WEEK 6: AUTONOMIC PHARMACOLOGY

AUTONOMIC NERVOUS SYSTEM

- major involuntary, unconscious,

automatic portion of the nervous
system.

- concerned primarily with visceral

functions (i.e., cardiac output, blood
flow distribution, digestion).

2 MAJOR DIVISION OF ANS

CHOLINERGIC PHARMACOLOGY
1. Parasympathetic ANS (PANS)
2. Sympathetic ANS (SANS)

Note: The table only shows the drugs under

FIBERS cholinergic.
• Parasympathetic – cardiac and smooth ACETYLCHOLINE
muscle, gland cells, nerve terminals.
• Sympathetic – sweat glands. - primary transmitter in all autonomic
• Sympathetic – cardiac and smooth ganglia and at the synapses between
muscle, gland cells, nerve terminals. parasympathetic postganglionic
• Sympathetic – Renal vascular and neurons and their effector cells.
smooth muscle. - primary transmitter at the somatic
• Somatic – Skeletal muscle (voluntary) skeletal muscle
ENTERIC NERVOUS SYSTEM neuromuscular junction.

- primarily controlled by the ANS. - activates nicotinic & muscarinic

receptors.
- consists of myenteric plexus and STEP 1: TRANSPORT AND SYNTHESIS
submucous plexus.
- Choline transferase (CHT): Na+/Choline
REMEMBER: symporter that transports choline
1. Myenteric Plexus – plexus of Auerbach. inside.
2. Submucous Plexus - plexus of Meissner.  Rate limiting step.

 Important step.
  Choline transport inhibited by
Hemicholinium.

Note: Kapag may hemicholinium hindi

makakapag transport and synthesize ng choline
kasi ma bablock niya agad.

- Choline acetyltransferase (ChAT):

enzyme uses free Acetyl CoA and choline
to synthesize Acetylcholine.

STEP 2: STORAGE

- Acetylcholine or ACh - is actively

transported into vesicles for storage by
vesicle- associated transporter (VAT).

 inhibited by Vesamicol.

STEP 3: RELEASE

Note:
Calcium Triggers
interaction fusion of ❖ N – icotinic
with vesicle
Entry of
SNARE membrane ❖ M – uscarinic
calcium
proteins with
(VAMPs terminal
and SNAPs) membrane
 M1 – sa NERVES
 M2 – sa PUSO
 Inhibited by Botulinum toxin.  M3 – sa TIYAN
 M4 and M5 – sa BRAIN
 Botulinum toxin - alter  Nm – sa SKELETAL
synaptobrevins to prevent release of
NON – SELECTIVE CHOLINERGIC AGONIST
ACh through the enzymatic removal
of 2 amino acids from one or more
of the fusion proteins.

STEP 4: TERMINATION

- degradation of ACh into choline and

acetate by acetylcholinesterase (AChE).

 Inhibited by indirect-acting
cholinomimetics (Carbamates &
Organophosphates)
NOTE: tandaan yung DUMB BELLS!
CHOLINO RECEPTORS
 Bradycardia – low heart rate.
 Emesis – nagsusuka.
 Lacrimation – nagluluha.
 Lethargy – fatigue.
  Salivation – naglalaway. DIRECT ACTING CHOLINOMIMETIC (NICOTINIC)

DIRECT ACTING CHOLINOMIMETIC - Activates ONLY nicotinic receptors.

(MUSCARINIC)

- activates ONLY muscarinic receptors.

NICOTINIC TOXICITY

- largely due to the nonspecific ganglionic

stimulation.

AFFECTING:
MUSCARINIC TOXICITY
1. Sympathetic
- This is seen in overdosage of muscarinic 2. Parasympathetic
agonists and certain types of 3. Neuromuscular junctions
mushrooms (genus: Inocybe)
- blockade of neuromuscular end plate
✓ CNS stimulation depolarization.
✓ EYE: miosis, spasm of
accommodation - leading to fasciculations and paralysis.

✓ LUNGS: bronchoconstriction ▪ CNS toxicity: stimulation

✓ GIT/GUT: excessive (convulsions) followed by CNS
gastrointestinal and depression
genitourinary smooth muscle TREATMENT:
activity
- Atropine for muscarinic excess
✓ Increased secretory activity - Diazepam & Anticonvulsants for CNS
(sweat glands, gastrointestinal stimulation, mechanical ventilation if
tract, airway, lacrimal glands) with neuromuscular blockade).
✓ Vasodilation Note: Anticonvulsants – are anti-seizure drugs.
TREATMENT: INDIRECT ACTING CHOLINOMIMETIC
- Atropine (Cholinergic antagonist)

Note: that the symptoms of muscarinic

poisoning are essentially the same with
organophosphate poisoning minus symptoms of
nicotinic excess.
Note: Note: pag nicotinic and muscarinic.

• Endrophonium [C] - used in myasthenia CHOLINERGIC ANTAGONISTS AT MUSCARINIC

gravis. SITES (PARASYMPATHOLYTICS)
• Neostigmine [C] - used in myasthenia
gravis.
• Parathion, Malathion – insecticides,
scabicide.
• Sarin, Tabin – nerve gases.
• Rivastigmine – available as transdermal
patch or parang salonpas.
• Donepezil – for Alzheimer’s dementia. Note:
ORGANO-PHOSPHATE POISONING
• Atropine (NS) – blocks all muscarinic.
- accidental exposure to toxic amounts of • Benztropine (NS) - blocks all muscarinic.
pesticides. • Scopolamine (M2) - blocks all
muscarinic.
- clinical manifestation: DUMBBELLS. • Ipatropium (M2) – blocks muscarinic
receptors in bronchial smooth muscle.
TREATMENT:
• Dicyclomine (M3) – blocks M3
• Atropine: addresses ONLY muscarinic receptors.
symptoms.
• Pralidoxime: addresses BOTH nicotinic
and muscarinic symptoms.

ANTIDOTE TO ORGANOPHOSPHATE
POISONING Note:

• Atropine - antidote for

organophosphate poisoning.
• Benztropine – parkinson’s disease.
• Ipatropium – acute asthma, COPD.
• Scopolamine – motion sickness.
• Dicyclomine – diarrhea.
• Oxybutynin – urinary urgency
Note: muscarinic lang. incontinence.
• Pirenzepine – peptic disease.

ATROPINE TOXICITY

 prototype nonselective muscarinic

blocker, found in Atropa belladonna
plant.

FEATURES OF ATROPINE TOXICITY

 1. Atropine fever (hyperthermia) - due to - Benign prostatic hyperplasia
inhibition of sweating
 Can precipitate further urinary
retention already present in this
2. Atropine flush (cutaneous vasodilation)
subgroup because muscarinic
antagonists will relax smooth muscle
• Decreased secretion
of the ureters and bladder wall.
• Tachycardia
• Arrhythmias (intraventricular Note: Benign prostatic hyperplasia – mga
conduction block) nangangapal na prostate.
• Constipation
CHOLINERGIC ANTAGONISTS AT NICOTINIC
• Blurred vision
SITES (GANGLION BLOCKERS)
• CNS toxicity
- competitive pharmacologic antagonists
ATROPINE TOXICITY MNEMONIC
at nicotinic acetylcholine receptors (NN)
• HOT as a hare (hyperthermia). of both sympathetic and
• DRY as a bone (decreased secretion). parasympathetic autonomic ganglia.
• RED as a beet (cutaneous vasodilation).
• BLIND as a bat (cycloplegia). - first successful agents for the treatment
• MAD as a hatter (CNS toxicity). of hypertension but were abandoned
due to severe adverse effects.
TREATMENT: Symptomatic

• Temperature control: use of cooling

blankets
• Seizure control: Diazepam
• To reverse antimuscarinic effect:
Physostigmine

Note: Yung gamot if may toxicity sa atropine

based sa symptoms kunware if ang concern mo Note: First medication or drug sana for
is fever gagamit tayo ng cooling blankets, kapag hypertension pero na banned na dahil sa severe
seizure naman diazepam and for reverse effects nito.
antimuscarinic effect naman is yung
CHOLINERGIC ANTAGONISTS AT NICOTINIC
physostigmine.
SITES (NEURO-MUSCULAR BLOCKERS)
CONTRA-INDICATIONS TO (MUSCARINIC
- used for complete skeletal muscle
BLOCKERS)
relaxation in surgery.
- Cautious use in infants
CLASSIFICATION:
 Since they are sensitive to the
1. DEPOLARIZING
hyperthermic effects of atropine.
 Succinylcholine
- Acute angle-closure glaucoma
2. NONDEPOLARIZING
 Since mydriasis can block the normal
drainage of aqueous humor.  Tubocurarine
  Pancuronium - Norepinephrine and Dopamine - are
 Atracurium transported into vesicles.
 Vecuronium
 inactivated by monoamine
ADRENERGIC PHARMACOLOGY oxidase in the cytoplasm.

❖ Norepinephrine  Monoamine oxidase inhibitors

(MAOi) - increase stores of NE
- Derived from the word “epinephrine”. and dopamine.

- The transfer of DOPA into vesicles is

- Primary transmitter at the sympathetic
BLOCKED by the drug Reserpine.
postganglionic neuron-effector cell
synapses in most tissues. STEP 3: RELEASE
EXCEPTIONS:

▪ Eccrine sweat glands (uses ACh).

▪ Vasodilator sympathetic fibers in Calcium
interacts with
Vesicle fuses
skeletal muscle. Entry of SNARE
with
calcium proteins
membrane
(vamps and
snaps)
- it is the immediate precursor of
epinephrine.

 Inhibited by Guanethidine.

 Promoted by Amphetamines and

Tyramine.

Note: Release of NE via these agents is calcium

INDEPENDENT.

STEP 4: TERMINATION

- diffusion and reuptake via NET and DAT

STEP 1: SYNTHESIS in synaptic cleft.
- Tyrosine - is hydroxylated by tyrosine
hydroxylase to DOPA.  Inhibited by Cocaine and TCAs.

 Rate-limiting step - metabolized by MAO and COMT into

 Inhibited by Metyrosine. metanephrines and VMA.

- DOPA - is decarboxylated to dopamine.  Inhibited by MAOi and COMTi.

- Dopamine - is hydroxylated to SITES OF AUTOMATIC DRUG ACTION
norepinephrine.

STEP 2: STORAGE
 - VasCONTRICTS renal blood
vessels.

• DOPAMINE – vasoDILATES renal blood

vessels.
Note: need tandaan yung table kasama to sa
exam. - Used also in shocks ESP with
renal shutdown.
ADRENOCEPTORS - Acts more on D1.
- receptors that respond to
catecholamines (NE, EPI and DOPA). • ISOPROTERENOL – beta din nag
wowork.
- β1 β2 β3 agonist.
- Used in asthma.

MOA OF SYMPA-THOMIMETHICS

- direct activation of adrenoceptors

Note: Adipose cells are fat cells.
 𝛂1: vasoconstriction, increases
ADRENERGIC AGONISTS BP, increase pulmonary vascular
(SYMPATHOMIMETICS) resistance.

 𝛃𝟏: increased HR, conduction,

and contractility of heart.

 𝛃2: bronchodilation in lungs

Note:  D1: vasodilation in splanchnic

and renal blood vessels.
• Epinephrine – agony ng lahat pero β 1 =
β2 > alpha meaning mas ginagamit siya - Indirect activation by increasing
for β 1, 2 & 3 compared sa α 1 & 2. concentration of available
catecholamines in the synapse
- More on BETA AGONIST.
 Amphetamine - release of
- Used in cardiac arrest /
stored catecholamines.
anaphylaxis.
- Not used in bronchospasm.  Cocaine - inhibition of reuptake.

DOPAMINE: DOSE DEPENDENT ACTIONS

• Norepinephrine – more on ALPHA
AGONIST.  LOW DOSE (0.5 to 3 mcg/kg/min)

 Stimulates D1 and D2 receptors

- Used in shocks.
- Has negligible β2 effects unlike  Leading to vasodilation,
epinephrine. decreased arterial blood
 pressure, and increased renal
and splanchnic blood flow
(natriuresis and diuresis will
occur)
Note: HYPERTENSION MEDICATIONS
 MEDIUM DOSE (3-10 mcg/kg/min)
• Clonidine – fast relief for bp.
 Stimulates β1 receptors (high
chronotropy and contractility) DISADVANTAGE: Kapag nag intake ng clonidine
minsan nagkakaroon ng rebound hypotension
 Results in increased cardiac meaning nababa sobra yung bp. Then, kapag
output tinigil pag take sobra naman tumataas which is
 HIGH DOSE (>10 mcg/kg/min) rebound hypertension.

 Stimulates α1 receptors • Methyldopamine – it is the ONLY SAFE

hypertension in pregnant patients.
 Leads to arterial and venous
vasoconstriction, increased • Clonidine and Methyldopamine – both
systemic vascular resistance, in alpha 2 agonist.
increased blood pressure.

 Reflex bradycardia may be seen • Apraclonidine – same as clonidine.

at this point.

Note: Pinapakita lang here is that yung

dopamine inaactivate yung D1 receptors in
different dosage and inactivate na rin yung alpha
and beta receptors.

CLINICAL APPLICATIONS OF SYMPATHO-

Note: Phenylephrine – decongestant & most
MIMETICS
common alpha.

- causes mydriasis WITHOUT cycloplegia.

Note: Phentolamine – aadminister lang if ever

Note: Additional info lang ito. biglang tumaas BP pag tapos itigil yung pag
intake ng clonidine.
ALPHA RECEPTOR AGONISTS
BETA RECEPTOR AGONISTS
Note:
Note:
• Dobutamine – is an acute heart failure
medication, ginagamit kapag hindi • Yohimbine – hindi na to ginagamit as
effective yung pumping system ng heart. medicine since nakaka elevate ng BP.

NON-SELECTIVE ALPHA BLOCKERS

- no specific alpha na binablock.

Note:

• Salbutamol [C] – for acute asthma

attacks.

SELECTIVE ALPHA BLOCKERS

Note:

• Phenoxybenzamine –
Pheochromocytoma
• Phentolamine - pheochromocytoma
and rebound hypertension.

BETA-ADRENOCEPTOR BLOCKERS
• Prazosin – benign prostatic hyperplasia
or pangangapal ng prostate. • Non-selective beta - blockers – usually
yung L pababa sa alphabet kunware
labetalol, levobunolol pero ang naiba
lang is yung carvedilol.
 • Selective beta - blockers – mga A to M - effective for hypertension and angina
sa alphabet pero ang naiba lang is yung (chest pain) and ideal because they’re
nebivolol. less likely to cause bradycardia and
abnormalities in plasma lipids.

- advantage in treating patients with

asthma because these drugs are less
likely to cause bronchospasm

- Labetalol – most used drug.

EFFECTS NOT RELATED TO BETA BLOCKADE

❖ Local Anesthetic Activity

- known as “membrane-stabilizing
activity.”
Note:
- means inhibition of action potential
• Bradycardia – masyadong bumababa propagation across the cell membrane
yung heart rate. similar to Na channel blockers that are
class I anti-arrhythmic.
• Propranolol – high first pass effect
meaning pag dumaan ng liver masyado - disadvantage when beta-blockers are
siya nababawasan. used topically in the eye.

 decreases protective reflexes.

 increases the risk of corneal

ulceration.

- absent in Timolol and Betaxolol making

them useful in glaucoma.

CNS DRUGS

❖ Local anesthesia

- refers to a loss of sensation in a limited

region of the body accompanied by
muscle paralysis and sympathetic
Note: blockade.
• Esmolol – shortest half-life.  recovery from clinically relevant local
INTRINSIC SYMPATHOMIMETIC ACTIVITY anesthetics should be spontaneous,
predictable and without residual effects.
- partial agonist activity.
 CARDIOVASCULAR EFFECTS
Most local anesthetics have intrinsic
vasodilator quality EXCEPT cocaine
Mepivacaine
Ropivacaine
Use with caution in patients with
preexisting cardiovascular disease
MECHANISM OF ACTION OF LOCAL because they may develop heart block
ANESTHESIA and arrhythmias
- block voltage-gated Na+ channels,
reducing influx of Na+, thereby TREATMENT: should be instituted during earliest
preventing depolarization sign of toxicity.

- relationship of local anesthesia with  Ensure oxygenation (supplemental

electrolytes. Oxygen) and ventilation (control airway
if necessary)
▪ Hyperkalemia - enhances local  Treat seizures with benzodiazepines.
anesthetic activity.
▪ Hypercalcemia - antagonizes ANTIDOTE:
local anesthetic activity.
- INTRALIPID - lipid emulsion
therapy.

ESTER LOCAL ANESTHETICS

LOCAL ANESTHETICS: SYSTEMIC TOXICITY

 adverse systemic effects following

INADVERTENT INTRAVASCULAR
injection or ABSORPTION of LA from site Note:
of administration.
• Cocaine – NOT vasodilator.
CNS EFFECTS - Stroke – common side effects.
Initial symptom of circumoral
Tongue numbness - Local and Topical anesthesia.
Metallic taste
Light-headedness or sedation
Restlessness • Procaine – vasodilator
Nystagmus - Local anesthesia.
Generalized tonic-clonic seizures
- Shortest half-life.
Cardiovascular depression
 • Benzocaine – vasodilator.
- Methemoglobinemia – side
effects.
- Local and Topical anesthesia.

• Tetracaine – vasodilator.
- Local, Spinal, Epidural and
Topical anesthesia. Note: mga pampakalma na gamot.

- Pag 2-3 hours lang operation we  Sedatives (ANXIOLYTICS)

used spinal anesthesia or
- drugs that reduce anxiety and
tetracaine.
exert a calming effect.
AMIDE LOCAL ANESTHETICS
- degree of CNS depression
should be the minimum
consistent with therapeutic
efficacy.

 Hypnotics

- drugs that produce drowsiness

Note:
and encourage the onset and
• Lidocaine – Cauda Equina Syndrome. maintenance of a state of sleep.
• Prilocaine & Mepivacaine –
- involve more pronounced CNS
Methemoglobinemia.
depression than sedation.
• Bupivacaine – most cardiotoxic out of all
local anesthesia. BENZODIAZEPINES
• Ropivacaine – longest half-line among
5 PRINCIPLES PPHARMALOGIC EFFECTS:
all local anesthesia.
1. Anxiolysis
• Shortest half-line – mabilis mawalan ng
2. Sedation and hypnosis
effect sa system.
3. Anticonvulsant actions –
• Longest half-line – matagal mawalan ng
4. Spinal cord mediated skeletal muscle
effect sa system.
relaxation
SEDATIVE-HYPNOTIC DRUGS
 5. Anterograde amnesia – a type of • Lorazepam and Alprazolam – anxiety
memory loss that occurs when you can't disorders.
form new memories. - intermediate acting.
- Nawawalan ng memory about • Diazepam – status epilepticus.
what is currently happening. - long acting.
• Hindi advisable ang BENZODIAZEPINES
Note:
since nag increase ng floppy infant
• Retrograde Amnesia - amnesia where syndrome and cleft risk (bingot).
you can't recall memories that were
BARBITURATES
formed before the event that caused the
amnesia. - puro TAL ang ending.
- Hindi na ma alala yung mga
nangyare years ago.

Notes:

• Thiopental – used to be the induction

agent of choice in anesthesia before the
discovery of propofol.
Note:
• Pentobarbital – insomnia and
• Epilepticus – nangigisay. preoperative sedation.
• Phenobarbital - seizure disorders.
- common sa mga bata usually
eto ang binibigay.

Note:
Note:
• Midazolam – anxiety, panic attacks.
- short acting. • CNS depression – effects nito ay
nakakatulog or nawawalan ng malay.
 NEWER HYPNOTICS • Ethanol - multiple effects on
neurotransmitters, CNS depression;
ANTIDOTE in methanol and ethylene
glycol poisoning.

ACUTE EFFECTS OF ETHANOL

CNS EFFECTS
Sedation
Note: Loss of inhibition
Impaired judgment
• Zolpidem – Zleep disorders Slurred speech
Ataxia
- effects reversed with
EFFECTS ON OTHER ORGAN
FLUMAZENIL. SYSTEMS
Slight cardiac depression
• Buspirone – for BUSY PEOPLE, always
Vasodilation
anxious. Hypothermia
- generalized anxiety disorder. Uterine muscle relaxation

- mas common compared kay

REMELTEON.
• Remelteon – sleep disorders.

ALCOHOLS

Note: nasa exams yung table na ito.

• BAC – blood alcohol level.

PHARMACOLOGIC MANAGEMENT OF CHRONIC

• Methanol (wood alcohol) - creates toxic ALCOHOLISM
formate, which causes visual
disturbance, come, seizures.

• Ethylene glycol (antifreeze) - creates

toxic aldehydes and oxalate, which
causes kidney damage and severe
acidosis.
 - also known as paralysis agitans:
neurodegenerative disease caused by
degeneration of dopaminergic neurons
in the substantia nigra.

 Dopaminergic neurons:
responsible for inhibiting
excitatory cholinergic output
from the striatum.

- classic triad of bradykinesia, resting

tremors and dystonia.

 progressive neurologic disease

characterized by:

1. Shuffling gait
Note:
2. Stooped posture
3. Resting tremor
• Naloxone – used in opioid overdose.
4. Speech impediments
- drug of choice. 5. Movement difficulties
6. An eventual slowing of
• Naltrexone – opioid dependence and mental processes
chronic alcoholism. 7. Dementia
- drug of choice.
• Disulfiram – alcohol dependence. Note:

PARKINSON’S MANAGEMENT • Bradykinesia – naninigas.

• Tremors – nanginginig.
• Dystonia – uncontrollable movements.

Note:

• Levodopamine – most common used

drug in Parkinson’s.

PARKINSON’S DISEASE
Note:

• Levodopa – most common for

Parkinson’s disease.
Note:
- ON - OFF phenoma – minsan
kapag hindi agad nainom yung • Selegiline – selective MAOB inhibitors,

next na gamot minsan these drugs DO NOT exhibit the “CHEESE

lumalabas agad yung EFFECTS”

symptoms. • Entacapone – acts in periphery

- Nagkakaroon ng tolerance ang • Tolcapone – acts in periphery & CNS

levodopa pag matagal ng - not usually ginagamit since yung

ginagamit then if hindi na effect is ORANGE URINE.

gumagana, SWITCH to • Amantadine – Livedo reticularis.

BROMOCRIPTINE. • Benztropine – Atropine.

ANTIPSYCHOTIC AGENTS AND LITHIUM

Note:
 • Lithium – most common drug in
BIPOLAR.
- classic drug.

ANTIPSYCHOTICS

TYPICAL ANTIPSYCHOTICS

Note:

• Typical or Classical Antipsychotics –

addresses positive symptoms Note:
(HALLUCINATIONS) of schizophrenia.
• Chlorpromazine – schizophrenia and
• Atypical Antipsychotics – address BOTH
manic phase of BPD or bipolar disorder,
positive and negative effects of
antiemetic.
schizophrenia,
o Manic - extreme happiness
o Depressive – biglang sadness
o PROTOTYPE OF ALL
ANTIPYSCHOTICS.
• Thioridazine – most muscarinic
blockage, has least EPS among the
typical antipsychotics.
• Haloperidol – most common.
o major tranquilizer given IM.
o highest potential EPS.
 o neuroleptic malignant • Risperidone – approved in the YOUTH
syndrome. (di pwede sa matatanda or sa sobrang
bata)
ATYPICAL ANTIPSYCHOTICS
• Aripiprazole – least sedating atypical.
o Hindi nakakaantok sa lahat.

LITHIUM

Note:

• Lithium – drug of choice for bipolar

disorder.
▪ Treatment of bipolar disorder
(manic-depressive)
Note: o decreases manic
behavior and reduces
• Olanzapine – causing weight gain.
both the frequency and
• Clozapine – prototype for atypical.
the magnitude of mood
o causing weight gain too.
swings.
• QUETiapine – sleep promotion and
maintenance.
 o protective effects against
suicide and self-harm.
• Used concurrently with antidepressants
during maintenance therapy.
o monotherapy with
antidepressants can precipitate
mania in bipolar patients.
• antipsychotic agents and/or
benzodiazepines are commonly required
at initiation of treatment because of
slow onset of action.

FLUNITRAPEZAM

- known as date-rape drug.

REMEMBER

• Dopamine -> Typical Serotonin

• 5ht3 -> Typical