Week 1

Lecture Outcome

● Autonomic outflow and distribution to the heart

● How heart rate is regulated by the ANS
● How force of contraction is regulated by the ANS
● The synthesis of catecholamines and acetylcholine
● Predict effects of drugs on cardiovascular system by virtue of their effect on
specific receptors or corresponding neurotransmitters
● Key risk factors, drugs and conditions involved in cardiovascular pathology

Notes: terminology “innervated”. Nerves that make up the SNS originate in the thoracic and
lumbar spinal cord. ANS neurons do not travel directly from the spinal cord to the targets but
instead expand from the spinal cord to clusters of neurons in the PNS known as sympathetic
ganglia.

PNS: Autonomic vs somatic motor systems

NOTE: CNS only works in one direction whereas PNS works in both; most sensory neurons are
unipolar

In both SNS and PNS, preganglionic fiber synapses with the postganglionic fiber. The cell body
of the postganglionic fiber has nicotinic acetylcholine receptors.

Autonomic motor system Somatic motor system

Preganglionic fibers in CNS → postganglionic fiber Myelinated nerves: CNS → skeletal muscle cells
ganglion → smooth muscle cells or gland cells or cardiac
muscle Body → Somatic nerves carry sensory signals → CNS

Automatically controlled muscles; maintains Consciously controlled muscles - sensory and motor
homeostasis; parasympathetic and sympathetic; PNS
nervous conduction is slower than SNS: PNS has
long, non-myelinated preganglionic fiber coming out
of PNS to synapse with a short postganglionic fiber.

Motor end plate: acetylcholine released into nicotinic

acetylcholine receptors

Component of PNS Component of PNS

Autonomic motor system

The autonomic motor system is divided into sympathetic and parasympathetic which are in
balance to maintain homeostasis.

● Sympathetic division: Fight or flight response

○ Anatomy of sympathetic outflow

○ Sympathetic postganglionic terminals and synapses:

■ Noradrenergic plexus: network of sympathetic nerves around the blood
vessel. Varicosities are little swellings in the blood vessel fiber that release
neurotransmitter or adrenaline
 ● Parasympathetic division: rest and relax.
○ Long unmyelinated preganglionic fibers coming out of the parasympathetic
nervous system. THUS parasympathetic nervous conduction is slower than
sympathetic. Synapse with a short ganglionic fiber.

Autonomic control of the heart

The Heart: Cranial nerve 10 comes out of the cranium and forms the vagus nerve. Carries
parasympathetic innervations. VAGAL = PARASYMPATHETIC RELATED.
Parasympathetic nerve innervates the sinoatrial node which starts every heartbeat. Many
other cells in the heart can spontaneously fire a heartbeat but the sinoatrial node does
the quickest. The atrioventricular node may take over in case anything happens to
sinoatrial node. Both the parasympathetic and sympathetic innervate the heart. The
parasympathetic slows down the heart while the sympathetic speeds it up. Noradrenaline
increases the force of heart contraction.
 Regulation of coronary blood flow:

Metabolites are a waste product of heart muscles that causes a vasodilator effect.
Increased cardiac work will use more nutrients and oxygen which increases waste
product content - including metabolites. THUS, INCREASED CARDIAC WORK =
INCREASED METABOLITES = VASODILATION = BLOOD FLOW TO HEART
RESTORED.

Increased blood flow in response to sympathetic stimulation is mainly due to

increased heart rate and contractility, overriding direct effects on blood vessels.

Coronary blood flow occurs mainly during diastole.

Vagal - parasympathetic (muscarinic Sympathetic (beta 1 receptors)

receptors - M2 cardiac)

Heart rate ↓ ↑

Contractility Slight ↓ ↑

Atrio-ventricular ↑ ↓
conduction time

Coronary blood vessels Vasodilation Vasoconstriction

Functional specificity of sympathetic outflow to cardiovascular system

Baroreceptor:
Detects pressure
Location: carotid body, aortic arch
Increases spontaneous firing in carotids and aortic arch when pressure increases.
Afferent impulses from the baroreceptors travel to the cardiovascular control
center in the medulla after detecting pressure. The cardiovascular control center
alters the ration of parasympathetic and sympathetic output to decrease
vasoconstriction.

Summary: baroreceptor detects pressure increase → message sent to brain stem

medulla → sympathetic output decreased → decreased vasoconstriction → decreased
cardiac output

Chemoreceptor:
Detects CO2
Location: carotid body, aortic arch
Increased oxygen usage = CO2 buildup → chemoreceptors detect CO2 increase →
sends brain stem a message → quicker breathing
 Thermoreceptor:
Detects temperature
Location:
Thermoreceptor detects increased heat → skin vasoconstriction decreases to release
heat (skin goes red)

Receptor activated Muscle vasoconstriction Skin vasoconstriction Cardiac sympathetic

(vasoconstriction)

Baroreceptor ↓↓↓ ↓ ↓↓

Chemoreceptors ↑↑ ↓ ↓

Thermoreceptors ~ ↓↓↓ ↑

Note: different inputs produce different patterns of sympathetic activation

Summary of autonomic control of the heart

Heart structure Sympathetic effect Adrenoreceptor Parasympathetic Cholinoceptor type

type effect

Sinoatrial node Rate ↑ Beta 1 Rate ↓ M2

Atrial muscle Contractility force ↑ Beta 1 Force ↓ M2

Atrioventricular Automaticity ↑ Beta 1 Conduction M2

node velocity ↓

Beta 1 Atrioventricular M2
block

Ventricular muscle Automaticity ↑ Beta 1 No effect M2

Force ↑

Note: how to read above table example - beta 1 increases rate, cardiac M2 decreases rate
 Summary of autonomic control of blood vessels

Organ Sympathetic effect Adrenoceptor Parasympathetic Cholinoceptor type

type effect

Large coronary Constriction Alpha 1 and 2 No effect -

Small coronary Dilatation Beta 2 No effect -

Muscle Dilatation Beta 2 No effect -

Viscera, skin, brain Constriction Alpha 1 No effect -

Erectile tissue Constriction Alpha 1 Dilatation M3

Veins Constriction Alpha 1 and 2 No effect -

Dilatation Beta 2 No effect -

Note: high beta 2 concentration in lungs, arterioles; a fright = vasoconstriction = pale skin

Sinoatrial node action potential

AKA slow action potential; no fast sodium currents in SA node action potential. Start of every
heartbeat is affected by the slope of phase 4 (how quickly threshold is reached to move into
phase zero depolarisation phase.

If current

● Mixture of sodium and potassium

● Activates on hyperpolarisation at the end of phase 3 at around -60mv signal start phase
4

The phases

● Phase 4: spontaneous depolarisation. Starts when If is activated. If drives the potential

back up towards -50 mV causing the transient T-type calcium channels to open. Once
reaching -40 mV, the L-type calcium channels.
● Phase 0: depolarisation phase. Starts with open T type transient calcium channels. Phase
0 is primarily driven by L-type calcium channels. If and T-type begins to close during
phase 0.
● Phase 3: repolarisation. End of an action potential. Potassium channels open → directs cations
 outwards + potassium follows its concentration gradient and goes out; most cells have more
potassium inside than out. Potassium concentration gradient sets up SA node for heartbeat;
injecting potassium removes the potassium gradient and stop heartbeat = death. The
hyperpolarisation at the end activates If current and at around -60mv signal starts phase 4.
Degree of activation determines slope of phase 4. Potassium channels open directing
cations outward thus depolarising the cell (and L-type channels close).

Note: depolarisation = moving up towards 0. Hyperpolarisation = moving down away

from 0 and increasing polarisation. Transient T-type calcium channel = open for short
duration. L-type calcium channel = open for longer duration.

Beta 1 activation → increase cAMP → steeper phase 4 → increased rate

M2 stimulation decreases cAMP → slower rate

ECG

Atrium muscles are the first to be activated in response to the SA node. P wave is
detected when atria fires in response to the SA node. Can’t exactly measure SA node
firing as the signal is too small and is not detected in ECG. Myocardium ventricle
activation

Myocardium
ventricle activation fires and
the QRS complex depicts this.

The T- wave is the

repolarisation at the
end. QT interval from the
start of the QRS complex to
the T- wave, the QT interval
can be affected by drugs.
NOTE:

Important not to have excessive potassium outside because potassium current drives the
repolarisation of the SA node following a heart beat; excessive potassium = gradient
dissipates = fail to recover from heartbeat
More potassium than sodium in funny current
Verapamil and nifedipine difference: verapamil binds inside the pore of calcium channel;
if calcium channel is activated more frequently, verapamil will spend more of the time in
open shape; thus verapamil preferentially targets cardiac L-type calcium channels
against the L-type calcium channels in the smooth muscle. Verapamil can block L-type
calcium channels in the smooth muscle of the vasculature and the cardiac electrogenic
cells. Can block calcium channels in a way that dihydropyridines can’t.

Autonomic Regulation of Sinoatrial Node

Above image

Shows the effect of

sympathetic
versus

parasympathetic innervation on sinoatrial node action potential

Shows that sympathetic and parasympathetic can change heart rate by changing the
slope of phase four; steeper the slope = quicker the firing

Cardiac Action Potential

The specialised sinoatrial muscle fibers do not contract and do slow action potential. All
cardiac muscle cells including atria ventricles do cardiac action potential AKA fast
response action potential. The muscle cells have low sodium and high potassium inside
the cell.

Resting phase 4:
membrane potential
maintained by
potassium current.
Equilibrium
potential at -94mV is “set-
point” determined by
balance of chemical gradient
(driving K+ out) and
electrical gradient (driving
cations in). Muscle cell
RESTING POTENTIAL -94
mV.

Phase 0: sodium instead of

calcium. Sodium drives action potential. Sodium channels open in response to adjacent
cells (gap junctions facilitate movement of ions therefore AP propagation). Na+ (cation)
follows a chemical gradient inward, raising membrane potential to near zero mV.

Phase 1: transient K+ outward slightly hyperpolarises cell

Phase 2: slow calcium current continues maintaining depolarisation (allowing calcium to

drive contraction by triggering release of calcium from SR). Slow L-type calcium
channels maintain a calcium potential near 0 mV for a long time - hence the constant
horizontal line as L-type channels open for a longer time. Consequently, the
sarcoplasmic reticulum releases more calcium in response to the calcium.

Phase 3: repolarisation due to increase in potassium conductance.

NOTE: difference between muscle cell and SA node cell: muscle cells have a resting
phase while the SA node do not.
Electric gradient drives cations in as it is negative in respects to the outside.
Every cell in the body has a sodium potassium pump which maintains low sodium inside
and high potassium inside, meaning a negative electrochemical gradient; despite cells
having different resting potentials, all are negative in respect to the outside.
Action of NE on pacemaker potential in SA node

Noradrenaline on the pacemaker potential of the SA node activates beta one receptors.

How does stress cause high blood pressure?

Stress causes more adrenaline in the bloodstream and more noradrenaline release by
sympathetic fibers in response to stress which increases the rate and force of contraction
which drives blood pressure up.

Action of ACh on pacemaker potential in SA node

Actions of NE and E on myocardial contractile cells

Beta 1 adrenoceptor activation → increased cyclic AMP activates protein kinases, which then
phosphorylate:

1) Slow calcium channels, promotion entry of more calcium from the extracellular space
 2) An SR protein that causes the SR to release more calcium and
3) Myosin, which increases the rate of myosin cross bridge cycling
4) In addition, phosphorylation of the SR calcium uptake pump removes calcium more
rapidly from the sarcoplasm, thus promoting relaxation

Noradrenaline synthesis

Tyrosine
(one of the
20 essential
amino
acids) →
hydroxylase converts tyrosine to DOPA → DOPA decarboxylase forms dopamine →
dopamine beta-hydroxylase forms noradrenaline → phenylethanolamine, N-
methyltransferase (in adrenal medulla) forms adrenaline

Adrenaline is a hormone and neurotransmitter (released at synapses)

Noradrenaline release and uptake

 ● TURNING OFF NORADRENALINE: NA released at the nerve terminal → NET
(NorEpinephrine transporter on presynaptic terminal) and EMT (extraneuronal
monoamine transporter on postsynaptic terminal) both turn off signals for NA.

Acetylcholine synthesis

TURNING
OFF ACETYLCHOLINE: Acetylcholine is metabolised instead of being taken up and sequestered
from the nerve terminal. Released via exocytosis. Rather than ACh, choline is taken up into
presynaptic terminals with a choline carrier. Thus, metabolism uptake (of choline) stops the
action of ACh.

Cardiovascular (CVS) Disease

What is CVD?

All diseases and conditions involving the heart and blood vessels
Main types in Australia are coronary heart disease, stroke and heart
failure/cardiomyopathy

Impact and severity of CVD

Major cause of death in Australia

43,963 deaths attributed to CVD in Australia in 2016
This means that on average, 120 Australians die from CVD each day, or one every 12
minutes.
CVD accounted for nearly 28% of all deaths in Australia in 2016, including 27% for males
and 29%m for females

Lifetime risks
 High blood pressure
High blood cholesterol
Smoking
Diabetes
Overweight
Obesity
Physical inactivity

Prevalence and cost

CVD accounts for 15% of the total burden of disease in Australia, second only to cancers
at 19% of the total burden
In 2012-13, $5.0 billion was spent providing healthcare to admitted patients with CVD.
This accounted for 11.1% of total admitted health expenditure - the largest share of health
expenditure of any disease group.

Heart attack vs heart failure

Heart Attack Heart Failure

Cholesterol → plaques → coronary artery blockage Weakened heart → reduced ability to pump

Decreased oxygen to region supplied by artery Left/right sided or both

lactate , pH changes, cell death Many causes eg. heart attack, hypertension, EtOH,
drugs

CDV drug therapy

Cardiovascular Disease Drug Therapy

Agina Nitrates
Beta-blockers
Calcium channel blockers (CCBs)

Myocardial infarction Anticoagulants

Thrombolytics
Antiplatelets

Cardiac failure Nitrates

Beta-blockers
ACEIs
Diuretics
Cardiac stimulants

Hypertension Pathophysiology and renin/angiotensin/aldosterone system (RAAS)

Angiotensin converting enzyme inhibitor (ACEIs) and angiotensin II type -
1 receptor antagonists, CCBs, beta-blockers, diuretics
Atherosclerosis Current lipid lowering drugs

Note: The kidney greatly contributes to the regulation of blood pressure

Coronary circulation and major sites of blockage

Major sites of coronary blockage

●
Circumflex
artery

obstruction
○ Lateral infarction
○ ECG changes in leads I and aVL and lateral chest leads (V4-6)
○ 20% of cases
● Left anterior descending artery obstruction
○ AKA widow maker
○ Artery of “sudden death”
○ Causes myocardial infarction with subsequent tissue damage and then death
○ Anterior infarction
○ ECG changes in anterior chest leads
○ 50% of cases
● Right coronary artery obstruction
○ Inferior infarction
○ ECG changes in leads II, III, and aVF
○ Can involve posterior septum
○ 30% of cases

Note: All three blockage points above come directly out of the aorta leaving the left
ventricle - which contains blood of high pressure. Thus, blood that comes into coronary
 arteries (including the above) are under high pressure.

ECG Triangulation

Standard 12 lead ECG includes:

● Leads on arms, legs and chest

● Ring around the heart is broken into different regions

P wave

● What part of the heart has the damage

will be shown by what leads or regions
have a difference in the electrical signal
compared with what is expected.
● Top 180 degrees is negative while the
bottom is positive

QRS Complex

● Depolarisation of ventricles
● Phase 1: depolarisation of the
interventricular septum
● Phase 2: depolarisation of the free
wall of the ventricles
● Phase 3: depolarisation of the
posterobasal wall
Reading ECG

1) Is there any electrical activity? (lack of activity when the patient is conscious suggests
that the electrocardiograph is not working or the leads have not been properly
connected; in an unconscious patient, it might reflect asystole)
2) Is the rhythm of the QRS complexes regular or irregular? Irregular could indicate
missing beats - ectopic beats (beats appearing or disappearing where they shouldn’t be)
3) What is the ventricular rate?
4) Is the width (ie. the duration) of the QRS complex normal or increased?
5) Is there detectable atrial activity?
6) What kind of correlation is there between the atrial and ventricular activity?

A three lead ECG called a Eindhoven triangle provides a good trace of QRS complex to measure
the beat to beat distance from the R at the peak to the next peak; R-R distance. Analyse
mathematically the distance and the variability of the standard deviation in those differences.

Components of ECG timings/axes

Note: aVR is upside down compared with an aVL

Coronary Heart Disease Causes

Coronary heart/ischemic heart disease main causes:

● Atherosclerosis leading to narrowing of the coronary arteries and transient ischaemia

causing angina pectoris due to lack of oxygen supply to the heart. Eg. walking up stairs
increases oxygen demand - heart attack occurs from an imbalance between supply and
demand of oxygen.
● Coronary thrombosis i.e. formation of blood clot or vasospasm which occludes the
coronary arteries to a myocardial infarction or heart attack. A ruptured plaque is
blocking coronary artery blood supply to a massive amount of tissue in the heart. The
 muscle tries to contract in the absence of oxygen and produces lactate as the use of
glucose is anaerobic.

Note:

Unstable angina leads to myocardial thrombosis

Ischemia- a condition in which blood flow (and thus oxygen) is restricted or reduced in a
part of the body
Coronary thrombosis- plaque has ruptured

Angina

Angina (a symptom of CHD)- type of chest pain caused by reduced blood flow to the
heart
Angina does not always mean a heart attack
Occurs when there is significant narrowing of coronary arteries (~70% stenosis); pain
only felt after significant stenosis
Results from a mismatch between oxygen supply to the heart and oxygen demand of the
heart
● Oxygen supply (major determinant blood flow):
○ Increases with vasodilation (increased blood flow)
○ Decreases with vasoconstriction and vessel narrowing, as occurs in
coronary artery disease (CAD)
 ● Oxygen demand (determined by cardiac workload)
○ Increases when heart rate increases, force of contraction increases and
blood pressure increases
○ Decreases when heart rate, force of contraction and blood pressure
decreases
Oxygen demand is determined by the cardiac workload
Oxygen supply is determined by:

● Coronary blood flow

● Oxygen carrying capacity of blood

Angina and transient coronary ischemia

Ischemia - insufficient oxygen supply to an organ to meet demand

During myocardial ischaemia metabolites such as lactic acid, potassium (cell death is
probably causing potassium leak), hydrogen, adenosine accumulate which may cause
pain; a feeling of a heavy weight or pressure on the chest may be felt; pain may be felt in
the chest, arm and/or neck

Angina may result from:

● Oxygen supply/demand imbalance (stable - on exertion)

● A ruptured plaque (unstable - potentially an emergency)
● Coronary artery vasospasm (variant - may occur at rest of during sleep)

Oxygen supply/demand imbalance can be treated by increasing oxygen supply (increase

blood flow) or decreasing oxygen demand (decrease cardiac work)

Physical factors regulating coronary blood flow (CBF)

1) The pressure exerted by the myocardium on coronary vessels during systole ≥

perfusion pressure so CBF occurs only during diastole; tissues only
get blood supply during diastole once the pressure is lower
2) When heart rate increases diastole shortens by a greater amount than systole, reducing
the ‘window’ for myocardial perfusion
3) During diastole the effective perfusion pressure is equal to the difference between aortic
and ventricular pressure (A-V): when aortic pressure decreases or ventricular pressure
increases, the ‘window’ for CBF is decreased
Cardiac Cycle

Systole

● Isovolumetric contraction: valves are closed = volume stays the same; contraction occurs
against closed valves.
● Ejection: valves open
● Isovolumetric relaxation: valves are closed, muscles are relaxing

Diastole

● Rapid filling

Deoxygenated blood from the body travels to

the right atrium via superior/inferior vena cava. The right atrium contracts and pumps blood
into the right ventricle via the tricuspid valve. Tricuspid valve closes once the right ventricle is
filled to prevent blood flowing back into the atrium. Right ventricle contracts and forces the
pulmonary valve to open as blood is pumped into the pulmonary artery. The deoxygenated
blood travels to the lungs and the pulmonary valve closes. The right atrium relaxes at the same
time, ready to accept another intake of blood.

Oxygenated blood from the lungs comes into the left atrium via the pulmonary veins. Left
atrium contracts to pump blood into the left ventricle through the mitral valve. Once the left
ventricle has filled with blood, the mitral valve closes. The left ventricle contracts, forcing the
aortic valve to open and allowing blood to be pumped into the aorta, then to the body. Aortic
valve closes to prevent blood overflowing into the left ventricle. Left ventricle relaxes, ready to
take the next intake of blood.

Arteries and Arterioles

Arteries Arterioles

Large beat-to-beat variation in blood pressure
Contribute 40% of total vascular resistance;
does not change in pressure much; arterioles
are a target for pharmacotherapy as they
contribute a large amount to the system’s
pressure

Systolic and diastolic blood pressure Moderate beat-to-beat variations in blood

measuring site pressure

Very elastic Receive sympathetic nervous innervation

regulating contraction

No parasympathetic innervation

In actively metabolising tissue local

metabolites produce vasodilatation

Capillaries and Veins

Capillaries are not a target for blood pressure therapy due to slow movement of blood. Veins are
a target for blood pressure therapy because it contributes to determining the preload (blood
amount coming back to heart).

Capillaries Veins

Flow rates are slow enough to allow exchange If a person loses a significant amount of
of gasses and nutrients by diffusion blood, there is widespread sympathetically
medicate venoconstriction

Over 24 hours 4000L of plasma flows Venous return is assisted by valves

through them

Entry of blood is controlled by precapillary Smooth muscle and elastic fibers form a
 sphincters and arterioles sheath around veins

Anti-Anginal Drug Classes

Nitrates

● From 1867
● Various formulations
○ Glyceryl trinitrate (GTN)
■ Fast acting (<5 min), short duration < 1h.
■ Sublingual tablet or spray
○ Isosorbide mono - or dinitrate
■ Longer acting (4-6h)
■ Oral tablet
○ Nitrates are metabolised to release nitric oxide (NO), which activates the enzyme
guanylate cyclase to produce cyclic GMP (cGMP)

● How organic nitrates work

○ Nitrate activates cyclic GMP → cGMP activates PKG kinase which inhibits myosin
kinase and reduces contraction

● Anti-anginal effects of nitrates: Nitrates dilate blood vessel in three areas

○ Coronary arteries: dilation of vessels increases blood flow and hence oxygen
supply to the heart
○ Arterial resistance vessels: dilation reduces total peripheral resistance and
afterload or work of the heart
○ Venous capacitance vessels: dilates decreases venous return and the preload as
less blood flows to the heart
 ● Side effects and limitations of nitrates
○ Headache due to vasodilatory effects of nitrate
○ Facial flushing due to vasodilatory effect of blood vessels in the skin
○ Postural hypotension (possibility of fainting as excessive vasodilation can cause
insufficient return to the brain), dizziness and reflex tachycardia;
○ Note: orthostatic reflex occurs when standing up: carotid body detects blood
pressure decrease due to pooling in the legs = heart rate increases; nitrates
counteracts orthostatic reflex which means standing up can make you feel faint

○ Note: many patients develop tolerance to nitrates if given for > 24 h: a nitrate
free period is built into the dosing regimen to prevent the headache side effect.

Beta-adrenoceptor antagonists (beta-blockers)

● From 1962
● Examples: beta-one selective (eg. atenolol, metoprolol)
● Antagonism of beta-one adrenoceptors has two main negative effects on the heart:
○ Inotropic effect (reduces force of contraction)
○ Chronotropic effect (decreases heart rate)
● Also reduces arterial pressure and therefore reduce cardiac afterload
● End result - less work for the heart i.e a decrease in oxygen demand.
● Side effects and limitations of beta-blockers
○ Bradycardia (slowing of the heart rate)
○ When not entirely beta-1 selective, unwanted beta-2 effects may occur such as
bronchoconstriction (due to blocking circulating adrenaline)
○ Fatigue (beta-1 and beta-2 effects)
○ Cold hands (likely beta-2 effect)
● Precautions/contraindications:
 ○ Asthma or COPD due to b/constrictor effect
○ Uncontrolled heart failure due to negative inotropic effect
○ Diabetes type 1 can mask somatic effects of hypoglycemia such as dizziness and
fainting

Calcium channel blockers (CCBs)

● Classified according to their chemical structure: dihydropyridines (eg. felodipine);

phenylalkylamines (eg. verapamil); benzothiazepines (eg. diltiazem)
● All bind to and block L-type Ca2+ channels
● All effect L-type calcium channels in vascular smooth muscle - particularly arteries
reducing systemic arterial pressure and cardiac afterload (decrease oxygen demand)
● Also increase coronary blood flow (increase oxygen supply)
● Verapamil also blocks cardiac L-type calcium channels which causes negative inotropic
and chronotropic effects (similar action to beta-blockers - decrease oxygen demand)

● Side effects and limitations of CCBs

○ Due to vasodilatory:
■ Felodipine: facial flushing, ankle swelling, headache and dizziness
■ Diltiazem: facial flushing, ankle swelling, headache
■ Verapamil: headache, dizziness; atrioventricular (AV) block and
bradycardia
○ Limitation of verapamil use
■ Interaction between verapamil and beta-blockers; due to the fact that
both have negative inotropic and chronotropic effects a combination can
cause severe hypotension and bradycardia.
○ Avoid grapefruit with all CCBs → toxicity

Alternate approaches to treatment of angina

● Prophylaxis i.e. prevention: “baby” aspirin and “stains”

● Non pharmacological interventions (lifestyle or, for severe cases, options include stents
and by-pass surgery)
● Tissue damage can be treated by coronary artery bypass graft
Heart Failure

Heart failure - cardiac output insufficient to meet circulatory needs of the body

Symptoms: breathlessness, ankle swelling (oedema) and fatigue

Usually due to damage caused by ischemia to the myocardium (cardiac muscle/myocytes)

Two major types: systolic failure (contractility/force of contraction reduced/HFrEF) and

diastolic

Left or right-sided ventricular heart failure

● Left
○ LV does not pump forward
○ pressure/fluid in pulmonary circulation increases
○ Causes congestion within pulmonary veins and leads to pulmonary oedema,
hypoxaemia, dyspnea, weakness and fatigue
● Right
○ Right ventricle does not pump forward
○ Pressure/fluid in systemic circulation increases
○ Causes congestion in veins and leads to peripheral oedema

Two major causes: ischaemic heart disease, hypertension

Consequences of heart failure

● Heart failure = reduced cardiac output = carotid sinus that detect pressure decrease firing and
also increase blood pressure → sympathetic nervous system activation
● Reduced cardiac output
● Reduced left ventricular ejection fraction (EF) of < 40% = HFrEF
● Compensatory mechanisms:
○ SNS activated (noradrenaline and adrenaline)
○ RAAS activated (angiotensin II and aldosterone)
○ NPS activated (natriuretic peptides)
● Compensated HF (no symptoms) when it gets worse and needs medication →
decompensated
● Lead to:
○ Fluid retention: positive (compensated) and negative (decompensated)
consequences
○ Vasoconstriction: positive (compensated) and negative (decompensated)
consequences
○ Long term: cardiac hypertrophy and fibrosis: largely negative consequences
● Median survival rates of around 3 years: 5 year mortality rate ~ 50%
Note:
● 5 liters blood in body
● Heart pumps ~ 70 mL each beat
● Approximately 1 miniature for one red blood cell to do a lap
● Blood flow: Left ventricle into aorta →systemic circulation → vena cava to right atrium →
right ventricle → pulmonary artery and circulation to left atrium → back to left ventricle
● Carotid sinus detects low blood pressure and attempts to increase it as a solution;
● Venous contrition brings more blood to heart
● Both afterload and preload is increased

Ejection Fraction
A measurement expressed as a percentage of how much blood the left ventricle pumps out with
each contraction. An ejection fraction of 60% means that 60% of the total amount of blood in
the left ventricle is pushed out with each heartbeat.

Normal EF ~ 50-75 %

40% is not good i.e. reduced EF

Drugs used in Heart Failure

Three main classes:

● ACEIs, ARBs (inhibit formation/block actions of angiotensin II)

● ß-blockers (inhibit SNS and RAAS activation)
● Aldosterone antagonists (inhibit Na+/water retention)

Other drugs/drug classes:

● Inotropic agents e.g. digoxin (cardiac stimulants)
● Combination therapy (valsartan + sacubitril = LCZ696) (block actions of angiotensin II +
potentiates NPS)
● Ivabradine (decreases HR – does not reduce contractility)
● Diuretics (used mainly to treat oedema)
● To reduce more serious cardiac events for patients “at risk” antiplatelets are used – e.g.
“Baby Aspirin” (refers to low dose aspirin)
 Week 2 -Antihypertensives

Hypertension
Hypertension = persistently high blood pressure

Associated with

● Decreased life expectancy

● Stroke
● Coronary heart disease
● Other end-organ D (retinopathy, renal failure)

NOTE: essential hypertension = hypertension in an elderly patient

Risk factors contributing to risk of vascular disease

● Smoking
● Obesity
● Hyperlipidemia (associated with alcohol)
● Diabetes
● Left ventricular hypertrophy

Prevention/Solutions

● Exercise
● Weight loss (if appropriate)
● EtOH and salt reduction
● Most patients require combination therapy (eg. amiloride and hydrochlorothiazide)

Many to many relationship in cardiovascular drugs

RAAS-Based Treatment Options for Hypertension

Drugs to treat hypertension are divided into RAAD and non-RAAS drug sections

RAAS is important in blood pressure regulation

If body (eg. baroreceptor) detects loss of blood pressure, it activates the autonomic nervous
system to maintain the vital spark

RAAS = Renin-Angiotensin-Aldosterone System

● Angiotensinogen is produced in the liver.

● Renin enzyme in kidneys converts angiotensinogen into angiotensin I. Renin is released into
blood → renin acts on circulating angiotensinogen → undergoes proteolytic cleavage →
decapeptide angiotensin I.
● ACE enzyme in lungs converts angiotensin I into angiotensin II. Angiotensin converting
enzyme (ACE) is in vascular endothelium, particularly in the lungs. ACE cleaves off two
amino acids to form the octapeptide angiotensin II. Heart, brain and vascular bodies can
also form Angiotensin II.
● Angiotensin II promotes aldosterone and vasoconstriction
Angiotensin II functions

● Constricts resistance vessels via angiotensin (type I) receptors

= increases systemic vascular resistance and arterial pressure
● Stimulates sodium transport (reabsorption) at several renal
tubular sites = increases sodium and water retention by the
body; water follows sodium, thus blood volume increases =
increases preload
● Acts on the adrenal cortex to release aldosterone =
aldosterone acts on the kidneys to increase sodium and fluid
retention
● Stimulates the release of vasopressin (antidiuretic hormone,
ADH - note: fluid inhibits ADH) from the posterior pituitary =
increases fluid retention by the kidneys
● Stimulates thirst centers within the brain
● Facilitates norepinephrine release from sympathetic nerve
endings and inhibits norepinephrine reuptake by nerve
endings, thereby enhancing sympathetic adrenergic functions
● Stimulates cardiac hypertrophy and vascular hypertrophy
RAAS: sites of drug action (reducing blood pressure)

Drug Function

Angiotensin II receptor receptor (type 1) Inhibits conversion of angiotensin I to II

blockers ARBs

ACE inhibitors (ACEIs) Inhibits conversion of angiotensin I to II

Renin inhibitors

Angiotensin Converting Enzyme

(ACE)

Mechanism of Action

● Abundant in the lungs

● Structure: Protein database
2YDM (PDM 2YDM)
● The venom in the bothrops
jararaca snake contains ACE
inhibitor (ACE I) which reduces
the victim’s blood pressure. First
synthetic inhibitor was made
using this.
Angiotensin Converting enzyme inhibitors

● Reduces blood pressure

● All undergoes metabolism before becoming the active metabolite
● Note: Captopril was the first made. Half life of two hours = drug was to be taken
frequently = not commonly used today

Prodrug Active Form

Enalapril Enalaprilat

Perindopril Perindoprilat

Ramipril Remiprilat

Clinical uses of ACE inhibitors and side-effects

● Clinical use
○ Hypertension, especially in presence of heart failure or stroke
○ Myocardial infarction
○ Diabetic nephropathy
○ Progressive renal insufficiency
● Contraindications
○ Pregnancy
○ Angioedema
○ Hyperkalaemia
○ Bilateral renal artery stenosis
● Side effects
○ Dry, persistent cough due to bradykinin build up
■ ACE can inactivate bradykinin (inflammatory mediator) which sensitises
non-susceptive C fibers to the effects of pain; increases bradykinin levels.
 Released in response to tissue damage. Can increase pain levels. Excess
bradykinin in lungs produces a cough and so ACE inhibitors (eg.
enalapril, ramipril, perindopril) produces a persistent dry cough.
○ Hyperkalaemia (increased risk with renal impairment)
○ Renal impairment
○ Infrequent angioedema

Angiotensin II receptor antagonists (“sartans”)

● Note: ATII receptors cause vasodilation and reduction in total peripheral resistance.
ATII receptors reduce secretion of aldosterone leading to sodium loss and diuresis. Thus,
ATII antagonists can cause sodium buildup - people with hypertension should avoid
excessive sodium intake.
● Clinical use
○ Hypertension, especially in presence of heart failure or stroke
○ Myocardial infarction
○ Diabetic nephropathy
○ Progressive renal insufficiency
● Contraindications
○ Pregnancy
○ Angioedema
○ Hyperkalaemia
○ Bilateral renal artery stenosis
● Side effects
○ Hyperkalaemia (increased risk with renal impairment)
○ Renal impairment
○ Infrequent angioedema
Direct inhibitors of renin activity

● Aliskiren licenced for treatment of hypertension and effective at reducing blood pressure
but no reduction in cardiovascular mortality and morbidity has been demonstrated

Aldosterone antagonists: eg. spironolactone

● Inhibit distal sodium retention and potassium secretion (only 2% sodium reabsorption
under aldosterone control at distal tubule so limited diuretic action)
● Direct aldosterone antagonists used after myocardial infarction or with heart failure
● Clinical use: reduces potassium excretion - potassium sparing agents combined with
loop diuretics where hypokalemia is an issue
● Side effects: hyperkalaemia (increased risk with renal impairment); hyponatremia
Non-RAAS Treatment Options for Hypertension

Antihypertensive drugs: calcium channel blockers, diuretics and beta-blockers

● MABP = mean arterial blood pressure = CO x TPR

● CO = cardiac output = heart rate (HR) x SV
● Stroke volume (SV): venous return, myocardial contractility
● Total peripheral resistance (TPR): blood viscosity, vessel radius, smoothness, length,
sympathetic tone

Directly acting vasodilators: calcium channel blockers

● CCBs block the alpha1 subunit of the L-type calcium channels

● L-type channels are an important calcium source for contraction of smooth and cardiac
muscle
● No contraction → vasodilation
● Calcium binds to calmodulin which encourages myosin light chain kinase to activate and
lead to the phosphorylated myosin, producing the contraction
● Note: skeletal and smooth muscle has troponin; cardiac muscle has calmodulin
Calcium channel blocking agents

● Dihydropyridines
○ Act preferentially to inhibit calcium entry into vascular smooth muscle
(arterioles)
○ Minimal effect on myocardial contractility and cardiac conduction
○ Relaxes vascular smooth muscles and cause peripheral vasodilatation
○ Clinical uses
■ Hypertension
■ Angina
○ Examples
■ Amlodipine
■ Felodipine
■ Lercanidipine
■ Nifedipine
○ Contraindications
■ Heart failure
○ Adverse effects
■ Peripheral vasodilation (peripheral oedema, flushing, headache,
dizziness)
■ Postural hypertension
■ Tachycardia
■ Palpitations
■ Chest pain
● Non-dihydropyridines
○ Preferentially inhibit calcium entry into vascular smooth muscle of blood vessels,
the heart and gastrointestinal tract
○ Clinical uses
■ Hypertension
■ Angina
■ Some cardiac arrhythmias
○ Examples
■ Verapamil (phenylalkylamine, acts
directly on the heart)
■ Diltiazem (benzothiazepine,
intermediate specificity)
○ Contraindications
■ Should not be used with a beta-blocker because of the risk of heart block
○ Adverse effects
 ■ Bradycardia
■ Constipation (especially with verapamil)
■ Atrioventricular block
■ Heart failure

Binding of calcium channel blocking agents

Amlodipine (dihydropyridine) Verapamil (non-dihydropyridine)

Indirect allosteric blocker binds to outer Binds to lumen of the pore which binds to
lipid-facing surface active state of the channel in rapidly firing
cardiac myocytes

Thiazide Diuretics

● Inhibit the reabsorption of sodium and calcium in the early distal convoluted tubule of
the nephron (inhibit sodium/calcium cotransporter in distal tubule). Lead to reduction
in blood volume (= reduced caridac output) and blood pressure.
● Contraindications
○ Should not be used if patients in glucose intolerant or has metabolic syndrome or
diabetes
○ Only for older patients because of increased risk of diabetes
● Adverse effects
○ Postural hypotension, dizziness
○ Hypokalaemia, hyponatremia
○ Hyperuricemia, hyperglycemia

Beta- Adrenoceptor
Antagonists (Beta Blockers)
 ● Mechanism of action includes
○ Block the effect of endogenous catecholamines on the beta-adrenoceptor
receptors of the sympathetic nervous system
○ Reduced cardiac output (block of beta-1 receptors in heart) - reduced rate and
force of contraction
○ Reduced renin release (block of beta1 receptors on juxtaglomerular cells in
kidney)
○ Note: propranolol = non-selective = likely to have unwanted effects
○ Clinical uses
■ Hypertension
■ Angina
■ Cardiac arrhythmias
■ Heart failure
■ Migraine
■ Tremor
○ Contraindications
■ Risk of developing diabetes
■ Asthma
■ Bradycardia
■ A-V block
■ Should not be used with verapamil
because of risk of heart block
○ Adverse effects
■ Bradycardia
■ Postural hypotension
■ Worsening of heart failure
■ Bronchospasm
■ Resistance to exercise

Rationale and treatment of heart failure

● Drugs that indirectly decrease workload of heart; Reduce pre- or afterload by

vasodilation and/or reduce plasma volume
○ ACE inhibitors and AT1R antagonists - ARBs (essentially vasodilatory and reduce
plasma sodium levels and plasma volume)
○ Beta blockers (decreased heart rate)
○ Aldosterone antagonists (decreased sodium levels + plasma volume)
● Drugs that directly stimulate the heart; known as inotropes, these agents increase the
force of contraction of the heart (increased cardiac output)
○ Inotropic agent
 ■ eg. digoxin. NaKATPase usually maintains high sodium outside the cell.
Sodium gradient usually powers calcium movement out of the cell via
exchange with outside sodium. Digoxin inhibits the NaKATPase and sodium
increases inside cell → reduced exchange of calcium with sodium → increased
intracellular calcium → contraction process

○ Sympathomimetic agents

■ eg. dobutamine. Beta1 adrenoceptor agonist. Increases force of contractility

with little increase in heart rate. Lesser agonist activity on beta2 receptors →
vasodilatation. Used in acute situations eg. after surgery to increase heart
activity but can kill someone with heart failure

○ Cardiac natriuretic peptides

■ Atrial cells store and release ANP (atrial natriuretic peptide); increases
renal sodium secretion
■ Ventricular muscle releases BNP (B-natriuretic peptide); opposes
ventricular fibrosis
■ Main effects of natriuretic peptides are to increase sodium and water
excretion, increase vascular permeability and inhibit release/action of
vasoconstrictor and salt-retaining hormones
■ Both ANP and BNP are inactivated by neprilysin (NEP)
■ Sacubitril inhibits NEP → increases circulating ANP and BNP which favors
sodium secretion
■ Combination drug - sacubitril with valsartan (50:50) = dual inhibition of
the RAAS and neprilysin (NEP)
● Slows degradation of natriuretic peptides, bradykinin,
adrenomedullin, thereby enhancing diuresis, natriuresis and
myocardial relaxation. Also inhibits renin and aldosterone
secretion, while selectively blocking the angiotensin II type 1 (AT
1) receptor reduces vasoconstriction, sodium and water retention
and myocardial hypertrophy
○ Ivabradine - Selective sinus node IF (funny) channel (predominantly potassium
channel) inhibitor
■ Heart rate is determined by pacemaker cells, controlled by the funny
current/channel
■ Funny channel is permeable to both sodium and potassium ions; it is
activated on hyperpolarisation (i.e during diastole)
■ Ivabradine selectively inhibits funny channel and lowers heart rate which
reduces myocardial oxygen demand
■ Ivabradine has no negative inotropic effects meaning it preserves
ventricular contractility
 Week 2 - Diuretics

Diuretics increase sodium and H20 elimination and reduce arterial blood pressure; water
follows sodium; water removal reduces blood volume - blood volume is part of the equation for
blood pressure

The renal system is a powerful mediator of homeostasis (hence a good drug target)

Kidneys maintain electrolytes and waste product concentrations in face of changing

diet/environment

Most drugs are cleared renally; renal system = crucial study

20% CO goes to kidneys

Glomeruli filter ~ 180 L fluid/day

99% filtrate reabsorbed by tubules → 1.8 L urine output/day

Reabsorption of fluid and solute in the kidney

Most of the sodium that is filtered is reabsorbed through the tubules; sodium is crucial, every
heartbeat requires it; every cardiac action potential starts with the sodium current (not
sinoatrial node which includes calcium)

Why is more potassium excreted than sodium?

To ensure extracellular potassium value is low; high extracellular potassium will

decouple the electrochemical potential for heart to beat

The Urinary Tract

The kidney maintains volume and composition of body fluids within narrow limits by
responding to disturbances in volume and composition of circulating blood

Includes:

Right and left kidney; outside cortex and medulla of each medullary pyramid (includes
nephrons aka functional unit of the kidney), renal pelvis at center of kidney where urine
exits,
Renal artery coming in
Renal vein going out
Ureters tubules comes out of renal pelvis and meets the bladder
 Urethra = exit tubule that is longer males than females

Nephron

Functional Anatomy of Nephron

Afferent arteriole; coming towards glomerulus

Efferent arteriole; away from glomerulus; once exiting glomerulus, it becomes
peritubular capillary where reabsorption and secretion goes around the tubule

Note: afferent arteriole = blood side; efferent arteriole = urine side

Nephron Blood Supply

1) Cortical nephrons → two capillary beds in series

Afferent arteriole → glomerulus → efferent arteriole → peritubular

2) Efferent arterioles of juxtamedullary nephrons → extend deep into medulla (vasa

recta)

NSAIDs constrict
afferent arterioles
Ace inhibitors
dilate afferent
arterioles
Triple whammy syndrome caused by diuretic coupling with an NSAID coupled with an ace
inhibitor
Renin release controlled by Macula Densa

Specialised macula densa cells in afferent arteriole ad tubules; on the distal tubule where it
touches the gloumerulus

Detect changes in flow rate and composition of tubule fluid

Signal for release of renin from granular cells of afferent arteriole

Regulation of body fluids

62.5% of TBW is intracellu.ar → 37.5% ECF

Dominant cation ECF = Na+

Dominant cation ICF = K+

Principal balancing anions in ECF = Cl- and HCO3-

Balancing anions in ICF = and organic anions; affected by diet coke which introduces
excessive phosphate into diet
Ubiquitous NaKATPase maintains Na+/K- gradient across cell membranes; cells are internally
negative with respects to the outside

Kidney adjusts water loss to match water intake

NaKATPase is ubiquitous in the body

NaKATPase keeps potassium in and sodium out

The pump is electrogenic (generates membrane potential)

3 Na+ extruded per 2 K+ taken into the cell; consequently cells have negative intracellular
charge wrt outside

K+ has a concentration gradient leading it out via K+ channels

Sodium important in maintaining Blood Volume: can be increased/decreased

Hypovolaemia

● Gastrointestinal sodium loss

 ○ Eg. vomiting, diarrhea, nasogastric suction
● Skin sodium loss
○ Eg. excessive sweating, burns
● Renal sodium loss
○ Eg. diuretics, mineralocorticoid deficiency, tubulointerstitial disease
● Internal sequestration
○ Eg. bowel obstruction, peritonitis, pancreatitis, crush injury
● Haemorrhage

Hypervolaemia

● Iatrogenic
○ Eg. salt loading (oral or intravenous)
● Renal sodium retention in generalised oedema states
○ Eg. congestive cardiac failure, cirrhosis, nephrotic syndrome
● Renal sodium retention in renal failure
○ Eg. acute and chronic kidney disease (usual case)
● Renal sodium retention in primary mineralocorticoid excess
○ Eg. Conn’s syndrome (note to oedema)

NOTE: severe hypovolemia → hypovolemic shock → death

Sodium regulation - maintaining balance

● Back of envelope calc.

● [Na+] plasma ~ 140 mM
● GFR ~ 144 L/day
● Na+ in filtrate = [sodium in plasma]x(glomerular filtration rate) = 140x144 = 20160
mM/day filtered
 ● Assume consumption of 100 mM Na+/day
● Must lose 100 mM to maintain balance (don’t want to go up and up_
● Must excrete 100mM Na+/day
● 100/20160~0.5% Na+ contained in glomerular filtrate must be excreted in urine
● Actual balance changes with environment eg. Nat+ intake

Sodium reabsorption in the Nephron

1 million nephrons in renal cortex

Filtrate travels from proximal tubule → loop of Henle → distal tubule → collecting duct
Specialised epithelial cells in each segment eg. thick ascending limb (TAL) cells have
extensive basolateral infoldings and abundant mitochondria
Site of action determines extent of effect on sodium secretion

MOA of Diuretics

Inhibition of Na+ reabsorption

1. Sodium/potassium/2 chloride co-transported (loop diuretics → frusemide)

2. Na+/Cl- co-transporter (thiazides)
 3. Na+ channels: {not the voltage dependent kind} amiloride (K+ sparing diuretic)
4. Spironolactone (K+ sparing diuretic)

Inhibition of water reabsorption

Osmotic effect, water reabsorption is decreased along with sodium (osmotic diuretics)

Sites of Diuretic Drug Action

1-3 previous slides act on luminal sodium uptake across apical membrane in specific segment

Different sodium uptake mechanisms in segments

But same sodium exit step (NaKATPase) on basolateral membrane in each segment

Spironolactone blocks cytoplasmic aldosterone R.

1) Loop diuretics
● Eg. frusemide, bumetanide
● MOA: inhibit sodium/potassium/2CL
transporter
● Increase delivery of sodium to distal nephron
→ loss of H+ and K+ (exchanged for Na+)
because gradient setup by basolateral
NaKATPase
● Increase excretion Ca2+, Mg2+
● Marked diuresis
● May cause up to 25% of the GF to be
excreted
● Clinical use of loop diuretics
○ Oedema: acute pulmonary oedema,
heart failure, hepatic cirrhosis
complicated by ascites, nephrotic
syndrome, renal impairment
○ Hypertension: optimal SBP/DBP: < 120/80 mmHg; stage 1 = 140/90
mmHg)
○ Heart failure
○ Hypercalcaemia
2) Thiazide diuretics

● Eg. hydrochlorothiazide, indapamide

● MOA: inhibit sodium/chloride cotransporter early distal tubule
● Moderate diuresis (sodium/water loss), also increase K+ and H+ excretion but decrease
Ca2+ loss
○ Potentially useful if risk of osteoporosis
● Vasodilatory effects
● Clinical uses of thiazide diuretics
○ Oedema
○ Hypertension
○ Heart failure
○ Nephrogenic diabetes insipidus
○ Prevention of recurrent stone formation in idiopathic hypercalciuria

3) Amiloride - Potassium Sparing Diuretic

● MOA: blocks sodium channels on apical membrane of late distal tubule of cortical
collecting duct
● Mild diuresis (Na+/H20 loss)
● Decrease K+ and H+ excretion, little effect on Ca2+ and Mg2+
4) Spironolactone - Potassium Sparing Diuretic

● MOA: blocks action of aldosterone at

cytoplasmic receptor decreasing sodium
reabsorption across basolateral membrane
● Mild diuresis (Na+/h20 loss) but marked
antihypertensive effects
● Decrease potassium and H+ excretion, little
effect on calcium and magnesium

So why the need for potassium sparing diuretics?

● Amiloride (and similar diuretics) are mainly used with potassium losing diuretics (loop
and thiazide diuretics) to prevent potassium loss in the urine
● Spironolactone (and other aldosterone antagonists) are used in hyperaldosteronism
(endocrine use), as well as for hypertension and heart failure

Osmosis
Osmosis is movement of solvent (eg. water) through a semipermeable membrane into region of
higher solute (eg. Na+) concentration, such that the solute concentrations (osmolality) become
equal on each side.

Osmolarity = conc/L
Osmolality = conc/Kg

Osmolality doesn’t change with

Mannitol is an Osmotic Diuretic

Freely filtered at the glomerulus (mannitol moves to the urine side easily); essentially an inert
molecule
MOA: increases the osmolarity of the tubule fluid causing water to be retained in the lumen of
the nephron, along with sodium
Marked diuresis with water and sodium loss
Limited clinical use: may be used for cerebral oedema associated with head injury after a road
traffic accident

Baby Aspirin
‘Baby’ refers to the dose of aspirin (not the size of the aspirin tablet nor that it is a drug for
babies)
Aspirin belongs to the class of drugs known as non-steroidal anti-inflammatory drugs commonly
referred to as NSAIDs
As an NSAID, aspirin has three main effects:

1) Anti-inflammatory
2) Analgesic (for pain)
3) Anti-pyretic (to lower body temperature). Doses (> 500mg) of aspirin are required for
these indications
4) Lower doses (30-100mg) aspirin prevent thrombus formation (i.e. a blood clot and are
used as secondary prevention of serious CVS events such as heart attacks and stroke

Aspirin Background
Aspirin inhibits the synthesis of prostaglandins - compounds converted from arachidonic acid
when cell membranes are damaged cell
After thromboxane and prostacyclin were discovered, aspirin became an anti-thrombotic
(antiplatelet) drug for the prevention of heart attacks and strokes
Antiplatelet drugs are reported to reduce the incidence of cardiovascular events by about 20-
25% in people with established cardiovascular disease

Aspirin forms over the years: salicin (derived from willow bark; willow bark tea)→ salicylic acid →
acetylsalicylic acid (aspirin)
Haemostasis and Thrombosis
Haemostasis

● Adhesion, activation and aggregation of platelets

● Formation of fibrin via the complex coagulation cascade - stops bleeding

Thrombosis; Virchow’s triad:

1) Injury to vessel wall (eg. plaque rupture)

2) Altered blood flow (eg. DVT on planes)
3) Abnormal blood coagulability

Unwanted effects of thrombosis

● An arterial thrombus: white thrombus - mainly platelets in fibrin mesh

● Venous thrombus: red thrombus - white head and red tail which can break away and
form an embolus eg. deep vein thrombosis (DVT)

Atherosclerotic plaque and formation of thrombus with platelet activation and blood
coagulation
Aspirin as anti-platelet drug?

Oral aspirin has a half-life of 15-20 minutes BUT it irreversibly acetylates the enzyme
cyclooxygenase COX-1 and COX-2

The irreversible binding means the effects of aspirin lasts as long as the lifespan of the platelet,
which is 7-10 dyas

Now, only low doses of aspirin are necessary to inhibit COX-1, much higher doses are required
to inhibit COX-2

In fact, as little as 30 mg daily of aspirin is required for near-complete suppression of platelet-

derived thromboxane A2 (TXA2)

Aspirin as Anti-Platelet Drug?

Both COX-1 and COX-2 catalyse the conversion of arachidonic acid derived from cell membrane
phospholipids to form prostaglandins or prostanoids
The most important prostanoids formed are TXA2 and prostacyclin (PGI2).
TXA2 is generated by COX-1 within platelets, in response to platelet activation. TXA2 then binds
its receptor on the surface of platelets, inducing irreversible platelet aggregation
Prostacyclin is produced by COX-2 within vascular endothelial cells; it opposes the effects of
TXA2 inhibiting platelet aggregation
At low dose aspirin inhibits COX1 more than COX2
So, low dose or baby aspirin reduces thrombus formation due to inhibition of TXA2 production,
and hence platelet aggregation

Metabolic pathway for synthesis of prostacyclin and thromboxane A2

Image below shows liberation of phospholipids due to damage of cell membranes; phospholipid
lipase A2 converts phospholipids to arachidonic acid aka eicosatetraenoic acid.
Cox produces endoperoxides which eventually leads to formation of prostacyclin, thromboxane
and prostaglandin (PGE2.
Platelet Activation
Multiple drug target sites exist for inhibition of platelet activation

Aspirin affects the production of cyclic endoperoxides

Snake Venom Medication

Several medications from snake venom
Eptifibatide, synthetic version of disintegrin from Barbours Pigmy Rattlesnake binds GP IIb-
IIIa: the last step in platelet aggregation
The GP IIb-IIIa binds to the clotting factor.
 Week 3
● Recognise and classify the major neurotransmitters and transmitter substances in the
CNS - amino acid transmitters, monoamines, neuropeptides, gases, purines etc.
● Explain the actions of neurotransmitters as excitatory or inhibitory in terms of their
(receptor) effects on membrane excitability
● Explain the normal synaptic events of neurotransmitters; synthesis, storage, release,
receptor action, reuptake and degradation
● Give examples of drugs that target CNS transmission and explain their mechanism of
action at the synapse – cocaine, ecstasy, amphetamines, benzodiazepines, fentanyl

What is so Special about the CNS?

All communication is neuron to neuron (c.f. PNS can be neuron to neuron OR neuron to effector
- neuron to muscle, gland etc.)
Many many different transmitter substances are involved in cellular communication (c.f. PNS
uses 2 transmitters)
It controls much of the body’s functions
Different parts of the brain control different functions and different transmitters are involved in
these functions

PNS transmitter system: cholinergic for somatic; cholinergic + Adrenergic for autonomic enteric
nervous system

Note: enteric nervous system is the only nervous system that works completely independently of
the CNS. Although ANS is considered involuntary, with mindful meditation, yoga etc. mindful
meditation, yoga etc. sympathetic drive can be reduced and increase parasympathetic drive
 Transmitter Substances (CNS)
Major inhibitory neurotransmitter of the brain and body = GABA

Revolution in pharmacy = peptides (chains) and transmitters are involved in transmission

Classical Transmitter Neuropeptides Gases Others

GABA Opioids eg. enkephalins Nitric oxide Neurosteroids eg.

allopregnanolone, DHEA

Glutamate Neurohypophysis eg. Carbon monoxide Purinergics eg. ATP

oxytocin adenosine

Glycine Somatostatins Lipid metabolites eg.

anandamide, 2-AG

Noradrenaline Tachykinins eg.

substance P

Dopamine

Serotonin (5-HT)

Histamine

Acetylcholine

Classical Neurotransmitters

Monoamines Amino acid transmitters Quaternary amines

Catecholamines GABA Acteylcholine

Noradrenaline Glutamate

Adrenaline Glycine

Dopamine

Indoleamines

Serotonin (5-HT)

Histamine
Fast vs
Slow

Neurotransmitters
Fast (millisec to seconds) act via ligand-gated ion channels

● GABA (GABAA, GABAC)

● Glutamate (AMPA, NMDA)
● Glycine
● Serotonin (5-HT3)
● Acetylcholine (nAChR)

Slow (seconds to minutes) act via G-protein coupled receptors

● GABA (GABAB)
● Glutamate (mGluR)
● Serotonin (5-HT1/2/4/5/6/7)
● Dopamine (D1, D2)
● Noradrenaline (alpha, beta)
● Acetylcholine (mAChR)
● Histamine (H1-4)

Notes:

● Transmitters cannot be strictly classified as fast or slow because all of them are both as
each act on different targets of receptors. Eg. GABA is fast acting when it is acting of
GABAA, GABAC receptors but slow acting when acting on GABAB receptors. EXCEPTION:
Glycine acts only in sensitive glycine receptors but is also a coagonist of the glutamate
NMDA receptor.
● Serotonin is a ligand-gated ion channel and so acts quickly on the 5-HT 3 receptor but
slowly on the other serotonin receptors.
● Speed of transmission is determined by the characteristics of the receptor - not the
transmitter
Inhibitory vs Excitatory Neurotransmitters
Inhibitory

● GABA (all)
● Glycine (strychnine-sensitive)
● Dopamine (D2)
● Serotonin (5-HT1)
● Acetylcholine (M2)
● Histamine (H3, H4)
● Noradrenaline (α2)

Excitatory

● Glutamate (most)
● Glycine (NMDA co-agonist)
● Dopamine (D1)
● Serotonin (5-HT2/3/4/5/6/7)
● Acetylcholine (nACh, M1, M3)
● Histamine (H1, H2)
● Noradrenaline (α1, β)

Notes:

● Net excitation or inhibition is determined by the nature of the transmitter and of its
receptor; most transmitters bind to receptors that are both inhibitory and excitatory
except GABA (all - a,b, c) which pass a certain point of development are inhibitory.
● Net excitation/inhibition is a consequence of changes in the cells’ iron fluxes - movement
of ions in and out of the cell
● Glycine is inhibitory except when it binds to NMDA co-agonist receptor

Ion Gradients and Excitability

Net excitation or inhibition is determined by the characteristics of the receptor

Movement of ions into/out of a cell can be gated by: ligand gated ion channels, voltage gated ion
channels, downstream effect + open/close ion channels when G protein coupled receptors are
activated; changes to the electrical potential of the membrane

Ions move down the electrochemical gradient

Neuron resting state ~ 70mV

Opening channels permeable to sodium = sodium moves from high outer to low inner
concentration.
Positive sodium or calcium ions moving inside cells = higher excitability
Ion conductance directly influences cell excitability

● Cation permeability increases probability of cell firing

● Anion permeability decreases probability of cell firing

Synaptic Transmission
Electrochemical
Action potential generated by influx of Na+ through voltage-gated sodium channel to cause
terminal depolarisation

What determines how likely a neuron is to fire?

● Distance of the neuron’s membrane potential from the threshold potential. Once hitting
the threshold potential, a nerve cell will fire - all or nothing; leads to terminal
depolarisation.
○ Eg. Resting neuron state ~ -70mV. Having an influx of positive ions to certain
parts of the cell (important for gating action potentials), will lift resting potential
to the threshold potential.
● Spatial and temporal summation leads to terminal depolarisation

Axon hillock is the most excitatory part of the cell; location of where action potential is
generated from.
Characteristics of a Neurotransmitter

Neurotransmitter- Chemical that transmits information to control behavior of cells at a short

distance

Transmitter is synthesised in the neuron and stored in vesicles in the nerve terminals
When neuron is activated, substance is released by a Ca2+ dependent mechanism (exocytotic
vesicular release)
Effect of nerve stimulation is mimicked or blocked by exogenous agent (Eg. agonist or
antagonist)
Mechanism present for termination of action (enzyme degradation or uptake)

Difference between a transmitter and hormone: eg. adrenaline is a neurotransmitter because it

is synthesised in the brain and released into other regions of the brain to a relatively short
distance. However, when adrenaline is released from the adrenal medulla and goes into the
bloodstream, it is a hormone.

Synaptic Targets of Neurotransmission

1) Synthesis:
● Precursor
● Synthesising enzyme to make neurotransmitter
 2) Storage of transmitter into vesicles
3) Release: when the cell is activated, the action potential comes down and calcium-
dependent exocytosis of the neurotransmitter from the vesicles into the synaptic space.
4) Action: neurotransmitters bind to the receptor
5) Re-uptake: mechanisms to take up the transmitter back into the cell or surrounding cells
through transporter (important drug action targets) to repackage into vesicles or
degradation
6) Degradation: occurs in surrounding cells or presynaptic cell; exception: acetylcholine is
degraded in the synapse by acetylcholinesterase and choline is transported back into the
cell

N0tes: Neurons rely

on synaptic
transmission; synapses are
targeted by

pharmaceutical drugs. Drugs cannot create new things but only modify what is already possible.

Presynaptic receptors are considered autoreceptors (auto = same family) or heteroreceptors

(hetero = different family)

Monoamine Synthesis
All the monoamines are synthesised from amino acid precursors

The precursor for dopamine, adrenaline and noradrenaline is L-tyrosine

Precursor for serotonin is L-tryptophan (needed in diet eg. banana)
Amino Acid Transmitter Synthesis
GABA is made from glutamate via the enzyme glutamic acid decarboxylase; GABA is important
as a neurotransmitter AND metabolically; Since Glutamate and GABA control balance between
excitation and inhibition in brain = crucial = have multiple synthetic pathways

GABA has two pools: metabolic

pool (in cell body) and neuronal
pool (terminals)

Neurons only: Glutamine is

the precursor to make
glutamate; GABA then derived
from glutamate

Acetylcholine Synthesis (and Degradation)

1) Acetyl CoA + Choline via choline acetyltransferase → acetylcholine + coenzyme A + water

2) Acetylcholinesterase breaks acetylcholine into acetate and choline; THIS PART OCCURS
IN SYNAPSE
3) Choline is transported back up into cell
Transmitter Storage

Active transport into vesicles (~1.1M) via vesicular transporter

Stored in a way that prevents leakage out of the vehicles into cytoplasm; to ensure control
concentration of transporter substance being released; excessive glutamate release =
convulsion; excessive GABA release = respiratory depression, coma, death
Often driven by H+ electrochemical gradient across vesicular membrane generated by ATP-
dependent H+ pump

Different transmitter substances have different vesicular transporters and diversity of

transporter types

Pathways
Serotonin: made in = raphe nuclei in the brain; released in multiple parts of the brain cortex and
areas of the striatum, thalamus, hypothalamus, hippocampus, amygdala, cerebellum
Noradrenaline is similarly distributed as serotonin but made in the locus coeruleus in the brain
stem mainly
Acetylcholine has three major pathways eg. hippocampal pathway
Dopamine is less distributed but still critical in major functional; projected to frontal cortex

GABA and
Glutamate
Almost all neurons in the brain have receptor for glutamate and GABA

About 50% of neurons release glutamate as an excitatory neurotransmitter

About 30-40% of neurons release GABA as an inhibitory neurotransmitter

Histamine
Cell bodies located in a small area of the hypothalamus and project to almost all parts of the
brain

Examples of Drugs that Target Synthesis, Storage and Release

Neurotransmitter Binding and Receptor Activation

Receptors
Transmitter Reuptake

Active transport into neurons via high affinity Na+ - dependent membrane transporter protein

Main mechanism for terminating synaptic action

Monoamine Degradation

In neuron by oxidative deamination by monoamine oxidase (MAO)

● MAO bound to neuronal and non-neuronal cell mitochondria

MAO isoforms

● MAO-A (degrades 5-HT, NA, Adr, DA)

● MAO-B (degrades DA)

Catecholamines also involve degradation via catechol-O-methyltransferase (COMT)

Amino Acid Transmitter Degradation

ACh

Acetylcholine is degraded in the synapse, NOT IN THE CELL

Examples of Drugs that Target Receptor Action and Re-uptake
 Week 3 - Recreational Drugs

Comparison of 4 different recreational drugs:

1) Heroin - opioid
2) Methamphetamine (aka ice) - psychostimulant
3) Cocaine - psychostimulant
4) Ecstasy - psychostimulant

History of opioid use

Opium has been used for thousands of years for recreational and analgesic purposes

Opium wars (Britain versus China, led to British rule of Hong Kong)

In an effort to create a less addictive opioid analgesic Bayer synthesised heroin and marketed as
a cough suppressant, analgesic and treatment for morphine dependence.

By the beginning of the 20th century, the recreational use of heroin was made illegal in most
western countries

In Australia, 0.2% of the population used opioids in the last 12 months

Tasmanian Opium Farms

Tasmanian Alkaloids

Grow around 50% of the world’s legal opiates ($100 million industry)

Morphine, codeine and thebaine derived from this plant

Multiple deaths from people stealing the plant

Derive a lot of the opioids from environment - many cannot synthesise in lab
Diacetylmorphine - Heroin

Opiates are naturally occurring alkaloids such as morphine or codeine

Heroin is the diacetyl derivative or morphine. In the body, it is rapidly deacetylated to

morphine, which is active on the receptors. This chemical change improves the PK of heroin and
can cross the blood-brain-barrier more rapidly, thus heroin gives a greater rush than morphine.

Morphine metabolites morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G)

Heroin has unique metabolites 6 monoacetylmorphine, more brain penetrant and can be used
as a marker of heroin use in forensics.

Metabolites are made in the liver from enzymes that break down morphine

Difference between morphine and heroin: the OH in morphine is replaced with an acetyl group
in heroin
Heroin and its metabolite 6-monoacetylmorphine are more lipophilic than morphine = greater
“rush”

Opioids - Pharmacological Effects

Analgesia (major use)
Euphoria (contributes to addiction)
Impaired cough reflex (anti-tussive)
Constipation (anti-diarrhoeal)
Nausea and vomiting (usually early in therapy; rare)
Tolerance and dependence (contribute to addiction)
Respiratory depression (cause of death pCO2)

There are naturally occurring opioids in our brain

and body. Opioid receptors are distributed densely
throughout pain pathways. Opioids limit ascending pain pathways but they can also activate
descending pathways which limit ascending pain messages getting to the brain. There are
multiple different types of opioid receptors.

Opioids have antitussive effect and peripherally restricted opioids do not get into the brain to get
you higher but can still impair the cough reflex

Opioids can cause constipation. But can be exploited to treat diarrhoea.

 opioid receptors are also found in the ventral tegmental area, in the midbrain and the output
nuclear accumbens. It extends axonal projections to the nucleus accumbens which releases
dopamine. This is the brain’s reward pathway called mesolimbic dopamine pathway and causes
addiction. Recreational drugs can boost dopamine levels in this pathway. Opioids can cause
neuro adaptive changes in this pathway that leads the pathway to think the drug is an important
stimulus for survival - theory of how addiction occurs.

Opioids have a narrow therapeutic window (the difference between dosage for therapy and
death is narrow) because they are respiratory depressants. Brain stem is crucial in maintaining
vital functions of the body, including respiration. Opioid receptors in the brain stem are housed
upon neurons that detect the partial pressure of CO2 gas. Once CO2 increases, those neurons
are activated which initiates the reflex to breathe and bring in oxygen. Opioids however shut
down this reflex, and people die of suffocation because they stop breathing. Overdose on heroin
requires an oxygen mask and a subcutaneous injection of an opioid receptor blocker called
naloxone.

Heroin Mechanism of Action

Heroin does not directly engage with the opioid receptor. It is broken down into its metabolites
or morphine which does.

opioid receptors are the most important for recreational, pleasure and reward purposes. It is
a G protein coupled receptor (GPCR). GPCR requires mobilisation of a G protein to bring about
Its effect on intracellular signalling mechanisms within the cell. opioid receptors are in the
membrane and neurons can possibly be around. Mainly coupled to an inhibitory G protein (Gi)
which can decrease production of cyclic AMP and activate ion channels; it activates the inwardly
Rectifying potassium channels. opioids can inhibit calcium channels that inhibit
neurotransmitter release. Calcium influx is crucial to release other neurotransmitters and in this
case, have a neuromodulatory function. Opioids generally have an inhibitory activity on the cell.
Needle Syringe Program (NSP)

NSPs provide sterile equipment to prevent blood-borne viruses

Injecting drug users are a major more of HIV transmission
Rapid outbreaks of HIV occur in cities without NSP
30,000 needles given out per month in Redfern
Overall, NSPs have saved Australia > 10,000 cases of HIV and >$500M

Gives clean needles to IV drug users to prevent sharing of needles

Opioid Fentanyl
80-100 times as potent as morphine
First synthesised in1959 by Paul Janssen
Found in transdermal patches
IV drug users remove fentanyl from the patches and inject it
Major killer in the US and increasingly in Australia
Now fentanyl analogues like alpha-methyl fentanyl have made it into the black market
The rise of Novel Psychoactive Substances (NPS)

Psychostimulant drugs
Methamphetamine
Amphetamine
Cocaine
MDMA

Methamphetamine (METH)
Methamphetamine is a synthetic homology of amphetamine first synthesised in japan in 1983
One of the earliest uses was in WWII; given in the war to keep people awake so they can fight for
longer or fly long haul planes. Also makes people hyper aggressive.
Highly addictive drug
Between 2010 and 2016 daily and weekly use of meth/amphetamines more than doubled, from
9.3% to 20%

Ice and powder forms are used

Crystal meth = ice is smoked; ingested in powder form nasally - snorting.
METH Pharmacological Effects
Initial effects:

● Euphoria
● Increased alertness and concentration
● Increased energy
● Increased libido
● Appetite suppressant

Side effects: increased heart and breathing rates, hypertension, irregular body temperature

Long lasting cognitive and emotional changes: paranoia, anxiety, depression, irritability,
hallucinations, mood swings, violent behaviours, chronic sleep disorder, memory loss, anorexia,
malnutrition.

METH - Mechanism of Action

Release of dopamine and blockade of monoamine transporters
Effects can last for several hours because of the long half-life of methamphetamine (8-30h
compared to 2h with cocaine)
“Binge and crash” pattern to the euphoric effects; effects dissipating
Very highly addictive drug due to the intense “rush” caused by dopamine release

Note: amphetamines in general massively increase dopamine in the brain’s nucleus accumbens
and takes a hold of the reward pathway.

Dopaminergic Pathways
How do amphetamines (including METH) boost dopamine by blocking dopamine transporters:

Proteins in membranes of neurons grab dopamine and drag it back inside the neuronal
cell for recycling. Amphetamine inhibits this which boosts dopamine levels in the
synapse. Amphetamines also reverse the polarity of the dopamine transporter and cause
it to pump dopamine from the neuronal cell into synapse to attain a boost of dopamine.

This impacts dopamine pathways including mesolimbic pathway (aka reward pathway) and
meso cortical pathway are implicated in addiction.

Schizophrenia is a link between excessive dopamine release and psychotic behaviour (eg.
hallucinations, delusions)
Hormonal link between dopamine - tuberoinfundibular dopamine pathway and the nigrostriatal
dopamine pathway which is important in motor function.

METH - Long Term Side Effects

“Meth mouth” aka bruxism is the grinding of the teeth as a consequence of methamphetamine,
psycho stimulants use
Highly addictive
Overdose risk even at low doses from cardiac failure
Neurotoxicity: long-term emotional and cognitive impairments due to neurodegenerative
damage to DA and 5-HT neurons and transporters, loss of gray matter, alteration of the integrity
of the BBB…

History of Cocaine Use

Derived from the Erythroxylum coca plant. South American Indians have chewed coca leaves for
thousands of years

Cocaine first isolated by Albert Niemann, a Ph.D. student in 1855

In the 19th century it was used as a local anesthetic, in coca wine and Coca-Cola (until 1906
when its addictive properties became clear); local anesthetic inhibit sodium channels but the
MOA for recreational euphoric effects of cocaine is through dopamine transporters inhibition.

Sigmund Freud at first embraced the use of cocaine but later abandoned this view after
discovering its highly addictive consequence.

Cocaine - Pharmacological Effects

Acute effects:

● Euphoria
● Appetite suppressant
● Increases alertness, self-confidence, sense of well-being, energy, motor activity, sexuality
and social disinhibition
● Increases HR and BP
● Has local anaesthetic actions

Side effects of repeated use:

 ● Eating and sleeping disorders, impaired sexual performance, respiratory problems,
convulsions, kidney failure, increased risk of stroke
● Cocaine is often used in binges followed by a severe “crash” with the user experiencing
intense depression, lethargy, hunger

Cocaine - Mechanism of Action

Presynaptic neuron releases dopamine to activate dopamine receptors on the postsynaptic
membrane. Dopamine transporter proteins grab on to the dopamine and drag it back in. cocaine
inhibits the transporter function which causes the greater levels of dopamine in the synapse.
Dopamine is a neurochemical reward.

Cocaine - Side Effects

5-50% purity only - unknown potentially toxic adulterants
Damage to nasal membrane and septum if snorted, tissue damage due to vasoconstriction when
injected
Excessive dosages - tremors and convulsions followed by respiratory depression and cardiac
arrhythmias
Chronic use can lead to 1) psychotic episodes and 2) cardiovascular issues
Cocaine increases the risk of MI, heart failure, cardiomyopathy, arrhythmias, aortic dissection,
endocarditis and other cardiovascular disease

NOTE: long-term cocaine users have an increased heart size - cardiomyopathy

Cocaine and CV Dysfunction

Cocaine increase sympathetic output, can have a local anaesthetic effect, can increase heart rate,
blood pressure, oxygen demand (which can lead to ischemia) and cause coronary spasms,
arrhythmias through the local anesthetic effect; all leads to death

Long-term

● Calcification and aneurysms (abnormal swelling in blood vessel wall) develop in

coronary arteries of cocaine users
● Myocardial infarction in cocaine users has a unique pathophysiology that is different to
typical myocardial
infarction
3,4-methylenedioxymethamphetamine (MDMA) - Ecstasy

MDMA was first synthesised by Merck in 1912 to be used as an appetite suppressant but was
never marketed
It was used in 1970’s to aid psychotherapy but was soon gradually abolished and the substance
banned in most countries
Popularised by Alexander Shulgin
Started to be used in the 1980’s particularly at underground rave parties

Can potentially be used to treat post traumatic stress disorder in Australia; Australia has
provided a regulatory pathway for psychiatrists to prescribe MDMA to the patients.

MDMA - Effects

In Sydney, ecstasy tablets contain about 40% MDMA… the rest being unknown constituents
Side effects: acute psychosis, panic attack, insomnia, involuntary teeth clenching, and seizures
Tolerance development (some might ingest up to 40 tablets over a weekend)
Unregulated supply of drugs leads to toxic contaminants; measured purity of MDMA in street
capsules in 40%.
Psychositmulant; thus can lead to psychotic episodes for some but rare
Can also lead to serotonin syndrome which can lead to seizures. It is a mixture of different
cognitive, auto autonomic and neuromuscular symptoms including seizure activity; not all the
time but can happen.

MDMA - Mode of Action

1) Binds the serotonin transporter and causes serotonin release via transporter-mediated
exchange
2) Blocks re-uptake of 5-HT; MDMA can also reverse the polarity of the transporters and
pump more serotonin 5-HT back into the synapse
3) Inhibits vesicular monoamine transporter (VMAT)
4) Inhibits monoamine oxidase (MAO)
5) Increased brain and plasma oxytocin concentrations

MDMA can cause a serotonin system because MDMA boosts dopamine, noradrenaline AND
serotonin. Boosts serotonin by inhibiting serotonin transporters similar to how cocaine inhibits
dopamine inhibitors. MDMA boosts oxytocin level - love; important hormone for mother and
child bonding + crucial in prosocial behavior.
Role of 5-HT in Nervous Function
5-HT implicated in:

● Hallucinations
● Mood
● Aggression
● Impulsivity
● Eating
● Sleeping
● Arousal
● Sleeping
● Sensory and pain
● Transmission

Does MDMA cause Brain Damage?

Long-term serotonergic neurotoxicity: in animals, MDMA causes dose-dependent reduction in

serotonin receptors and transport proteins in addition to axonal damage in the striatum,
hippocampus and prefrontal cortex.
Elevated body temperature accelerate the neuronal damage (it appear to be reversible to some
extend in rodents, but not in primates, probably caused by oxidative stress
5-HT depletion may explain some of the reported consequences of heavy MDMA use:
impulsivity, depression and memory loss
 Week 4 - Recreational Drugs

Cannabis

Cannabinoids 101

● Cannabis is a plant that makes a thick substance full of compounds called cannabinoids.
There are more than 100 of these chemicals in cannabis. They cause drug-like reactions
in your body. CBD (cannabidiol) and THC (tetrahydrocannabinol) are the most common
cannabinoids found in cannabis products.
● Cannabis-like drug
● Phytocannabinoids come from plants
● Main psychoactive constituent of cannabis is delta^9-terpenophenolic compounds AKA
delta^9-THC
● Cannabidol and tetrahydrocannabinol are isomers - have the same chemical formula;
difference: cannabidiol has a ring structure unlike tetrahydrocannabinol + cannabidiol
does not activate cannabinoid receptors

● Phytocannabinoids
○ Cannabidiol
■ Registered drug in Australia in the form of Epidiolex to treat intractable
epilepsy; does not have THC-like psychoactive effects (not intoxicating)
○ THC
■ Partial agonist (efficacy - increasing concentration on the excess; full
agonist = 100% while partial agonist ~ 50% of the maximal response)
■ Psychoactive effects (intoxicating)
■ Reduces seizures
● Synthetic Cannabinoids
○ Agonist
○ Structurally similar to THC
○ 30 times more patent as THC at the cannabinoid receptors
○ SR141716 antagonist synthesised blocks cannabinoid receptors to stop the effects
of THC at the receptor
○ Synthetic cannabinoid receptor agonists (SCRAs) proliferate through renegade
chemists making it illegally and distributing it in the marketplace. They make
different analogues to escape forensic roadside
○ Can provoke seizures; most likely due to impact on cannabinoid receptors
● Endocannabinoids
○ Synthesised in human
○ Naturally occurring cannabinoids in the brain and body
○ Activates cannabinoid receptors