Download PHARMACOTHERAPEUTICS -study of rational use of drugs in the

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PHARMACOTHERAPEUTICS
-study of rational use of drugs in the Mx of diseases
Autonomic drugs (variety of clinical uses)
a.
Anatomy and physio of Autonomic nervous system (ANS)
b.
Sympathetic drugs
c.
Parasympathetic drugs
Anatomy and Physiology of ANS
ANS is an effector of the CNS (ANS performs the fxn of the CNS) NOTE: other effector of CNS is
Somatic NS
CNS - brain and SC
Key diff. Of ANS from somatic NS
a.
ANS is a 2-neuron system while Som.NS is a 1-neuron system {draw} second neuron has
the cell body outside the CNS (in SomNS, body is in CNS) {draw} preganglionic fiber is axon
of neuron number 1 while postganglionic fiber is the axon of neuron number 2
b.
Presence of ganglia in ANS (absent in SomNS) ganglion - collection of nerve cell bodies
located outside the CNS [dendrites are so small so illustration of neuron is usually body at
axon lang)
c.
Action/effect: ANS - automatic, independent, involuntary ; SomNS - voluntary (skeletal
muscle)
Synaptic Neurotransmission - describes the transmission of impulses across an interface
(interface bet. Neurons and bet. Neuron and its target organ)
3 important parts of synapse (the interface) {draw}
o Presynapse - important in synthesis, storage and release (by exocytosis) of NT ; may contain
presynaptic receptors (role in regulatory / autoreceptors - when stimulated will inhibit
further release of NT)
o Synaptic cleft - where NT are released and may be the site of metabolism of NT (e.g
acetylcholinesterase - Ach)
o Postsynapse - primary location of majority of receptors (pag hindi inispecify na presynaptic
receptor, assumed na postsynaptic yun) ; metabolism of NT(postsynaptic enz.)
NOTE: role of Ca -- induce release of NT ; increase in presynapse during neurotransmission and will
stimulate the process of exocytosis of NT
Different synapses : ANS - 2 synapses ; SomNS - 1 synapse
Nomenclature: {draw}
Synapse type
Presynapse name
Postsynapse name
ANS 1st synapse
Preganglonic fiber
Ganglion
ANS 2nd synapse
Postganglionic fiber
Target organ
SomNS (the only synapse is called the NMJ)
Somatic nerve
Neuromuscular endplate
Divisions of the ANS
o
Sympathetic
o
Parasympathetic
o
Enteric - 3rd division of ANS ; intrinsic (found at that site only) autonomic innervation of
the intestines; discovered in isolated tissue experiments - intestines preserved their
secretions and activity ; The extrinsic are the symp and parasymp.
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Mediated by 2 plexuses (nerve networks):
Auerbach
Meissner (both are responsible for motility and secretions
Involves diff. Set of NT:
ATP
VIP (vasoactiveintestinal peptide)
Substance P
Neuropeptide Y
Criteria
Sympathetic = adrenergic
Parasympathetic = cholinergic
1.
9.
Thoracolumbar (exit together with
T1-T12 and L1-L5)
Craniosacral (CN 3,7,9, 10) and
S1-S4
Near the Spinal Cord
(paravertebral, pre-vertebral
chains)
Near target organ
2.
9.
Anatomic {draw}
Origin / roots of
fiber
Ii. Location of ganglia
{draw}
Iii. Length of fiber
Pregang.
Postgang.
NT
Pregang
Ii. Postgang
Receptors
(postsynap)
9.
Ganglionic
Short
long
Long
Short
Ach
NE [NOR-epi means NO CH3 at
Nitrogen], Epi [with CH3],
Dopamine
Ach
Ach (both Ach kaya cholinergic)
Nicotinic (NsubN or Nn) **Nm predominantly found in somatic
NS, in neuromuscular endplate
Nicotinic (NsubN or Nn) thus pag
ganglionic blocker you block
both
Alpha, beta, dopamine (D)
Muscarinic (M), nicotinic (N)
3.
Ii. Target organ
4.
Responses /
effects
9.
Generalresponse
Ii. Specific
Heart
Eyes Pupils
Bronchi
GIT walls
sphincters
Urinary bladder
Detrussor
Trigone
Fight/flight/fright responses - all
Rest and digest responses - all
stresses (always think sympathetic, maintenance
so opposite, parasym na)
Inc HR (tachycardia)
Dilate (mydriasis)
Bronchodilation
Relaxation
Closure (both may lead to
constipation = ileus)
Dec HR (bradycardia)
Constriction (miosis)
Bronchoconstriction
Contraction
Opening (both may lead to
peristalsis)
Relax
Closure (both will lead to urinary
Contraction
Opening both will lead to
Sweat glands
retention)
Apocrine (palms and soles) - inc.
sweating
1.
2.
3.
4.
1.
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urination = enuresis =
micturation)
Eccrine Sweat glands
(thermoregulation and widely
distributed) - inc. sweating
SYMPATHETIC DRUGS
Biosynthesis of cathecolamines
Receptors, location and responses
Sympathomimetics = agonists
Sympatholytics = antagonist
BIOSYNTHESIS OF CATECHOLAMINES
Locations: sympathetic postgang fiber, adrenal medulla, CNS
Steps:
Active uptake of precursor aa = tyrosine
Conversion of tyrosine to DOPA [ tyrosine ---Tyrosine Hydroxylase---> DOPA
(dihydroxyphenylalanine) *rate limiting step - slowest*
Can be inh by metyrosine (methyl tyrosine)
Formation of 1st cathecol. = dopamine [ DOPA ---DOPA decarboxylase---> dopamine *central,
peripheral - may limit avail. Of DOPA in BBB*
Vesicular uptake of dopamine at presynapse -- dapat mastore agad si dopamine rationale: MAO
enzyme readily destroy dopamine at the presynapse --- can be inh by reserpine (thus inh symp
response)
Vesicular metabolism of dopamine to NE within the vesicles [ dopamine ---dopamine Bhydroxylase---> NE (major symp NT)]
**happens only at adrenal medulla, not in symp postgan fiber** NE ---PENMT
(phenylethanolamine N-methyl transferase---> Epi (adrenaline) {structure}
Exocytotic release of NT *postgang symp fiber ----> NE*
Can be inh by guanethidine and guanadrel
Can be stimulated by ephedrine, amphetamines, angiotensin II (impt in DI), tyramine (pero di tayo
naghaHTN kasi may MAO tayo sa presynapse,unless Px is on MAOi)
FATE OF CATHECOL. (NE) AT THE CLEFT
Binding to postsynap receptors
Metabolism by COMT and MAO
Re-uptake of NE via Uptake 1 transporter (it goes back to presynap)
NE is conserved and returned to presynap
Major mech. Of loss of NE from cleft (70%)
Can be inh by drugs such as Cocaine, TCA (tricyclic antidepressants), NaRI or NRI (NE or
noradrenaline reuptake inhibitor)
2.
Receptors, Locations and Response
Receptors
1.
Location
Response
Alpha
i.
Alpha 1 (Gq
Smooth muscles [VP of RP]
Contraction
linked)
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ii.
2.
Alpha 2
(part of vascular s.m
tone / vasomotor area
- cont. releases NE and
causes b.v. To be
constricted)
Vascular s.m. (blood
vessels)
Prostatic s.m. &bladder
trigone and sphincter
Radial muscles of iris
(move away from pupils
{draw}
Pilomotor s.m.
Presynaptic (Gi linked)
CNS - inh release of NE
Postsynap (Gq linked)
Vascular s.m.
Sedation, depression
Peripheral vasodilation
Peripheral vasoconstriction
Beta
i.
ii.
Beta 1 (Gs
linked)
[HJ]
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Heart (dominant
adrenergic Recep.)
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Juxtaglomerular (JG)
apparatus
Beta2 (Gs
linked)
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Smooth muscles [BUVS]
Bronchial s.m.
Uterine s.m.
Vascular s.m. Of blood
vessels that supply the
skeletal m.
Skeletal m. (SomNS)
o
NM endplate
(postsynap)
o
iii.
ii.
Muscle cells
Beta3
Dopamine (D)
i.
D1
D2-D4
Inotropism - inc. in strength
of contraction
Chronotropism - inc. in HR
(tachycard)
Dromotropism - inc. rate of
conduction across AV
node{draw} - shorten delay
Renin release
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3.
Vasoconstriction
Contraction ---> urinary
retention (esp. when prostate
is enlarged)
Contraction ---> shortened
radial m. ---> mydriasis
Contraction ---> goosebumps
/ gooseflesh
adipose
[R & S b.v. ; GIT & CNS]
Renal and splanchnic
(abdominal) b.v.
Relaxation
Bronchodilation
Uterine relaxation (for premature labor)= tocolysis
Vasodilation(so you can
tolerate exercise longer
otherwise, easy fatigability)
Musc. Contraction --->
tremors (Inderal(R) - controls
tremors)
Movement of K into cell
(inward K conductance)or
transcellular shift of K into
cells --->
Hypokalemia (musc.
Weakness) SE of B2
overstimulation
Lipolysis
Peripheral = GIT
CNS
3.
a.
b.
c.
A.
Vasodilation (renal
vasodilation - inc. filtration so
GFR inc. ---> diuresis)
Loss of peristalsis ---> nausea
and vomiting (stretching of
stomach stimulates irritant
Chemicals that may cause
vomiting)
Levo-dopa ---> causes nausea
and vomiting (SE)
Behavior and perception
regulation
Modulation of motor
activities (shuffling gait, rigid
if low Dopamine)
SYMPATHOMIMETIC DRUGS (adrenergic agonist)
Direct acting adrenergic (directly stimulate the receptors)
Indirect (produce a sympathetic response by inc. levels of cathecol.)
Centrally-acting sympathomimetics
DIRECT ACTING ADRENERGIC AGONIST -directly act on receptor
i.
Non-selective agonists - stimulate>1 general receptor (alpha + beta +/- D)
Natural Cathecolamines (NE, Epi, Dopamine)
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Pharmacodynamics: greater affinity for B than for A.
LOW DOSES ---> stim. B
HIGH DOSES ---> stim. B + stim. A (e.g. Epi: B1 = B2 (low dose) ---> A1 (high dose)
; NE: B1 ---> A1 ; Dopamine: D1 ---> B1 --->A1 [NO NATURAL A2 AGONIST, ONLY
EPI STIM. B2)
Pharmacokinetics: very poor PO bioav. Thus routes are parenteral (IV, SQ),
inhalational
Poor oral bioav. - they are very acid labile, very extensive First Pass effect, can
limit their own absorption (they're all A1 agonist thus they are all
vasoconstriction thus less perfusion)
Metabolism: (1) COMT (2) MAO
Common metabolite: VMA- vanillyl mandelic acid (3-methoxy-4-hydroxymandelic acid) - important in Dx of Pheochromocytoma (adrenal medulla)
Clinical Uses of Cathecolamine:
 Epinephrine - 1st line cardiac stimulant (1st choice in Advanced Cardiac
Life Support - use of drugs and machine that introduce electric shock) [1-3
mg every 3-5 mins (give it until Px is revived) IV]
 Anaphylactic shock / anaphylaxis, and anaphylactoid rxn [0.30.5 mg SQ every 15-20mins up to 3 doses] anaphylaxis /
anaphylactic shock and anaphylactoid - excessive histamine
release from cells but anaphylaxis & shock involves IgE
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mediated(allergy); anaphylactoid - NOT allergic (can be a
direct effect of opioids)
NOTE: additional benefit of Epi - stabilize mast cell membrane
(thus prevent further release of histamine)
 Local vasoconstrictor given with local anesthetic (lidocaine)
 Mx of glaucoma [Dipivefrin (R) - pivalic ester derivative of Epi
and is hydrolyzed in aqueous humor to release Epi]
Norepinephrine - 1st line inotropic in the mx of septic(infection) shock
(hypotension that does not resolve or improve with IV fluid) route: IV
infusion
Dopamine - route: IV infusion
Dose
Effects
1-3 mcg/kg/min
Stim. D1 receptor ---> renal vasodilation (inc GFR
) ---> diuretic
2-5 mcg/kg/min
Additional B1 stimulation----> inotropic effect
>/=
5mcg/kg/min
Additional A1 stim. ---> vasoconstriction
Use: Mx of septic shock, cardiogenic shock(hypotension due to cardiac
problem), acute heart failure that are complicated by oligouria (<500mL
urine in 24 hrs) /anuria (<50mL urine in 24 hrs) /low GFR
Common Toxicity of Cathecolamines
a. B1 overstimulation ---> tachyarrhythmias
b. A1 overstimulation ---> peripheral vasoconstriction ---> digital necrosis
ii.Selective - stimulate 1 general type (alpha or beta or D)**pag selective almost synthetic**
1.
B-nonselective agonist - selective for B but does not choose bet. B1 and B2
e.g. Isoproterenol - synthetic catecholamine; alternative inotropic IV infusion for
shock states or acute Heart failure
 Historical use: bronchial asthma (1st drug for bronchial
asthma to become available as metered dose inhaler)
SE: tachyphylaxis (rapid development of tolerance) to
B2 but not to B1 effect therefore Px keep on inc. dose -- Px died earlier due to B1 overstimulation
(tachyarrhythmia) kaya ngayon ginagamit na lang siya
for B1 effect
2. B1 selective agoinst
Dobutamine - IV infusion ; 1st line drug in Mx of cardiogenic shock and acute HF
3. B2 selective agonist
a. Tocolytics - ritodrine, isoxsuphrine, terbutaline (control premature labor)
b. Mx of bronchial asthma (and sometimes COPD)
1. SABAs - short acting B2 agonist
Salbutamol (US - albuterol) ; terbutaline
Route: inhalational (metered dose inhalers MDI) whatever
device you use, there is no advantage, same effect pa din ;
P.O.; Terbutaline only - SQ
1st line bronchodilators in acute asthma attacks
2. LABAs - long acting B2 agonist
Salmeterol (MDI), formoterol (MDI), bambuterol - PO
Alternative controllers in bronchial asthma
Recent recommendation : Px should be removed from LABAs
due to inc. hospitalizations and death (but ok pa din for COPD)
c. Other uses:
 Adjuncts in the Mx of hyperkalemia (to make K go into cell)
 Terbutaline - Mx of symptomatic bradycardia (has more significant
B1 effects than the other - hindi sila pure B2 ha, preferred lang,
pero meron pa din, may ratio lang - binding affinity is greater in one
receptor over the other
d. SE: tachycard, palpitations (augmented by other agents with inotropic or
chronotropic activity) ; hypokalemia (--->muscle weakness), tremors,
tolerance (fenoterol ---> never given as single agent)
4. A1 selective agonist - hypertensive agents
Phenylephrine, propyhexedrine, methoxamine, oxymetazoline,
tetrahydrozoline, Xylometazoline
Effects: vasoconstriction
Risk: Urinary retention
Clinical uses:
 nasal decongestants (colds) - dimetapp (R)- PPA replaced by PE
decolgen neozep etc. (PO or intranasal)
 Mx of hypotension (IV)
 Local vasoconstrictors (SQ) together with local anesthetics
 Ocular decongestants - eye redness
 Methoxamine - stimulate few A1 receptors in the heart ---> Mx of
arrhythmia
SE / Toxicities:
 Systemic agent (PO / parenteral)
 exacerbate HTN due to vasoconstricting effect - elicit Hx of HTN
from Px - avoid if Px has Hx of HTN and if with concurrent use
of MAOi (remedy: intranasal)
 Precipitate urinary retention in Px with BPH (remedy: intranasal)
 Tolerance - as nasal decongestant ---> given only for nmt 5 days
(beyond 5 days, decongestant effect is lost)
 Nasal spray
 Rhinitis medicamentosa (rebound congestion / rebound
hyperemia) when intranasal A1 agonist is used beyond 3 days
(limit ito){draw} you give vasoconstrictor to reduce space and
permit air but in rebound, blood vessels will dilate even more.
Rebound - worse than the original. Congested b.v are dilated,
mucus narrow down passage way so give vasoconstrictor but
beyond 3 days, may tolerance so b.v will dilate even more.
5. A2 agonist
i.
ii.
Clonidine (apraclonidine, brimonidine) ; methyldopa ; guanfacine,
guanabenz
Effects: presynaptic CNS A2 receptors
SE: sedation, depression **sedation - avoid activities that require full
mental alertness ; practical note - dont give them to Px with occupations
requiring full mental alertness** sa pilots and pwede lang for allergy Loratadine, phexophenadrine **
** depression - do not give to Px with Hx of mental depressions**
Common clinical use:
 Mx of HTN - hypotensive agents / anti-HTN
Clonidine - active drug by itself (Route: PO, IV, Intranasal)
PO and IV effects: stim. Of postsynap A2 in the peripheral b.v. --->
vasoconstriction (when in sys. Circ) -initial but transient response
stim. Of presynap CNS A2 receptors --->
vasodilation(when in brain) cross BBB - final longer
lasting effect
** you see both but at diff. Times** insert: may initially
cause transient inc. In BP
Clinical Uses:
 Alternative in Mx of HTN - useful in HTNsive crisis and Mx of HTN in
Px on hemodialysis (practically non-functional kidneys ---> machine
clean blood - directly dilate b.v. They are in the blood - removed
also in the blood, give clonidine kasi anti-HTN effect is in the brain :)
and you do not hemodialyse the brain. Ahehehe. So for Px on
Hemodialysis, give a drug that will act not on the b.v since they will
just be removed. Give a drug that will control BP areas in the brain.
 Nasal spray (local effect) - nasal decongestant
 Related drugs: apraclonidine, brimonidine (act only on nasal
mucosal bv)
 Alternative in Mx of ADHD
SE: will talk about this later
 Clonidine-withdrawal-induced-rebound HTN (even worse than
untreated state, higher BP)
 Can occur even in just 1-2 missed doses
 Remedies: simply re-institute clonidine (drink missed
dose) ; give other drugs - Labetalol ; give Na
Nitroprusside IV infusion if Px goes into HTNsive crisis
Methyldopa - alpha-methyl-DOPA
MOA: prodrug ---> cross BBB ---> in the brain = metab. To yield active drug
Metabolism in the brain: A-Methyl-DOPA ---DOPA decarboxylase---> Amethyl Dopamine ---Dopamine-B-hydroxylase---> A-methyl NE [active
drug, false NT (looks like NE- stim. A1 and B1 and NO A2 effect) but this
false NT has NO A1, NO B1 but has A2 effect]
Clinical Use:
 Mx of HTN in pregnancy (very few drugs can be given to pregnant
women) but NOW Nifedipine, hydralazine, labetalol are also used
for HTN (pre-eclampsia, eclampsia, gestational HTN, chronic HTN in
pregnancy)
SE:
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Sedation, depression (syempre)
Hepatotoxicity at doses > 2g/day (limit dose ito)
Positive Coombs test - indicate presence of Ab that can cause
hemolytic anemia - can be caused by methyldopa and pens
(immunohemolytic anemia - assoc. With pens)
6. D1 - selective agonist
Fenoldopam
Effect: vasodilator (IV) esp. in abdominal vessels
Use: adjunct or alternative in Mx of HTNsive crisis
Common SE: diuresis and natriuresis (but not that common)
B.
INDIRECT-ACTING SYMPATHOMIMETIC
Effect: Inc. in conc or level of NE at the cleft
i. Re-uptake inhr. - inh. The mech. Of loss of NE from cleft [TCA, cocaine, NRI]
ii. Releasers - stim. Exocytotic release of NE [amphetamine, ephedrine]
Ephedrine
 "ma huang"
 Dual MOA
 Direct receptor agonism at the A1, B1, and B2 **nonselective**
 Stim. Release of NE into the cleft **more significant mechanism**
 Clinical Use:
 Nasal decongestant - involves direct application into the nostrils (ephedrine soln)
 Mx of acute Hypotension esp. during surgery (IV bolus)
 SE:
 Exacerbate HTN - risk of HTNsive crisis in Px on MAOi (ContraIndicated even as nasal
decogestant)
 Risk of tachyarrhythmia
 Palpitations
 Illicit use: performance enhancer and fat burner
C.
CENTRALLY-ACTING SYMPATHOMIMENTICS
Amphetamine (methamphetamine), methylphenidate / mephenidate, phentermine,
phenmetrazone, PPA = phenylpropanolamine
 Clinical Use:
 Mx of Attention deficit Hyperactive disorder (ADHD)[DOC: methylphenidate alternative:
amphetamine - can cause adult onset ADHD, clonidine, TCAs, SSRI]
Mephenidate MOA: unkown, proposed: release more NE until maubos ang stores --->
bababa NE levels
 Anorexiants / appetite suppressants - 'dieting pills' [phentermine, phenmetazone]
Ionamine - phentermine in diff. Dosage forms (ion exhange resin)
 Mx of narcolepsy [amphetamine phentermine]
 SE:
 Risk of addiction (uppers sila e) amphetamine - most addictive (US - ADHD secondary to
addiction)
 PPA - inc. hemorrhagic stroke in young women(due to dieting pills)
 Phentermine - inc. risk of primary pulmonary HTN in young women (due to dieting pills)
- will die in 2-3 yrs when symptomatic na
4.
a.
b.
a.
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SYMPATHOLYTICS = ADRENERGIC ANTAGONIST
Alpha-blockers (A-adrenergic antagonist)
B-blockers (B-adrenergic antagonist)
ALPHA BLOCKERS
Effects:
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Vasodilation
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Relieve urinary retention
Types:
i.
Nonselective A-blockers - block both A1=A2
a.
Irreversible: Phenoxybenzamine
b.
Reversible: Phentolamine
ii.
Selective A1-blockers (-zosin) - Prazosin, Doxazosin, Alfuzosin, Terazosin, Tamsulosin
iii.
Selective A2-blockers - Yohimbine, Rauwolfscine
Clinical Use:
o
Mx of HTN inPx with Pheochromocytoma
o
Mx of Sx in Px with Raynaud's syndrome
o
Mx of HTN in BPH
o
Mx of urinary retention in BPH (together sila ng former bullet)
o
Phenoxybenzamine - Mx of Sx of Carcinoid syndrome
o
Phentolamine - Mx of erectile dysfunction (injected directly to penile shaft) **viagra (R)
and andros (R)- sildenafil citrate, cialis (R) tadalafil, levitra (R) vardenafil - PO**
**pheochromocytoma - hypersecretory tumor or hyperplasia of adrenal medulla ---> excessive
release of NE & Epi (NE > Epi kasi hindi na nakoconvert si NE to Epi, narerelease na agad)
Clinical manifestations:
 Hypersympathetic (paroxysmal HTN, tachycard., palpitations, nervousness, inc. hostility
(rare), sweating
Diagnosis:
 Radiographic = MRI or CT Scan (showing adrenal medulla or tumor)
 Biochemical = demonstrate excessive conc. Of catecholamines - check urine or serum
VMA assay
Mx of HTN in pheochrom. (may proper sequence of Tx)
 Give A-blocker first then add a B-blocker
 If reversed (B-blocker before A-blocker): you will worsen HTN
NE 100 mole.
70B receptors
70A receptors
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They will all go up to B receptors first (higher affinity dito), so 30 na lang pupunta sa A.
**if mauna A, 70 punta agad sa A thus vasodilation right away kasi blocked na si
vasoconstricting effect ng A1. If sabay si A at B, ibablock si B agad, so may 30 lang na
punta sa A, thus may vasoconstriction pa din, hindi kasi lahat blocked.
Choice of A-blockers: Phenoxybenzamine, Phentolamine, A1-blockers
Blocking A2 receptors will worsen pheochromo.
**Raynaud's syndrome - digital vasospasm in response to a cold environment
 If (+) pain = (+) ischemia ongoing ---> need to treat: vasodilators ; if mag-infarct na --->

b.
necrosis (irreversible)
 Tx: A-blockers, CCBs
**Carcinoid syndrome - malignancy or CA involving enterochromaffin cells (storage sites of
serotonin - 90% of all serotonin) of the intestines
o
Hyper secretion of serotonin
Clinical Manifestation:
 Flushing
 Watery diarrhea
 Severe HA
o Cant be surgery - malingant na ito pag symptomatic na
o Tx: control serotonin Sx (palliative treatment - symptomatic relief na lang) ---> 5-HT
antagonist *phenoxybenzamine - has 5-HT blocking effect
SE:
 A1 blocker - first dose phenomenon: orthostatic / postural HTN + syncope (transient loss
of consciousness)
Seen with the very first dose, any sudden inc. in dose and concurrent use of other
anti-HTNsive
Remedies: give all doses at bedtime (Px will not lose consciousness kasi asleep na) ;
start low go slow; avoid use of other anti-HTNsive (A1 blocker is the DOC for HTNsive
Px with BPH)
B-blockers
Classification:
i.Based on selectivity
1. Nonselective B - the rest of olols and alols are here
2. B1 selective = cardio selective BB (alols and olols)
Bisoprolol, betaxolol
Esmolol
Acebutolol, atenolol
Metoprolol
NOTE: all BBs (cardioselective, nonselective) are generally CI in BA and COPD (may effect pa
rin sila sa A receptors, preferred lang si B receptor)
ii.Based on intrinsic sympathomimetic (agonist) activity = partial agonist = mixed agonist antagonist
Carteolol
Labetalol
Acebutolol (less common A more common si atenolol)
Pindolol (less common P more common si propanolol)
Advantage: less assoc. With rebound tachycard./HTN when withdrawn
iii.Based on membrane stabilizing activity = local anesthetic effect = quinidine (class IA antiarrhyt)
like effect (Na chan. Blockers)
Pindolol
Acebutolol
Labetalol
Propranolol
Metoprolol
Disadvantage: cannot be given as topical opthalmic drops (may local anesthetic effect kasi
so di recognized foreign bodies ---> ulceration and infection of cornea)
iv.Based on the presence of alpha-blocking activity
 Mixed A-B blockers (e.g. Labetalol &Carvedilol)
***shortest acting is esmolol - avail. only as IV)***
o
o
o
o
o
o
o
o
o
o
o
o
o
Clinical Uses:
First line drugs for HTN esp. useful if with prior Hx of MI
MOA:
i.
MAJOR MECH -Ability to block B1 receptor in JG apparatus ---> dec. in renin
release
ii.
Block of B1 in the heart ---> dec. in inotropic activity
Mx of Angina Pectoris
DOC in long-term Mx of CSAP (chronic stable angina pectoris)
Mx of arrhythmias
Propranolol
Esmolol
Acebutolol
Mx of stable CHF - do not require ICU admission anymore (if ICU - unstable) ; Px have
responded very well to at least 2 weeks of anti-CHF Tx regimen
 Add on Tx, given at very low doses
 ONLY THREE DRUGS FOR CHF: Metoprolol (2.5-10mg/day) **pero sa HTN
50mg/day**, Bisoprolol, Carvedilol
Mx of glaucoma
Mxof sympathetic Sx of hyperthyroidism
Prophylaxis for migraine
Familial tremors / stage fright / performance anxiety
SE:
Mask Sx of hypoglycemia (autonomic Sx) - tachycard., palpitations, diaphoresis (cold
sweats), tremors ---> all due to Epi in response to hypogly ---> epi goes up
** NOTE: counter regulator hormones in response to hypogly. -(1) Epi (resp. For initial
manifestations of hypogly) ; (2) glucagon, (3) growth hormone, (4) cortisol [first 2 are fast
acting, latter 2 are slow acting] ----> CNS phase : coma & death
UNFORTUNATELY: BB BLOCK THESE SX! So matutulog siya, patay na!
 CAUTION: advise DM Px on hypogly therapy to monitor blood sugar more frequently if
they are on BBs.
 Very helpful ang BB for DM Px
Bradycardia and heart block
Dyslipidemia
Hyperuricemia
Withdrawal of therapy: rebound tachycard./HTN if abruptly withdrawn [REMEDY: taper
dose over 10-14 days before stopping Tx] - less risk if you use PAL
CI: i. canadian and australian guideline: should NOT given to age > 65 yrs ; HR < 60 ; with preexisting heart block
Ii. Current Tx of a non-DHP CCB (diltiazem, verapamil ---> same affect na kasi sila)
iii. Unstable CHF (CHF with ongoing exacerbation ; CHF Px not yet stabilized on
conventional Tx)
iv. Reduced exercise tolerance
C.
1.
2.
3.
4.
1.
PARASYMPATHETIC DRUGS
Biosynthesis
Receptors, location, response
Parasympathomimetics / cholinergic agonist
Parasympatholytics / cholinergic antagonist
BIOSYNTHESIS OF Ach:
Location: in all preganglionic fiber (symp at para) ; parasym postgang fiber ; somatic nerves, CNS
(brain)
Steps:
o Active uptake of choline into the presynapse {draw}
Rate-limiting step (slowest)
Can be inh. By hemicholiniums
o Formation of Ach (single step metab.)
Choline + acetyl CoA ---Choline acyl transferase---> Ach
o Vesicular uptake of Ach (at the presynapse) - Ach mole. Are concentrated within vesicles
(each vesicle can contain 10k-50k mole. In one vesicle
Can be inh. By Vesamicol
o Quantal release of Ach into the cleft (quantal - millions of Ach being released at any given
time)
Can be inh. By Botulinum toxin / botox
FATE OF Ach AT THE CLEFT
Can bind to postsynap receptors
(most impt fate) metabolism by Acetylcholinesterase (AchE) ---> highly efficient (that's why
you need quantal release of Ach)
Ach ---AchE---> choline + acetate
CHOLINESTERASES:
a. Acetylcholinesterase - true cholinesterase = RBC cholinesterase ; Very specific for Ach
b. Butyrylcholinesterase - Pseudo cholinesterase = PLASMA cholinesterase ; not specific can act on any ester except Ach
o
o
2.
Receptors, Location, Response
Receptors
1.
Location
i.
Muscarinic
M1
ii.
M2
Nerves that supply gastric
glands (branches of vagus
nerve CN10)
Nerves that supply the
heart (branches of vagus
Response
Gastric acid secretion
Bradycard., (-) dromotropism
(slow rate of conduction across AV
node [vagotonic response]
iii.
M3 (Gq linked)
nerve)







2.
Nicotinic (N)
i.
Nn (neural)
ii.
Nm (muscular
- not autonomic,
somatic ito)





Smooth muscles
Eyes (circular m. Of
pupils)
Eyes (ciliary muscles)
Bronchial s.m.
GIT (walls)
GIT (sphincters)
Urinary bladder
(detrussor muscle)
Urinary bladder
(sphincter and trigone)
Exocrine glands
Lacrimal
Salivary
Bronchial
GIT
Eccrine sweat gland
Ganglia, CNS (both found
in S&P)
NM endplate
3.
Pupilloconstriction (miosis)
Contraction = accommodation
(ability to recognize objects that
are near your face)
Bronchospasm /
bronchoconstriction
Contraction (thus lead to
peristalsis)
Relaxation = opening (thus lead to
peristalsis)
Contraction (thus lead to
urination)
Relaxation = opening (thus lead to
urination)
**diuresis - inc urine volume not
pass out urine**
Secretion
Lacrimation
Salivation
Inc. bronchial gland secretion
Inc. GIT secretion
Sweating
Stimulation (may it be Sym/Para)
Skeletal m. contraction
PARASYMPATHOMIMETICS = CHOLINERGIC AGONIST
a.
Direct-acting Cholinergic agonists - stim. Directly cholinergic receptors
i.
Choline ester
Acetylcholine (M, N)

Betacholine / Urecholine

Butanechol (? - ets)(M)

Methacoline (M, N)

Carbachol (N, M)

ii. Cholinergic alkaloids
Pilocarpine (M)

Muscarine (M)

Nicotine (N)

Lobeline (N)

b. Indirect-acting cholinomimetic - do not stim. Receptors BUT can inc. conc. Of Ach in the cleft
MOA: inh. AchEsterase [anti-cholinesterases]
i. Short-acting anti-cholinesterase - duration of axn does not exceed 30mins (15-20 mins
on ave)
Chemical structure: amino alcohols

Inhibition: reversible

e.g. Edrophonium (tensilon (R))

ii. Intermediate-to-long-acting (2 hrs up to less than 24 hrs - 2<X<24)
Chemical: organocarbamates (carbamyl esters)

Inhibition: reversible

e.g. Neostigmine, Physostigmine, pyridostigmine, ambenonium, demecarium

iii. Very long-acting agents - duration is days to weeks
Chemical: organophosphates

Inhibition: depends on duration of exposure

1st 24-48 hrs ---> potentially reversible
> 24-48 hrs -----> definitely Irreversible (due to "aging" of PO4 bond which
is a covalent bond - like forming a new mole.)
 e.g Ecothiophate
Malathion, Parathion
Isofluorophate
Sarin, Tabun, Soman (nerve gases for chemical warfare)
iv. Miscellaneous agents - useful for AD (alzheimer's dementia)
Rivastigmine, Tacrine, Donepezil

o
o
o
o
o
o
o
o
Clinical Uses of cholinergic agonists:
Dx and Mx of Myasthenia Gravis
Mx of neuromuscular blocker toxicity -useful to counteract effect of curare derivatives
(atracurium etc.) --->respiratory paralysis
 Edrophonium - more commonly used in clinics (curare effect is short lived, Neostigmine
(for arrow poision yey!) - long acting ito so Px may develop cholinergic crisis kaya
edrophonium and gamit but as antidote, ito ang gamit
Mx of glaucoma
 Drugs: ecothiopate, carbachol
Mx of non-obstructive ileus
 Pilocarpine (direct acting cholinergic alkaloid) comb. With physostigmine(indirect
acting), bethanechol
Mx of atropine poisoning (previously: physostigmine - 1980's)
1990's - higher ang risk for CNS effects than benefit ni physostigmine
NOW: Neostigmine (quat. ammonium Peripheral agents), pilocarpine, NO LONGER
PHYSOSTIGMINE EVEN IN SEVERE CASES
If may seizure give anticonvulsant (diazepam)
Mx of urinary retention in BPH
 Bethanechol = urecholine
Smoking cessation
 Nicotine, lobeline (pcog)
Mx of AD
 Rivastigmine, Tacrine, Donepezil
Myasthenia Gravis








4.
Autoimmune disease char. By presence of Ab that are directed vs. Ach receptors "anti-ACR
antibodies"
ACR that are commonly destroyed are the Nm receptors
Assoc. With hyperfunctioning / tumor of thymus gland (big when young, responsible For
maturation of Tcell / T lymphocyte)
SSx: progressive muscle weakness
Initial: late afternoon drooping of eyelids (subject to fatigability) ---> late afternoon
weakness (cant seem to rise from a seated position) ---> generalized m. Weakness
(paralysis)
Final: paralysis of the diaphragm (live na lang if put in mechanical ventilator)
Dx:
 Immunologic - documenting/ assaying presence of anti-ACR Ab
 Pharmacologic - Tensilon(R) test (short lived improvement in muscle strength) ---> inject
tensilon ---> in a matter of minutes, she will regain strength ---> 15-20 mins droop
again and cant stand up again
NOTE: another use of Tensilon (R) in MG is to differentiate bet. CHOLINERGIC CRISIS
and MYASTHENIC CRISIS
Now able to walk etc then all of a sudden weak again even on treatment, consider if
(1) overtreating Px / cholinergic crisis or is the Px(2) undertreatment / myasthenic
crisis
Weak and then becomes weaker (skeletal muscle contraction then spasm --->
weakness [?]) with tensilon - overtx
Weak then becomes strong with tensilon - undertx
Tx: (cholinergic agonist)
 Neostigmine, Pyridostigmine, Ambenonium
 Immunosuppressants (prednisone at high dose)
 Removal of thymoma or thymus remnants (thymic stripping)
Cholinergic SE and toxicities:
 Diarrhea
 Urination
 Miosis
 Bradycard
 Bronchospasm
 Emesis
 Lacrimation
 Salivation & Sweating
Mx of Toxicities:
 Primary Tx (DOC) for toxicities with ALL cholinergic agonist - Initial Tx is Atropine (base
treatment)
 For organoPO4 poisoning ONLY - special tx - when organoPO4 is <24-48 hrs duration Regenerator compounds - Oximes
-PAM (pralidoxime) ; DAM (diacetyl monoxide) ; but you still have to give atropine
(base tx ito e)
PARASYMPATHOLYTICS = CHOLINERGIC ANTAGONIST
a.
Anti-muscarinic = anticholinergic (si antimuscarinic siya ang nirerefer na anticholinergic)
= atropine-like effects or SE
 Prototype: anti-muscarinic all through out = Atropine




Effects due to M1 block- dec. in GIT secretion
M2 block - tachycard. And (+) dromotropism ---> Vagolytic effect (remember
vagotonic?)
M3 block: s.m ---> relax
 Eyes - mydriasis, Cycloplegia / loss of near vision (Blind as a bat)
 Cycloplegia - relaxation / paralysis of ciliary m. ---> move
towards each other ---> can close canal of schlemm --->
absolute CI: narrow-angled glaucoma
Ciliary muscles contract - move away from each other - open
canal of schlemm
Ciliary muscles relax - move towards each other - close canal
of schlemm
 Glaucoma - problem is inc. in IOP due to inc. aq. Humor vol.
 may be overproduction (normal drainage) - angle is
open or open/wide-angle glaucoma
 problem in drainage (normal production) - narrow-angle
glaucoma
 Complication if given cycloplegic ---> angle will
close ---> acute angle closure glaucoma (can cause
blindness in 24-48 hrs --> retina will be impinged --> madami b.v and optic nerve is there)
 Bronchi - bronchodilation
 GIT - constipation & ileus
 Urinary bladder - urinary retention
 Exocrine glands - dec. secretion (lacrimal, saliva, etc.) / drying effect (Dry
as a bone)
 Anhydrosis - absence of sweating (eccrine - thermoregulator)
 Complication: hyperthermia / atropine fever
(potentially fatal in children) - hot as a hare / hot as hell
 Flushing / cutaneous vasodilation (so that heat will be
released) - red as a beet
 CNS effects (atropine can cross BBB)
 CNS agitation, confusion, seizure, acute psychotic reaction mad as a hatter - give diazepam
Clinical Uses of Atropine
 Topical: mydriatic-cyclopegic
 Systemic (IV): Mx of symptomatic bradycard. Or heart block
 Mx of anti-Ach overdose (organoPO4)
 Given with diphenoxylate (opioid anti-diarrheal - can cross BBB --->
minimal euphoria, loperamide cant cross BBB) to minimize risk of
addiction with diphenoxylate
 e.g. 10 tablets ---> they will experience the alice in wonderland
due to atropine toxicity so they will stop :) ahahahaha
 Other anti-muscarinics
1. CNS-acting:
a. Scopolamine
 Sedative (dreamless sleep)


Use: anti-motion sickness
Historical use: obstetric anesthetic - "twilight sleep"
Scopolamine(sedative) + morphine(analgesic)
b. Biperiden (akineton(R))
Benztropine (cogentin (R))
Trihexyphenidyl (artane (R))
 Use: adjuncts in tx of parkinsonism; Mx of some Sx of
EPS(extrapyramidal Sx) assoc. With anti-psychotic tx
2. Eyes - mydriatics-cycloplegic
a. Atropine - topical (effect lasts for 72 hrs)
b. Homatropine
c. Tropicamide
d. Cyclopentolate
 Mydriatics: indicated to allow full exam of retina (if pupils are
constricted, it will be hard to examine retina)
 Cycloplegics - to relax ciliary m. In the mx of eye pain due to ciliary
spasms (infections/inflammation)
 CI: in Px with narrow-angled glaucoma as mentioned a while ago
3. Bronchi = bronchodilators
a. Ipratropium Br - usually comb. With salbutamol (albuterol in US)
Combivent (R)
b. Oxytropium
c. Tiotropium
 Choice bronchodilator in COPD
 Alternative adjunct bronchodilator in BA
4. GIT and urinary bladder
a. M1-selective blockers - useful for hyperacidity (adjuncts)
 Pirenzepine, Telenzepine
b. M3-blockers - useful for GIT and urinary bladder conditions
Hypermotility disorders ---> abdominal cramps
Urinary incontinence, abdominal colic
 Hyoscine-N-butyl bromide
 Dicycloverin
 Glycopyrrolate, clidinium, dicyclomine
 Methscopolamine
b. Anti-nicotinic - may specific group names
i. Neuromuscular blockers
Target receptor: Nm (kaya these drugs act on somatic NS)
a. Depolarizing ('stimulate') irreversible noncompetitive Nm blocker
e.g. Succinyl choline MOA: irreversibly STIMULATE Nm receptor but it is
IRREVERSIBLE
2 phases of effects
 Phase 1: continuous and tetanic skeletal m. Contraction[cycle ito na
may contraction-relaxation] w/o relaxation (sa succinyl choline,
puro contraction lang) so yung muscle contraction dito ay
INEFFECTIVE ---> muscle fatigue and loss of Ca ions

Phase 2: skeletal muscle paralysis (flaccid paralysis) kasi wala na
Ca2+ to stim. Contraction
b. Non-depolarizing reversible competitive Nm blocker
MOA: directly INHIBIT Nm receptor ---> skeletal muscle paralysis agad
e.g. Curare derivatives (from natural product L-tubocurarine)
2 classes:
 Isoquinoline structure (-curium)
Atracurium, mivacurium
 Steroidal nucleus (-curonium)
Pancuronium, vecuronium
Clinical Uses:
Skeletal muscle relaxants during surgery (muscles should be retracted in abdominal
surgery)
Side Effects / toxicities:
Shared toxicity: diaphragmatic muscle paralysis
** in case of prolonged paralysis - antidote: edrophonium (clinics) and
neostigmine ( board exam)
 Succinyl choline SE: muscle pain
 myositis or rhabdomyolysis (break down of muscles) ---> HYPERKALEMIA
(kasi cells burst/breakdown so lalabas K) ---> heart may stop
---> myoglobinemia (myoglobin
is toxic to renal tubules) = acute
tubular necrosis (ARF)
 lactic acidosis due to severe muscle contraction
 Malignant hyperthermia = Neuroleptic (anti-psychotics) Malingnant
Syndrome (congenital defect in SR muscles ---> massively release Ca)
when they are exposed to succinyl ---> Ca released super ---> contraction
super ---> muscle breakdown and metab. ---> body temp goes up (Fatal)
DOC: Dantrolene ; Alternative: Bromocriptine (dopamine agonist)
For succinyl choline toxicity: Ca2+ supplement IV
 Tubocurarine SE: anaphylactoid rxn (due to direct histamine releasing effect of
tubocurarine on mast cells)
ii. Ganglionic blockers
Target receptor: Nn in the ganglia
Non-specific (block both Sym and Parasym ganglia)
No longer used clinically due to non-spec. effects
Historical use: Hexamethonium, Mecamylamine, Trimethaphan camsylate
 Alternatives in HTNsive emergency cases
Effects: (mixed)
 Mydriasis, tachycard, constipation, urinary retention (all are parasym
block)
 Vasodilation (sym block) anhydrosis (both para and sym block)
** all tissues are dominantly innervated by the parasympathetic EXCEPT
blood vessels & sweat glands**