- Basic info

Innervation of heart:

Sympathetic Parasympathetic -- CNX (vagus nerve)

● Chronotropy (↑HR) ● tonic inhibition of heart

● Inotropy (↑contraction) ● Mediated by ACh (M2-AChR)
● Automaticity
● Lusitropy (rate of myocardial relaxation)
● Dromotropy (AV node conduction)
● Mediated by adrenergic receptors, NA
and adrenaline

Adrenoreceptors
α1: Gq → activate phospholipase C → IP3/DAG → Ca2+ → postsynaptic vasoconstriction
- α1B: renal/splanchnic, skeletal vasoconstriction; ↑smooth muscle contraction: vascular,
ciliary muscle, GI and bladder sphincter, uterus
α2→ Gi/Go→ inhibit adenyl cyclase → ↓cAMP → post and presynaptic vasoconstriction
- α2B: inhibit NT release and lipolysis; inhibit insulin release and lipolysis; sedation and
analgesia, platelet aggregation
β -> adenyl cyclase →↑cAMP, Ca channels
- β1: +ve inotropy chronotropy dromotropy (HR), renin
- β2: smooth muscle relaxation (bronchial, vascular, GI and bladder, uterus), cardiac effects;
↑glycogenolysis (liver and muscle), gluconeogenesis, insulin release, ↓mast cell histamine
release
- β3: brown fat: lipolysisin, adipose

D1,D5 → Gs coupled adenylate cyclase → ↑cAMP

D2/3/4 → inhibit adenylate cyclase → ↓cAMP; D2/3 → ↑K flux via K channels

Receptor activity to natural catecholamines

α1 A=NA>D>iso Vasoconstriction
GI SM relax, GU contraction
Salivation
Liver glycogenolysis
Bladder and GI sphincter contraction
Ciliary muscle
Uterus

α2 A=NA inhibit NT release and lipolysis; inhibit

insulin release and lipolysis;
sedation and analgesia,
Attenuation of sympathetically mediated
 responses (inhibit NA release) platelet
aggregation

β1 iso>A=NA=D +ve inotropy chronotropy dromotropy

(HR), renin

β2 iso=A>>NA>D Bronchodilation
Vasodilatation
Relaxation of visceral smooth muscle
(uterus)
Hepatic glycogenolysis
K influx into cells
Insulin release
↓mast cell release histamine
Muscle tremor

β3 Lipolysis
Brown fat

D1/ Modulate extrapyramidal activity in CNS

5 Peripheral vasodilation of renal and mesenteric
vessels → ↑RBF and GFR
Inhibit Na reabsorption by inhibit
Na/K/ATPase

D2/ ↓pituitary hormone output

3/4 Emesis
Inhibit further NA release

α β D

Agonist NA=adrenaline Isoprenaline, D1: dopamine

>isoprenaline adrenaline>NA (D1>b>a)
α1:phenylephrine , β1:dobutamine Fenaldopam
oxymetazoline D2: bromocriptine
α2:
dexmedetomidine,
mivozerol,
etomidate, pethidine

Partial agonist α1: ergotamine β1:

α2: clonidine dichoroisoprenaline,
oxeprenolol,
alprenolol
β2: salbutamol,
terbutaline,
salmeterol

Antagonist α1: prazosin, β1: atenolol, Chlorpromezine,

 doxazosin metoprolol haloperidol
α2: yohimbine, β2: butoxamine Droperidol,
idazoxan metochlopramide
Domperidone → ↑GI
motility

Sympathomimetics
Classification:
1. Natural catecholamines
- Epinephrine: secreted by adrenal medulla
- Norepinephrine: release by postganglionic sympathetic fiber
- Dopamine: precursor of adrenaline+NA but functions as a transmitter in its
own right inthe brain and periphery
2. Synthetic catecholamines
- Isoproterenol
- Dobutamine
3. Synthetic noncatecholamines
Indirect-acting
- Ephedrine
- Mephentermine
- Amphetamine
- Metaraminol
Direct-acting
- Phenylephrine
- Methoxamine

structural -activity relationships

NA

Structure Activity Change

Catechol ring OH group at position 3 and 4 Loss of OH gp → more

→ specific for COMT indirect action and loss of
metabolism affinity for receptor
Tyramine, amphetamine,
 ephedrine

amphetamine
Loss of OH gp → more lipid
soluble → more CNS effects
Amphetamine, ephedrine
OH gp at 3 +5 -> β2
selective

Beta carbon Presence of OH gp → more

direct action
No OH gp → reduce
interaction withα and β
receptors

Alpha carbon Methyl gp → resistant to Metaraminol

MAO, increase α2 receptor Alpha methyl NA
activity

Amine gp Increase bulkiness of Isoprenaline

substituents on N atom → Salbutamol
increase β receptor activity,
less susceptible to uptake 1,
increase resistance to MAO

Natural catecholamines
Primary mechanism for offset is re-uptake by nerve terminals, reused or metabolized by
MAO

Secondary mechanisms - diffuse away from nerve and metabolized by COMT

(catechol-O-methyl transferase) to VMA (Vanillylmandelic acid)
Noradrenaline metabolized to normetadrenaline
Adrenaline metabolized to metadrenaline
Excreted by kidneys as VMA
Epinephrine
PK Naturally occurring catecholamine
Short T0.5 2min
Metabolized by MAO and COMT in liver, kidney and
blood to inactive VMA and metadrenaline, excreted
in
urine

MOA alpha and beta adrenoceptor agonist

- Low dose beta-effects predominate
- High dose alpha-effects predominate

PD CVS:
Low dose → beta effect predominate
- Increase CO,
- increase Cardiac O2 consumption
- Increase coronary artery vasodilation
- decrease diastolic BP
- decrease SVR in low dose
High dose → alpha effect predominate
- increase SVR in high dose
Respi:
- bronchodilator
- increase MV
- increase PVR
CNS - increase MAC, increase pain threshold
Decrease splanchnic BF and RBF
Metabolic derangements - increased glycogenolysis
increased BSL, increased insulin (beta) then
reduction
(alpha), increased glucagon and lactate, lipase,
increase
renin and aldosterone

Norepinephrine

PC clear colourless IV solution, 1mg-2mg/ml.

Infuse via central vein 0.1 to 1 microg/kg/min, titrate for effect

PK ● Metabolism - exogenous NA metabolized by mitochondrial monoamine

oxidase in liver,
brain and kidney, as well as cytoplasmic COMT (catechol-O-methyl-
transferase)
● Excreted in urine, main product is VMA (3-methoxy-4-hydroxymandelic acid)
● (Compared to endogenous NA - active uptake back to nerve terminals or
metabolized by
MAO, or diffuse away from nerve, metabolized by COMT to VMA or
normetadrenaline)
 PD direct and indirect alpha-1 agonist, weak beta agonist
α 1 -adrenoceptors: vascular smooth muscle Gq-proteins→ IP3 signal transduction
pathway → activate smooth muscle
Constrict both arteries and veins (more pronounced in arterial resistance vessels →
increase SVR)
Beta: inotropy and chronotropy

CVS
- increase BP and SVR, may decrease CO.
→ increase afterload → DBP → coronary perfusion pressure
- peripheral vasoconstriction
- increase myocardial O2 consumption
- coronary artery vasodilation
- increase PVR(venoconstriction) → venous return → increase preload
Renal
- decrease RBF
GIT
- Decrease splanchnic BF/HBF
In excess - HTN, bradycardia, headache, peripheral ischaemia

Storage
- Contained in high concentrations in vesicles bound to ATP (4 per NE) and protein
chromogranin A as reversible complex
- ATP has transmitter function at adrenergic synapses, responsible for fast excitatory
synaptic potential for rapid phase of smooth muscle contraction
Metabolism and biotransformation
- Termination of action of A and NA by:
1. Reuptake into nerve terminal
● Major mechanism for NA termination at synapse (in CNS: MAO)
● Not important for adrenaline
● Requires ATP, Mg
● Inhibited by cocaine
2. Dilution by diffusion from junctional cleft and uptake at non-neuronal sites
3. Metabolic transformation:
Enzymes widely distributed throughout body including brain
Highest conc in liver and kidney
● COMT: extraneuronal in liver and kidney, post synaptic
● MAO: outer surface of mitochondria esp in adrenergic neurons
- Enzymes in biotransformation
MAO (monoamine oxidase)
- Non-specific enzyme breaks down all amine (NE, 5HT, histamine)
- Present in nerves, brain, intestinal mucosa, liver
- MAO converts catecholamines to corresponding aldehydes → broken down in
periphery to corresponding carboxylic acids by aldehyde dehydrogenase
-
types Substrate Present in
 MAO-A NE, 5HT Intestinal mucosa, peripheral
nerves, placenta, brain(30%)

MAO-B Phenylethylamine, tyramine Brain, liver, platelets

-
MAOI:
- Antidepressants
- Actions:
1. ↑brain MAO in hrs, inhibit breakdown of 5HT, catecholamines
2. ↑NE in nerve terminal → activation of post-synaptic adrenergic
receptors
3. ↑SNS: ↑HR, temp, mydriasis
4. ↑CNS activity: agitation, seizures, coma
5. ↓MAP: secondary to false NT eg octopamine in SNS nerve
terminal
- Most MAOI non-competitve and block hepatic microsomal enzymes
-
Non-selective Hydrazines: phenelzine
Non-hydrazines:
tranylcypromine

Selective MAO-A: new drug

Drug interaction:
Narcotics (pethidine)
MAO-B: selegiline, rasagiline
Inhibit 5HT reuptake → accumulation
of 5HT → serotonin Sx
Unpredictable hyper or hypotension
Hyperpyrexia
Coma
Less reaction with morphine and
fetanyl

Tramadol R+ tramadol:
Weak u agonist, stimulate pre-
synaptic 5HT release
Inhibit 5HT reuptake
S- tramadol: inhibit NA reuptake

Potential for serotonin syndrome

Sympathomimetic Food: cheese, wine, liver,chocolate →

amines/vasopressor tyramine causing hypertensive crisis

Indirect sympathomimetics Massive release of catecholamines →

Eg ephedrine uncontrolled hypertensive crisis

TCA/SSRI Serotonin syndrome

hypo/hypertension, hyperpyrexia,
coma, convulsions

Levodopa HT (action inhibited by carbidopa)

 Barbiturates ?increased sedation

Linezolid Weak MAOI activity

- Periop Mx:
1. Continue
2. Avoid fentanyl/indirect sympathomimetics
3. Use direct acting sympathomimetics in small doses as
vasopressor
- Toxicity: prolonged duration, need 14d to avoid adverse effect
- Acute hepatic necrosis
- Red-green color blindness
- Anemia nad thrombocytopenia
- Orthostatic hypotension
- Hypoglycemia
- Tremor, insomnia

COMT (Catecho-O-Methyl Transferase)

- Substrate specific enzyme
- In cytoplasm of liver, kidney, brain and synaptic cleft
- Require Mg for activity
- Catalyse transfer of methyl group from S-adenosyl methionine to 3-OH gp to
form 3 methoxy products
- Main final metabolite of A and NA is 3 methoxy 4 hydroxy mandelic acid
(VMA)
- Only 2-3% of circulating catecholamines are conjugated to glucuronic acid/sulphuric
acid → excreted directly in urine
- Termination of physiological action of NA by presynaptic neuronal uptake

Dopamine

PC Precursor to NA and A

PK

PD MOA: adrenergic and dopaminergic receptors, release NA from nerve terminals

Dose <2ug/kg/min: stimulates dopamine receptors → vasodilatation
- DA1, DA2 receptors
- Increase renal blood flow, urine flow and sodium excretion (inhibit Na
reabsorption in PT)
- NA release, direct stimulation of alpha and beta (lose effect with time
due to depletion of NA stores in periphery and heart)
Dose 2-5ug/kg/min: increase cardiac contractility and CO with minimal change
in HR/BP/SVR
Dose 5-10ug/kg/min: also stimulate beta-1 receptors → increase CO/BP/HR
Dose >10ug/kg/min: stimulates alpha → vasoconstriction → increase SVR
- increase intrapulmonary shunt (increase CO), but pulmonary
vasoconstriction can occur.
- stimulates receptors in the zona glomerulosa of the adrenal cortex to
 decrease aldosterone secretion
- selective increase in renal and splanchnic blood flow
- inhibits TSH and prolactin release as well as other potential negative
effects on anterior pituitary function
- side effects include nausea/emesis, tachyarrhythmias (particularly AF),
anginal pain, profound vasoconstriction (including if local extravasation
(treat with phentolamine]) and impairment of hypoxic ventilatory drive

Synthetic catecholamines

Isoproterenol

Dobutamine

PC - Clear, colourless IV solution

- racemic mixture of levo and dextro enantiomers
- Infusion, titrate to effect
- 1-40mcg/kg/min, onset = minutes

PK - VD 0.2L/kg
- Hepatic metabolism via COMT
- Inactive metabolites excreted in urine

PD - Synthetic beta-agonist (direct stimulation), beta 1 > Beta 2

● levo:
○ alpha 1 agonist -> vasoconstriction
○ beta 2 effects -> inotropy
● dextro
○ beta 1 and beta 2 agonist + alpha 1 blocking effects - -> inotropy with some
vasodilation
Indication:
● for low CO states from sepsis, post MI, cardiogenic shock
not routinely used in septic shock because it can lower systemic
vascular resistance, thus leading to a risk of hypotension
● Cardiac stress testing
CVS effects:
- Beta-1 - increased HR, SA and AV conduction enhanced (little effect on HR at
dose <10ug/kg/min)
- Increased contractility
- Increased CO
- Increased Myocardial O2 demand
- SVR can fall because of Beta-2 stimulation
- May precipitate arrhythmia
Renal:
- May increase urine output with increased CO
- No effect on splanchnic vessels
 - Hypoglycemia
S/E:
● pulmonary artery vasodilation
● increase HR-> dysrhythmias, tachycardia
● headaches
● anxiety
● tremors

Synthetic noncatecholamines
Indirect acting

Ephedrine
PC clear colourless liquid 30mg/ml
for IV, IM or SC, PO
Diluted to 5mg-6mg/ml in NS
Dosing 5-6mg

PK multiple routes PO/IV/nasal/IM/SC, well absorbed,

minimal hepatic metabolism,
mostly excreted unchanged in urine
T1/2 4hrs
● Ephedrine increases post-synaptic noradrenergic receptor activity by (weakly)
directly activating post-synaptic α-receptors and β-receptors, but the bulk of its
effect comes from the pre-synaptic neuron being unable to distinguish between
real adrenaline or
noradrenaline from ephedrine.
● Ephedrine, mixed with noradrenaline, is transported through the noradrenaline
reuptake complex and packaged (along with real noradrenaline) into vesicles
that reside at the terminal button of a nerve cell.

PD MOA: Ephedrine has both indirect and direct actions on SNS

Its indirect effects are
due to the stimulation of postganglionic sympathetic
nerve endings to release norepinephrine.
As norepinephrine is a weak b2-receptor agonist, these
effects are primarily a and b-1-receptor mediated .
Ephedrine direct effects are less potent than natural
catecholamines, but do provide some b2- receptor
activation.
Inhibits monoamine oxidase
CVS: Increase HR, CO, BP, increase Coronary artery
blood flow, increase Myocardial O2 consumption.
Resp: Bronchodilation, increase RR,
Renal: decrease RBF, decrease GFR.
Tachyphylaxis may occur if NA stores depleted, after
 30mg given

others Maternal:
Increases blood pressure
Tachycardia
The benefits of ephedrine include its longer length of action compared to
phenylephrine, and its chronotropic effect
Fetal:
associated with lower umbilical artery (UA) pH when compared with
other vasopressors, such as phenylephrine.
● Ephedrine crosses the placenta to a greater extent than phenylephrine, may
lead to
increased fetal metabolic activity and subsequent reductions in fetal arterial pH.

Metaraminol

PC

PK Effective within 1-2min, lasts 20-60min, hepatic metabolism

PD Mainly alpha-1 agonist, some beta activity. Increase SVR, increase BP, increase
coronary BF, increase PVR, increase RR, increase TV, decrease uterine blood
flow, may cause uterine
contraction. decrease CNS blood flow, increase BMR, lipolysis, increase BSL by
inhibiting
insulin release. Can cause tissue necrosis if extravasate

Amphetamine

Mephentermine

Direct-acting

Phenylephrine

Physiochemical clear, colourless liquid

for IV injection
10mg/ml, for dilution in NS to 100microg/ml pre
Dosing is 50-200microg or infusion

PK 95% protein binding

Metabolized by monoamine oxidase in liver
Metabolites excreted in urine
Rapid increase SVR lasting 5-10min

PD MOA: Synthetic noncatecholamine, functions s

 norepinephrine with direct action at a1receptor
Less potent, and longer acting than norepinep
Unlike other synthetic noncatecholamines,
phenylephrine’s indirect actions are minimal.
Results in venoconstriction , which is greater th
arterial constriction, and predictably increases
pressure by increasing both SVR and preload
of minimal b-2-receptor activity, phenylephrine
cause tachycardia, but instead can cause refle
bradycardia with increasing blood pressure.
CVS: increase SVR, increase BP, decrease H
Renal: decrease RBF

Maternal effect Because of minimal b-2-receptor activity, phen

does not cause tachycardia, but instead can ca
bradycardia with increasing blood pressure.

Fetal effect In a studies comparing phenylephrine to

ephedrine in obstetric anaesthesia, the only
difference identified was that women given phe
had neonates with higher
umbilical arterial pH values, by 0.03 pH units.
Umbilical arterial base excess was greatest am
neonates born to mothers receiving
phenylephrine.
● May reduce the incidence of maternal intrao
nausea and vomiting better than
ephedrine

Methoxamine
Others

Milrinone
PC yellow solution
PB 70%, VD 0.45L/k
Hepatic metabolism,

PK inhibits PDE III and r

cAMP in cardiac and
increase intracellular
contractility. Alters C
relaxation of vessels

PD CVS effects:
- increase SV, increa
- increase cardiac in
- no increase in card
- Decrease SVR
- decrease PVR
- Can cause hypoten
- Less tachycardia th
- May rarely cause a
CNS - headache
May increase AV no
patients with AF/flutt