Download Pharmacology

Pharmacology
Topic
Drug
Actions
CHOLINOMI
METIC
Directly
ACh
Muscurinic:
i) CVS:
 HR,
 CO ( as Atrial contracn and
 vasodilation (NO on endothelium)
= BP
Choline Ester
Mimic the actions of
Ach by binding to and
stimulating ACh
receptors
Muscarinic receptors
(i)
all effector organs
innervated by postgang para
(ii)
sweat glands
(iii)
endothelial
cells
(non-innervated)
where they mediate
NO-dependent
vasodilation.
(iv)
CNS
ii) Non Vascular SM:
a Lungs – bronchoconstriction
 GI - motility (peristalsis) and
secretion
 Bladder – contracn of detrusor;
relaxatn of trigone and sphincters
s
iii) Exocrine Secretions:
 Salivation

GI secretions
 Sweating
 bronchial Secretions
iii) Eye:
 Contracn of ciliary body = fat lens
accommodation for near vision
 Contracn of Sphincter Pupillae
(circular muscle of the iris) =
constricts pupil (miosis)
improves drainage of aq fliud,
intra-ocular P
 Lacrimation
Applications
Unwanted
Effects
Does not differentiate
between muscurinic and
nicotinic e.g. skeletal
muscle contracn and symp
activity
b) Indirectly
(Anticholinest
erase)
Bethanechol
– mildly modified
from ACh
– Choline Ester



Pilocarpine
(Pilocarpus - shrub
growing in SA
Alkaloid
 Selective Agonist at muscurinic
 Not a substrate for cholinesterase
enzyme
Physostigmine
Carbamyl Ester
Muscurinic
Dose related – ACh activity at all musc
Competes w/ Ach for
active site on enzyme,
CNS: tertiary gp enter
Sp to Muscurinic – selective to M3
Limited access to CNS
Resistive to degradation
LOW dose -
Reversible
Donates carbamyl gp
to enzyme,
Reactivated by slow
hydrolysis
/neostigmine
musc
Excitabily w/ possible convulsions
 Oral
3-4 hrs
Muscurinic
 CO, HR = BP
 nausea, vomiting
 colic, sweating
 impaired vision
 glaucoma
-miosis,
local
 Xerotosma (dry mouth)
1) Glaucoma:
IOP drainage by miosis
Local- eye drops
Local muscle twitiching
2) Atropine
Poisoning:
Overcomes musc effects,
iv
CNS
effects
MODERATE - + effect at all ANS,
Symp effect
HIGH – toxic dose: dep block at gang
Depression, unconsciousness, R failure,
death
Weak neuromuscular effects
- greater effect on ANS
Ecothiopate
Irreversible
Organo-P
Has labile gp F/
organic, inactivates
enzyme by
Phosphorylation =
same
1) Glaucoma
local
Local muscle twitching
1) Organophosp poisoning
if protective clothing not
2)
worn:
a
agriculture –insecticides
 Musc activity, brady,
3)
hypo, brochocons, sweat,
biological warfare – nerve gases saliva, miosis, fixed for near
stable
Recovery –synthesis:
wks
vision
 Neuromusc juncs effect:
muscle twitching, dep block,
paralysis of diaphr
/ DYFLOS Highly
lipid solubleEasily absorbed thru
skin, nasal mucosa,
lungs
 die of CNS effects – R
failure
Treatment: atropine iv,
artificial resp, pralidoxime iv
which reactives plasma
chlolinesterase
2) peripheral nerve
demyelination = weakness
and sensory loss
Bind with high affinity
CHOLINOCE
PTOR
ANTAGONIS
T
Nicotinic/gang
lion blocking
Activity depends on pre-existing
stimulation: level of tone
Hexamethonium /
Trimetaphan
Block transmission at
all ANS
Except skeletal
neuromuscular
i) CVS
– BP
–Impaired postural reflexes
–
renin secretion
ii) Non-vascular SM
–GI tract –
motility
–Bladder – impaired emptying
–Urinogenital - impotence
–Lungs – bronchodilation
iii) Eyes –
•dilated pupil,
•accommodation fixed for far vision,
•impaired light reflex
•Inhibition of exocrine glands
Trimetaphan:
 controlled short lasting (2 3 minutes) hypotension in
surgery;
iv
Hexamethonium
No longer clinically used
–Sweat, –Salivary, –GI –Bronchial
–Lacrimal
Muscarinic
Cholinoceptor
Antagonists
Atropine
–Derived from deadly
nightshade
–Belladona alkaloid
i) CVS
–Initial
in HR (CNS effect)
–Subsequent mild tachycardia
–Cutaneous flushing (histamine effect)
–No change in BP
•Hyoscine
ii) Inhibition of exocrine glands
Block receptors:
iii)Eye
–Dilated pupil (mydriasis)
–Impaired light reflex
–Accommodation fixed for far vision
– IOP
i) Post-gang para
ii) Post-gang symp,
that use Ach
Block "muscarinic"
the CNS.
iv) smooth muscle
–Bronchodilation
– contracn of ureter and bladder
– contracn of gallbladder and bile ducts
–Little effect on the uterus
GI tract:
–Difficulty swallowing
– motility
v) CNS
–Initial excitation (atropine only)–
Depression –tranquility, amnesia
–Overdose :Coma, Resp depression,
Death
NEUROMUS
CULAR
BLOCKING
DRUGS
•Dont Affect Consciousness
•Dont Affect Pain Sensation
Assist Resp (Until Drug Inactive Or
Antagonised)
Atropine i.v.
–Sinus brady
–oral, i.m.
Well distributed
Metabolism: Hepatic–t1/2: 23h
Atropine
 Dry mouth
 Blurred vision
Urinary retention
–Tropicamide local, short
acting
– dilate the pupil to view the
retina
 young children who eat
deadly nightshade berries.
Atropine poisoining
Characterised by
 hyperactivity

CNS
Hyoscine, transdermal
depression
–Prevention of motion sickness  body temperature
 periph musc block – i.e. dry
–Parkinson’s
mouth, etc.
Ipatropium
inhalation
Asthma
Obstructive airways disease
–Peptic ulcer disease
–Irritable bowel syndrome
–Facilitate endoscopy
Treated
anti-cholinesterase drugs
which penetrate the CNS,
e.g. physostigmine
• Diazepam /
Baclofen: (Central
Processes ) /
Dantrolene: (Propagn
Of AP Along Muscle
Fibre + Muscle
Contracn)
Spasmolytics :
•Local Anaesthetics
Conduction Of Nerve
Ap In Motor Neurone
•Hemicholinium
•Ca2+ Entry
Blockers
•Neurotoxins
Ach Release
Non
Deoplarising
Tubocurarine
(Prototype)
Depolarisation Of Motor End-Plate
A
AP Initiation
 Relaxation Of Skeletal
Muscles During Surgery (=
Less Anaesthetic)
Competitive
Post Synaptic
Competitive
nAChr
Antagonist
• 4° Ammonium
Compound (Alkaloid)
70 - 80% Block Necessary
Found In S. American
Plant (Arrow Poison)
•Graded Block = Different Proporn Of
Fibres Blocked
Pancuronium
leads to: Flaccid Paralysis of
1. Extrinsic Eye Muscles (Double Vision)
2. Small Muscles Of Face, Limbs, Pharynx
3. Resp Muscles
Gang Block ( TPR)
Histamine Release From
Mast Cells
 Permit Artificial Ventilation
Hypotension
Iv- highly charged
Doesnt Cross Bbb / Placenta
Onset: 2 - 3 Min
Actions Reversed By Anticholinesterases
e.g. Neostigmine (+ Atropine)
Tachycardia (Arrhythmias
??):
 Reflex
 Blockade Of Vagal
Ganglia
40 - 60 Min (Long)
Bronchospasm
Not Metabolised excrete 70%Urine; 30% Bile
(Care If Renal Or Hepatic
Function Impaired)
Apnoea (Always Assist
Respiration)
Secretions: Bronchial &
Salivary)
Depolarising
(Agonists)
SYMPATHO
MIMETICS
Suxamethonium
( Succinylcholine)
Adrenoreceptors
A1, a2, b1, b2, b3
all organs: by post-gang symp, bronchial
SM, CNS
A1: w/ imp of adrenergic activity vasoconstricn: skin, mucous memb,
salivary, abdo

sweating – thick and viscous
 male genitalia: ejaculation
 Constricn of iris radial muscles =
mydriasis
 bladder: constricts trigone and sphincter
 ureter: motility and tone
 stimulates tears

saliva
 Liver: glycogenolysis, gluconeogenesis =
G
 lipolysis
 GI:
motility and tone, contacn of
sphincters
A2: Inhibition of transmitter release,
contraction of
vascular SM, CNS.
B1:
 HR and contractility
 lipolysis
 renin secretion
relaxation of GI
B2:
 Glycogenolysis, gluconeogenesis
 Skeletal muscles vasodilation
 Bladder: Relaxes detrusor
 Dilate trachea and bronchioles
 Relaxation of uterus
relaxation of visceral SM
β3- Lipolysis
•G-protein coupled :
–type 2 receptor
–response slow: sec - min
•2nd messenger:
– a1 coupled to the PLC / IP3
– a2, b1, b2 aden cyc ( cAMP)
Directly
acting symp
Mimic actions
of NA/A by
binding to and
stimulating
adrenoceptors
Adrenalineemergency hormone
CVS
 HR and contractility B1-
b1=b2>a1=a2
 a1vasoconstricn greater b2 vasodiln =
peripheral resistance
( blood supply to
skeletal muscle and
lood supply to skin,
g.i.t., mucusa)
=
CO
BP
SM
•Lungs – Relaxation of tracheal and
bronchial SM =Opens up airways
Metabolism - Increases energy supply
–
blood levels G (glycogenolysis and
gluconeogenesis in muscle and liver)
–
blood levels of free fatty acids
1. Acute allergic reactions
and anaphylactic shockType
1
hypersensitivity
reactions
(i.v.)
Inhibits release and opposes
the inflammatory mediators
which cause a fall in BP and
breathing difficulties.
i) CVS:
tachycardia,
arrythmias, cold extremities,
severe hypertension
ii) Reduced and thickened
mucous
secretions
(dry
mouth)
ii) Tremor due to effects on
skeletal muscle
2. As a cardiac stimulant (overdose) = to cerebral
(i.v.) in:
haemmorhage and
e.g. acute manage heart block pulmonary oedema.
3. To maintain BP during
spinal anaesthesia (i.v.).
4. To prolong the duration of
(lipolysis in adipose tissue)
local anaesthetics
eye
Constricts the radial muscle–Mydriasis
(pupillary dilatation)
5. To treat glaucoma (eye
drops): prodn of aq humour
6. COPD
Phenylephrine
a1
1. stop superficial bleeding
from skin and mucous memb
same as adrenaline;
more resistant to
COMT but not MAO.
2. dilate pupil (eye drops)
without cycloplegia (loss of
accommodation
for
near
vision) or loss of light reflex.
3.nasal decongestant
(nose
drops;
vasoconstrictor
Clonidine
a2 adrenoceptor
mediated presynaptic inhibition of
NA release
Isoprenaline
B1 = B2
Less susceptible to
Uptake 1 and MAO
than adrenaline;
Symp
oral
hypertension
·a2
migraine
·central action in brainstem within
baroreceptor pathway to symp
oral/ iv
heart block (cardiogenic
shock, acute heart failure or
myocardial infarction);
i.v
asthma discontinued
plasma t ½ 2 hrs
Dry mouth,
Sedation, dizziness
bradycardia,
nausea, constipation.
Tachycardia (reflex),
dysrhythmias
Dobutamine
B1 > B2
heart block
•(Lacks isoprenaline’s reflex
tachycardia)
i.v.
t ½ 2 mins (rapid metabolism
by COMT)
Salbutamol
(ventolin)
B2>B1
asthma : (inhalation)
- relaxation of bronchial SM
- inhibition of the release of
bronchoconst subs from mast
cells.
synthetic
catecholamine
•Reflex tachycardia
•tremor
•caution with cardiac
patients, hyperthyroidism
and diabetes (i.v.use)
threratened uncomplicated
premature labour: iv
resistance to MAO
and COMT
INDIRECTL
Y ACTING
SYMP
Cocaine
A2 : prevents uptake by MAO so A/NA
Tyramine: cheese
reacn’
false’ neurotransmitter
dietary aa
(cheese, red wine and
soy sauce
SYMP
ANTAG
Problems:
MOAs inhibited
(antidepressant drugs eg.
phenelzine)
= ingestion of foods
containing tyramine cause a
hypertensive crisis.
Not a problem when normal mechanisms
for degradation of monoamines are in
operation
Hypertension
�Cardiac Arrhythmias
�Angina
�Modify Plasma Lipid levels
�Glaucoma
 Blocks presynap β- NA
 Kidney : blood vol and renin.
 heart:
HR and CO
 Arterioles- peripheral resist due to less
renin & pre-synapt β block
 CNS- controls BP
B antagonist
1) Hypertension:
sustained diastolic arterial
pressure greater than 90
mmHg
Bronchoconstriction – (β2−
lungs)
Caution: asthmatics pts,
bronchitis.
2) Anxiety states - to control
somatic symptoms eg
palpitations and tremor.
� Cardiac Failure – Pts w/
heart dis need some symp for
normal CO
3)Migraine prophylaxis.
4)Benign essential tremor.
� Hypoglycaemia - G
controlled by liver β2warning diabetic (sweating,
palpitations, tremor) of G
Use B1 .
� Fatigue - CO and
muscle perfusion.
� Cold Extremities - no βvasodilat in skin
� Bad Dreams
Propranolol
Β1+ Β2−
Non-Selective
at rest, causes little change in
HR, CO or arterial pressure,
but effect of exercise or excitement on
arrhythmia's that occur
during exercise or mental
stress
1st clinical βantagonists
� maintains Reflex vasoconsn so postural
hypotension /exercise
less problematic.
refractory period of the AVN
= thus interfering with AV
conducn in arterial
tachycardias, and to slow
ventricular rate.
Class II
Antiarrhythmics
Atenolol
Β1−Selective
antagonise NA on heart
but also any tissue β1.
cardio-selective drugs
� Less effect on airways than non-selective
drugs, but not safe w/ asthmatic
Labetalol
Dual acting β1 and α1
antagonists,
β1 : α1 (4:1)
BP by via peripheral resis – via
block of α1 in blood vessels & β1 effects
on renin/neurotransmitter release.
� No change in HR and CO
metoprolol
β1-
HR
� systolic blood pressure.
� cardiac contractile activity.
without affecting bronchial
smooth muscle. (low dose)
ANGINA- myocardial
oxygen demand.
higher dose selectivity is lost
and resembles propranolol
� Carteolol
hydrochloride,
timolol, maleate.
� rate of aq humor prodn by
blockthe receptors on the ciliary body.
Which normally respond to symp and A
Glaucoma
� betaxolol
hydrochloride
: β1 antagonists
� in arterial pressure (α- = periph resis
� Postural hypotension.
� Cardiac output/heart rate – reflex
response to fall in arterial pressure (β-
A
adrenorecepto
r antagonist
Non-selective
Phentolamine
� vasodilan and
� GIT motility
BP due to block α1
� not clinically used
diarrhoea
concomitant α2 block
tends to NA = reflex
tachycardia occurs with any
BP lowering agent
Prazosin
A1
Methyldopa
False Transmitter
released like NA
� less active than NA
on α1-= less
vasoconstrictn
� more active on
presynaptic (α2),
autoinhibitory
feedback mechanism
operates more
strongly, release
below normal
α1-antagonists Plasma
Lipid Levels-
� Vasodilatn and
arterial P.
� Less tachycardia than non-selective
as don’t NA
�veins dilate, venous P, CO
�less Hypotensive.
� LDL ,
HDL
� antihypertensive
� postural hypotension is
troublesome.
� Taken up by NA neurons.
� Decarboxylated and hydroxylated to =
false transmitter, α-methyl-NA.
� Not deaminated within neuron by MAO
and so accumulate in larger quantities than
NA , and displaces NA
from synaptic vesicles.
hypertensive patients with
renal
insufficiency or
cerebrovascular disease.
Dry mouth
� Sedation
� Postural hypotension
(particularly in elderly)
� Male sexual dysfunction
� Parenchymal injury in the
liver resembling viral
hepatitis.
hypertensive pregnant
women, has no adverse effects
on foetus
Renal blood flow is well maintained, widely despite crossing bloodplacenta barrier
� CNS effects, stimulates vasopressor
centre in brain stem to inhibit symp
� used very infrequently.
�LDL and (VLDL) levels and total
triglyceride levels.
(HDL)
risk factors for coronary artery dis.
DRUGS
AFFECTING
THE HEART
Symp:
•inc force of contraction (+ve inotropic)
•inc HR (+ve chronotropic )
•inc automaticity
•red cardiac efficiency (i.e. cardiac O2 consumption inc >
cardiac work)
•activate B1: stimulate adenyl cyclase = inc prodn of
cAMP from ATP, intracellular messenger = inc Ca – effect
on L-type channels and sarcoplasmic reticulum and
stimulate Na-K ATPase in cardiac myocyte
Changes in preload and afterload
•Inc preload (venous return) inc force of contraction (Frank
Starling effect)
•Inc afterload dec stroke vol
Heart failure: serious condn w/ high
mort
heart does not adequately perform
funcn as a pump (or only does so at
elevated filling pressures).
= fluid retention, oedema and fatigue.
•due to ischaemic heart disease,
hypertension, cardiomyopathy of a
combination of these conditions
•ACEI (ARB), beta-blockers and
spironolactone have been shown to
improve survival.
Para:
Cardiac slowing and dec automacity
Inhibiton of AV condn
inhibit symp stimulation of heart
1. Angina
2. Post myocardial infarction
3. Cardiac dysrhythmias
4. Hypertension
5. Chronic heart failure
6. thyrotoxicosis, glaucoma, anxiety
states, migraine prophylaxis, benign
essential tremor
7. improve post MI
1.
2.
3.
4.
Organic
Nitrates
glyceryl
trinitrate
isosorbide
mononitrate,
Affect the preload
Predominantly venodilators, dec venoreturn and cardiac
work,
release NO in SM and relaxes them, inc in venous
capacitance
–antiplatelet agents
–coronary artery vasodilators
–reduce systemic arterial tone
(afterload).
Caused by vasodilation
• hypotension, headaches and flushing
•Excessive/prolonged use: tolerance –
i.e. a loss of effect and benefit.
nicorandril
open K (ATP)
B-Blockers
competitive
antag badrenoceptors
propranolol
(non-selective),
atenolol (B1 selective)
Longer acting; transdermal patch
first pass’ metabolism by liver.
sublingual tablet or spray: rapid relief
Bronchoconstriction
Worsening of cardiac failure
Bradycardia (heart block)
Hypoglycaemia (diabetics on
insulin)
5. Fatigue
6. Cold extremities and worsening of
peripheral arterial dis
7. CNS effects (lipophilic agents) e.g.
nightmares
of angina
short t ½ (~5 mins).
Vasodilation affects the arterial circ
Calcium
antagonist
1) Cardiac and
Verapamil (and diltiazem less) affect L-type channels in
SM actions
heart and blood vessels.
a)
bind to L-type calcium channels and reduce Ca2+ entry
Phenylalkylami into cardiac and SM - relax
nes (e.g.
verapamil - -ve ionotropic and chronotropic actions
Verapamil)
b)Benzothiazepi
nes (e.g.
Diltiazem)
1. Hypertension
2. Angina
3. Anti-dysrrhythmics (verapamil >
diltiazem, )
4. Negative inotropic effect
(verapamil > diltiazem,
Verapamil: heart block, heart failure
and constipation
Longer acting
Flushing headaches, hypotension,
ankle swelling
Antidysrhythm endogenous mediator produced by the metabolism of
adenosine triphosphate (ATP).
ic agents
A1: hyperpolarize cardiac tissue and slow conduction
Adenosine
through AVN.
Iv: terminate superventricular
tachyarrhythmias (SVT).
short-lived (20-30s)
safer than verapamil.
•Chest pain, shortness of breath,
dizziness and
Verapamil
Calcium antagonist
Inhibits AV-node conduction
Paroxysmal SVT
atrial fibrillation (no abnorm conducn
pathways).
Amiodarone
Complex action probably involving multiple ion channel
block and possibly anti-thyroid action
Antidysrhythmic: superventricular
and ventricular tachyarrhythmias
accumulates in the body (t½ 10 100days)
Cardiac
ionotrpes
Dobutamine
b1 agonist
inc force contraction w/out any major effect on heart rate.
acute heart failure e.g. after cardiac
surgery or in cardiogenic or septic
shock
2) SM actions
Dihydropyridin
es (e.g.
amlodipine)
dec Ca2+ entry into SM
only affect blood vessels.
•Inhibitors of phosphodiesterase: inhibit breakdown of
cAMP in cardiac myocytes.
1.
2.
3.
4.
5.
6.
photosensitive skin rashes
hypo- or hyper-thyroidism
pulmonary fibrosis
corneal deposits
neurological, GI disturbances
nausea
impair survival in chronic heart failure
and are rarely used.
milrinone
Cardiac
glycosides
Digoxin
DRUGS AND
VASCULATU
RE
ACE
Inhibitors
inhibit Na-K-ATPase (Na/K pump).
Accumulate Ca2+: dec Na+ release and inc Na+/Ca2+
exchange = inc force of contraction
dec rate of conduction through the AVN (result of central
vagal stimulation)
slows ventricular rate in atrial
fibrillation and relieves symptoms in
chronic heart failure
(common and severe)
•dysrhythmias (e.g. AV conduction
block, ectopic pacemaker activity)
•Clinically imp interactions w/ drugs
that reduce digoxin excretion and
tissue binding (e.g. amiodarone,
verapamil) or agents that reduce
plasma [K+] (e.g. diuretics).
prevent the conversion of ang I to ang II by ACE
1.
2.
3.
4.
5.
6.
1. Cough (ACEI)
2. Hypotension
3. Urticaria / Angioedema (ACEI - v.
rarely)
4. Hyperkalaemia (care with K
supplements or K sparing diuretics)
5. Fetal injury
6. Renal fail:pts w/ renal art stenosis
prevent the degradation of bradykinin (and other kinins)
enalapril
hypertension
heart failure
post-myocardial infarction
diabetic nephropathy
progressive renal insufficiency
pt: high risk of cardio disease
Ang receptor
blockers
ARB or AIIA
non-comp antag
of type 1 (AT1)
receptors AngII
losartan
•Clinical experience less extensive than ACEI
Both inhibit the hypertensive and Na+ retaining effects of
angII
Aldosterone
antagonist
Spironolactone
inhibits the Na retention
heart failure
resistant cases of hypertension.
limited diuretic effects
B Blockers
Comp antag breceptors
b1 antagonists: hypotensive action not understood
do not dec peripheral resistance (PVR) (except partial
agonists / vasodilatory beta blockers).
1.
2.
3.
4.
Hypertension
alternative for ACEI in pt who cannot
tolerate ACEI (e.g. Chronic heart
failure).
Same
inc angII levels and do not prevent actions on AT2
Angina
Post myocardial infarction
Cardiac dysrhythmias
Chronic heart failure
hyperkalemia
steroid-like effects: gynaecomastia,
menstrual probs, testicular atrophy.
Atenolol B1
5. Hypertension
6. thyrotoxicosis, glaucoma, anxiety
states, migraine prophylaxis, benign
essential tremor
Calcium
Blockers
1. dec renin release by the kidney
2. dec NA release by symp
3. lipophilic: exert central sympatho-inhibitory actions:
less marked rise in PVR on chronic as opposed to acute
administration.
reduce Ca2+ entry into cardiac and smooth muscle cells
Verapamil & diltiazem Dihydropyridines:
Vasodilators
Hydralazine
dilates arteries/arterioles. Consequently it induces reflex
tachycardia.
Rarely used except in pre-eclampsia /
pregnancy-associated hypertension
Organic nitrates
nitroprusside
nitric oxide (NO) donors and vasodilate arteries, esp veins.
Propranolol
lipophilic
angina
Nicorandil
NO donor and KATP channel opener.
A blockers and
sympatholytics
antag a1
doxazosin competitive
Arterial
vasodilat that
inhibit
vasoconstrict
effects of symp
on blood
vessels
clonidine - Centrally acting antihypertensive
penoxybenzamine irreversible
combined w/ antihypertensives in
resistant hypertension
long-lasting a-blockade in
pheochromocytoma (combined with a
beta blocker).
Use often limited by adverse effects
a-methydopa (a2-adrenoceptor agonists),
moxonidine (imadazoline agonist)
Reserpine depletes neuronal NA.
trimetaphan Short acting ganglion blockers,
anaesthesia to dec BP
Vasoconstricto
rs
Sumitriptan
constricts large arteries and inhibits trigeminal nerve
migraine attacks,
Sympathomim
etic
Adrenaline: catecholamine, produced by the adrenal gland
ergot alkaloids
Agonist at 5HT1D recep
cardiac arrest
anaphylactic shock
contraindicated in pt with coronary
dis.
usefulness is limited by side effects.
HAEMOSTAT arrest of blood loss from damaged blood vessels.
a rapid, potent, localized response to vascular damage.
SIS
1. Vasoconstriction
2. Platelet aggregation (clumping)
3.Coagulation to produce a fibrin clot
cofactor in synthesis of clotting factors: fibrinogen – fibrin
Vit K
Synth by bact in mesh
GI
+ w/ carboxyglutamic acid inc modification of factors
Promote Coag
THROMBOSI
S
In vivo
Clot: in vitro
pathological formn of haemostatic plug w/in vasculature
in the absence of bleeding
Virchow’s Triad
1) Injury to the vessel wall e.g. rupture of athero plaque
2)Stasis e.g. atria of heart during atrial fibrillation, veins
of the legs following restricted movement on long flights.
3)Abnormal coaguability of the bloode.g. late stages of
preg, during treatment w/ certain oral contraceptives
Arterial (white
thrombus)
atherosclerosis. platelets and leukocytes in a fibrin mesh.
Interrupts blood flow= ischemia/ infarcn of tissue beyond.
Venous (red
thrombus)
blood stasis. Small platelet component large fibrin
component. break away= embolus wh/ lodges in lungs or
(if it comes from the left heart or carotid) the brain.
1.
2.
3.
4.
promote coag: haemophilia
staunch haemorrhage
following surgery
after anti-coagulant Therapy
1. Newborn babies to prevent
haemorrhagic dis
2. stop bleeding in excess anticoag
Haemophilia – lack of factor VIII
= fresh plasma, conc factor 8 and 9
Drug therapy used to treat or prevent
thombosis
(or thromboembolism) acts in 3
distinct ways
antiplatelet
anticoagulant
fibrinolytic
form in heart in pt w/ atrial fib
Treatment – antiplatelet drugs and
fibrinolyitic dugs
anticoagulants
Anticoagulants
Natural
1) Warfarin
2) Heparin
3) Low
Molecular
Weight
Heparin
(LMWH)
Anti Platelet
Aspirin
1.TFPI – tissue factor pathway inhibitor
2. Protein C – activated by thrombin, inactivates factors
VII and V
3. Antithrombin III – activated by heparin inactivates
thrombin
- prevents the activation of vitamin K
drug interactions:
1) inhibit cyt P450- antibact– erythromycin - antifungal– fluconazole
2)induce cyt P450: -Anticonvulsants – Phenobarbital
3) drugs which inhibit platelet function: - aspirin
4)drugs which displace warfarin from plasma proteins
-aspirin
-activates anti-thrombin III which inhibits factor Xa
and thrombin by binding to the active serine sites.
LMWH same effect on Xa but less on thrombin.
Reversal: Stop IV
. Give IV protamine
- binds to heparin to produce an inactive complex
Irreversibly inhibits COX-1.
Inhibits the production pf TXA2 in platelets
-oral, absorbed quickly from GI,
peak blood conc:1h,
pharmaco effect delayed:12 – 16h,
peak after 48h and last 4-5 days –
slow turnover of clotting factors
binds strongly to plasma prot (99%
albumin): small vol of distribn.
Metab: hepat mixed funcn cytP450
1. haemorrhage (especially into the
brain or bowel
2. teratogenicity (not given to
pregnant mothers
reverse effects:
Low doses of vitamin K
- Fresh frozen plasma or prothrombin
complex
concentrate can be infused if a rapid
reversal
Anticoag act monitored by
International Normalised Ratio
(measures prothrombin time)
oral - Poorly absorbed
subcut: delayed 1 hour
iv: Imm onset Short t½ .
saturation kinetics (t½ inc w/ inc
dose). Anticoag act measured.
longer t½ , exhibits 1st order kinetics,
act does not require monitoring.
oral
Highly plasma protein bound
1) Bleeding
2) Thrombocytopenia
3) Osteoporosis :(assoc with long
term therapy over 3 months)
4) Hypersensitivity: chills, fever,
urticaria and even anaphylaxis
GI sensitivity
Clopidrogel
pro-drug
inhibits fibrinogen binding to glycoprotein IIb/IIIa
receptors
=In aspirin sensitive pt
Amciximab
Streptokinase
Non-enzymatic
protein.
Alteplase
recombinant
tPA.
Fibrinolytic
Antag of the glycoprotein IIb/IIIa receptor.
This is a hybrid murine/human monoclonal Ab wh/ : use in
acute coronary syndromes- in combination w/ heparin and
aspirin- to prevent ischemia in pts w/ unstable angina
Derived from culture of B-hemolytic streptococci.
Binds to plasminogen causing a conformational change
exposing the active site, causing plasmin activity.
Activated plasmin degrades fibrin.
works better on plasminogen bound to fibrn that to soluble
plasminogen in the plasma : clot sensitive. It activates
plasmin that then degrades fibrin and dissolving the clot.
Oral
Peak plasma conc: 4hrs after a single
dose but inhibitory effect on platelt
not seen until after 4 days of regular
dosing
Iv
Binds rapidly to platelets. Cleared
with platelets. Antiplatelet effect
persists for 24-48hrs
IV – 30 –60 min infusion
Bleeding
GI haemorrhage, diarrhea,
rash
In some patients neutropenia
Bleeding
May potentially be immunogenic
Bleeding
May potentially be antigenic
Rapidly cleared t1/2 12-18 mins
Iv 30min infusion
Rapidly cleared t1/2 12-18 mins
1) Acute MI
admin w/in 12h or onset of sympt dec
the mortality rate
2)Acute thrombotic stroke- w/in 3h
3)Deep vein thrombosis, pulmonary
embolus, acute
arterial thromboembolism, local
thromboembolism in
the anterior chamber of the eye.
bleeding
LIPID
LOWERING
DRUGS
“ Atherosc is an inflamm fibroploriferative disorder”
LDL:Assoc w/ atherosc and CHD events
•10% incr = 20% incin CHD. main target to prevent CHD
• risk factors: –low HDL–smoke –hypertension –diab
increase pancreatitis risk
HDL :protective effect
•lower HDL, the higher the risk
•HDL low when triglycerides high
•HDL lowered by smoking, obesity and physical inactivity
TRIGLYCERIDES: incr risk of CHD
–? low HDL and more atherogenic LDL (small dense )
•Normal triglyceride levels <200mg/dl (2.3mmol/l)
•Very high triglycerides (>1000mg/dl, 11.3mmol/l)
CHOLESTROL – A Modifyable risk factor
•USA, 37% (102 million): high(>200 mg/dL, 5.2mmol/L)1
•EUROASPIRE II, 58% pts w/ CHD had high cholesterol
(³5 mmol/L, 190 mg/dL)2
10% dec in total cholesterol:
–15% dec in CHD mort (p<0.001)
–11% dec in total mort (p<0.001)3
Statins
Simvastatin
dec LDL by 25%-35% = dec CHD morbidity/mortality
• dec in all-cause mort in 2° prevention and in cardiovasc
mort in 1° prevention
(clinical trials and regression studies)
support treatment in various pt gps: –
women –elderly –diab
dec inflamm response
Fibrates
activation of PPAR (peroxisome proliferator activated
receptors) alpha and gamma receptors
Ezetemibe
Inhibits cholesterol absorpn
Absorbed then activated as glucuronide
thiazolidinediones (glitazones) used in
diab
NON
STEROIDAL
ANTI
INFLAMMAT
ORY DRUGS
- inhibit rate limiting enzyme, cyclo-oxygenase (COX)
-inhibit synthesis of Prostanoids: no effect on the act of
preformed, pre-released or exogenously admin prostanoids
24 million prescriptions/pa in UK
Average prescribing rates, 246 scripts/1000 pop in UK
1. Analgesic (relieve pain):
•Toothache, headache, backache
-taken occasionally
•Some postoperative pain
•Dysmenorrhea (menstrual pain)
–dec fever e.g.Influenza
prostanoids: Prostaglandins and thromboxanes e.g. PGE2 –Dec inflamm e.g.Rheumatoid
Lipid mediators from arachidonic acid
arthritis •Osteoarthritis • musculo
• in most tissues •Are not stored preformed, but are made
•Soft tissue injuries (strains and
and released imm • many prostanoid receptors •many
sprains)
•Gout
actions, not all pro-inflamm:
2. Antipyretic (reduce temp)
1.Hyperalgesic (enhances sensitivity to pain):
3. Anti-inflamm:
peripheral nociceptors more sens to chemical and thermal
-high doses and long periods
stimuli wh/ cause pain
4. Closure of ductus arteriosus in the
NSAID prevents PG synthesis: prevents stimulation of PG newborn
receptors on nerve endings= Nociceptors not sensitized and 5. Prolongation of gestation and
the perception of pain is reduced = Pain relief
labour
6. Management of Familial
2.Pyretic (raises temp) by “re-setting” hypo thermostat.
Adenomatous Polyposis
stimulates hypothal neurones: inc body temp
7. Prevent Alzheimer’s dementia
Normalised temperature by correction of the hypothalamic
thermostat
NSAIDS dec raised temp
8. Aspirin: anti platelet
3. Immune and Inflamm pathways:inc prodn of proinflamm cytokines: IL-23, IL-6 –Th2 cytokines IL4, IL5
–granulocyte-macrophage colony-stimulating factor
•inhibits prodn: –Th1 cytokines such as IFNg and IL2
NSAIDS inhibit PGE2 and other prostanoids
4. Vasodilator (inc oedema): dilates precapillary arterioles
–Synergises w/ other vasodilators eg histamine and
bradykininns
•Indirectly inc perm of post-capillary venules
nsaids: dec dilatation, Red inflamm (dec oedema)
5. gastric cytoprotecn: Inhibits acid secretion and inc
mucus secretion in stomach
nsaids prevent: inc HCL = gastric ulceration
6. Modulate glomerular blood flow and Na+ and water
reabsorn in the kidney
- PGE2 enhances renal blood flow and therefore GFR
NSAIDS : red GFR = renal ischaemia, and salt and water
retention
Cox-1 made all the time •Ubiquitous •Physiological
Cox-2 •Inducible (in response to sp stimuli) by leucocytes
•pro-inflamm
• physiological funcn: –regulate ovulation, parturition
Ibuprofen
typical NSAID
inhibits COX-1 and COX-2 reversibly
(short lasting)
Celecoxib
Selectively inhibits COX-2
• less effect on the GI
–dec risk of hospitalisation for serious
GI effects
–dec need for additional drugs to
prevent GI side-effects
•No effect on nephrotoxicity
• NICE recommendations: used in pts at high risk of GI
side effects, –history of ulcers/GI bleeding –over 65
–Pts taking other drugs wh/ inc GI side-effects
–Patients needing maximal doses of NSAIDS long-term
Aspirin
Binds more to COX-1 irreversibly inhibits COX enzymes
•Acetylates an aa in active site = actions long-acting
–reversed by de novo synthesis of new cox
Physiological side effects
rofecoxib (trade name: Vioxx)
discont: inc risk of CVD if long-term
(>18 months).
therapeutic doses: irreversibly
1.Gastric irritation and ulceration: dec
cytoprotection of the stomach
2.Nephrotoxicity: dec renal blood
flow
3.Bronchospasm in sens asthmatics
4.Prolonged bleeding times due to
inhibition of platelet aggregation
Covalent binding of Aspirin confers its anti-aggregatory
property which is unique among NSAIDS
serious effects in overdose
Paracetamol
No anti-inflamm
not an NSAID
inhibits prostanoid synthesis in brain but not in periphery
•may work by inhibiting a novel isoform of cyclooxygenase (COX-3)
good analgesic for mild-to-moderate
pain
• anti-pyretic
very safe drug
overdose : irreversible liver failure
–reactive, but minor metabolite (Nacetyl-p-benzoquinoneimine)
normally safely conjugated w/
glutathione.
–If glutathione is depleted the
metabolite oxidises thiol groups of key
hepatic enzymes = cell death
DIURETICS
1) Osmotic
Mannitol
Drugs that act on the renal tubule to promote the excretion
of Na+, Cl- and H2O.
1. Inhibit reabsorpn Na+ and Cl- = promote excretion
2. Inc osmolarity of tubular fliud delivered to collecting
duct = dec osmotic gradient across the epithelia prevent
reabsorption of water
1) Hypertension
2) Salt and water overload due to
•Acute pulmonary oedema
•Chronic heart failure
•Liver cirrhosis plus ascites
•Nephrotic syndrome
•Renal failure
3)Acute hypercalcaemia
Filtered by the glomerulus but not reabsorbed
1)Inc osmolarity of tubular fluid = dec H2O reabsorpn
where the nephron is freely permeable to water, i.e. –prox
tubule –descend loop –collecting duct =Inc H2O excretion,
2)Small inc in Na+/Cl- loss
Iv
Pharmacologically inert
1) Cerebral oedema
2) Raised intraocular pressure
3) Prevent acute renal failure
Weak diuretics
on proximal tubule
1) Prevent the reabsorption of HCO3- and Na+
2) dec H2O reabsorption
+
+
Acetazolamide 3) Inc Na to distal tubule: inc K loss
4) Inc tubular fluid osmolarity : dec H2O reabsorpn in
collecting duct.
• inc urine vol , Na+, HCO3 -( an alkaline urine) K+ loss
2) Carbonic
Anhydrase
Inhibitors
3)
Loop
Frusemide
(furosemide)
Powerful diuretics – promote the excretn of 30% of the
filtered Na+ load
ascending loop
1) Inhibit co-transporter system = inhibit Na+ and Clreabsorption = dec osmolarity of the medullary interstitium
2) Assoc inhibition Ca2+ & Mg2+ reabsorption
3) Inc Na+ to distal = incr Na+/K+ exchange =inc K+ loss
4) Inc osmolarity of tubular fluid delivered to collecting
duct + dec osmolarity of the medullary interstitium =
dec H2O reabsorption
inc: urine vol •loss of Na+, Cl- and K+ •loss of Ca2+ and
Mg2+ • Hypovolaemia • Metabolic alkalosis
prompt short-lasting, powerful diuresis
•Sometimes called a ‘high ceiling’ diuretic
Glaucoma
1) Acute pulmonary oedema
2) Oedema due to heart, liver or
renal disease if refractory to other
diuretics
3)Acute treatment of hypercalcaemia
4) Hyperkalaemia
5)Acute renal failure
6)Hypertension if assoc w/ renal
failure (piretanide: gd vasodilator)
oral or i.v.
Distribution – strongly bound to
plasma proteins
Clearance – secreted into the renal
tubular fluid, excreted unchanged
Transient expansion of ECF vol and
associated hyponatraemia
Headaches, nausea and vomiting
1) K+ loss
2) Mild metabolic acidosis
3) Self-limiting action
1. Hypokalaemia
2. Metabolic alkalosis
3. Loss of Ca2+ and Mg2+
4. Hypovolaemia and hypotension,
particularly in the elderly
5. Nausea
6. Allergic reaction
7. Deafness (rare)
t ½ : – short – 1-2h
Duration – short – 3-6h max
5) Thiazides
bendrofluazide
(bendroflumet
hiazide)
early distal tubule: block electroneutral Na+/Cl- co-transp
1) Impaired reabsorpn of Na+ and Cl2) Inc Na+ late distal: inc Na+/K+ exchange, inc K+ loss
3)Dec Mg2+reabsorpn
4)Inc Ca2+ reabsorption
5)Incr osmolarity of tubular fluid entering the collecting
duct: dec epithelial osmotic gradient = impaired H20
reabsorpn = inc urine vol
a) Hypochloraemic alkalosis
b) Vasodilation
c) Inhibition of insulin secretion - diabetogenic due to
opening of K+ channels
d)Inhibition of uric acid secretion
Diazoxide nondiuretic
thiazide,
6) K+
Sparing
vasodilator and diabetogenic actions.
Weak diuretics late distal tubule block Na+/K+ exchange
max of 5% of filtered Na+ load is excreted.
1) Hypertension – initial action due to
dec blood volume but long-term
effects due to vasodilation
2) Mild heart failure
3) Severe resistant oedema
4) Prevent recurrent stone formn in
idiopathic hypercalciuria
5) Nephrogenic diabetes insipidus
(paradoxical
oral, well absorbed
Distribution –bind to plasma prot
•Clearance – compete w/ uric acid for
secretion into the renal tubule
•Excreted unchanged via the urine
•Onset of action: 1-2h
•Duration of action
–‘Short acting’ – 12-24h (e.g.
bendrofluazide)
–‘Long acting’ - >24h (e.g.
chlorthalidone
1) control K+ levels
1) Inhibit Na+ and K+ secretion in the late distal tubule
2) Inc osmolarity of tubular fluid entering the collecting
duct: reduced reabsorption of water
3) Dec H+ secretion into the tubular fluid
4) Dec uric acid secretion (competes with uric acid for
secretion into the tubular fluid)
amiloride,
Inhibitors of aldosterone-sensitive Na+ channels
1) Hypokalaemia
2) Metabolic alkalosis
3) Hyperglycaemia – exacerbation of
diabetes mellitus
4) Uric acid retention – possibility of
gout
5) Rarely. hypersensitivity reactions
(rashes, blood dyscrasias)
6) Rarely, hyponatraemia
better tolerated
–Poorly absorbed orally
–Competes with uric acid for secretion
into the renal tubule
–Slow onset of action (4-6h)
–Duration 24h
–Excreted unchanged via the urine
Spironolactone and amiloride
–Hyperkalaemia
–Metabolic acidosis
spironolactone
Aldosterone receptor antagonists
Primary and Secondary
hyperaldosteronism
–Well absorbed orally
–Promptly converted to active
metabolite, canrenone
–Onset of action slow (several days)
Actions on other steroid receptors:
•Gynaecomastia
•Menstrual disorders
•Testicular atrophy
ANTI
INFLAMMAT
ORY BOWEL
DRUGS
•Pathogenesis not completely understood
•Probably due to defective interaction between mucosal
immune system and gut flora
•2 x 1014 bacteria in gut •genetic factors are important
1. Supportive therapies
- Fluid/electrolyte replacement
- Blood transfusion/ oral iron
- Antibiotics
Immune system distinguish between pathogenic and nonpathogenic, excessive response = inflamm
2. Possible curative therapies
Treatment of symptoms:
a) treatment of active disease
-Glucocorticoids eg Prednisolone
ulcerative colitis: more common
•Th2- mediated autoimm reacn •Th2 cytokines esp IL-13
•T cell clones limited capacity to expand
•No defect in T cell apoptosis
•Confined to mucosa and submucosa •Begins in rectum
•May spread proximally, but remains confined to colon
•Inflamm is continuous
•Surgery is curative
crohns (more extensively studied)
•Th1-mediated dis •Th1 cytokines imp e.g. IFNg, TNFa
•Florid T cell expansion •Defective apoptosis of T cells
•Not confined to mucosa and submucosa
•affect any part of small or large intestine
•Inflamm may be patchy and discontinous
•Abcesses, fissures and fistulae are common
•Less responsive than UC to drugs
•May recur after resection
b) prevention of relapse or remission
- Aminosalicylates eg Mesalazine
- Immunosuppressives eg
azathioprine
3. Possible Curative Therapies:
- Anti-TNFa eg Infliximab
IBD
Inc:10 - 20 new cases/100,000 pop/yr •Peak inc 20 – 40 yr
Prev: 100 - 200 /100,000 pop •More common in women
•Inc incidence in first degree relatives
•diff between ethnic groups
•Severity of sympt depends on extent and location of dis
•rectal bleeding w/ mucous discharge, diarrhoea, abd pain,
anorexia, Wt loss, fever, other extra-GIT symptoms
•Rarely fatal, due to modern therapy, dec quality of life
Glucocorticoid
s
Prednisolone,
Fluticasone,
Powerful anti-inflamm and immunosuppressive
•Activate intracell Glucocorticoid Recept = +ve/ -ve
transcription factors
•Dec influx and activate pro-inflamm cells
Before GCs, IBD had a high mort
1) reduces/delays need for surgery
2) treatment of severe active IBD.
•However, better to use other drugs to
1)Osteoporosis :
inc osteoclast
dec osteoblast
Inc risk of Gastric ulceration - dec
prostaglandins in stomach
budesonide
Derived from
cortisol
–Dec adhesion molecules on endothelial cells and
leukocytes
–Dec synthesis of some chemokines
•Dec prodn of mediators causing signs of inflamm by dec
synthesis of: –cytokines and their receptors (IL-1, TNFa)
–Proteolytic enzymes (e.g. elastase)
–Enzymes catalysing mediator synthesis (eg COX)
–Eicosanoids (eg prostaglandins and leukotrienes)
–Nitric oxide
maintain remission
•Start w/ high dose and taper down
•Use drug with high therapeutic index
(e.g. fluticasone)
•topically •use oral or topically (fluid or foam
enemas or suppositories) wh/ is
degraded locally e.g.Budesonide
imuunosurppressive:
•Dec Ag presentn
•Dec prodn of mediators (e.g IL-2, IL-4, IFNg):
•Dec cell proliferation and clonal expansion
Suppression of HPA axis -ve fdback
on pit & hypo
2) Type II D : oppose acn of insulin;
inc gluconeogenesis
inc glycogenolysis
Hypertension: cause Na+, Cl-, water
retention,
inc receptors response to
catecholamine
3) Susceptibility to inf immunosupp
4)Skin thinning, bruising and slow
wound healing: dec connective tissue
turnover and repair
5) Muscle wasting and buffalo hump:
dec storage of G in muscle, inc
fat deposn
Aminosalicylat
es
Sulfasalazine
(first),
Mesalazine,
olsalazine
Anti-inflamm •dec synthesis of eicosanoids
•dec free radical levels •dec inflamm cytokine prodn
•Dec leukocyte infiltration
•No immunsuppress effects
• aminosalicylate = sulfasalazine: split by colonic flora
into: 5-ASA (therapeutic) and Sulfapyridine
maintain remission and prevent
relapse
5
aminosalicylic
acid (5-ASA)
Mesalazine (–33% released in upper SI, remainder in
distal ileum and colon
Absorbed: Small bowel and colon
1) Olsalazine(2x5-ASA molecules linked by azo bond)
Colon,
Metab by colonic flora and liver
2) Balsalazide ( 5-ASA linked to carrier molecule)
Colon
metab by colonic flora
Controlling absorption: = gradual release
Topical (suppositories, enemas)
•pH-dependent release capsules ( SI)
•Slow release microspheres ( small and large bowel)
Limited use in the treatment of active
IBD
Sulfapyridine causes most of the sideeffects
Azathioprine
pro-drug:
degrades
spontaneously
in vivo= active
form 6mercaptopurine
by gut flora
Immunosuppressive
interferes w/ purine biosynthesis, wh/ interferes with DNA
synthesis and cell replication
•It impairs: –cell- and Ab-mediated immune responses
–lymphocyte proliferation –mononuclear cell infiltration
–synthesis of Ab
•It enhances: –T cell apoptosis
1) Crohn’s disease
2) maintaining remission
3) May induce remission in some
cases of active disease
4) May dec glucocorticoid dose or
postpone colostomy
1)Bone marrow suppression
2) If admin w/ drugs wh/ inhibit
xanthine oxidase e.g. allopurinol, (
treatment of gout), 6 –Mercaptopurine
levels rise and blood dyscrasias may
result
Infliximab
Crohn’s: Th1-mediated autoimm response
and TNFa plays imp role in dise pathogenesis
•Anti- TNFa dec activation of TNFa receptors in gut
•Dec Prodn of cytokines, infiltration and activation of
leukocytes
•Also binds to memb assoc TNFa
•Mediates complement activation and induces cytolysis of
cells expressing TNFa
•Promotes apoptosis of activated T cells
ANTI
EMETIC
DRUGS
only when cause of the nausea/vomiting is known,
otherwise they mask the diagnosis of potentially serious
conditions, e.g. digoxin excess, diabetic ketoacidosis.
Promethazine
 comp antag at histaminergic (type H1), cholinergic
(muscarinic, M) and dopaminergic (type D2) receptors.
 Order of potency of antag act: H1> M > D2 receptors
 Acts centrally (labyrinth, NTS, vomiting centre) to block
activation of vomiting centre.
Anti Tumour
Necrosis
Factor
phenothiazine
derivative
 c.f. other phenothiazines, wh/ are used as neuroleptic
drugs, have a different order of potency with greater
antagonistic effects at D2 receptors.
 Orally , Onset of action 1-2 hrs Max effect circa 4 hrs
Duration of acn 24 hours
Metocloprami
de
dopamine
receptor
antagonist.



Order of antag potency: D2 >> H1 >>> Musc receptors
Acts centrally, especially at CTZ
Acts in the GI : -inc SM motility (oesophagus to SI
- accelerated gastric emptying
note: care must be taken with the bioavailabilty of coadministered drugs
eg.
- adsorption and effectiveness of digoxin reduced
- nutrient supply compromised; imp in DM
1) CD: Successful in pts w/ refractory
dis and fistulae
Curative rather than palliative
•iv •Very long half-life (9.5 days)
•Benefits can last for 30 wks after a
single infusion
•Most pts relapse after 8 – 12 wks
•repeat infusion every 8 weeks
•4x - 5x inc inc of TB and other inf
•not be used if evidence of sepsis (eg
an abcess): risk of septicaemia
•Worsening of heart failure
•Can be immunogenic – therefore
given with azathioprine
• used by specialists where adequate
resuscitation facilities available
because of the risk of anaphylaxis
1. Motion sickness – prophylactically,
but some benefit if taken after the
onset of nausea and vomiting
2. Disorders of labyrinth eg,
Meniere’s dis
3. Hyperemesis gravidarium
4. Pre- and post-operatively (sedative
and anti-muscarinic).
5. Relief of allergic symptoms
6. Anaphylactic emergency
7. Night sedation; insomnia







Dizziness
Tinnitus
Fatigue
Sedation (‘do not drive or operate
machinery')
Excitation in excess
Convulsions (children more
susceptible)
Antimuscarininc side-effects
Used to treat nausea and vomiting
In CNS
assoc w/:
 drowsiness
1.uraemia (severe renal failure)
 dizziness
2.radiation sickness
 anxiety
3.GI
disorders
- accelerates transit of intestinal contents (from
duodenum to ileo-coecal
valve)
 extrapyramidal
reacns; children
4.cancer chemotherapy (high doses)
more susceptible (Parkinsonian-like
eg. cisplatin (intractable vomiting)
syndrome: rigidity, tremor, motor
restlessness)
orally / i.v.; rapidly absorbed;
note: No anti-psychotic actions
extensive first pass metabolism
In the endocrine system
crosses BBB, placenta
 hyperprolactinaemia
 galactorrhoea

disorders of menstruation
Hyoscine, antimuscarinic drug


Ondansetron,
5HT3 receptor
antagonist
Order of antagonistic potency: Muscarinic >>>D2 = H1
receptors
Acts centrally, especially in the vestibular nuclei, NTS,
vomiting centre to block activation of vomiting centre.
Atropine is less effective
orally (peak effect in 1-2 hours), i.v.,
transdermally
Acts to block transmission in visceral afferents and CTZ.
1. prevent anticancer drug-induced
vomiting, esp cisplatin
2.radiotherapy-induced sickness
3.post-operative nausea and vomiting
orally; well absorbed, excreted in urine
ANTI ULCER
DRUGS
1.Prevention of motion sickness
2.Has little effects once nausea/emesis
is established
3.In operative pre-medication
integrity of GI mucosal barrier is imp: to maintain a dis
free state.
protective factors lubricate ingested food and protect
stomach from attack by acid and enzymes:
1.mucus from gastric mucosa creates GI mucosal barrier
2.hco3- ions trapped in mucus generate a pH of 6-7 at
mucosal surface
3.locally prod prostaglandins stimulate mucus and HCO3prodn (paracrine action) and inhibit gastric acid secretion
factors wh/ convert food into a thick semi-liquid paste
(chyme) have potential to damage the mucosal barrier:
1.acid secretion from parietal cells of the oxyntic glands in
the gastric mucosa
2.pepsinogens from chief cells wh/ can erode mucus layer
imbalance of the protective and damaging factors:
peptic, duodenal and gastric ulcer disease
helicobacter pylori inf= damage to mucosal GI barrier
–inc acid and/or dec HCO3- prodn
–dec thickness of mucus layer
–inc pepsin type I
–decr mucosal blood flow cause: not fully understood
risk factors: genetic predisposition, stress, smoking
prevalence: 1:10 of the pop in dev countries
eliminate cause of mucosal damage
- promote ulcer healing
- gastric ulcers
duodenal ulcers
Typical anti-muscarinic side-effects:
 drowsiness
 dry mouth,
 cycloplegia
 mydriasis
 constipation (not usually at antiemetic doses)



headache
sensation of flushing and warmth
increased large bowel transit time
(constipation)
•gastroesophageal disease (gerd)
stomach and duodenal contents reflux into oesophagus
(oesophagitis)
- occasional and uncomplicated gerd
- heart burn, may treat by self medication w/ antacids and
h2 antag
- progress to premalignant mucosal cells and potentially
oesophageal adenocarcinoma
•treat w/ PPIs (drugs of choice) or H2
antag (less effective)
•combine w/ drugs that inc gastric
motility and emptying of the stomach
eg. DA2 receptor
antag(metoclopramide
A)
antibiotics
eliminate
helicobacter
pylori (gram
-ve bacterium
–50-80% pop worldwide are chronically inf (low grade inf
cause gastritis)
–10-20% develop peptic ulcer dis or neoplasia
(mechanisms unknown - genetic/virulence of strain)
–100% of pts w/ duodenal ulcer and 80-90% with gastric
ulcer are infected
•compliance
•dev of resistance
•adverse response to alcohol,
especially with metronidazole
(interferes with alcohol metabolism
•risk factors for acquiring infection–unknown
•methods of transmission – uncertain
–socioeconomic condns
–contact with animals and contaminated faeces
•success of eradication (aim for 90% eradication within 714 days)
–inf may be difficult to eradicate
–if eradication is part of treatment recurrence of duodenal
ulcer after healing falls from 80% to 5%
eg2
1)h2 receptor
antag
2)
clarithromycin
3) bismuth
B) inhibitors
of gastric acid
secretion
1. omeprazole,
proton pump
inhibitors
triple therapy” best practice in treating peptic ulcer :
single not effective, dev resistance
1) metronidazole (active against anaerobic bact and
protozoa) or amoxycillin (broad spectrum antibiotic),
depending on pattern of local resistance
2) clarithromycin AB w/ a macrolide structure; inhibits
translocation of bacterial tRNA)
3) proton pump inhibitor (ppi) :–improves AB efficiency
by inc gastric ph which improves stability and absorption
inhibit basal and stimulated gastric acid secretion from the
parietal cell by >90%
1–triple therapy
2–peptic ulcers resis to h2 antag
3–reflux oesophagitis
• irreversible inhibitors of the h+/k+ atpase
•oral ; as enteric coated slow-release
• inactive at neutral ph
•weak base: accumulates in the cannaliculi of parietal cells; formulations
concentrates its action there and prolongs its duration of
action (2-3 days) and minimises its effect on ion pumps
elsewhere in the body
rare
•oral , well absorbed
less effective at healing ulcers than
ppis
2. cimetidine,
ranitidine
histamine type
2 recep antag
3.
antimuscarinic
inhibit gastric acid secretion by approximately 60%
C)
cytoprotective
enhance mucosal protection mechanisms and/or build a
physical barrier over the ulcer
1. sucralfate
polymer
containing
aluminium
hydroxide and
sucrose octasulphate
acquires a strong -ve charge in acid environment
•binds to positively charged groups in large molecules
(proteins, glycoproteins) resulting in gel-like complexes
•these coat and protect the ulcer, limit h+ diffusion and
pepsin degradation of mucus
•inc pg, mucus and hco3- secretion and red h. pylori
oral
remains in g.i.t
2. bismuth
chelate
acts like sucralfate
used in triple therapy (resistant cases)
3. misoprostol
stable
prostaglandin
analogue
mimics acn of locally produced pg to maintain the
gastroduodenal mucosal barrier
4. antacids
DRUGS OF
ABUSE
• - rare
•relapses likely after withdrawal of
treatment
little use as anti-ulcer drugs
co-prescribed with oral nsaids when used chronically
•nsaids block the cox enzyme required for pg synthesis
from arachidonic acid therefore, reduction in the natural
factors that inhibit gastric acid secretion and stimulate
mucus and hco3- prodn
mainly salts of al3+ and mg2+
•neutralises acid, raises gastric ph, reduces pepsin activity
1)Narcotics/Painkillers – opiate like drugs e.g. heroin
2) Depressants – ‘downers’
e.g. alcohol, benzodiazepines (valium), barbiturates
3) Simulants – ‘uppers’
e.g. cocaine, amphetamine (‘speed’), caffeine
metamphetamine (‘crystal meth’)
4)Miscellaneous – e.g. Cannabis, Ecstasy (MDMA)
• constipation
•reduces absorption of some other
drugs (eg. antibiotics and digoxin
•diarrhoea, abdominal cramps, uterine
contractions
•do not use in pregnancy
• non-ulcer dyspepsia
effective in dec duodenal ulcer
recurrence rates
 Snort’ – Mucous membranes of
nasal sinuses, Slow absorption
 Eat’ – GI tract, Very slow
 ‘Smoke’ – Small airways and
alveoli ; Rapid apsorption
 Inject’ – Veins ; Rapid
Mesolimbic dopamine system – Central ‘reward’ pathway
Ventral tegmental area → Nucleus Accumbens
(VTA)
(NAcc)
NAcc → Dopamine = Reward (End pt for drugs of abuse)
→ Oral < Intranasal < Intravenous <
Inhalational
Cannabis
Cannabis/Marijuana; Hashish/Resin; Hash Oil –
Main active
ingredient that
acts on thbrain
<>9-THC
(Tetrahydrocan
nabinol):
Dronabinol
Nabilone
CB1 receptors- brain: Hippocampus/cerebellum/cerebral
cortex /basal ganglia
D9-THC +
CBD:
Sativex
Cannabis Sativa
= <>9-THC
(inc potency)
Cocaine
Erythroxylum
coca
CB2 receptors - periphery:Immune cells ; Endogenous
Anandamide
Pharmacodynamics :
1. Psychosis, Schizophrenia!!
2. Food intake – Hypothalamus
3. Memory loss – Limbic regions
4. Psychomotor performance – Cerebral cortex
5. Peripheral effects;
6. Immunosuppressant
7. Tachycardia/vasodilation
 Paste’~ 80% (Cocaine sulphate) Extracted using an
organic solvent. Impure!
Iv, oral, intranasal: absorbed
through mucous memb lining the sinuses = slower
absorption - 100–500 ng/mL.
 Cocaine HCl – Passed through an acidic aqueous
solution (HCl); the solution is neutralized and the
cocaine is extracted by recrystalization. heat labile.
Iv( rapid absorp), oral, intranasal
 Crack –precipitate out cocaine using an alkaline solution
(e.g. sodium bicarbonate). Inhalation: rapid absorption
plasma concentration = 500–1000 ng/mL.
 Cocaine freebase - dissolve in a non-polar solvent e.g.
diethyl ether. inhalation
reward pathway: Inhibit reuptake of dopamine in NAcc.
neuropharmacology: blocks plasma memb transporter for
dopamine (DA) (and has less potent effects on the
norepinephrine (NE), and serotonin (5HT) transporters).
Local anaesthetic effect – blocks sodium channels
Pharmacokinetics;
Inhalation – 50% Oral – 10-15%
Onset = Seconds - Minutes
Tissue t1/2 = 7 days
Metabolised:
Liver - 11-hydroxy-THC
Excreted: GIT – 65% Urine – 25%
Inc regulation of CB receptors:
1)Multiple
sclerosis/pain/schizophrenia –
regulatory
2)Fertility/obesity/stroke – pathology
‘Autoprotection’ – Dronabinol,
Sativex
‘Autoimpairment’ - Rimonabant
75-90% - ecgonine methyl ester
benzoylecgonine - liver
Onset = Seconds
T1/2 - 20-90min
renally excreted.
1)Cardio: MI
Inc symp:
Platelet aggregation: vasoconstriction
And inc HR
2) dec in cerebral blood flow
3)inflammation in the walls of the
brain vessels (vasculitis).
Nicotine
Volatile: (95%) Nitrogen, Carbon Monoxide/Dioxide,
Benzene, Hydrogen Cyanide
Particulate: (5%) Alkaloids, Tar
Pharmacodynamics
Low dose – Symp via peripheral receptors (or direct effect
on brain) → ↑ HR and BP.
Higher doses - Binds to nicotinic receptors. Ganglionic
stimulation and catecholamine release from adrenals.
Very high dose – Ganglionic block and vagal stimulation.
Effects on reward pathway:
nicotinic located somatodendritically on dopaminergic
VTA neurones – directly ↑ firing rate.
Chronic smokers – Plasma nicotine levels between 2040ng/ml
 Nicotine spray – 1mg20-50%
Particulate droplets reach the small
airways and alveoli. Rapid absorption
from the lung (faster than i.v.).
Distributes rapidly to different tissues,
incl the brain (within 10-20s).
 Nicotine Gum – 2-4mg
50-70%
 Cigarettes – 6-11mg
20%
 Nicotine Patch – 15-22mg/day 70%
Hepatic CYP2A6: 70-80% to conitine
(lung and brain)
Elimination half life – 2-3h.
Onset = Seconds
Tissue t1/2 = 2-3h
CVS effects:
↑ blood coagulation.
↑ myocardial work: inc HR and SV
↓ oxygen carrying capacity of blood
(due to carbon monoxide)
Coronary and peripheral
vasoconstriction
↑ LDL and VLDL, FFA and ↓ HDL
↑ risk for atherosclerosis,
myocardial infarction, cardiovascular
disease
Metabolic effects:
↑ metabolic rate
↓ appetite
lipolysis, FFA, VLDL, dec HDL, Inc
TXA2, dec NO
Parkinson’s; - brain CYPs
Alzheimer’s: dec b-amyloid toxicity
Dec amyloid precursor protein (APP)
Endocrine: ↑ACTH/cortisol
OPIATES
AND OPIODS
alkaloid derived from the poppy, Papaver somniferum
specific ‘opioid’ receptors used by the endogenous opioid
peptides:
–Endorphins –Enkephalins –Dynorphins/neoendorphins
Located CNS: Presynaptic inhibitory function G-protein
•Activation = dec cAMP
Three main types u, k and d
1.analgesia: •Dec pain perception •Inc pain tolerance
2.Depression of respiration (medulla)
3.Sedation
4.Euphoria
5. Dysphoria
6.Depression of cough centre (anti-tussive)
7.Stimulation of chemoreceptor trigger zone
•They are used clinically as analgesics
•They are potentially fatal in overdose
•They are drugs of abuse
•Morphine
•Heroin
•Codeine
•Methadone
••Naloxone - antagonist•
tolerance
–Pharmacokinetic – not a problem
––Tissue tolerance – principal cause
dependence–Withdrawal assoc w/
•Psychological craving
•Physical withdrawal (like flu)
–Rarely occurs in pts taking morphine
long-term for analgesia
Receptor-selective ligands do not
differentiate between the wanted and
unwanted effects of opioids
Overdose:
1. Coma
(nausea/vomiting)
8.Stimulation of the oculomotor nucleus = miosis
9.GI tract: dec gastric emptying, decGI motility, inc water
absorpn = constipation
10. inc histamine release; Suppression of medulla
=dec BP
2. Respiratory depression
3. Pin-point pupils
4. Hypotension
Treatment: Naloxone (opioid
antagonist) i.v.
Morphine
Acute or chronic pain
• oral (high first pass), i.m. or i.v.
•Distribution: wide
•Metab: hepatic – conjugation
•Duration: - 3-6 h
Heroin
(diamorphine)
Similar to morphine but–
Enters brain more quickly = greater ‘rush’
–Shorter acting
Codeine
(3-Methyl
Morphine)
1. Mild pain (weak analgesic vs. morphine)
2. Anti-tussive at sub-analgesic doses
Oral, converted to morphine
Causes severe constipation
Pethidine
(Meperidone)
Weak agonist
Used in obstetrics as excreted without conjugation
orally or i.m.
Methadone
•Weak agonist •Little euphoric action
•Used in chronic pain and substitution therapy
orally,
long duration of action (24h)
Fantanyl
•Highly potent, u –selective
•Used in anaesthesia (intra-thecally) also in acute pain
i.v., epidurally or transdermally
Short-acting
ADDICTION
AND
COMPULSIV
E
BEHAVIOUR
GP 200 pts suffer
• 1/5 hospital beds alcohol related conditions.
• 50% in An E in the evenings or at weekends probs assoc
w/ alcohol or drugs
Addictive substances and processes are a significant
contributory factor to many major illnesses.
1. Cancer of the lung: nicotine addiction.
2. Heart attacks: nicotine addiction, alcoholism,
compulsive overeating, drug addiction.
3. Liver disease: alcoholism, compulsive overeating, drug
addiction.
Dis of human spirit
• Abstinence = ‘dry drunk’
• affects abstract qualities such as
syndrome: mood disturbance and the
hope, trust, beauty, honour, innocence. resulting blame and self-pity.
These are not intellectual
characteristics. The disease of the
• mood altering process of reaching
human spirit requires the spiritual
out to help others within the
treatment of the Twelve Step
Anonymous Fellowships. A.A. is the
Programme.
primary treatment, not an add-on
extra.When A reaches out to help B
• Given appropriate continuing
anonymously it is A who feels better.
treatment, the mood disorder resolves •
4. Accidents: alcoholism, drug addiction
5. Diabetes: compulsive overeating.
and the long term consequences are
avoided.
• Emotional probs factor to the body/mind
interrelationship and affect a wide range of clinical
conditions. managed by doctor rather than referred to
psychiatrists or counsellors.
• In GP, 20% of all consultations are primarily emotional.
is primarily a disease of feeling rather than of thought.
• From one of the most devastating
clinical conditions of all, patients can
get into full remission provided that
they continue the spiritual treatment
on a daily basis.
Assessing ‘why?’
– Preoccupation.
– Use alone.
– Use primarily for mood altering effect.
– Use as a medicine.
– Protection of supply.
– Using more than planned.
– Higher capacity than others.
– Continuing despite damage.
– The tendency to cross addict.
– Drug seeking behaviour.
– Drug dependent behaviour.
– Continuing despite repeated concern of
others.
consequences
– Emotional.
– Behavioural.
– Social.
– Marital.
– Professional.
– Intellectual.
– Educational.
– Financial.
– Legal.
– Spiritual.
– Physical.
Shorter PROMIS Questionnaire: addicts to be
distinguished from the normal pop and medical students.
• same ten questions are asked on sixteen different
• An addictive nature is a chronic
illness and therefore requires life-long
treatment by attending an appropriate
Anonymous Fellowship and working
the Twelve Step Programme.
Inappropriate treatments:
• Medicinal treatment (antidepressants, tranquilisers, sleeping
tablets, mood altering painkillers,
Methadone etc): alternative
addictions.
• Naltrexone and other antieuphoriants, or antabuse and other
deterrents,
• Psychotherapy as an adjunct to the
Twelve Step Programme.
Emotional trauma does not appear to
lead to addictive behaviour in the
absence of genetic predisposition
(assumed from the Shorter PROMIS
Questionnaire).
• Inpatient or outpatient treatment in
a Minnesota Method (Twelve Step)
Treatment Centre may be helpful if
patients find it impossible to maintain
recovery in the community.
Research:
• Project MATCH compare the long
term outcome of alcoholic patients
treated with Cognitive Behavioural
Therapy, Motivational Therapy and
Twelve Step approaches.
The initial results: all 3 equally
successful but
addictive behaviours. Answers given on a range 0- 5,
depending upon relevance and intensity.
• The clinical cut-off point is a score of 20 out of 50 on
any individual outlet.
Clusters of addictive behaviour
1. Hedonistic’: alcohol, recreational drugs, prescription
drugs (antidepressants, tranquilisers, sleeping tablets and
mood altering pain killers), nicotine, caffeine, gambling
and risk taking, sex and love addiction.
2. Nurturant of self: food (binging, vomiting, starving,
purging) stimulated primarily by refined carbohydrates
(sugar and white flour), exercise, work, shopping and
spending.
3. Relationship addiction (using other people as if they
were drugs) and compulsive helping (using oneself as a
drug for other people).
• indicates spread of someone’s addictive behaviour
• Pts need to be abstinent from all addictive substances
and behaviours in a cluster
a genetic predisposition. Perhaps each addictive cluster is
determined by a separate gene.
• evolutionary advantage of a hedonistic gene
• all addictive behaviour originates in a defect in the
neurotransmission systems in the mood centres of brain.
• Pts discover for themselves the mood altering effects.
The inner sense of emptiness (involutional melancholia)
should be distinguished from sadness, (which is a response
to distressing circumstances) and is relieved so that
patients feel normal when they take a mood altering
substance or process. The effect wears off in time and
therefore the process is repeated.
i) all therapy was given 1 to 1 but
Twelve Step approaches are
essentially a group process.
ii) some patients in the CBT and
ME groups also went to AA
Dual diag:
• Depression and addiction are
synonymous and should not be
treated medicinally.
• Sadness is a normal human
response to distressing circumstances
and should also not be treated
medicinally.
• Attention Deficit Hyperactivity
Disorder (ADHD) early signs of an
addictive nature. Current
recommended treatment is with
Ritalin (an amphetamine). Cocaine
or Heroin would probably be equally
effective and equally damaging.
• Compulsive helping is the mirror
image of primary addiction.
• The addict wants to be fixed and the
addictive behaviours are blame and
self-pity.
• The compulsive helper needs to be
needed and the addictive behaviours
are care-taking (far beyond normal
helping) and self denial.
• The two fit together in a mutually
destructive relationship.
• Professional helpers need to
understand the boundaries between
normal helping and compulsive
helping so that they do not make
matters worse.
• Addicts need to be confronted
(politely and with understanding for
their illness) on their behaviour and
not enabled to carry on with it
without getting the consequences.
ADVERSE
DRUG
REACTIONS
AND
INTERACTIO
NS:
Classify;
A) Onset
 Acute: Within 1 hour
 Sub-acute: 1 to 24 hours
 Latent : > 2 days
B) Severity
 Mild: requires no change in therapy
 Moderate: requires change in therapy, additional
treatment, hospitalisation
 Severe: disabling or life-threatening , = death
Requires or prolongs hospitalization, Causes disability
Causes congenital anomalies, Requires intervention to
prevent permanent injury
C)Type
A Augmented pharmacological effect
• extension of pharmacologic effect
• usually predictable and dose dependent
• responsible for at least two-thirds of ADRs
• e.g., atenolol and heart block, anticholinergics and dry
mouth, NSAIDS and peptic ulcer
B
•
•
•
Bizarre: idiosyncratic or immunologic reactions
includes allergy and “pseudoallergy”
rare (even very rare) and unpredictable
e.g., chloramphenicol and aplastic anemia,
ACE inhibitors and angioedema
Epidem
 substantial morb and mort
 incidence vary w/ study methods,
population, and ADR definition
 4th to 6th leading cause of death
among hospitalized patients*
 6.7% inc of serious ADRs*
 0.3% to 7% of all hosp admiss
 annual costs in the billions (?$120
billion in US)
30% to 60% are preventable
1.
2.
3.
4.
5.
6.
7.
8.
Causes:
Antibiotics
Antineoplastics*
Anticoagulants
Cardiovascular drugs*
Hypoglycemics
Antihypertensives
NSAID/Analgesics*
CNS drugs*
•
•
–
–
•
•
Detection:
Subjective report: pt complaint
Objective report:
direct observation of event
abnormal findings
physical examination
laboratory test
C
Chronic: assoc with long-term use
• involves dose accumulation
• e.g., methotrexate and liver fibrosis, antimalarials and
ocular toxicity
• diagnostic procedure
yellow card scheme
• 1964 after thalidomide
• run by the Committee on Safety of
D
Delayed: delayed effects (largely dose independent) Medicines (part of the
• carcinogenicity (e.g. immunosuppressants)
Medicines Control Agency)
• teratogenicity (e.g. thalidomide)
• entirely voluntary
• used by docs, dentists, nurses,
E
End-of-treatment
coroners and pharmacists
• includes blood products, vaccines,
 Withdrawal reacn: Opiates, benzodiazepines,
contrast media
corticosteroids
• for established drugs only report
 Rebound reactions: Clonidine, B-block, corticosteroids
serious adverse reactions
 “Adaptive” reactions: Neuroleptics (major
(fatal, life-threatening, needing
tranquillisers)
hospital admission, disabling)
• for “black triangle “ drugs (newly
 allergic reactions
licensed, usually <2 years)
• Type I - immediate, anaphylactic (IgE)
report any suspected adverse
e.g., anaphylaxis with penicillins
• Type II - cytotoxic antibody (IgG, IgM)
Incidence of drug drug interactons:
e.g., methyldopa and hemolytic anemia
• True incidence difficult
• Type III - serum sickness (IgG, IgM)
• Data for drug-related hospital
antigen-antibody complex
admissions do not separate out drug
e.g., procainamide-induced lupus
interactions, focus on ADRs
• Type IV - delayed hypersensitivity (T cell)
• Lack of availability of
e.g., contact dermatitis
comprehensive databases
• Difficulty in assessing OTC and
pseudoallergies:
herbal drug therapy use
Aspirin/NSAIDs – bronchospasm
• Difficulty in determining
ACE inhibitors – cough/angioedema
contribution of drug interaction in
complicated patients
• Sometimes principal cause of
ADRs with specific drugs
drug interactions:
eg statins
A)Pharmacodynamic
drug’s effects in the body
• Receptor site occupancy
– Synergistic actions of antibiotics
– Overlapping toxicities - ethanol & benzodiazepines
– Antagonistic effects - anticholinergic medications
(amitriptyline and acetylcholinesterase inhibitors)
Deliberate interactions:
• levodopa + carbidopa
• ACE inhibitors + thiazides
• penicillins + gentamicin
•
B) Pharmacokinetic
body’s effects on the drug
i)Absorption,
• Chelation
– Irreversible binding of drugs in the GI tract
– Tetracyclines, quinolone antibiotics - ferrous sulfate
(Fe+2), antacids (Al+3, Ca+2, Mg+2), dairy products
(Ca+2)
ii) Protein binding effects
• Comp for protein or tissue binding sites
– Inc in free (unbound) conc = inc pharmacological effect
• Many interactions previously thought to be PB
interactions, were found to be primarily metabolism
interactions
• PB interactions are not usually clinically significant
but a few are (with warfarin)
iii)Changes in drug metabolism
Phase 1 and 2
• inhibited or enhanced by coadmin of other drugs
• CYP 450 system has been the most extensively studied
– CYP3A4, CYP2D6, CYP1A2, CYP2B6, CYP2C9,
CYP2C19 and others
• Phase 2 metabolic interactions (glucuronidation, etc.)
occur, research in this area is increasing
Cyp450 subs:
• Metabolism by a single isozyme (predominantly)
– Few egs of clinically used drugs
– Egs of drugs used primarily in research
• Metabolism by multiple isozymes
• Imipramine: CYP2D6, CYP1A2, CYP3A4, CYP2C19
– If co-admin with CYP450 inhibitor, some isozymes may
“pick up slack” for inhibited isozyme
Cyp450 inhibitors: very rapid
– Cimetidine, Erythromycin, Ketoconazole, Ciprofloxacin
– Ritonavir etc, Fluoxetine etc, Grapefruit juice
salbutamol + ipratropium
Cyp450 inducers: takes hours/days
– Rifampicin Carbamazepine (Phenobarbitone)
– (Phenytoin) St John’s wort (hypericin)
vi) Alteration in elimination: renal tubule
- probenecid and penicillin (good)
- lithium and thiazides (bad)
• Pharmaceutical
- drugs interacting outside the body (mostly
IV infusions)
ALCOHOL
ethanol
(c2h5oh)
soluble in water
i.e. mix with
water & drink
% ABV x 0.78 = g alcohol/100ml (abv = alcohol by
volume)
absolute amount of alcohol in a drink can be calculated
1 unit = 10ml or 8g of absolute alcohol
1 unit = ½ pint/1 glass of wine/single measure spirits
nb – no consistency!!
longer carbon
chain = inc lipid
solubility = inc
potency
sniffed
%abv x volume (ml) / 1000
number of units in a given volume of beverage
methanol is too
dangerous
safe?
men < 21 units/week
women < 14 units/week
-exceed these levels – 27% men & 13% women (-)
Uncharged and
\highly lipid
soluble
Rapidly
absorbed from
the mucous
membranes of
the stomach and
gut (Slowed by
First-pass hepatic metabolism i.e.
rapidly cleared from portal vein blood
However, saturation kinetics at low
alcohol concentrations
= rapid absorption (e.g. empty
stomach/drinking games!)
= high portal vein conc
=liver enzyme saturation
=ethanol escapes into systemic
circulation
approx 400,000 people in uk with alcohol related problems
(5% men, 2% women)
impt. – alcohol has low pharmacological potency = large
amounts required to produce effects and little selectivity
minimal effects at 20-40mg/100ml (10-20 x can be lethal)
however;
effects generally occur between 40-100mg/100ml
General
5-10% excreted unchanged in the
urine (variable) and expired air
(constant) - breathalyser test
(80mg/ml blood @ 35mg/100ml
expired air)
Current research;
Phosphatidyl ethanol (PEth) –
Detectable in blood for 3 wks
(3 units/day)
Fatty acid ethyl esters (FAEEs) –Long
term detection in hair. Can distinguish
between light and heavy drinkers
hangover:
1. nausea: alcohol irritates the
stomach lining → vagus and
sympathetic stimulation → vomiting
center of the medulla
2. headache: vasodilation effect of
alcohol → ↑ pressure in the cranial
cavity. (may also ↑ histamine and
serotonin levels
3. fatigue: major cause = sleep
deprivation. "rebound effect" → lose
depressive effect as BAC (blood
alcohol conc) ↓ = overstimulation
4. minor cause = alcohol ↓ blood
sugar levels
5. restlessness and muscle tremors:
cns excitation exists during the
hangover phase e.g. tremors, ↑ h.r.,
and ↑ bp
6. polyuria and polydipsea ↓ ADH
secretion
symptoms commence hrs after the last
ingestion of alcohol (peak as BAC →
0)
cause:
food)
Rapidly
distributed
throughout
body water
(dependent on
tissue blood
flow)
Depressant effect (primary effect ) (cns agitation)
degree of cns excitability: environment, personality
a)non-social – excitation ↓ \ sedation/drowsiness
b)social setting – huge sensory input. loss of inhibition
enhances effects
A) cns effects: acute
1. complex = relationship between behaviour of cells and
organ as a whole is unclear
2.ethanol has low potency = low selectivity and = all
regions of cns are affected
Theories
 inc gaba inhibition (- cl- flux)(?? sedative/anxiolytic
effects)
 inhibit ca2+ entry through voltage gated ca2+ channels
 (inhibits transmitter release)
 inhibit NMDA receptor function (dec effect of
glutamate)(?? loss of memory – amnestic effects)
 enhance 5-HT-meditated effects
 (?? mood control, inhibition of pain pathway,
hallucinogenic)
 cortical region : impairs –
(a) sensory function i.e. mood changes e.g. inc self
confidence, euphoria, dec powers of discrimination and
concentration, memory loss
(b) motor function i.e. slurred speech, prolonged reaction
time, loss of coordination
 corpus collosum - passes info from left brain (rules,
logic)
 to R (impulse, feelings) and vice versa.
 hippocampus - memory.
 hypothalamus - controls appetite, emotions,
temperature,
 and pain sensation.
 cerebellum - controls movement and coordination
 basal ganglia – perception of time
blood levels –
- likelihood of car accident
20-40mg/ml (minimal effects
50mg/ml
80mg/ml (legal driving limit) x 4
up to 150mg/ml (90% - gross
intoxication)
x 25
300mg/ml (coma – via reticular
activating region)
4-500mg/ml (death –depression of
resp control center)
beneficial effects –
2. dec mortality from coronary artery
disease (men 2-4 units/day);
3. inc HDL
3. inc tPA levels /dec platelet
aggregation (i.e. antithrombotic
effects)
(nb presence of polyphenols in red
wine may produce superior effect)
1.dehydration – liver/kidney need
water to process alcohol
2.toxic metabolites – direct effects
3.sleep deprivation
4.congeners – toxic effects
cure: don’t drink!! replace
water/vitamins; bed rest
pharmacological intervention =
disulfiram (aversion therapy)
inhibits aldehyde dehydrogenase 
acetaldehyde accumulation
high levels of acetaldehyde 
flushing, tachycardia,
hyperventilation, panic/distress
useful in discouraging recovering
alcoholics from drinking (no ffect
without alcohol present)
genetic polymorphisms (within asian
population);
common variation in enzyme aldehyde
dehydrogenase = alcohol intolerance
rarer variation in enzyme alcohol
dehydrogenase = prone to alcoholism
tolerance to effects of ethanol occurs
rapidly (1-3 weeks with continuing
ethanol administration)
due to: pharmacokinetic tolerance,
tissue tolerance
cellular adaptation, ?? others
dependence = overpowering craving
for alcohol
physical withdrawal characterized by;
tremor, hallucinations, convulsions,
behaviour disturbances, nausea, fever
 reticular activating system – consciousness
chronic effects –
1. dementia – cortical atrophy/dec vol cerebral white
matter
2. ataxia – cerebellar cortex degeneration
3. wernicke-korsakoff syndrome (thiamine def)
4. wernicke’s encephalopathy(degeneration in structures
around 3rd ventricle & aqueduct): confusion, eye
signs, ataxia
6. korsakoff’s psychosis - memory impairment –
8. (changes in dorsomedial thalamus)
9. sensory-motor peripheral neuropathy – affects lower
limbs
B) liver: chronic
alcohol = hydrogen and acetaldehyde
= impairment = mitochondrial fatty acid oxidation
triacylglycerol
glycerol + = /
cell
(adipose tissue)=blood= fatty acids
mitochondria
=
triacylglycerol
hepatitis: – blood + hepatic cytokine changes
(e.g. - il-6 and tnf-a)
liver tissue regenerates after alcohol induced damage
cirrhosis: hepatocytes cannot regenerate fast enough!
fibroblasts (connective tissue cells) overproduce
= dec in active liver tissue
 fat accumulation (fatty liver)  liver inflammation
(hepatitis)  irreversible hepatic necrosis/fibrosis
(cirrhosis)
(diversion of portal blood flow around fibrotic liver can
cause oesophageal varices to develop which can bleed
suddenley and catastrophically)
cause -
 release of fatty acids from adipose tissue
(due to  sympathetic discharge)
impaired fatty acid oxidation (due to metabolic load
imposed by alcohol)
contributory factor = chronic malnutrition
C) cardio- acute:
1. cutaneous vasodilation: i.e flushing (causes warm
feeling but - heat loss)
2. central depression of sympathetic outflow
chronic:
 atrial arrythmias; prolong conduction times and
heterogeneous inc in refractory period, acute negative
inotropic effect mediated by direct interaction with cardiac
muscle cells
 alcoholic cardiomyopathy: myocyte and nuclear
hypertrophy, interstitial fibrosis, and myocyte necrosis
D) gi tract: acute–
 inc salivary and gastric acid secretions
reflex –
 taste - salivary secretions
 irritant effect i.e. - histamine release ® - hcl
 (nb may be due to fermentation products)
 stimulation of sensory nerve endings
chronic: direct effect damaging the gastric mucosa ( prop
to dose)
inc gastric bleeding (?? gastritis or gastric ulcers)
E) endocrine: acute–
dec vasopressin: direct effect at hypo = polyuria (i.e.
diuresis) \water & electrolyte loss = dehydration
(hangover!!)
chronic– inc acth /impairment of hydrocortisone
metabolism = pseudo-cushing’s syndrome (e.g. fat
redistribution) - direct action at anterior pituitary
- dec testosterone secretion/ inc inactivation
= feminisation/impotence
(impaired testicular steroid synthesis, enhanced
testosterone inactivation by liver enzymes)
F) lipid metabolism/platelet formation – in small doses
-  thrombosis formation  risk of atherosclerosis/
ischaemic heart disease
cause -  hdl   cholesterol esterification   plaque
formation
 thromboxane a2  platelet aggregation
G) foetal development –
foetal alcohol syndrome; (mothers drink at least 4
units/day)
abnormal facial development (+ other anatomical abnorms)
growth retardation, mental retardation
(smaller degrees of ethanol-related abnormality may occur
very frequently)
cause - inhibition if cell division/migration??
GABA-ERGIC
TRANSMISSI
ON
•gaba (γ-aminobutyric acid), glycine = neutral aa inhibitory i) motor activity [cortex, cerebellum,
•glutamate, aspartate = acidic aa excitatory
cord]
(l-homocysteate?)
ii)extrapyramidal activity [basal
ganglia]
distribution: cortex, cerebellum, Hippocampus, corpus
iii) emotional behaviour [limbic
striatum, hypothalamus
system]
Ø
dorsal horn of sp. cord
v) endocrine function [hypothalamus]
Ø
little in pns
•most neurones respond (» 30% of synapses)
•short inhibitory interneurones
•some longer tracts (striato-nigral;cerebellar)
widespread inhibitory action in cns (both pre and post
synaptic)
neurotransmission
1) synthesis: glutamate = (gad) = gaba
•gad immunohistochemical labelling
2) storage & release: nerve terminals (vesicles), exocytosis
3) receptors: gabaa & gabab
4) inactivation: reuptake (neuronal & glial)
na+ - dependent; energy dependent; saturable
5) metabolism:
GABA= gaba-t = succinic semialdehyde =
SS Dehydrgoenase = Succinic Acid
mitochondrial enzymes
inhibitors of gaba metabolism: large inc brain gaba - eg
•sodium valproate (epilim) – both gaba-t and SSDH
•vigabatrin (sabril): gaba-t
gabaa receptors: postsynaptic
•cellular moa: Cl-, hyperpolarisation(IPSP), inhibit firing
•agonists: gaba, muscimol, benzodiazepines, barbiturate
•antagonists: bicuculline (competitive)
picrotoxin (non-competitive)
Øconvulsants
Ø important experimental tools
gabab receptors: presynaptic
•inhibit NT release: autoreceptors, heteroreceptors
(dec DA release)
•cellular moa: g-protein-linked, dec ca2+ conductance,
= dec NT release
/ inc k+ conductance = hyperpolarisation
•agonists: gaba, baclofen muscle relaxant (sp. cord) =
spasmolytic drug
•antagonists: phaclofen, saclofen (competitive)
ANXIOLYTIC
S,
SEDATIVES
AND
HYPNOTICS
bzs & barbs
:-i)no activity alone (allosteric action)
ii)different binding sites and different mechanisms
Ø bzs - frequency of openings
Ø barbs - duration of openings
7. naesthetics (barbs only :
thiopentone)
2. anticonvulsants (diazepam;
clonazepam; phenobarbital)
3.anti-spastics (diazepam)
iii)barbs less selective than bzs
dec excitatory transmission
other membrane effects
= may explain: induction of surgical anaesthesia
Ølow margin of safety
4. anxiolytics
5. sedatives / hypnotics
anxiolytics: remove anxiety without impairing mental or
physical activity (“minor tranquillisers”)
sedatives: reduce mental and physical acitvity w/out
producing loss of consciousness
hypnotics: induce sleep
ideally:
i)
have wide margin of safety
ii)
not depress respiration
iii)
produce natural sleep (hypnotics)
iv)
not interact with other drugs
v)
not produce ‘hangovers’
vi)
not produce dependence
Barbiturates
non-selective cns depressants
Phenobarbiton
e
Pentobarbiton
e
Thiopentone
largely superseded (sed/hyp) by bzs (1960’s)
CCl3CH(OH)2
1. GAs (thiopentone)
2. anticonvulsants (phenobarbital)
3. sedative / hypnotics: Øamobarbital
– severe intractable insomnia
t½: 20-25 hrs
®
CCl3CH2OH
chloral
hydratetone
benzodiazepine »20 available; all act at gabaa receptors
s
•all similar potencies & profiles
anxiolytics: (‘long-acting’) diazepam (valium),
admin.:well absorbed p.o.
peak [plasma] » 1h (oxazepam
i.v. V status epilepticus
•distn: bind plasma prot strongly
(not drugs of 1st choice)
1. low safety margins: depress resp,
overdosing lethal (use forced alkaline
diuresis)
2. alter natural sleepØ(dec REM)=
severe
hangovers/ irritability
3. enzyme inducers
4. potentiate effect of other cns
depressants (e.g. alcohol)
5. tolerance (p’kinetic & tissue)
6. dependence:
withdrawal syndrome (insomnia,
anxiety, tremor, convulsions, death)
•sedation, confusion, ataxia (impaired
manual skills)
slower)
•potentiate other cns depressants
(alcohol; barbs)
chlordiazepoxide (librium), nitrazepam
short acting: oxazepam - hepatic impairment, t ½ 8hrs
highly lipid soluble = wide distn
•metabolism: usually extensive (liver)
•excretion: urine - glucuronide
sedative / hypnotics: (‘short-acting’) temazepam,
conjugates
oxazepam, lorazepam
•duration of acn: varies
long acting: nitrazepam- day, anxiolytic effect,t½ 28hrs
i)
short-acting
ii)
long-acting: slow metabolism
•wide margin of safety: overdose- prolonged sleep rousable and / or
- flumazenil
active metabolites
•mild effect on REM sleep
•do not induce liver enzymes
liver = trichloroethanol
other
sedative/hypno •moa unknown
•wide margin of safety (children and elderly)
tics
chloral hydrate
other
anxiolytics
propranolol improves physical symptoms
tachycardia (b1), tremor (b2), ‘stage fright’
buspirone•5HT1a agonist
slow onset of action (days / weeks) •few side-effects
DOPAMINER
GIC
PATHWAYS
OF THE
BRAIN
dopaminergic pathways
1) nigrostriatal - control of movement: cell bodies
originate in the substantia nigra zona compacta and project
to the striatum
2) mesolimbic: emotion - cell bodies originate in the
ventral tegmental area and project to the nucleus
accumbens, frontal cortex, limbic cortex and olfactory
tubercule
3) tuberoinfundibular system:regulate hormone
secretion - short neurones running
from the arcuate nucleus of the hypothalamus to the
medial eminence & pituitory gland “d1 like family”: • d1 & d5
• 2nd messenger - inc in camp, • postsynaptic
•tolerance (less than barbs; ‘tissue’
only)
•dependence: withdrawal syndrome
similar to barbs (less intense)
- withdraw slowly
•inc free [plasma] by e.g. aspirin,
heparin
• found mainly in nigrostriatal & limbic system
“d2 like family” • d2, d3 & d4
• second messenger - dec in camp or inc in k+
• pre & postsynaptic
• limbic - d2, d3, d4
• nigrostriatal - d2
• pituitary - d2
PARKINSON’  rest tremor, rigidity, bradykinesia, poverty of blinking,
S DISEASE
impassive face, dribbling, swallowing diff, monotony of
speech and loss of volume of voice
Degeneration of  disorder of posture:- flexion of neck and trunk, lack of
dopaminergic
arm swing
nigrostratal
 depression, taste disturbance/ parosmia, pain
neurones
 autonomic dysfuncn: constipation, postural hypotension,
urinary frequency, urgency, impotence, inc sweating,
seborrheic dermatitis
= loss of pigmented cells of pars compacta of substantia
nigra, locus coeruleus (ascending na neurons) but to a
lesser degree.
• other areas affected but not in all cases: dorsal vagus
nucleus, neuleus basalis of mynert, other subcortical nuclei
biochemical changes: marked dec in caudate nucleus
/putamen dopamine content
• need to loose 80-85% of the dopaminergic neurons and
deplete 70% of the striatal dopamine before symp appear
L- DOPA
Enzyme DOPA decarboxylase also present in peripheral
tissues.
• 95% of admin L-DOPA metabolised to dopamine
in the periphery - major side effects of nausea &
vomiting.
• Peripheral DOPA decarboxylase inhibitor + L-DOPA.
• Preparations:- Sinamet (Carbidopa + L-DOPA)
Madopar (Benserazide + L-DOPA)
Effectiveness of L-DOPA declines with time!
• After 6 years of therapy
• Dyskinesias (54%) • On-off oscilations (64%)
• Visual hallucinations & other psychological probs (17%)
=Hypokinesia, rigidity & tremor Start
w/ low dose of drug and inc dose until
max benefit
w/out side effects
chronic
• Dyskinesias – Abnorm movements
of limbs & face.
Occur w/in 2 yrs of treatment.
Disappear if reduce dose but clinical
symptoms reappear!
• “On-Off” effects – Rapid
fluctuations in clinical state. Off
periods may last from mins to hrs.
Occurs more with L-DOPA
Dopamine
Agonists
Bromocriptine
• Lisuride
• Pergolide
• Ropinirole
• Cabergoline
• Apomorphine
MAO
Inhibitors
Deprenyl
(selegiline)
• Act on D2 receptors
• Longer duration of action than L-DOPA
• Smoother & more sustained response
• Actions independent of dopaminergic neurons
• Incidence of dyskinesias is less
COMT
Inhibtors
Tolocopone
(peripheral)
Entacapone
(peripheral +
CNS)
• CNS - Prevents breakdown of dopamine in the brain
• Peripheral - COMT in the periphery converts L-DOPA
to 3-0-methyl-DOPA (3-0MD). 3-OMD and L-DOPA
compete for same transport system into the brain.
COMT inhibitors stop 3-OMD formn = incr bioavailability
of L-DOPA, Thus more L-DOPA converted to dopamine
in CNS = dec L-DOPA dosage!
SCHIZOPHR
ENIA
1 % of pop
• Positive symptoms - Delusions, hallucinations, Thought
Onset - Adolescence or young adult.
disorders.
Two types:
• Negative symptoms - Withdrawal, Flattening of emotional A) Relapsing and remitting
• Selective for MAO-B, predominates in dopaminergic
areas of CNS.
Actions are w/out peripheral side effects of none-selective
MAO-I’s
Acute:
• Nausea - prevented by Doperidone
(peripheral acting antag)
• Hypotension
• Psychological effects Schizophrenia like syndrome w/
delusions, hallucinations, confusion,
disorientation & nightmares
• Common - Confusion, dizziness,
nausea/vomiting
• Rare - Constipation, headache,
dyskinesias, drowsiness &
hallucinations
Can be given alone in the early stages rare - hypotension, nausea/vomiting,
of the disease.
confusion and agitation.
Or in combination with L-DOPA,
reduce the dose of LDOPA by 30-50%
Strong
hereditary t
• First degree
relatives (10%)
, monozygotic
twins, one of
whom has
schizophrenia
(50%)
responses.
B) Chronic and progressive.
Dopamine hyperactivity underlies at least +ve symptoms
• Dopamine agonists e.g bromocriptine can induce various
psychotic reactions.
• anti-schizophrenic drugs are dopamine receptor antag.
• In drug naïve patients PET scans show inc dopamine
receptor numbers.
• 6 fold inc in number of D4 receptors
Aetiology - Unknown but several
theories.
• Slow viral linked with auto-immune
process
• Developmental abnormality ~
anatomical changes in
the temporal lobes & amygdala
(Mesolimbic system)
Neuroleptics
antagonists at
dopamine “D2
like” receptors.
• block other receptors e.g. 5-HT, = side effects.
• Clozapine: not selective between D1 and D2
receptors but does have a high affinity for D4 receptors
that have been shown to be inc in schizophrenia.
• Drugs treat positive symptoms but not the negative ones!
• Delayed effects, takes weeks to work. Initially
neuroleptics induce an increase in DA synthesis and
neuronal activity. This declines with time.
Endocrine Effects - DA is involved in
the Tuberoinfundibular system that
regulated prolactin secretion.
Neuroleptics inc serum prolactin=
breast swelling (men & women) and
lactation in women.
• Block muscarinic receptors:
e.g blurring of vision, inc intra-ocular
pressure, dry mouth, constipation,
urinary retention.
Anti-emetic effect
– Block DA receptors in the
chemoreceptor trigger zone.
Phenothiazine: control vomiting
and nausea induced by drugs (e.g
chemotherapy), renal failure.
–Block histamine receptors = control
motion sickness.
Extrapyramidal - Block of dopamine
receptors in nigrostriatal system=
“Parkinson” like side effects.
• Acute dyskinesias - inc in
cholinergic function.
Develop at onset, reversible on drug
withdrawal or anti-cholinergic drugs.
• Tardive dyskinesias - Involuntary
movements, often involving
the face & tongue. 20% pts after
several months or years of therapy.
Made worse by drug withdrawal or
anti-cholinergics. May be related to
proliferation in pre-synaptic
DA receptors or drug toxicity.
Incidence is less with atypical
drugs.
GENERAL
ANAESTHETI
CS
1. Induce a loss
of
consciousness
at low conc
2.Induce an inc
in lack of
responsiveness
at higher conc’
ranging from
simple
chemically inert
gases to
complex
barbiturates
inhalation
vapours :ether,
chloroform),
Halothane/
Enflurane
gases:cyclopro
pane, Nitric
oxide
• Intravenous
Thiopental
• Etomidate
 Loss of consciousness
 Suppression of reflex responses
 Analgesia (relief of pain)
 Muscle relaxation
 Amnesia
‘The potency of G.A. inc in propn to its oil:water partition
coefficient’ – site was lipid bilayer portion of nerve memb
But;How does a change in the lipid bilayer result in a
dysfunctional membrane protein?
Effects are produced by ;
1. Reduced neuronal activity
2. Altered synaptic function
vary greatly in their ability to induce
analgesia, muscle relaxation and
amnesia.
Therefore, other drugs are used!
• Relief of pain (analgesia) –
Opioid (e.g. i.v. fentanyl)
• Muscle relaxation –
Neuromuscular blocking drugs (e.g.
suxamethonium)
• Amnesia – Benzodiazepines (e.g.
i.v. midazolam)
• Inhibit synaptic transmission by:
dec transmitter release
• dec postsynaptic response.
Anatomically in the thalamus, cortex and hippocampus.
Anaesthetics solubility in different media is expressed as
“partition coefficients”, : ratio of conc of agent in two
phases at equbm.
blood:gas partition coefficient main factor that determines
the rate of induction and recovery from an inhalation
anaesthetic. lower coefficient, faster induction and
recovery.
oil:gas partition coefficient measure of fat solubility and
determines potency of anaesthetic, influencing the kinetics
of distribution in body. high oil:gas partition coefficient
(i.e. High lipid solubility), delayed recovery
1. poteniate GABAA receptor funcn (and glycine
receptors). Less potent than iv and show no subunit
selectivity (altered synaptic function).
2. Inhibits nACh (altered synaptic function)
3. Facilitate TREK (background leak) potassium channel
opening (reduced neuronal excitability).
Dec NMDA receptor funcn (altered synaptic function).
• Potentiate GABAA receptor funcn (altered synaptic
function) – most abundant, fast inhibitory, ligand-gated ion
channel in CNS Propofol
Ketamine Midazolam
At a cellular level at synapses either
pre or post synaptically.
•
Rapid induction and recovery:
flexible control over the depth of
anaesthesia.
•
Agents with high lipid solubility
(eg. Halothane) accumulate gradually
in body fat to produce a prolonged
hangover effect.
Local
Anaesthetics
Drugs which
reversibly block
neuronal
conduction
when applied
locally
1. Prevent generation and conduction of APs
2. Don’t influence resting membrane potential
3. influence:Channel gating,
4. Selectively block:
Small diameter fibres
Non-myelinated fibres
Surface tension
 LAs are weak bases (pKa 8-9)
 Infected tissue
2. Infiltration anaesthesia
 Directly into tissues → sensory
nerve terminals, Minor surgery
 Adrenaline co-injection (NOT
extremities)
5. Spinal anaesthesia
 Sub-arachnoid space – spinal roots
 Abdominal, pelvic, lower limb surgery
 ↓ b.p.; prolonged headache
3. IV regional anaesthesia
 i.v. distal to pressure cuff
 Limb surgery
 Systemic toxicity of premature cuff
release
6.Epidural anaesthesia
 Fatty tissue of epidural space – spinal roots
 Uses as for 5) and painless childbirth
 Slower onset – higher doses
Lidocaine
amide
1. Surface anaesthesia
 Mucosal surface (mouth, bronchial
tree), Spray (powder)
 High conce → systemic toxicity
4.Nerve block anaesthesia
 Close to nerve trunks e.g. dental
nerves
 Widely used – low doses – slow
onset
Vasoconstrictor co-injection
i.



CNS
stimulation
restlessness, confusion
tremor
ii.CVS
 myocardial depression
 vasodilatation
 ↓ b.p.
Paradoxical
Na+ channel blockade
Cocaine
ester
i.CNS: euphoria, excitation
ii.
CVS: Symp
 ↑ C.O.
 vasoconstriction
 ↑ b.p.
ANTI
CONVULSAN
TS
epileptic
seizure:
manifestation of
an abnormal
and excessive
synchronised
discharge of a
set of cerebral
neurones
syndrome, not a
disease (cf.
Anaemia)
Seizures are
sudden and
transient
(“paroxysmal”)
Benefits: Seizure suppression (dec in Sz-related harm)
Harms: Psychosocial consequences (illness status, selfesteem, education, employment)
phenytoin
Partial epilepsy
and and status
epilepticus
Effect of other drugs on PHT
• Amiodarone, cimetidine, Isoniazid - Potent inhibitors of
PHT metabolism, with increased levels
• Aspirin - displaces PHT from protein binding –
• Valproate - displaces PHT and also inhibits PHT
metabolism = toxicity
Mechanism:Blo
ckade of vgated Na
channels
Factors influencing decision to treat
• Number of seizures at presentation
• 1 seizure – risk of further 50%
• >2 seizures – risk of further seizures
80%
• Seizure type and severity
• Cause of seizure
Factors influencing AED choice
• Personal preference
• Dogma rather than scientific knowledge
• Partial epilepsy - CBZ first line
• Generalized epilepsy - VPA first line (LTG in woman of
childbearing age)
• Many are “broad spectrum” & used in both generalized
and partial epilepsy: e.g., VPA, TPM, LTG
• ESM - childhood absence epilepsy only
• CBZ, VGB, GPT may worsen generalized epilepsy
(absence and myoclonic seizures)
Pharmacokinetic variation
• Bio-availability: age, gender,
generic formulations
• Distribution:Vd (muscle, fat),
Protein binding (hepatic/renal
disease, pregnancy, age)
• Metabolism:Biotransformation
(Phase I & II enzymes)
• Excretion: Renal disease, age
• Drug interactions:
Induction/inhibition of liver enzymes
Pharmacodynamic: Genetic variation
drug receptors
e.g., polymorphic variation GABAA
receptor sub-units and BDZs
• T ½ :Mean 20 hours
– Hepatic metabolism: oxidation
(CYP2C9 >2C19), hydroxylation,
conjugation
Potent hepatic enzyme inducer ,
P450 enzyme inducer - D/Is
renal excretion of non-active
Effect of PHT on other drugs
metabolites
• warfarin- Complex pharmacokinetics, w/ an initial inc in – Saturable kinetics: conc dependent.
anticoagulation, after wh/ conc dec. Monitor INRs
i.e., non-linear kinetics (rising quickly
• CBZ, LTG, TPM, corticosteroid, cyclosporin,
after point of enzyme saturation)
praziquantel levels all lowered
– Highly (70-90%) protein bound so
• Estrogen containing OCP efficacy reduced Vit K
free PHT levels helpful in some
deficiency (pregnancy)
circumstances (displacement
Idiosyncratic & dose-related ADRs
Teratogenicity
• Background risk MCM = 1.5%
• Risk 1 AED = 3-5%
• Risk 2 AEDs = 5-10%
• Risk of individual drugs not clear
• Background risk NTD=0.2 - 0.5%
• Risk VPA = 1 -2%
• Risk LTG/CBZ = 0.5 - 1%
• Weigh up risks from Szs (accident,
injury, death), against risk of
teratogenicity
• Book early (AFP and high res US
• FA 5mg daily, dec risk of NTD
• Vit K in enzyme inducing AEDs
Wrong AED, poor control, worsening
of epilepsy
Ataxia, dizziness, sedation,
hypersensitivity, rash, fever, gingival
hypertrophy, folate deficiency,
megaloblastic anaemia, vit K
deficiency, depression, hirsutism,
peripheral neuropathy, osteomalacia,
reduced bone density, hypocalcaemia,
hepatitis, vasculitis, myopathy,
coagulation defects, bone marrow
hypoplasia
Avoid combination where possible.
Start low, unless urgent, when can
load IV
carmazepine
Partial and
secondary
generalized
seizures
Mechanism:Blo
ckade of vgated Na
channels
• (auto-induction): Steady state reached at about 1/12
• t ½ : 5-26 hours
• Metabolism: Hepatic oxidation then
conjugation. Potent hepatic enzyme
inducer
Active metabolites: carbamezepine
epoxide
Ataxia, dizziness, sedation,
hypersensitivity, rash, fever, diplopia,
vit K deficiency, depression,
impotence, osteomalacia, reduced
bone density, hyponatraemia,
hepatitis, bone marrow dyscrasias,
nephritis
lamotrigine
Partial and
generalized
epilepsy - wide
spectrum
Mechanism:Blo
ckade of vgated Na
channels
Effect of other drugs on LTG
• Enzyme inducing drugs dec half-life and lower levels
(e.g., CBZ, PB, PHT)
• VPA inc half-life tob60 hours, doubling levels and can
precipitate toxicity/severe rash
• C-OCP can lower levels by 1/3 (as can pregnancy)
• dosage modified according to co-medication
(introduction and withdrawal). Eg, adding to valproate comedication, initiate drug at very low doses and
incrementing the dose very slowly will lower the incidence
of rash. If adding valproate to LTG, then half dose of LTG.
• t ½ : 29 hrs (monoPx), 15 hrs
(enzyme inducing co medication), 60
hrs (valproate co-medication)
• Metabolism:
Hepatic
glucuronidation (no phase 1
metabolism).
No hepatic enzyme induction.
Main advantage is that it is usually
well tolerated, but high incidence of
rash (2%), sometimes severe.
Effect of LTG on other drugs
does not inhibit or induce hepatic
enzymes, so does not alter metabolism
of OCP or warfarin
if rash develops, stop AED
immediately
valporate
Partial or
generalized
epilepsy - wide
spectrum
Mechanism:inc
GABA by a
variety of
mechanisms
Effect of VPA on other drugs
• potent inhibitor of both oxidation and glucuronidation
• PHT, PB, LTG levels all inc
• CBZ-epoxide levels increased
T ½ : 4-12 hrs (tds dosing)
Severe hepatic toxicity (especially
young), pancreatitis, drowsiness,
encephalopathy (ammonia driven),
tremor, blood dyscrasias, hair thinning
and loss, weight gain, endocrine
(PCO).
viagabatrin
Mechanism: Irreversible inhibition of GABA
Transaminase
Partial epilepsy (partial or secondary generalized Szs)
infantile spasms (esp in TS)
Effect of other drugs on CBZ
• PHT, PB induce CBZ metabolism
• VPA 4x inc in CBZ-epoxide levels - inhibits epoxide
hydrolase. LTG inc epoxide levels to a lesser extent.
• Macrolide AB (e.g., erythromycin) inhibit CBZ
metabolism: can inc levels 2-3X (avoid!)
Effect of CBZ on other drugs
• Ca2+ channel blockers (diltiazem/verapamil) can double • Dec (e.g., PHT, VPA, LTG)
CBZ levels (nifedipine has no effect)
• OCP - inform patients
• Fluoxetine may increase CBZ levels
• Warfarin
• Metabolism: Hepatic oxidation,
conjugation. Potent inhibitor
of hepatic enzymes
Effect of other drugs on VPA
• Levels dec by hepatic enzyme inducers (PHT, PB, CBZ)
• Antacids may impair absorption
Some NSAIDs, aspirin, phenylbutazone displace VPA
from its albumin binding sites and may result in toxicity
Elimination half-life: 4-7 hours
Metabolism: Renal excretion
without metabolism
headache, blood dyscrasia, ataxia,
diplopia and dizziness, sedation,
insomnia, mood disturbance.
Visual field constriction in 30% limits
it use. Neuro-psychiatric
D/I with PHT (dec level
ANTI
MICROBIALS
should be toxic
for the parasitic
cell but
innocuous for
the host.
Selective toxicity depends on the existence of exploitable
biochemical differences between the parasite and host cell
wh/ depends on how far apart the host and parasite are in
evolutionary development.
e.g. Prokaryotes (cells w/out nuclei - bact) - easier to kill.
Eukaryotes (cells with nuclei - protozoa) - more similar
biochemically to cells of the host, more difficult to kill.
Affect folate
Folate is
required for
DNA/RNA
synthesis in
both Man and
bacteria.
• Bact synthesise folate: P-aminobenzoic acid
• Sulphanilamide: structural analogue of P-aminobenzoic
acid and competes for enzyme dihydropteroate wh/ is
involved in the synthesis of folate. Interfere w/ bact
metabolism and are bacteriostatic : (arrest growth of bact
but do not kill them, allows host defence to increase)
• Peptidoglycan: cell wall of bact
• Some bact cell wall is many layers thick. Each layer
consists of multiple backbones of amino sugars –
alternating N-acetyl-glucosamine and N-acetylmuramic
acid residues – later of which have short peptide side
chains which cross-link to form a lattice.
= wall very strong and can resist high osmotic pressures.
• b-Lactam antibiotics e.g. penicillin inhibits the
formation of peptidoglycan. Bacteriocidal
•Tetrahydrofolate: co-factor in thymidylate synthesis
(pathway which has a differential sensitivity of human and
bact enzymes to drugs)
•pathway is identical in M and man - key enzymes,
dihydrofolate reductase , is more sensitive to folate
antagonist trimethoprim in bacteria than in man
• human enzyme is very sens to effects of the folate
analogue methotrexate
• sulphonamides affect earlier stage in same metabolic
pathway i.e. folate synthesis, they potentiates acns of
trimethoprim.
Folate
antagonist
Sequential
blockade
Combination -
Diff between bact and eukaryotes
1. Cell Wall –peptidoglycan: supports
the underlying memb wh/ is subject to
osmotic pressure.
2. Genetic – No nucleus, genetic
material forms a single chromosome
wh/ lies loose in cyto
3. Plasma memb – Bact memb contain
no sterols : differential penetration to
chemicals.
4. Protein synthesis – Bact ribosome’s
consist of 50s and 30s subunits, whilst
mammalian ribosome’s consist of 60s
and 40s subunits
• Readily absorbed in GI
• max plasma conc 4-6 hours.
• Side Effects:
•oral
•absorbed from GI tract
•widely distributed throughout the
tissues and body fluids.
• Reaches high conc in the lungs and
kidney.
•uses: - urinary tract and resp inf
• 2/3 of each drug is protein bound
• half of each is excreted w/in 24 hrs
•
•
• Mild/moderate (do not warrant
withdrawal) nausea & vomiting,
headache, mental depression.
• Severe (warrant withdrawal)
hepatitis, hypersensitivity reactions,
bone marrow suppression.
• Wide spread resistance but imp
since gave rise to diuretics
(acetazolamide & Thiazides),
tuberculostatic agents, oral
hypoglycaemics (sulphonylureas)
• nausea/vomiting and skin rashes.
• small dose of sulphonamide wh/ is
used in co-trimoxazole has serious
side effects e.g. hypersensitivity
reacns, wh/ are not dose related.
•
co-trimoxazole
sulphamethazo
le and
trimethoprim
B lactam antag
Penicillin
cephalosporins
carbapenems
• effective at 1/10 / < of needed if given on its own.
• uses: - inf w/ pneumocystis carinii: pneumonia in pts
w/ AIDS, high doses.
•The basic nucleus of penicillin is 6-aminopenillanic acid,
which consists of a thiazolidine ring linked to a b-lactam
ring. Penicillin’s may be destroyed by enzymes - amidases
and b-lactamases.
•Interfere w/ synthesis of bact wall peptidoglycan - inhibit
transpeptidation enzyme that cross links the peptide chains
attached to the backbone of the peptidoglycan.
• Benzylpenicillins:active against a wide range of bact,
• poorly absorbed (injection) and susceptible to blactamases. Synthetic penicillin’s have been produced to
try and overcome these problems (over 50 types).
Resistance: 1) Prodn of b-lactamases by bact e.g. staphylococci.
genetically controlled and can be transferred from one
bacterium to another. Solution - use b-lactamase inhibitors
e.g. clavulanic acid: covalently binds to enzyme at or
close to its active site.
2) dec in perm of outer memb dec ability of drug to
penetrate to target site.
3) The occurrence of modified penicillin-binding sites.
• Same as penicillin’s, interfere with peptidoglycan
cephalosporin
synthesis.
Cephalexin
(oral),
• Resistance to this group of drugs has increased. Gram Cefuroxime & ve bact have the gene encoding for b-lactamase wh/ is
more active in hydrolysing cephalosporins than penicillin.
Cefotaxime
(parenteral)
Resistance also occurs if there is dec penetration of drug
due to alterations to outer memb proteins or mutations of
the binding site proteins. They are bactericidal.
• orally,: absorbed to differing degrees
depending on stability in acid and
adsorption to food.
• widely distributed in body fluids,
passing into joints, pleural and
pericardial cavities, into the bile, the
saliva and the milk and across the
placenta.
lipid insoluble they do not enter
mammalian cells= do not cross readily
BBB unless meninges are inflamed,(
reach effective therapeutic conc).
Elimination is renal and occurs
rapidly, 90% being by tubular
secretion.
• Relatively free from direct toxic
effects.
• hypersensitivity reacns: breakdown
products of penicillin combine w/
host protein and become antigenic.
E.g. skin rashes and fever, acute
anaphylactic shock.
• broad spectrum penicillin’s: gut
bacterial flora : GI tract disturb.
• orally but mostly parenterally, i.m.
or i.v.
• Widely distributed, passing into the
pleural, pericardial and joint fluids and
across the placenta. Some cross BBB
(e.g. cefoperazone, cefotaxime):
bacterial meningitis.
• Excretion:kidney, by tubular
secretion, but 40% of ceftriaxone and
75% of cefoperazone is eliminated in
the bile.
• different b-lactam AB bind to diff
binding proteins: combine two or even
more of these agents and achieve
synergistic action
Hypersensitivity reactions,
Some cross reaction occur, about 10%
of penicillin sensitive individuals will
also be allergic to cephalosporins.
Nephrotoxicity (esp w/ cephradine).
Diarrhoea; with oral cephalosprins.
Affect protein • Active transported into bact and interrupt protein
synthesis. Compet w/ tRNA for the A binding site.
sysnthesis
Bacteriostatic, not bactericidal.
Tetracycline’s
broad-spectrum • Spectrum: - Very wide Gram +ve and Gram -ve,
antibiotics that
mycloplasma, Rickettsia, Chlamydia, some spirochaetes
have a
and some protozoa (e.g. amoebae).
polycyclic
• resistance : development of energy-dependent efflux
structure.
mechanisms which transport the tetracycline’s out of bact,
but alterations of the target, the bacterial ribosome also
occur.
• orally , parenterally.
• absorption from gut is irregular and
incomplete, and is improved by the
absence of food.
• Since tetracycline’s chelate metal
ions (e.g. iron)= non-absorbable
complex, absorpn dec by presence of
milk, certain antacids and iron
preparations.
• wide distribution, entering most
fluid compartments.
• Excretion: bile and by glomerular
filtration in the kidney. accumulate if
renal funcn impaired.
• Doxycycline exception, excreted
into GI via the bile.
•orally , parenterally
chloramphenic • binds to 50S subunit of ribosome and inhibits
transpeptidation.
ol
•absorbed
Inhibition of
• Spectrum: - Wide spectrum of activity, including Gram - •max conc in plasma w/in 2 hours.
protein
ve and Gram +ve bact. bacteriostatic
•widely distributed through tissues and
synthesis .
Resistance: prodn of chloramphenicol acetyl-transferase
body fluids includ the CSF.
and is plasmid mediated. R plasmids containing
•30-50% plasma protein bound
determinants for multiple drug resis for chloramphenicol,
• t½: 2 hrs.
streptomycin, tetracycline’s, etc. may be transferred from
•10% excreted unchanged in urine
one bacterial species to another by 'promiscuous plasmids'. •inactivated in the liver.
Derivatives of chloramphenicol w/ terminal OH on the
•Metabolite being excreted via the
side-chain replaced by fluorine are likely not to be
kidney and the bile.
susceptible to acetylation and thus to retain antibacterial
activity.
•polycations & highly polar; not
aminoglycoside •inhibit bact protein synthesis by binding to the 30S
subunit of the ribosome = alteration in codon:anticodon
absorbed in GI tract.
s - e.g.
recognition = misreading of mRNA and producn of
gentamicin
• i.m. or i.v.
defective bact proteins.
• Binding to plasma proteins is
minimal.
•penetration through cell memb of the bact depends on
oxygen-dependent active transport system, wh/
•do not enter cells, nor cross the BBB
chloramphenicol can block.
into the CNS.
•Bactericidal, enhanced by agents that interfere w/ cell
•Plasma t ½ 2-3 hrs.
wall synthesis.
• Elimination: glomerular filtration in
Resistance: - inactivation by microbial enzymes, the genes kidney.
for which are carried on plasmids.
•Tissue conc inc during treatment and
• GI disturb: direct irritation and later
to modification of the gut flora.
• Because they chelate Ca: deposited
in growing bones and teeth, = staining
and bone deformities.
• not given to children, pregnant
women or nursing mothers.
• Phototoxicity (sensitisation to
sunlight) with Demeclocycline.
Minocycline:vestibular disturb
(dizziness and nausea), freq of dose
related.
• High doses of tetracycline’s dec
protein synthesis in host cells - an
anti-anabolic effect.
•depression of bone marrow:
pancytopenia - dec in all blood cell
elements - occur in very low doses and
rare
•new-borns: inadequate inactivation
and excretion = 'grey baby syndrome' vomiting, diarrhoea, flacidity, low
temp and an ash-grey colour - 40%
mortal
•Hypersensitivity, GI disturbances and
other alteration of the intestinal
microbial flora.
• Ototoxicity:progressive damage to
and destruction of the sensory cells in
the cochlea and vestibular organ of
the ear.
• Nephrotoxicity - damage to kidney
tubules . reversed if use of the drug is
stopped. Since elimination is renal,
their nephrotoxic action can impair
their own excretion and a vicious
cycle can be set up. =,Plasma conc
monitored regularly.
failure of penetration (overcome by concomitant use of
penicillin and/or vancomycin which synergies with
aminoglycosides)
lack of binding of drug due to mutations that alter the
binding-site on the 30S subunit.
can reach toxic levels after about a
week of unmodified dosage.
antimycobacte
rial
TB
(Mycobacteriu
m tuberculosis)
& and leprosy
(leprae)
isoniazid
prob : after phagocytosis, the M can survive inside
macrophages, unless 'activated' T cell lymphokines.
rifampicin
most active
antituberculosis
agents
•Binds to and inhibits DNA-dependent RNA polymerase in
prokaryotic but not eukaryotic cells.
•active against other Gram +ve and many Gram -ve
species.
• enters phagocytic cells and can kill intracellular M
•Pharmacokinetics: - Rifampicin is given
1st phase 2 months
three drugs used concomitantly:
isoniazid, rifampicin, pyrazinamide
(plus ethambutol if the org is
resistant).
2nd:, continuation 4 months, two
drugs: isoniazid and rifampicin;
• Readily absorbed from the GI
•
• parenteral injection
• widely distributed: tissues, body
fluids, CSF.
• penetrates into necrotic tuberculous
lesion.
• Metabolism:acetylation, depends on
genetic factors that determine
whether a person is a slow
(t1/2=3hours): better therapeutic
response.
• rapid(t1/2= 1.5 hours) acetylator
•orally
• infrequent, fewer than 4% e.g. skin
•widely distributed in tissues and body eruptions, fever, GI tract disturbances.
fluids.
•excreted partly in urine and bile,
undergoing enterohepatic cycling.
•progressive metabolism:
deacetylation during repeated passage
through liver. metabolite retains
antibact act but less well absorbed
from GI tract.
pyrazinamide
•inactive at neutral pH but tuberculostatic at acidic pH.
•effective against intracellular org in macrophages, since
after phagocytosis the org contained in phagolysosomes in
wh/ pH is low.
TBw/ HIV.
=combination drug therapy: dec the emergence of
resistant org,
• activity limited to mycobacteria.
bacteriostatic on resting org and can kill dividing bacteria.
passes freely into mammalian cells : effective against
intracellular org
inhibits the synthesis of mycolicacids, imp constituents of
the cell wall and peculiar to mycobacteria.
• well absorbed , oral
• widely distributed, penetrating into
meninges
• excreted:kidney- glomerular filtrate
Spectrum: - effective against many
aerobic Gram -ve and Gram +ve bact.
They may be given together with
penicillin in infections caused by
Streptococcus, Listeria or
Pseudomonas aeruginosa.
• longer treatment is needed in some
situations e.g. meningitis, bone/joint
involvement, drug resistant cases.
• arthralgia (assoc w/ high conc of
plasma urates).
• GI tract upsets, malaise and fever
are reported.
ANIT
FUNGAL
DRUGS
Fungal inf: are
termed mycoses
nystatin
fungal inf of the
skin and GI
tract.
miconazole
Azole gp of
synthetic
antimycotic
agents with a
broad spectrum
of activity
ANTI VIRAL
• virus-specific
enzymes:
targets for
drugs.
• antiviral
agents effective
while virus is
replicating.
acyclovir
Inhibiton of
nucleic acid
1)Superficial - Affecting skin, nails, scalp, mucosal memb.
•Dermatomycoses - inf of skin, nails and hair caused by
dermatophytes. commonest due to Tinea orgae.g. Tinea
pedis - causing 'athlete’s foot'.
•Candidiasis - yeast like org wh/ infect the mucous memb
of the mouth (thrush), or vagina, or skin.
2)Systemic inf - Affecting deeper tissues and organs.
• polyene macrolide. no absorption from mucous memb of
the body
• Binds to cell memb and interferes w/ perm and w/
transport funcn.
• forms a pore in memb, the hydrophilic core of the
molecule = transmemb ion channel.
• selective acn, binding to memb of fungi and some
protozoa, less avidly to mammalian cells and not at all to
bact.
block synthesis of ergosterol, by interacting w/ enzyme for
conversion of lanosterol to ergosterol= resulting depletion
of ergosterol alters fluidity of memb and interferes w/ acn
of memb assoc enzymes. = inhibition of replication,
inhibition of the transformation of candidal yeast cells into
hyphae - the invasive and pathogenic form of the parasite.
•Primary systemic fungal inf rare and
occur in defined endemic areas of the
world.
•UK commonest is candidiasis - inf w/
a yeast like orr
•
• smallest infective agent, w/ nucleic acids (either RNA or
DNA) enclosed in a protein coat or capsid.
DNA viruses: poxvirus (smallpox),
• viruses share many metabolic
herpes viruses (chicken pox, shingles,
processes w/ host cell: diff to find
herpes and glandular fever),
drugs that are selective for the
adenoviruses (sore throat,
pathogens.
conjunctivitis), and papillomaviruses
• Problem:by the time a viral inf
(warts).
becomes clinically detectable, the
RNA Viruses: orthomyxoviruses
process of viral replication is usually
(influenza), paramyxovirus (measles,
far advanced and chemotherapeutic
mumps), picornaviruses (colds,
intervention is very difficult.
meningitis, poliomyelitis), retroviruses
(AIDS), arenavirus (meningitis, Lassa
fever).
• intracellular parasites w/ no metabolic machinery
• replicate: attach to and enter a living host cell and use its
metabolic processes. The receptor on host cell to wh/ virus
attaches are normal memb constituents( e.g. ion channels,
neurotransmitter receptors, integral memb glycoproteins)
= receptor/virus complex enters cell by endocytosis:virus
coat may be removed
nucleic acid of virus then uses cell's machinery for
synthesising nucleic acid and protein and the manufacture
of new virus particles.
•
guanosine derivative w a high sp for herpes simplex: more
sensitive than other herpes viruses: glandular fever or
shingles.
•
• specificity for fungi; due to drugs
• Rare. Limited to nausea and
greater avidity for ergosterol (fungal
vomiting when high doses are taken
membrane sterol) than cholesterol, the by mouth. V.rare - Rash.
main sterol in the plasma membrane in
animal cells. It is effective against
most fungi and yeast’s.
•
•
•
•
iv systemic infections
orally for GI infections
short plasma t ½
given every 8 hours.
Orally: 20% of dose is absorbed peak
plasma conc in 1-2 hrs,
i.v; plasma conc 10- to 20- x
• Relatively infrequent, most
commonly being GI tract
disturbances, blood dyscrasias.
• minimal.
• Local inflammation can occur
during i.v. if there is extravasation of
syntheis
against cytomegalovirus (CMV): glandular fever in adults
or severe disease e.g. retinis, resulting in blindness in
individuals with AIDS.
• converted to monophosphate by thymidine kinase - the
virus sp form of this enzyme being very much more
effective in carrying out the phosphoylation than the host
cells' thymidine kinase = triphosphate by host cell kinases.
• only activated in infected cells.
• Acyclovir triphosphate inhibits viral DNA-polymerase,
terminating the chain. 30x more potent against the herpes
virus enzyme than host enzyme.
• Acyclovir triphosphate is fairly rapidly broken down
within the host cells by cellular phosphatases.
AZTazidothymidin
e
Zidovudine
analogue of
thymidine.
•retroviruses -HIV- active inhibitor of reverse transcriptase.
•phosphorylated by cellular enzymes to triphosphate form,
where it competes w/ equivalent cellular triphosphates wh/
are essential substrates for formn of proviral DNA by viral
reverse transcriptase (viral RNA-dependant DNA
polymerase);
•its incorporation into the growing viral DNA strand = in
chain termination.
•Mammalian alpha DNA polymerase is resistant. However,
gamma DNA polymerase in the host cell mitochondrion is
fairly sensitive to the compound and this may be the basis
of unwanted effects.
1. In pts w/ AIDS: dec incidence of opportunistic inf
(Pneumocystis carnii pneumonia), stabilises wt, reverses
HIV-associated thrombocytopenia, stabilises HIV assoc
dementia and dec viral load.
2. HIV +ve before onset of AIDS in combination wi/ other
drugs: prolong life expectancy.
3. HIV +ve mothers dec risk of transmission of virus to the
foetus by 66%.
4. subjects who have been accidentally exposed to HIV
e.g. hospital worker, rape victims, condom problems etc
topically.
widely distributed: conc in CSF 50%
of plasma.
excreted in kidneys by glomerular
filtration and by tubular secretion.
the solution, which is very alkaline.
• Renal dysfunction when i.v.; slow
infusion dec risk.
• Nausea and headache
•Resistance due to changes in the viral
genes coding for thymidine kinase or
DNA polymerase has been reported
and acyclovir-resistant herpes simplex
virus:pneumonia, encephalitis in
immunocompromised pts.
orally, bio-availability 60-80 % due to
first pass metabolism,
peak plasma conc30 mins.
i.v.
•little plasma protein binding so no
drug interactions due to displacement
by other drugs.
• mammalian cells by passive
diffusion -passes to CSF and brain.
•metabolised to inactive glucuronide
in the liver,
• 20% of active form excreted in urine.
• Common: anaemia and neutropenia.
• Uncommon: GI disturbances, skin
rash, insomnia, fever, headache,
abnorms of liver function, and
myopathy. Confusion, anxiety,
depression, and a flu-like sy.
• Resistance: In most pts therapeutic
response wanes w/ long-term use, esp
in late-stage. virus dev resis to drug
due to mut = aa subs in viral reverse
transcriptase and these genetic
changes accumulate progressively.
Thus, virus is a constantly moving
target. Resistant strains can be
transferred between individuals.
• loss of efficacy due to: dec
activation of zidovudine to
triphosphate, inc virus load due to dec
in immune mechanisms and inc
virulence of the pathogen.
Cytotoxic
drugs drugs
that modify the
growth of cells
and tissues.
Anti-cancer agents:
 To eradicate disease
 Induce a remission
 Control symptoms
Control of immune responses in organ transplantation
 Management of autoimmune disease
 Neoplasia (new growth)
 Neoplasm,: uncontrolled proliferation only – benign
 Neoplasm,: uncontrolled proliferation, invasiveness and
metastases – malignant.
The Cancer Cell Phenotype
 Disregard of signals to stop proliferating.
 Disregard of signals to differentiate.
 Capacity for sustained proliferation.
 Evasion of apoptosis.
 Ability to invade.
 Ability to promote angiogenesis.
Alkylating
agents Interfere
with
transcription
and replication.
Anti
metabolites
Block or
 antiproliferative.
 Do not affect invasiveness and
tendency to metastasise.
 used as combinations to dec chances
of drug resistance.
 Will affect all rapidly dividing
normal tissues as well as tumour.
1. Alkylating agents and related
compounds.
2. Antimetabolites
3. Cytotoxic antibiotics
4. Plant derivatives
5. Miscellaneous agents
Fast growing cells
immunopharm Azathioprine, methotrexate and
 Inhibit cell division
cyclophosphamide
 Cell cycle specific drugs: Bone
 Primary funcn of immune system: protect host from
marrow, GI tract epithelium,Hair &
invasion.
nails, Spermatogonia
 system is responsible for causing autoimmune disease
and rejecting allogenic tissue grafts after transplantation.
Slow growing cells
 Cytotoxic drugs:used as immunosuppressants, but at
 Introduce DNA mutations
much lower doses than used to treat cancer.
 selective action on lymphocytes which drive the immune  Cell cycle independent (alkylating
agents)
response.
Secondary tumours
 Covalently bond with nucleophiles.
 Nitrogen mustards
 Reactive group is a carbonium ion.
 cyclophosphamide
 bifunctional.
 Guanine N7 is main target, also N1 and N3 of adenine
and N3 of cytosine.
 Can cause intra- or interchain crosslinks.
 Folate antagonists e.g. methotrexate,:interfere with
thymidylate synthesis.
 Pyrimidine analogues e.g. fluorouracil : interfere with
 Difficult to find differences
between cancer cells and normal
 Need to produce a near total cell
kill.
 far advanced before diagnosis.
Tumour cells can be:
 Dividing (sensi to anticancer treat)
 No longer able to divide (not a
problem)
 Resting in G0 phase (insensitive to
anticancer treatment and could start
dividing again after chemotherapy).
1.
2.
3.
4.
5.
6.
7.

Myelotoxicity.
Impaired wound healing.
Depression of growth (children)
Sterility.
Teratogenicity.
Loss of hair.
Nausea and vomiting
subvert
pathways in
DNA synthesis.
2’-deoxythymidylate synthesis.
 Purine analogues e.g. Azathioprine inhibits purine
synthesis.
 Actinomycin D (Dactinomycin) intercalates DNA and
Cytotoxic AB
Direct
interferes with topoisomerase II.
interaction with  Doxorubicin inhibits DNA and RNA synthesis.
DNA.
 Bleomycins metal-chelating glycopeptide Ab: degrade
DNA. active against non-dividing cells.
 podophyllotoxins e.g.etoposide, inhibit DNA synthesis.
Plant
Causes cell cycle block at G2.
derivatives
 The vinca alkaloids e.g. vincristine,:binding to tubulin
and inhibiting polymerisation into microtubules. prevents
spindle formation.

miscellaneous
1. Hydroxyurea inhibits ribonucleotide reductase.
2. Cisplatin interacts with DNA causing guanine
intrastrand cross-links.
3. Procarbazine inhibits DNA and RNA synthesis and
interferes with mitosis at interphase. Metabolically
activated by cytochrome P450 and monoamine oxidase to
alkylate DNA (N7 and O6 of guanine).
hormones
 Can inhibit tumours in hormone-sensitive tissues.
 Gonadotrophin-releasing hormone analogues
e.g. Goserelin

iv.

chemotherapy but are not
technically cytotoxic.
RESPIRATOR Ventolin). selective β 2-adrenoceptor agonist.
Y
Salbutamol,
salmeterol
aminophylline
(
symptomatic relief of asthma. an increase in camp
PDE inhibitor),
ipratropium
bromide
muscarinic antagonist
metacholine
, stable analogue of ACh, on airways conductance
(Conductance : opposite of resistance – the more
conductance decreases, the harder it is to breathe
Leukotriene
C4 is a locally produced bronchoconstrictor,
enyzme 5-lipo-oxygenase (5-LO or 5-LOX) is the rate
limiting enzyme
Histamine
bronchoconstrictor. released in airways as part of an
allergic response, for example in patients with asthma
(anticholinergic
inhaled