Pharmacology lecture
CNS
3
rd
Stage
1
ANTI-DEPRESSANT DRUGS: -
Drugs that used in treatment of depression can be classified into following groups:-
1-tricyclic antidepressant agents include :-
a-Nnortriptyline , amitriptyline , clomipramine , imipramine , trimipramine ,
lofepramine , dosulepin , doxepin ].
Itoral or parentral AD agents , amitriptylin is a tertiary amine type , clomipramine –
imipramine – desipramine all are dibenzazepine type , while protriptyline &
nortriptyline are dibezocycloheptene type . their mode of action include the most
important effect are decrease reuptake of norepinephrine & sreotonine . amitriptyline
inhibit both serotonine & NE , while desipramine more selective & potent inhibit only
NE .
They well absorbed via GIT but their anti-depressant effects required several weeks
to occur , they are highly protein binding predominately to α1-acid glycoproptein .
because of their long half-life a single daily dose can be use to improve patient state
. their metabolism in the liver some of the drug & its metabolites excreted into bile to
be undergo enterohepatic circulation reabsorbed . their excretion in the urine & small
amount in the feces .
Drug
Dose
Nortriptyline
Adult dose 25 mg X 3 increase by 25-50 mg in weekly interval to 200 mg
maximum dose 300 mg , elderly dose 25 mg at bedtime increase to 10 mg
X 3 & 20 mg at bedtime maximum dose 150 mg , child 12 years & above
10 mg X3 & 20 mg at bedtime maximum dose 100 mg /day, child age 6-
12 years 10-30 mg /day or 1-5 mg/kg/day in divided daily dose
Amitriptyline
Like nortriptyline
Clomopramine
Adult dose 10 mg increase to 30-150 mg /day as single night dose or
divided daily dose maximum dose 250 mg , elderly dose 10 mg increase
to 30-50 mg /day
Imipramine
Adult 25 mg X 3 /day increase to 150-200 mg at each week interval while
elderly dose10 mg up to 30-50 mg
Desipramine
As for nortriptyline but not recommended for patient under 12 years old
Pharmacology lecture
CNS
3
rd
Stage
2
Dosulepin
Adult dose 75-150 mg in divided daily dose or single night dose , elderly
dose 75 mg /day
Lofepramine
70 mg tablet 2-3 time a day
Trimipramine Adult dose 50-75 mg , elderly dose 10-25 mg
doxepin
Adult dose 30-300 mg according to the patient response , elderly
dose 10-50 mg
Their clinical use include major depression , diabetic neuropathy , hiccups , insomnia
, pain , migraine prophylaxis , panic & phobic disorder .
Their caution & contra-indication are [asthma , alcoholism , lactation , pregnancy ,
BPH , Parkinson disease , hyperthyroidism , hepatic disease , IM injection , MI ,
abrupt stopping , children , DM , elderly , glaucoma , GIT disease , respiratory
depression , urinary retention , seizure & suicidal ideation ].
Their adverse effects :-
-CNS include drowsiness , sedation , dizziness , anxiety , excitation & confusion ,
other like seizure , .
-CVS reaction that due to their direct quinidine-like action , anti-cholinergic effect&
their potentiate of NE include ventricular tachycardia , palpitation , hypertension ,
orthostatic hypotension .
-Peripheral nervous system tremor from NE reuptake blockade , Parkinson in elderly
patient .
-ocular manifestation like blurred vision , mydriasis , increase IOP .
-GIT like dry mouth , constipation , urinary retention , abdominal pain , anorexia ,
nauseas , vomiting , & jaundice .
- allergic reaction as photosensitivity , vasculitis , erythema , fever , urticaria .
-on endocrine as sexual dysfunction , like decrese libido , impotence , breast
enlargement etc .
Pharmacology lecture
CNS
3
rd
Stage
3
b-tricyclic anti-depressant + phenothiazine as combine therapy include
[fluphenazine + nortriptyline ][ perphenazine + amitriptyline ] :- motival consist
of fluphenazine hydrochloride 0.5 mg + nortriptyline hydrochloride 10 mg that used
for mild-moderate anxiety & for treatment of depression use as one tablet three times
a day for a maximum 3 months duration . contra-indication in case of grand mole
epilepsy , renal or hepatic damage , sever cardiac insufficiency , blood dyscarsias ,
acute MI , heart block , mania , pregnancy & lactation .caution in case of DM ,
glaucoma , CV disease , liver disease , adrenal medulla tumor psychosis patient with
suicidal tendency etc . their adverse reaction include acute dystonias , akathesia ,
parkinsonism like syndrome , nasal stiffness , dry mouth , maturation difficulty ,
impotence , weight gain , hypotension , tachycardia , hypothermia , seizure + anti-
cholinergic effects ,tremor
2-5HT- reuptake inhibitors (selective serotonine reuptake inhibitors -SSRIs)
include:-[cipramil , citalopram , fluoxetine , fluroxamine , sertraline , paroxetine
, faverin , firoxamine ] . fluoxetine :-it is oral AD agent , it is the prototrype of
SSRIs& has longer half-life than other SSRIs , their structure distinct than other AD
agents , used for treatment of alcoholism(in dose of 20 mg orally daily once , 20 %
reduce alcohol consumption if give in 60mg/day in patients with no adverse effects or
of minimal response monthly increasing of 10-20 mg /day , maximum dose 80 mg in
dose above 40 mg need to give it in 2-3 divide daily dose morning & at noon doses .
) , [anorexia nervosa , obesity](in dose 20 mg /day , many patients need dose by 20
mg to achieve maximal benefit , then as above ) ,panic disorder(in dose 20 mg orally
, patient treated with 10-70 mg improve over a period of 6-11 weeks , then as above )
, orthostatic hypotension( effective in 80% of the patients , if give in dose of 20 mg
once daily for6-8 weeks ) , major depression(in dose of 20 mg orally daily , 85% of
patients not need to increase above 20 mg ,then as above ) .their mode of action their
most important effect is the enhancement of action of serotonine due to highly specific
serotonine reuptake blockade at the neuronal membrane , it is of less sedative effects
–anticholinergic effect & CV effects than do tricyclic AD due to dramatically decrease
binding to receptors of histamine , Ach & NE . well absorbed orally from GIT , food
Pharmacology lecture
CNS
3
rd
Stage
4
delay their absorption rate but not their extent , of some first pass metabolism , highly
protein binding 94 % , well body distributed & cross BBB & placenta + breast milk .
their metabolism in the liver into several metabolites their only active one is
norfluoxetine active as parent agents , it is the slowest elimination agent in SSRIs ,
their half-life 2-3 days mostly excreted in the urine & to less extend in the feces .
Their caution & contra-indication are elderly , lactation , mania , suicidal ideation ,
seizure , renal impairment , hepatic & cardiac disease , DM , ECT .
Their adverse effects are :-
a- CNS reaction like anxiety , nervousness , insomnia , drowsiness, fatigue , tremor ,
headache , while sedation less problem , it is a drug induce seizure , their extra-
pyramidal symptoms like dystonia , torticollis & akathesia , all anti-D can transform
D into mania such treated with therapeutic dose of lithium + valproate or
carbamazepine .
b –GIT like nausea , vomiting , in 20 % subsided within few weeks & some time need
stop medication , other anorexia , diarrhea , dyspepsia , , weight loss exceeding 5% of
the body in 10-15 % of the patients .
c-skin like pruritus , alopecia , acne , contact dermatitis .
d-hypoglycemia .
e- visual impairment like blurred vision .
f-CVS it is less CV toxic than tricyclic AD , sinus bradycardia , orthostatic
hypotension , palpitation ,angina.
g- pain in back , joints , limb& muscle , other like anemia , upper respiratory tract
infection or pharngitis , nasal congestion , sinusitis , cough , dyspnea . sexual
dysfunction , hypothyroidism , it cause a syndrome of inapropiate secretion of anti
diuretic hormone.
Pharmacology lecture
CNS
3
rd
Stage
5
3-selective noradrenalin reuptake inhibitors like :- robexetine : use in treatment
of depression , in dose 4 mg twice daily increase if necessary to 10 mg after 3-4 weeks
, maximum dose 12 mg . not use in case of hypersensitivity , pregnancy & lactation .
caution in renal or hepatic impairment , seizure , urinary retention , glaucoma , BPH ,
cardiac disease . their adverse effects like [very common one as insomnia , dry mouth
, constipation , sweating , . common one as tachycardia , palpitation , vasodilatation ,
taste pervasion , postural hypotension , vertigo , UTI , chill , testicular pain , urinary
retention etc .
4-mono-amino-oxidase inhibitor (MAOI) like
a-hydrazid group like isocarboxazid(used in treatment of depressive illness. Its dose
up to 30 mg as single or in divide daily dose after 4 weeks increase to 60 mg for
maximum 6weeks , maintenance dose 10-20 mg up to 40 mg . contraindicated in case
of liver disease , CHF , phaeochromocytoma , , jyperthyroidism , pregnancy , lactation
. caution in case of elderly & seizure . their adverse effects like induction of mania or
confusion state , sever hypertensive reaction , insomnia , postural hypotension ,
dizziness , drowsiness , fatigue , maturation difficulty , ankle edema , rashes , jaundice
, weight gain .) & phenelzine :-it is oral MAOI-type anti-depressant , it is hydrazine
derivative , it irreversibly inhibit MAO like other like isocarboxazid , pargyline , only
tranylcypromine binding reversibly . it used for vtreatment of atypical D , major D ,
psychotic D, nonendogenous D panic & phobis disorder (in dose of 15 mg X3
increase rapidl;y to 60 mg /day – 1 mg /kg /day as soon as response occur reduce the
dose slowly over several weeks to 15 mg /day maximum dose 90 mg , maximum
therapeutic effect onset between 2-6 weeks , not recommended foe patient under 16
years , , in elderly patient as 15 mg each morning increase to 60 mg than as for adult
( as migraine prophylaxis(in dose 30-60 mg /day) .
their caution & contra-indication {alcoholism , asthma , lacatation , bronchitis , BM,
seizure , schizophrenia, suicidal ideation , renal impairment & disease , pregnancy ,
phaeochromocytoma , Parkinson’s disease , mania , hyperthyroidism , hypertension ,
HF , CV disease , arrhythmia ].
Pharmacology lecture
CNS
3
rd
Stage
6
Their adverse effects are :- the development of hypertension crisis is the most serious
effects , symptoms indicating the potential hypertension include sinus tachucardia or
bradycardia , angina , palpitation , sever headache , mydriasis , photophobia , nausea
, vomiting stiff neck . intracranial hemorrhage from increase BP may be fatal , on
development of hypertensive crisis the medication stop immediately . orthostatic
hypotension may also develop need more gradually increase the dose . peripheral
edema . anti-cholinergic reaction like drowsiness , constipation , confusion …etc .
sexual dysfunction . appetite stimulation & weight gain . tremor , fatigue ,
hyperreflexia , insomnia , , nystagmus , parenthesis, mania , agitation , elevating of
hepatic enzyme . anemia , thrombocytopenia , leucopenia .
Abrupt withdrawal of the drug cause withdrawal syndrome that manifested within 24-
72 hour .
b- non-hydrazide derivative like tranylcypromine & moclobemide(used in
treatment of major depression & social phobia in dose of 300 mg upto 600 mg in
divided daily dose after meal . contra-indication acute confusional state ,
phaeochromocytoma , co-administration with pethidine-selegiline- 5HT reuptake
inhibitor –dextromethorphan , hypersensitivity . caution in case of sever hepatic
impairment , thyrotoxicosis , schizophrenia , suicidal tendency , pregnancy , lactation
. their adverse effects like [sleep disturbance , agitation , anxiety , restlessness ,
irritability , dizziness , headache , dry mouth , visual disturbance , edema , nausea ,
vomiting ]) .
5-dibenzaepine like carbamazepine : it is oral anti0-convulsive agent structurally
similar top tricyclic anti-depressant , that used for treatment of partial & tonic-clonic
seizure , it is preferable over phenobarbital for children because of it has fewer adverse
effects , also it is effective in treatment of neurological origin pain like trigeminal
neuralgia , it is also effective in treatment of some psychiatric disorder including
manic-depression –explosive aggression . for treatment of seizure used in dose
of200mg X2 or 100 mg X4 for 12 years old & above increase weekly internal by 200
mg till maximum response achieved for child 6-12 years half the dose of adult
Pharmacology lecture
CNS
3
rd
Stage
7
regimen. For treatment of neuropathic pain 100 mg X2 to maximum dose 600-800 mg
till side effect become intolerable . for treatment of persistent hiccup 200 mg X 3 /day
. for treatment of mania + major depression either alone or combine with lithium in
dose of 200 mg X2 increase every 3-4 days to achieved serum concentration of 8-12
microgram/ml , usual dose 600-1200 mg in divide daily doses . their mechanism of
action it block use-dependent sodium channel , inhibiting sustained repetitive firing ,
it reduce post-tetanic potentiation of synaptic transmission in the spinal cord , pain
relief associated with block of synaptic transmission in the trigeminal nucleus , it also
possesses anti-cholinergic / anti-diuretic / anti-arrhythmic / muscle relaxant / anti-
depression ( possibly through blockade of nor- epinephrine release ) / also of
neuromuscular-blocking properties , it is a potent enzyme inducer & able to induce its
own metabolism .
It is use orally of slow & variable absorption via GIT , their suspension more rapidly
absorbed than tablets, give every 8 hour , 85% their bioavailability it is lipophilic &
appear in CSF , brain , duodenal fluid , bile , saliva , it cross placenta & accumulate n
the fetus , also distributed into breast milk(60% of serum conc.) , 76?% of the drug
protein binding . it metabolize in the liver by oxidation to an active metabolites .
plasma half-life 25-65 hours initially ?& 12-17 hours after repeated dosing . it excrete
in the urine 72% as un-conjugated metabolites & only 3% as unchanged drug , the
remainder excrete in the feces . their contra-indication & caution are [alcoholism ,
(atonic, petit mal & myoclonic) seizure , AVblock , breast feeding & pregnancy ,
psychosis , hepatic disease , elderly , hematological disease , glaucoma , renal disease
& impairment , cardiac disease ] .
Their adverse effects :-
-- hematological toxicity like fever, pharyngitis , oral ulceration , bruising , bleeding
, leucopenia , thrombocytopenia , etc .
-- CNS like dizziness , drowsiness , fatigue , ataxia , blurred vision , diplopia ,
hallucination , sedation , tolerance usually develop , confusion , agitation .
Pharmacology lecture
CNS
3
rd
Stage
8
-- GIT like diarrhea , nausea , vomiting , abdominal pain , constipation , anorexia ,
rarely hepatitis appear .
-- hyponatremia in elderly patients + water intoxication .
-- CV like arrhythmia , AVblock , syncope , CHF , hypertension , hypotension .
-- skin toxicity like alopecia , urticaria , erythema multiforme .
-- other like sexual dysfunction as impotence , interstitial nephritis . .
6-lithium salts : used in treatment of manic-depression & in treatment of recurrent
depression , used in dose to maintain serum lithium level range 0.6-1 mmol/L after
12 hours , contra-indication in case of Addison’s disease , renal or cardiac disease ,
lactation . caution in pregnancy , elderly ,. Their adverse effects like nausea , diarrhea
, tremor , muscles weakness , vertigo , thirst , CNS& ECG disturbance , weight gain ,
edema , typo-typerthyroidism , rash , polydipsia .
7- heterocyclic agents include
a-second generation agents like
1- amoxapine of dibenzoxapine type :- it is structurally similar to the old form
tricyclic AD & share similarity with phenothiazine . use to treaed depression , their
onset of action faster than that of amitriptyline . act by enhancement the effects of nor
epinephrine & serotonine by blocking the reuptake of various neurotransmitter at
neuronal membrane , also it block dopamine receptor and can cause dyskinesia . . it
is rapidly absorbed via GIT , widely distributed in the body , . it metabolite in the liver
completely to active metabolites like 8-hyroxyamoxapine(half-life of 30 minutes ) &
7-hydroxyamoxapine (half-life6.5 hours) the metabolites excreted as conjugate form
in the urine . their dose 50 mg X2-3 /day increased to 100 mg X2-3 times /day within
the first week of treatment for elderly patient 25 mg X 3 .
Their contra-indication- caution & their adverse like tricyclic AD agent .
Pharmacology lecture
CNS
3
rd
Stage
9
2- tricyclic related agents like mianserine , trazodone[used to improve all
symptoms of depression types including that associated with anxiety , used in dose
150 mg daily as single or in divided daily doses after meals increase upto 300 mg ,
maximum dose 600 mg , in elderly used in dose 100 mg as single or in divide daily
dose , maximum dose 300 mg . contra-indication in case of hypersensitivity & first
trimester of pregnancy . caution in case of seizure , sever hepatic-renal- cardiac
diseases , pregnancy & lactation . their adverse effects like [drowsiness , nausea ,
vomiting , headache , dizziness , weakness , weight loss , tremor , dry mouth , edema
, postural hypotension , bradycardia , tachycardia , blurred vision , insomnia , skin
rash, confusion ] .
3- tertacyclic anti-depressant agent like maprotiline , use in treatment of
depression especially when the sedation required . used in dose initially 25-75 mg as
single or in 3 divided daily doses . adjusting after 1-2 week according to necessary ,
maximum dose 150 mg /day . in elderly patient used in dose 30 mg as single dose or
10 mg three times a day , increase upto 25 mg threes times a day or 75 mg single
daily dose . contra-indicated in case of mania , sever renal or hepatic disease , seizure
, narrow angle glaucoma , urinary retention , recent MI , hypnotic or psychotropic
drugs uses , MAOI , hypersensitivity , lactation . caution in pregnancy(stop the
medication at least 7 weeks before expected day of delivery ) , postural hypotension ,
CV disease , hyperthyroidism , elderly , suicidal tendency , ECT , increased IOP ,
chronic constipation , contact lenses . their adverse effects like [convulsion , skin rash
, anti-cholinergic effects , impaired reaction ] .
b- third generation include :
1-nefazodone a newer oral anti-depressant agent with a mode of action distinct from
other anti-depressant agents .structurally similar to trazodone but less causing of
sedation or orthostatic hypotension . it is effective as other anti-depressant in treatment
of major depression , it is of no CV toxicity . their mode of action[ involve both
serotonergic & to less extend noradrenergic system within the serotonergic it is a
potent antagonist at 5HT type 2 post synaptic receptor also it inhibit pre-synaptic
Pharmacology lecture
CNS
3
rd
Stage
10
serotonine reuptake but this consider as a second important mechanism of action by
both it increase amount of serotonine available to interact with 5HT receptors , within
the noradrenergic it inhibit nor epinephrine uptake but this loss on chronic uses , it
also antagonist α1 adrenergic receptor by this effect it induce sedation , muscle
relaxation , CV effect like hypotension , reflex tachycardia ] . it is rapidly absorbed
via GIT & completely , 20% their bioavailability due to extensive first pass
metabolism , food delay its absorption , widely distributed into body tissues including
CNS , 99 ?% are protein binding , their metabolism by n-dealkylation & aliphatic +
aromatic hydroxylation via hepatic cytochrome P450 their metabolites like
hydroxynefazodone of the same profile of the parent agent & other metabolite
triazoledione of one-seventh activity of the parent agent their half life range 2-8 hours
while their metabolite 1.5-4 & 4-8 hours respectively . their excretion in urine 55% &
in feces in 20-30& their elimination prolong by hepatic or renal impairment .their
indication include major depression & premenstrual syndrome .food decrease their
bioavailability so take one hour prior or 2 hours after meal . thgeir dose in patient
more than 18 years old 100 mg twice daily increase by 100-200 mg every interval not
less than week , effective dose 300-600 mg , elderly patient 50 mg twice increase as
above . their contraindication & precaution include [angina , cardiac disease ,
bradycardia , dehydration , elderly , hepatic , lactation , mania , MI , pregnancy , stoke
, suicidal ideation ] . their adverse effects are : dizziness in 175% , drwosiness in 25%
, xerostomis , nausea , vomiting , blurred vision , confusion , somnolence , orthostatic
hypotension , constipation , headache , dyspepsia ,appetite stimulation , insomnia
,chill , flu-like syndrome , fever , pruritis , .
2- 5HT + noradrenalin reuptake inhibitor as combine agents like venlafaxine ,
use in hospitalize & outpatients , used in dose of 37-5 mg X 2 /day with the food ,
may need to increase upto 75 mg X 2/day after several weeks in case of sever
depression initial dose 75 mg X 2 to be increase every 2-3 days , maximum dose 375
mg . conta-indicated in case of lactation & pregnancy , concomitant use with MAOI ,
hypersensitivity , patients under 18 years old . caution in renal or hepatic impairment
, seizure , manis , MI , increased intra-cranial pressure etc . their adverse effects like
Pharmacology lecture
CNS
3
rd
Stage
11
[very common one nausea , insomnia , dry mouth , somnolence , dizziness ,
constipation , sweating , , common one like hypertension , palpitation , vasodilatation
,anorexia , dyspepsia , vomiting , abdominal pain , chills , pyrexia , anxiety , confusion
rash , urinary frequency , decrease libido etc ] .
3-serotonergic & noradrenergic enhancement agent like mirtazapine that
antagonize α1 , 5HT2, 5HT3 receptors. Used in dose of 15-30 mg daily titrate
according to the response usual effective dose 15-45 mg as single night dose or in 2
divided doses withdrawal gradually when the symptoms free for 4-6 months . contra-
indicated in case of hypersensitivity , pregnancy , lactation . caution in case ofrenal &
hepatic impairment , BPH , recent MI , hypotension , angina , DM , glaucoma . their
adverse effects like increase of appetite , weight gain , edema , drowsiness these are
common , un-common like increase liver enzymes , dizziness , headache , rare one
like rashes , mania , othrostatic hypotension , restless legs , tremor ,
convulsion , etc ].
8- Amino acid like L-tryptophan . used only in the hospital for treatment of sever
& disabling depression of more than 2 year duration & refractory to other agents .
tablet of 50 mg to be use as 2 tablet three times a day , maximum dose 12 tablet daily
, contra-indication in case of pregnancy , lactation , history of eosinophilia myalgia
syndrome . caution used in elderly , & in patient with renal or hepatic impairment .
their adverse effects include[raised eosinophils , sever myalgia , drowsiness , nausea
& headache ].
9- anti-manic like valoproic acid that used for treatment of convulsion . their dose
750 mg in 2-3 daily divided dose & increase gradually till reach therapeutic dose (1-
2 g) , tablet should swallowed & not chewed . contra-indication in case of
hypersensitivity , sever liver disease , porphyria .
10-thioxanthene like flupentixol . for treatment of depression with or without
anxiety in dose of 1-2 mg as morning single dose , maximum dose 3 mg in divided
daily doses . contra-indicated in case sever depression that require ECT or
hospitalization , in case of manic patient . pre-caution in case of pregnancy , lactation
Pharmacology lecture
CNS
3
rd
Stage
12
& withdrawal gradually . their adverse effects include [insomnia , restlessness , tremor
, dizziness , visual disturbance , headache , migraine & hyperprolactenaemia ,
akinesia ] .