - 'r- ' t7 '? --,2'-5HTa receptoré. - - - - - - .- - - .- . - - - .




3-Tvrosine kinase-linked receptors: .x-- -..- -

,. s.e ''

(..Examplcs include: growth hormone aladt.instllillwq'recelltors.

lnsulin receptors are made up oi- i'i subunits (domainsl: 2 (4 subunits onthe cell membrane and 2 p subunits transfixing the cell membrane (seeendocrine pharmacology).

TDNA- linked intraeellular reeeptors (Gene aetive reeeptorsl:z.... ,clcpu-l.- -. erost id hormones and vitalpjn D receptors are found in the cytoplasm

. u.' h fl/-roid hormo-p-uqy r:j.?)%- rs are present in the nucleus.y .w , . ,..; w ereas y t-p. î :;....2.7 ' h@'f' ' : .---.------------, - - .- - -------..-.---.- ---. - -----. - :---. . -.u y. . > w ''. c(.y--.- --Thé-y- regulate gene transcrlption, translation Ot m -RNA

, and protein,-: - ' $,,17'

q' c.''X' synthesis that is why the have slow onset ofaction (see endocrine.'b . . . ;' ' :. >

pharmacology).

B-pharmacological Actions'. the actions of the drtlg may be:('-hlwoeal actions (also known as topical actions) where the drug acts at theslçt of applica oti n, e.g. skin ointm ents and eye drops.y# .. . = . v...w &- w-- - w,.om.ww - $

-' lsystemic actions: the drtlg reaches the systemic circulation and ist ..

bistributed to differènt systems as CNS, CVS, respiratory system , etc.t'jlReflex actions (also called remote actionsl: e.g. drugs that elevate

--. -- ''w..n...V'--

7 i 1 blood pressure as Nàradrenaline lead to ''reflex bradycardia''@ 'XCF 11Z4 ï.> throtlgh vagal stimulation.

r #yL




tuL;l TW

Dosage of Drugs (#taA't?/t?g#.'* Therapeutic Dose.. lt is the dose required to achieve therapeutic effect inan adulf male of average weight (70 Kg.).wLoading Dose: lt is the dose adm inistered at the beginning oftherapy inacute conditions as acute heart fàilure to reach the steady state plasmaconcentrâtion (Css) rapidly. lt is tlsually a large dose and it lnay lead totoxicity 'if applied to drugs with low therapeutic index as digoxin.

Loading dose (LD) = Vd X Css

*klàintehance Dose: lt is dose given regularly t() maintain Css and isequivalent tp the am ount of drug eliminated.

Maintenance dose = clearance of the drug (Cl) X Css X Dose interval (T.)

Maintenance dose (MD) = Cl X Css X Tm

N. B. :

l -'l-he smaller the dose interval (-I'm), the smaller the maintenance dose.2-ln case of IV infusion there is no dose interval and the m aintenancedose = lnfusion rate = Cl X Css3-clearnce (Cl): it is the volume of the body fltlids cleared from the drugin a unit time, measured in mL. / minute (the volume of body lluids tiomwhich the drug is rem oved by metabolism and /or excretion in a unit

time).Clearnce = constant ot-elim ination X Vd

C1 = Kel X Vd

C1 = 0.693 X Vdt 1/2

*Minimal elfective dose: the lowest dose required to produce atherapeutic effect.*M aximal Tolerated Dose.. lt the maxim tlm dose that can be safelyadm inistered w ithout inducing toxic effeets.* Meclian Eïective Dose (1'f.?é42).. lt is the dose that induces a specifictlzerapeutic effect in 50% of experimental aninzals.*liedian Toxic Dose (7D..jpX It is the dose that indtlces a partictllar toxiceffect in 50% of experimental animals.wM edian- Lethal D ose /1./7..j-//..,) lt is the dose that illdtlces death in 50% ofexperim ental anim :ls. 'wlherapeutic Index.. = LD5()/EDs() .lt is a m easure of drug safety; thehigher the index the safer the drtlg.




Factors A#'ti#/#/z7g the .Dt)s'c andAction ofDrugn('''/'-.,1gc..* lnfants (younger than 2 years) and children require smaller doses thanadults due to:1- Underdevelopment of hepatic microsom al enzym es.2- Lower level of plasm a proteins and low binding capacity.

3- Reduced renal excretory function.

J ' V, . . . y) . , y.... ,. ..2:. .. ... ) , .'ftcr?- N.B. some drugs as digitalis are rapidly ntetabolized in children than in'J .. .- -.. -.- . ''--- -'' '' ' ' ' ' ' ' '' ''

àdults and accordingly they neetf-highéf dbses (children are more tolerantto digitalis than adults). y a(l' r,'a ?> '', #* lnfant's dose is calculated according to Clark% f'.t?lrzaz//t7.'Infant dose = Adult dose X weiRht in pounds or kveight in Ak

.' 7o o ,-c sye t150 yj.sl: h'r ; .' N

.'z. Child dose is calculated according to Ttiz/zlg- -' bknxll.lnula.. .-skss-zsChild dose zuadult dose X Age in l/etzza - ,:':7, .'','.e'VC'

Age in ywzr,s 4 12*child dose can also be calculated according to Ltillinz's Formula:

4- lmm ature B.B.B.

Child dose = Adttlt dose X a4yr, in y'etar,y20

a l* * -1 he dose can be plso calcqll

-As-d by t eh percentagcmethod:Age Percent ofzztihtlt

oose1 month'. 10% .1 year: 2510.3 years: 331$.7 years : 50$$.

' 7 5 % > '!J ,X. L-nX' - 1 f U12 years. .

.W '

. Elderly between 60 ap-.d 70 Ayars mjpty l2q0f the adult dose and those' irett/lrb'ft ''J-'hesadut--qlt'àùse due to:over 70 years requ ,

1' '-'1- Weakness of hepat c microsomal enzymes.excretory functions.2- Reduéed renal

X-modv Weight..*'l'he m ore the body weight thelligher the dose except in cases of ed

-.çpl.aor

--pf twhich are not taken into cpnsideration..>.-* .,013. csvz' patients due to éxceskive btldy l'at jpctèayk the: d.osç. ..of

.,&. --' li op/lilké' drujs and reduce that otl''ydi' ojhilkc. ttrugs. '' ''(? v- t ,,x,t'p?

, 3-Botlv usbr/-tzcp Area..7 .z r a.xx.... . wThis is a'tïzibri Acqllptemarameter for calculation ot doses than age and*T%vrwJj -% %-= 'v'''' ..> wbody weight and it can be obtained trom speuific charts

.

Infant's dose = A dult dose X illfant's spyface areag = j ys mz)1.73(Adult body sur ace area . .

f xj/' ':.

. n ',.zl .,.4 trî .- . 6 j .1. cc /''Wl'''l # (s' C M V' ' Hg .. , . .

.. v. y. , u .

'1 ! ''8? t-, Iv --.'z,.- f. : .




'x lny .tz'J o,.@ &; I.;.'' .,ç

Q' -..- ,-,.). o. '

f-* t:l -'

kw c, xrp-hcw c ;4-Sex (Gender) : ,* Females

. usually require smaller doses than males of the same ag

becatlse: 1!

1- Female sex hormones are hepatic microsomal ènzyme inhibitorsvvuchc-cen/yéwv,'-,r:whereas male sex hormones act as inducers.

-

. . ,--------.-... .,)2- Females contain hlgher body fat. '''?.p,-..lvz

, , k vv ' .tf*-special situations in femalesr-t. ..-.

l..--- -.Dul:ing .mçn-ç-lg-atiqn avoid drugs that may cause bleeding as aspirin4;.-... ....x. . fa./r .. . -... ..<? * ''< 7 '-- ' ' '- - ' -' ' '-' .j #' g .-. .....-...-- .... ... j p ( u Jq.- c-t::o q- f-joa s lr-v.w 'wwweu ..- and--êâgtb-/

-pi.l go -.4- ,-: - ,L; r

.-....t...---.=s...,a . .. . ... ,......----v, c,.'

-------- . z-.s..-. -nrrlxrt:. .r. r:? .-.IïïLqj)b . . .

. . .....-,- . -,.- - -. - ---. -. ;-.- - . . . . - . -. ... -. -.:. . -.. -- .. -'-2- D,'-7''''''= id teratogelllc drugs (as aspirin cortisone, ACE . c.''.<... - .. tlrlng Prejnancy aVO , fvvs, psms-yjaj... .,sp.

''--

idlïi-bltorj- cvcllzlne- mecllzlne) and titèrlnè Wlmulants (oxytoclc drugs as '-'v - . z :. - p ., .2 ?r? ï Gkr..t *' e ' . . . . ... .. . . .. - -euw.isgwruqFsà:.sfc.s...o.C drg 'otalhlne, PG analogs as misoprosto ).

. '

3- 'fffi-rfg- 'lactation avoid harm ful drtlgs excreted in breast m ilk aschloram phenicol, antithyroid drugs, morplline, and oral anticoagulants.s-Route ànl Time ofyjdministration:* Oral dose is higher than parenteral and S.L. doses to compensate forfirstpass effect (GIT and hepatic).@ S.C. dose is higher than I.M . due to Iess vascularity of subcutaneoustissue compared to skeletal m uscles.*'l''he route of adm inistratioh aftkcts the action of som e drugs as

. ,b.);.., --,'?.p -> il'q /, l ,), ''oêJ..- ts? t R? .-? kc. ,c n /t?,-.magnesium sulphate

. ; 77- ..)-nt,./-/:::. -::7, h: k''-''-. r> .--.

- lt acts as a cholagogue (in small dose) and ls-urgativ: (in large dose) ifgiven orally.

; .. . .r .It actfras a- deh dmtin .-ggent (as) .tp.* - , , .'=- -t ' . l-oy, retentlon Cnema.n -/1 1 ' ';b() M

. Jt acts as

in acute gyle ucoma) if given rectally asbrsb ; kn zs erz--zlan anticonyptsant and sk-eletal musçle relaxant if given by I.V. . .:-.-.-.-.....--. . -...-......- .. .....-.... .-.... . u lpu tr,y y r.rrsx,cry .infusion

. phxj V'< .tJz , -.;j@M ost drugs are better given orally befbre meals because the presence of r.food may reduce absorption, but irritant drugs as NSAIl3S are better givenR 1 - T ? -1 --@. Cl- IXCa S. c0 .u1- r,rz

6- I'olerance: 4.yty,

*Definition: failure to obtain the ustlalresponse by the usual dose.* 1% es 'yp . j j ), fpyg.v1 Con enital which is either: -,'?A' R ial' negros are tolerant to the mydl'iatic action of ephedrine.- JC .

B-SPç.. cjes: yqhbi-jt are tolçrant to the systemic actions of atropine due to.- -- ..-- - - -- - a o moy u .... çft'-'--- the presehce of atr 'opill-èesfir/ase (attopinase) in their plasma.> - - * '

-lndividual: this is ue ib géii-é-ik variations.-j- c uited: long use of drugs as morphine, barbiturates, nicotine, ethyl

2. Q'' 1 hol and amphetamine leads to acqtlired tolerance which is usuallyr,v,! a co ,

t reversible, and may occur to some -not all- actiolls of the drug (seemorphine).N

', k-l!t-'''.f




nicotine and barbiturates- .y' .;cz ''J f TJ.'Tz :'

z-pharmacodynamak gguses: long use of dttugs leads to ''down-re ulation''xr'eu Y'G F ! .R* ? N * v xe ' . - v . .< 2 *M-'*

.y v of receptors or deptetiqp of endogenous transmitters. Ani al insulln.S ' lk u6acn:uo rzyy '; kkjj.rs: ,.,,.m.....,....p ? . u a....- m...-...... ..,.,. .... - ., - . p y yajind-pxç-s.y. n.. tsjbody fbrmatlo-h- v.,.;-..-y ..t-, z-z;'z r-:fl'. .r?1;E . x y =.. --....... .. ....' ' .'- '--''-' '- ' -'- '- '' .

* Vpeciàf types of acquired tolerance:v r -fachyphylaxis'. acute acquired tolerance (see effeet 0f ephedrine on

-tL -rr$'-t? ' %: :1- t -î:71 %',- -. ' q ; d' ABP). ',' ï. .A.... . ' - c.yvu.sc j- m-f ross tolerance'. occurs between drugs having similar effects as morhine

,

-

barbiturates, or ethyl alcohol with general anaesthesia (all are CNS

':, ecauses of acquired tolerance:- l-pharmacp

-k--l.uç--gri ti s: HME inducers asi

.-. . gincrease their own m etabolism.

.#' .C11.1!!17ï)41;t ,u% 1P.., . 11i;i!;,,-'ûp;)'... -F: .,.--, ' - ''.th;---: . '...-, -. -.

7- Dependence: lt is either'.A- Psychic dependence = l-labituation: sudden cessation ofthe drug doesnot catlse withdrawal symptom s but m ay cause emotional distress for ashort tim e, e.g. m ethylxanthine beverages as tea and cotxke.

B-psvchic and Physical dependence = Addiction:Sudden cessation of the drug leads to severe -and m ay be fatal-withdrawal symptom s ''Abstinence syndrom e'' wllich are the reverse ofthe drug actions, e.g. opiates (morphine, heroin, and codeine), ethylalcohol, barbittlrates, and nicotine.8- Stpersensitivilv zzqntolerance: lt is an exaggerated normal drugresponse. lt is due to upregulation ofreceptors, dtte to inhibition ofmetabolizing enzymes, or due to diseases as thyrotoxicosis (seeadrenalinè). lt requires reduction of the dose.9- Hvpersensitivi;v = Allergv:

, '

*lt is an abùonnal unpredictable drug response dtle to antigen-antibodyreaction (the drug or a metabolite acts as al1 antigen or binds to a hapten).*1t does not occur on the first exposure t() the drug which sensitizes thepatient but occtlrs on subsequent exposures, and is not dose-dependent.lManifestations.. skin rash-udicaria-pllotosellsitivity (skin rash onexposure to stln-lightl-asthnaa-angionetlrotic ed. ema-anaphylactic shock-bone marrow depression (blood dyscrasias) by chloramphenicol,sulphonamidessdipyrone, and thioam ide antitllyroids-cholestatic hepatitis

and jaundice by clllorpropamide, testosterone, chlorpromazine, and alphamethyldopa.*cross allergy occurs between drugs having the same chemical strtlctureas sulphoàamides and thiazide diuretics, or between drtlgs having thesamç mechanism of action as aspirin and other NSAIDS in astllmaticpatients.1 0- Idiosvncracv:lt is an 4bnormal unpredictable drug responsedue to genetic detkcts.

(44k. *J




Dru s Idiosyncratic reaction. V 'Succinylcholine: l-stlcclnylcholine apnea in patients with

pseudocholinesterase deficiency.

' z-M alignant hypertherm ia.Halothane: M alignant hyperthetm ia

.

-

'-J j'Aspirin- Primaquine- Hemolytic anemia ln patients wit APhenacetin- deticiency of Gw6-PD.Sul honamides:tsoniazid- Hydralazine Peripheral n-etlritis in slow acetyi-ators.

'X**Hydralazine'. SLE- like syndrome m slow acetylators.

* Corticosteroids.. E levate lOP and induce glaucoma

1 1- Pathological state: the action ofthe drug oceurs only in thepresence of pathological conditions

, e.g. aspirin lowers high bodytemperature to norm al but does not lower normal body temper

ature(aspirin is an antipyretic not hypothermic).

12- A'zpti//tpz/tz/ state:To distinguish between the real pharmaeodynam ic etïkk:t of a drug f'romthe psvtholoaical effed; a ''Placebo'' is used (dtlmmy medication made

of an inert substance as starch or sugar).I3-cumulation..lt occurs when the rate of drug adm inistl-ation exceeds the rate ofelimination (by metabolism and excretion), e.g. cardiac glycos

,ides

especially digitoxin, and guanethidine. lt is more Iiable with drtlgsfollowing zero order kinetics (see later).l4-l-lruz-Drug Interactions t/)z,l/g Combinationsl:W 11e11 2 Or m ore drugs are administered together interactions lnay Ocetlr

p

which are either beneficial (e.g. thiazide diuretics are combined witlz K+-sparing diuretics), or harmful (e.g. loop diuretics and aminoglycosides areototoxic drugs).l-pharmacoceutical interactions'.They occur before drug administration as during drug fbrmulation(Calcium salts cause chelation of tetracyclines il4 capsulesl- mixing ofdrugs with IV fluids (Calcium salts with Nal-1CO3)- lnixing of drugs inthe same syringe (Protamine zinc insulin with soltlble insulin).Il-pharm acokinetie interactigps:l-Absorption: antilnuscarinic drugs as atropine and propanthelineincrease absorption of digitalis- antacids decreases absorption of

38




tetracyclines, digitalis and ACEabsorption of any other

inhibitors-cholestyrallaine decreasesdrug if given concom itantly

.z-Distribution: a dnlg m ay displace other drugs from their plasma proteinbinding sites leading to toxicity

, e.g. N SAIDS as aspirin and loopdiuretics as frusemide displace warfarin catlsing bleedi

ng, quinidinedisplaces digoxin leading to digitalis toxicity

.

3-M etabölism '. HME inducers (as nicotine, phenytoin, barbitutates,rifampicin, ànd androgens) increase elimillation of drugs metabolized by

these enzymeg; whereas HM E inhibitors (as cinaetidille, female sexh

orm ones, chloramphenicol, erythromyein, and grape fruit) reduceclearance and m ay catlse toxicity.

4-Excretion: quinidine and verapam il ducrease renal excretion t)f digoxin

,and probenicid decreases active secretion of penicillin (prolongs theadion of penicillin) and thiazides and loop ditlretics (antagonizes theirdiuretie action).

lll-pharmacodynam ic lntera-ctjo-ns-: may lead to:

l-Addition = Sum mation: the result of 2 active drugs given togetherequals the algebrïc sum of their individual actions (1 + l = 2)

.

z-potentiation: the result of an active dl'tlg with an allnost inactive drug ismore than the action of the active drug alone (1 + 0 h l)

, e.g. eaftbine andbarbtturàies potentiate the analgesic effbct of aspirin.3-synergism : the result of adding 2 active drugs is m ore than the algebric

sum (1 + 1 > 2), e.g. rifampicin + isoniazid in T.B. and penicillin +aminoglfcosides in serious infections.4-Antagonism : which m ay be:A-pharmacoloaical: agonist + antagonist; it may be competitive (asacetylcholine + atropine, adrelzaline + propranolol, noradrenaline +prazosin) or non-competitive (noradrenaline + phenoxybenzamine)

.B-phvsioloaical: 2 different compounds act on 2 different receptors

èausing 2 opposing actions as adrenaline and histam ine.

C-chem ical: chemical antacids neutralize excess 11Cl, and protam ine

sulphate neutralizes excess heparin.

5- * Reversal of action: Adrenaline reversal after alpllal-blockers.N .B.. ''Drug-Food interactiont''. tyram ine found in yoghourt aad cheeseleads to hypertensive crisis in depressed patients treated by M A

, Oinhibitors (cheese reaction).l5- * Biological variations.

Fundamentals ofwpharmacokineticsPlasma /7t7//--//'/) time = t1/2.'*lt is the time needed for the plasm a drug concentration to be redueed by50% (tlle time needed to eliminate 50% ofthe drtlg il1 plasma)

.




*1t is constant for drugs followiny ''First order kinetics'' but is variablefor drtlgs following ''Zero order klnetics'' (see later).*lt is used to estim ate the time needed to reach the ''steady stateconcentration = Css'' of dnlgs following tirst order kinetics:Css is reached after 4-5 t1/2.

First tlp#cr kinetics and Zero order k-inetics:First order kinetics Ztdrta order kinetics

1-A constant percentage (%ltfractlon- l-A constant amount or number of molesproportiofl) of the drug is eliminated in ofthe drtlg is eliminated in tlnit time

.

tlnit tim e.2-The elim ination process is proportional 2-The elilnination process is fixed and isto the drug plasm a concentration. Drugs not proportional to the drug plasm awill reach a plateau w ith repeated doses

. concentration. Drugs do not necessarilyreach a plateau with repeated doses.

3-constant t 1/2 whatever the dose. 3-variable t 1/2: it increases as the drug

concentration (dose) increases.4-l-inear kinetics: linear log. zl-Non-linear kinetics.concentration-tim e curve.

Q

JL

ttxw-qs'Yj

'-j--ipm.-

s-Non-saturable kinetics: no enzym e s-saturable kinetics: saturation of thesaturation occurs. fnetabolizing enzyme or the carrier

transporter occurs with highconcentrations.

6-ltess liable to cum tllation and toxicity. 6-l-iable to cumulation and toxicity.'/-M ost drtlgs obey first order kinetics. 7-liïxamples of drugs that follow zero

Order kinetics: large doses Of aspirin-pllenytoin-alcohol.(Small doses of such drugs follow firstorder kinetics as the enzymes are not#atuVYC2.yV!-),

--s.,---.-- - --..---'.#l . Also absorption from slt prepalutions, depot preparatlolls as Scimplants, andam otlnt is absorbed in a tlnit tilue.

transdermalpatches lbllows zero ordel' as a constant

40




Adverse Effects and Toxicitv o,f DrugsA-unpredictable adverse effects..l-Allergy. z-ldiosyncracy.

B-predictable adverse etfects..l-side effbct: unavoidable action of the drug not related to the dose

, e.g.atropine causes dry m outh.z-secondaty effect: e.g. prolonged use of broad-speetrum antibioticsèspecially if incompletely absorbed orally'causes stlperinfection andvitam in B and K deficiency.

3-overdpse: e.g. hypoglycem ia dtle to overdose of insulin.

4-l-lepatotoxicity: e.g. by halothane.

s-Nephrotoxicity: e.g. by aminoglycosides.6-Neurotoxicity = N erve dam age'. e.g. ototoxicity by am inoglycosidesand loop diuretics.7-rreratogenicity.

s-Bone marrow suppression (blood dyscrasias).g-rrolerance, dependence, and addiction.

lo-lntolerance (supersensitivity).l l-latrogenicity: drug-induced (physician-induced) disease; e.g. aspirincauses ljeptic ulcer, alpha methyldopa and reserpine cause parkinsonism .

lz-carcinogenicity: by toàacco smoking.13-Drt1g interactions.

* Adverse drug elfects are c/tvxx//zc// into:Type W =predictable undesirable side e//-,c'/A'..lnclude: side effects - overdose toxicity - Stlpersensitivitx - Secondaryeffects - C ytotoxicity (hepato-, nephro-, neuro-toxicity) - Druginteractions.

Type B =unpredictable side eyects..lncltlde: Hypersensitivity and idiosyncracy.

Type C Luzchronic etfects:lnclude: Tolearnce and dependence - latrogenicity.Tvpe D =LDe/qpe# eyects:lncltlde: Teratogenicity - M tltagenicity -- Carcinogenicity.Type E 'zœnd of use effects:lnclude'. rebound effect after sudden withdrawal of clonidine and betablockers - acute Addisonian crisis after sudden withtlrawal ofcorticosteroids - withdrawal sympton'ls (abstinence sylldronle) in addictsto morphihe, heroin, alcohol, barbittlrates, tobacco.. .

4 1




D rugs in Geriatrics

(Geriatric Pharmacology), k '

As noted before; elderly patients between 60 and 70 years require 2/3 ofthe adult bose, and those over 70 years tequire only l/2 of the adult dose.This is becapse of the following changes:A-pharmatokinetic t?/cz??2gt?5'.'l-Absorption: the rate of absorption isaffeded. This is because of:

slower but tlte extent is usually not

-delayed gastric emptying.-decreased blood tlow to GIT.-impaired lntestinal motility.-elevated pl-l of the stomach.z-Distribution:-reduced lean (muscular) body mass.-reduced total body water (Vu of water soluble drttgs as paracetamol isreduced).. :-increased total body fat (Va of tàt soluble drugs as benzodiazepines isincreased).-decreased serum album in which leads to increased free fraction of drugswhich m ay cause serious adverse eflkcts as warlitrin , btlt a-acidglycoprofein is increased.3-Elim inationa.M etabolism '. the hepatic blood tlow is reduced and the activity of HM E is

decreased (phase l reactions are more aftbcted thall phase 1l)Renal elim ination: renal excretory tknction is decreased with age andreduces elimination of many drugs as digoxin, l-lz-blockers, andgm inoglycosides as streptomycin.B-pharmacodvnamic changes..-Decreased receptor sensitivity as redtleed l'esponse to jl-blockers.-Exaggerated response to CNS depressallt drugs as allalgesics andhypnotics.-lncreased risk of postural hypotension (may be dtle to disturbedbaroreceptors) and that is why drugs causing postural hypotension arebetter avoided.

Other problems in geriatrics:l -polypharmacy: may cause serious drug interactions, so it is advisable touse m ipimal number of drugs.




z-Disturbances in memory, vision, and hearing wllicll impairscom pliance.

D rugs in PecliatricsDi

.ïerençes :e/wepn pediatrics tz/tt/ J#l///-&'l-luarger volume of body water.z-laower body fat.3-Less plasma proteins.4-l-ess active HME (less ability to coqjugate drugs as chloramphenicolleading to toxicity = gray baby syndrome).s-laess mature BBB, i.e. it is m ore permeable to drugs leading to CN Stoxicity.6-taess efficient renal clearance which may be partictllarly dangerous witham inoglycosides.'7-M ore tölerant to som e drugs as digitalis and * atropine.8-Amphetam ine and ephedrine cause sedation in children but they causeCNS stimulation in adults.




1 general pharmacology-1

Documents

names nomenclature of

oac ssvntheiic drugs

steroid ring

catechol ring

specific chem ieal ring

g interactions

prepared usingj

fefkrrett g