POISONING
• Strong alkali or acids can damage
DEFINITIONS
• Poison: substance that causes
disturbances to an organism when
a sufficient amount is absorbed.
• Toxin: produced biologically.
• Venom: toxin injected by bite/sting.
• Toxicology: characterization of
potentially adverse effects of
foreign chemicals [dose-response
relationship].
• Toxicity: inherent capacity of a
chemical, including drugs, to cause
injury (can be via skin contact,
inhalation, or ingestion).
COMMON TARGET TISSUES
• Lungs (vapours or toxic gases)
• Liver (ingested drugs)
• Brain (high blood flow)
• Kidneys (high blood flow)
• Heart (ionic gradient disturbances)
NON-SELECTIVE ACTIONS
• Local irritation / caustic effects
- At site of exposure/application.
- Injury caused by denaturing
macromolecules (proteins/cleaving
chemical bonds >> malfunction).
Note: you would not follow A-H order
almost any tissue they come into
contact with.
SELECTIVE ACTIONS
• Interferes with specific biochemical
pathways.
• Chemical has to be absorbed and
distributed to a specific pathway
(e.g., Rattex, paracetamol).
• Rattex (rodenticide/superwarfarins)
contains high levels of warfarin and
interferes with the vit K pathway.
• Paracetamol – depletion of
glutathione needed for conjugating
the toxic metabolite NAPQI.
• Paracetamol poisoning is relatively
common.
IMMEDIATE & DELAYED ACTIONS
• Some poisons have toxic actions
which lead to symptoms quickly
following exposure, e.g.,
organophosphate poisoning (AChE
inhibition can cause immediate
symptoms).
• Severe iron poisoning has 3
phases:
1. Early phase – 0.5-2hrs
2. Quiescent phase – up to 12hrs
3. Life-threatening phase
MANAGEMENT
- Arterial blood gas
in real life; giving the antidote (G) - Electrolytes and glucose
would usually come first. - Liver and kidney function tests
- FBC & clotting profile
• Airway (e.g., coma in TCA - Urinalysis
overdose) - ECG
• Breathing & oxygenation (e.g., - Plasma poison concentration
respiratory depression in opiate (e.g. paracetamol)
overdose); non-rebreather mask at
15L/min for giving oxygen
• Circulation & cardiac monitoring (IV DECONTAMINATION
fluids for hypotension; blood test)
• Skin
• Diagnosis & Decontamination
• Enhancing drug clearance - E.g., organophosphates,
• Frequent re-evaluation & Further hydrofluoric acid.
symptomatic care - Remove clothing and wash
with soap and water.
• Give antidote
- Remember PPE!
• Help
• Eyes
- Irrigate with tap water / normal
DIAGNOSIS
saline for 15-30 minutes.
• Hx from pt & relatives: • Airway
- Toxic substance - E.g., organophosphates
- Time of ingestion
inhalation.
- Amount ingested • Gastric
• NB! Beware of inaccurate reporting - Emesis/lavage
& mixed ingestion. - Activated charcoal
• Collateral Hx is important - Whole bowel irrigation
especially in comatose pts.
• Also important to note the reason
for ingestion. EMESIS
• Examination – to determine what
• Useful when time since ingestion is
clinical syndrome is present.
less than 1 hour.
• The eyes can give several clues as
• Used for children only (not adults).
to which poison the patient has
• Only used if charcoal is not
been exposed to.
indicated.
• Special investigations:
• There are 2 methods to induce
emesis:
1. Stimulation of pharynx
2. Ipecacuanha
• Contraindications:
- Impaired level of
consciousness (risk of aspiration)
- Corrosive substance (would
damage tissue again on its way
back up)
- Hydrocarbons
- Risk of seizures
• Ipecacuanha is a syrup used to
induce vomiting.
GASTRIC LAVAGE
• Useful if…
- Time since ingestion is <1-2hr.
- Large amount of toxic solid
substance.
• Not routine.
• Use LARGE-bore catheter (32-40)
- 200-300ml tap water in adults.
- 10ml/kg body temperature
saline in children.
• Only a small amount of fluid is
used, so as to minimise risk of
gastric contents entering the
duodenum.
• Need to remove whole tablets – pts
don’t chew.
• Airway protection is important –
head down, left lateral position.
• Contra-indications:
- Corrosive substances
- Hydrocarbons
- Risk of GI haemorrhage
• Important to monitor
decontamination.
• Evidence for benefits of both
emesis and gastric lavage is
limited.
ACTIVATED CHARCOAL
• Preferred method over emesis and
gastric lavage.
• Useful if…
- Salicylates, paracetamol,
barbiturates, digoxin, or TCAs.
- Time since ingestion is <2hrs
(longer if pt has delayed gastric
emptying).
• Consider MDAC in…
- Severely poisoned patients.
- Sustained-release tablets.
- Enterohepatic cycling
(oestrogen, TCAs).
- Drugs secreted into bile or
intestine (e.g., digoxin).
• Should not be used for…
- Strong acids or alkalis
- Iron salts
- Lithium
- Petroleum products
- Cyanide
- Endoscopy due
- Cases where antidote can be
administer orally
• Adverse effects:
- Vomiting
- Constipation / diarrhoea
- Intestinal obstruction
• Monitoring:
- In stool 6hrs later.
- Hydration
• Dose:
- Oral/NG tube administration.
- Adults – 50-100g in slurry with
500ml water.
- Kids – 10-50g in 100-300ml
water.
• There is a risk of intestinal
obstruction if the patient is
dehydrated.
• Mix with water or soft drink; and for
children possible bribery with
sweets.
• MDAC – Multi dose activated
charcoal.
• If antidote for a poison is available
orally, rather give antidote instead
of activated charcoal.
WHOLE BOWEL IRRIGATION
• Uses a PEG-electrolyte solution
orally (large volume).
• Stimulates peristalsis.
• Useful in cases such as lethal
doses iron and body packers.
• Contraindications:
- Bowel obstruction/perforation
- Ileus
- Compromised airway
• PEG (polyethylene glycol) and
electrolytes combination solution is
used to cleanse the colon before
certain medical tests, colon
surgery, or for whole bowel
irrigation. It is a laxative which
works by inducing diarrhoea.
• Patients should have their head up
at 30degrees for bowel irrigation.
ENHANCING DRUG CLEARANCE
• Urinary alkalinisation
• Haemodialysis
• Charcoal haemoperfusion.
URINARY ALKALINISATION
• Used in salicylate overdose.
• Increases elimination by
maintaining urine pH > 7.5.
• Administration – IV sodium
bicarbonate.
• Needs to be done at a high care
facility (where potassium can be
monitored).
HAEMODIALYSIS
• Diffusion of solutes across a semi-
permeable membrane.
• Required when there is renal
impairment or clinical deterioration
despite supportive treatment.
• Used for salicylates, lithium, and
methanol poisonings.
• Limitations –
 • Hypertension:

INFECTIOUS
CHARCOAL HAEMOPERFUSION nitrite; sodium
- Often short duration. thiosulfate
• Removal of toxic substances by - Usually due to anxiety or Digitalis Digoxin-immune
adhesion to activated charcoal. stress as a result of event. fab

DISEASE
• Extracorporeal – large volumes of - Use benzodiazepines and Methanol Fomepizole
blood passed over absorbent sodium nitroprusside. ethylene glycol
Heparin Protamine
substance. • Arrhythmias:
sulphate
• Removes barbiturates,

EMERGENCY:
- Bradycardia – e.g., B-blockers
Lead Dimercapto-
carbamazepine, and theophylline. (use atropine, pacing). succinic acid
• MDAC is as effective for many - Tachycardia – e.g., Mercury; Dimercaprol
drugs. cocaine/stimulants (use arsenic; gold
• Limitations – benzodiazepines). Organo- Atropine SEPSIS
- Stable VT – e.g., TCAs (use phosphates; pralidoxime
sodium bicarbonate, lidocaine). carbamates; • Sepsis (previously known as
nerve gases “severe sepsis’) is defined as
clinical evidence of infection
FURTHER SYMPTOMATIC CARE GIVE ANTIDOTE together with 2 or more of the
following (qSOFA score):
Monitor patients and treat: Poison or Antidote(s) - Altered mentation (GCS<15).
Syndrome - Respiratory rate ≥ 22min.
• Seizures (e.g., cocaine)
Digoxin Digoxin immune - Systolic BP ≤ 100mmHg.
• Hypoventilation (e.g., opiates)
fab • Organ dysfunction and/or lactic
• Hypoglycaemia (e.g., salicylates) Paracetamol Acetylcysteine acidosis are hallmarks of severe
• Hypothermia/hyperthermia Opioids Naloxone; sepsis.
• CVS compromise nalmefene; • Mortality about 10% (with
• Liver/kidney failure naltrexone appropriate treatment!).
Benzodiazepines Flumazenil
• qSOFA = quick Sequential [sepsis-
Iron Deferoxamine
CVS COMPROMISE related] Organ Failure
Acetaminophen N-acetylcysteine
Assessment.
Anticholinergic Physostigmine
• Hypotension: agents • Sepsis does not have to be
- Hypovolaemia (due to Carbon Oxygen (+/- associated with a positive culture.
diarrhoea & vomiting), vasodilation. monoxide hyperbaric
- Use fluids, vasopressors, and chamber) SEPTIC SHOCK
inotropes. Cyanide Amyl nitrite
• Defined as sepsis with hypotension
pearls; sodium
(systolic BP<90 or >40 fall in
 systolic BP) persisting despite fluid
challenge.
• Fluid challenge: 500mL isotonic
crystalloid over 30 mins with BP &
pulse monitoring.
• Septic shock is a form of
distributive shock due to
vasodilation. Therefore it must be
treated with a vasoconstrictor, e.g.
epinephrine infusion.
• Hydrocortisone (200mg/day in
divided doses) improves shock and
may reduce mortality (well
tolerated).
• Mortality is about 40% (with
appropriate therapy).
PATHOGENESIS OF SEPSIS
• The pathogenesis of sepsis is
complex. Activation of pattern
recognition receptors activate
innate immunity, giving rise to an
excessive pro-inflammatory
response.
• Neutrophils, coagulation &
complement are activated.
• Vasodilatation is the hallmark of
sepsis.
• Capillary leak is common and can
cause extensive oedema.
• Reversible organ failure occurs as
with other causes of critical illness.
• Neuroendocrine responses are
important, resulting in a catabolic
state.
• A period of profound immune
suppression occurs after sepsis
due to activation of anti-
inflammatory responses, which
predisposes patients to secondary
infections.
MANAGEMENT OF SEPSIS
There are 3 ways in which clinicians
can improve the outcome of
sepsis/septic shock:
1. Start appropriate resuscitation
& general support measures
urgently, e.g. oxygen, fluid
balance with isotonic
crystalloids (colloids are
harmful in sepsis), inotropic
agents (typically epinephrine
infusions) for shock.
2. Select empiric antimicrobials
that are appropriate for the
likely infecting organism/s
(always give intravenously &
give a loading dose!).
3. Give the empiric antimicrobials
as soon as possible!! Each
hour delay is associated with
about 8% increase in mortality.
• Very important to NOT give the
patient oxygen if they are not
hypoxic!
IMPORTANT PHARMACOKINETIC • When available, therapeutic drug
ISSUES IN SEPTIC PATIENTS monitoring should be done (e.g.
anticonvulsants, aminoglycosides,
• Absorption of drug from GIT is vancomycin).
often poor or absent (adynamic
Sepsis can either increase or
ileus may occur in sepsis).
Absorption from intramuscular or decrease drug concentrations:
subcutaneous routes is poor due to
• The increased cardiac index
altered haemodynamics. (increased clearance), and the
Therefore, all drugs, especially presence of leaky capillaries and/or
antimicrobials, must be given altered protein binding, both lead to
intravenously. a low serum drug concentration.
• GFR initially increases in sepsis, • The presence of end organ
which increases the rate of dysfunction (e.g. hepatic / renal),
clearance of drugs eliminated by leads to decreased clearance,
the kidneys. Subsequently kidney which results in high serum drug
function may become impaired due concentrations.
to acute tubular necrosis (part of
multi-organ failure from sepsis).
Dose adjustments of drugs
eliminated by the kidneys is difficult
in acute kidney injury as estimating
GFR is difficult.
• The volume of distribution (Vd) is
increased due to leaking
capillaries, therefore the loading
dose needs to be increased. This
is especially important with water-
soluble drugs (which have a small
Vd) like vancomycin and the
SEVERE CAP
aminoglycosides.
• Other PK factors include reduced • CAP = community acquired
metabolism and altered distribution pneumonia.
– these are variable and • It is very important to assess the
unpredictable. severity of CAP!!
• The simplest way of assessing the - Streptococcus pneumoniae but can be regained eventually BACTERIAL MENINGITIS
severity of CAP is using CURB-65: - Haemophilus influenzae when they return.
Confusion - Klebsiella spp. & other aerobic • The features of severe malaria The key therapeutic issues are:
Urea elevated (>7mmol/L) gram- bacilli include any of the following:
• URGENT administration of
Respiratory rate >30/min - Staphylococcus aureus - Decreased level of
antimicrobial. This should be given
BP low (syst. <90 or diast. ≤60) consciousness
PLUS… at the referring primary care centre
65 or older age - Seizures
if the diagnosis is suspected, or
• A score of 1 point is given for each - Prostration (inability to drink or
before the lumbar puncture is this
category above. This can also be • Macrolides to cover “atypical” sit unaided)
is delayed (e.g., pending a CT
done without the urea (CRB-65 bacteria… - Shock
scan), or if the CSF on lumbar
score). - Legionella spp. - Acidosis
puncture appears turbid, or if there
- Chlamydophila pneumoniae - Severe anaemia (Hb <7g/dL)
CURB-65 are any clinical features to suggest
- Mycoplasma pneumonia - Visible jaundice
Score Mortality Action meningococcal meningitis, or if the
• About 25% of CAP cases are - Renal impairment
0-1 1.5% May be suitable cell count or other CSF features
caused by atypical organisms. - Parasitaemia ≥5% of red cells
for outpatient suggest the diagnosis.
• Other resuscitative and general - Hypoglycaemia
therapy
- Respiratory distress • Select an empiric antimicrobial that
2 9.2% Hospitalise supportive measures (notably
will cover the likely organisms (in
3+ 22% Treat as severe oxygen) are critically important. • If a patient is unwell in ways not
nearly all age groups, apart from
CAP • Antimicrobials must be listed above, then it is
neonates, this will currently be an
commenced intravenously. recommended to initiate treatment
IV dose of a 3rd generation
s for severe malaria (by giving
CRB-65 SEVERE MALARIA cephalosporin – either ceftriaxone
antimalarials intravenously rather
Score Mortality Action or cefotaxime).
than orally.
0 1.2% May be suitable • Severe Plasmodium falciparum • Use high doses as many
• Vomiting is also common in
for outpatient malaria has a mortality of about antimicrobials, including the b-
malaria & intravenous treatment
therapy 20%. lactams, cross the BBB poorly.
should be given.
1-2 8.2% Hospitalise • P falciparum is the cause behind • The role of adjunctive
• Other resuscitative and general
3-4 31% Treat as severe 90% of malaria cases in Africa. corticosteroids is controversial.
support measures are critically
CAP • All non-immune people are at risk. Studies in high income countries
important as for severe sepsis.
In endemic areas (year-round show a limited benefit for children
• Vigorous fluid resuscitation
If the score indicates severe CAP, transmission) only pregnant and adults, but this has not been
dangerous as it can precipitate
then it is essential that empiric women, young children, and HIV+ replicated in low-middle income
ARDS.
are at risk of severe malaria. countries; likely due to late
antimicrobials cover all the likely • For severe malaria treatment
organisms: • It takes about 3 years for a person presentation, HIV co-infection, or
should be commenced urgently
to lose their immunity to malaria TB meningitis mimicking bacterial
with intravenous artesunate.
• Broad spectrum b-lactam to when they leave an endemic area meningitis. Therefore, adjunctive
cover…
 corticosteroids are no longer
recommended in South Africa.
TDM
• TDM (therapeutic drug monitoring)
is measurement of drug
concentrations in body fluids,
usually plasma or whole blood,
sometime serum, to individualise
dosing, and to maintain drug
concentrations within a target
range.
• An assumption is mage that
equilibrium exists between plasma
and tissue concentrations.
RATIONALE FOR TDM
• Close relationship exists between
plasma concentration of a drug and
the clinical effect.
• Assumption of equilibrium between
plasma and tissue compartments –
Distribution.
• Dose of drug and the clinical effect.
WHY IS TDM IMPORTANT?
Why monitor plasma drug
concentrations?
• Avoid toxicity.
• Optimize dose & improve efficacy.
• Assist in diagnosis.
• Assess adherence.
HOW CAN TDM ASSIST WITH DX
• Failure of therapy: distinguish
between genuine drug resistance,
non-compliance, and adverse
effects that mimic the disease
state.
• Overdose: plasma measurement
may distinguish drug-induced
symptoms from organic disease
(e.g. coma caused by sedative
overdose). This may affect the
management (e.g. use of a N-
acetylcysteine in paracetamol
overdose).
• Drug abuse: confirmation of
abstinence, e.g., narcotic treatment
programmes, athletic screening.
• Adherence is a non-direct benefit
of TDM. We do not perform TDM
specifically to assess adherence,
but the use of TDM can tell use
whether a patient is adherent.
TDM IN CLINICAL PRACTICE
• Diseased states: e.g. renal
impairment (could potentiate
toxicity).
• Transplantation:
immunosuppressive drugs have a
narrow range, so TDM is done to
prevent rejection while minimising
toxicity.
• Psychiatry: lithium and TCAs.
• Cardiology: digoxin.
• Infectious disease: antimicrobials
such as rifampicin, vancomycin,
amikacin, and gentamicin.
• Epilepsy: anticonvulsants such as
phenytoin, valproic acid, and
carbamazepine.
EXAMPLES OF DRUGS THAT
REQUIRE TDM
• Aminoglycosides (gentamicin &
amikacin) – toxicity relates to
trough concentrations.
• Vancomycin – efficacy dependent
on time of drug above MIC and
overall drug exposure over time.
• Anticonvulsants (phenytoin,
carbamazepine) – large
interpatient variability.
• Digoxin – small therapeutic range;
toxicity is main concern.
• Theophylline – small therapeutic
range; toxicity is main concern.
WHEN IS TDM INDICATED?
• Individualise therapy, achieve
target plasma drug concentrations:
- Enhance efficacy
- Avoid/minimize toxicity.
• Patients:
- Lack of clinical response
(antibiotic – vancomycin)
- Suspected toxicity (digoxin)
- Anticonvulsants (interpatient
variability? Adherence?)
• Co-morbidities:
- Drug-drug interactions
- Renal/hepatic impairment
- GI problems (malabsorption)
• Special populations
- Pregnancy (anticonvulsants)
- Paediatrics
FACTORS AFFECTING PK
• Age
• Weight
• Sex
• Genetics
• Disease
• Drug interactions
Note: PK = what the body does to the
drug, i.e. absorption, distribution,
metabolism, & elimination.
WHICH DRUGS ARE SUITABLE
FOR TDM?
Principles of TDM:
• Higher inter-patient variability in
plasma concentrations.
• Narrow therapeutic range
(generally considered small if it is
less than 2).
• Good correlation between plasma
concentrations and clinical effects.
• Pharmacological effect persists
and is dependent on the plasma
concentration.
• Availability of cost effective,
accurate drug assays with rapid
turnaround time and a small blood
volume requirement.
EXAMPLE: PHENYTOIN
• Concentration-time profile
unpredictable in an individual –
difficult to interpret
pharmacokinetics.
• Capacity – saturable metabolism
(i.e., zero order kinetics).
• Small dose increases can produce
disproportionate rises in blood
levels and toxicity.
• The elimination of phenytoin is
dose-dependent. At very low blood
levels, phenytoin metabolism
follows first-order kinetics.
However, as blood levels rise
within the therapeutic range, the
maximum capacity of the liver to
metabolize phenytoin is
approached. Further increases in
dosage, though relatively small,
may produce very large changes in
phenytoin concentrations. In such
cases, the half-life of the drug
increases markedly, steady state is
not achieved in routine fashion
(since the plasma level continues
to rise), and patients quickly
develop symptoms of toxicity.
Phenytoin Toxicity
Conc. Effects • When goal is to determine if low • Rapid elimination.
(mmol/L) clearance is leading to toxicity – • Inaccurate timing of sample.
<55 Rare side effects sample just before next planned
55-110 Occasional mild dose to reveal accumulation. If the concentration is higher than
horizontal nystagmus expected, this may be due to…
on lateral gaze Note: avoid drawing blood until
110-165 Nystagmus absorption is complete. Some drugs • Error in dosage regimen (too
165-220 Ataxia, slurred speech, (e.g. digoxin and theophylline) take much).
tremor, nausea, several hours to distribute to tissues; • Decreased renal/hepatic function.
vomiting others (e.g. aminoglycosides) • Slow elimination.
220-275 Lethargy, confusion, distribute rapidly.
hyperactivity If there is no response despite
therapeutic concentration, this may be
>275 Coma & seizures
due to…
• Altered receptor sensitivity
PRACTICAL CONSIDERATIONS
(tolerance).
• Is the lab able to measure this Some questions to consider when
particular drug? interpreting:
• What biological sample should be
used? • Is this due to therapeutic failure or
• What is the optimum time to take clinical toxicity?
the sample with respect to the last • Was the sample taken at steady-
dose taken? state, trough, or peak?
• Is there an accepted ‘therapeutic • Was the appropriate sampling time
range’? recorded?
INTERPRETATION OF RESULTS • Where is the concentration relative
WHEN TO TAKE THE SAMPLE to ‘target’ range?
• Accurate dosing history is • Should the dose be modified?
• When goal is dose adjustment – essential. If precise dosing time is How?
sample just before next planned unknown, a drug concentration
dose when concentration is measurement loses all predictive NB: treat the patient, not the lab
minimum. value. result!!
• When goal is to determine if
efficacious concentrations are If the concentration is lower than CONCLUSION
expected, this may be due to…
being achieved – sample shortly
• TDM is required for
after dose. • Incorrect dose given (too little). pharmacotherapy optimization.
• Non-compliance of patient.
• It reduces drug related toxicity and
can improve efficacy.
• Needs to be done correctly, else it
has little clinical utility.
• Knowledge deficits - Better drug management
• Prior experience - Lower costs
• Acquired habits • Definition of essential medicines:
• Cultural beliefs essential medicines are those that
satisfy the priority healthcare
- Monitor response
- Review therapeutic objections
- Review tolerability
- Make timely decision to
continue, change or stop treatment

RATIONAL
Patient: needs of the population at all
times. WHAT IS A P-DRUG?
• Patient demand
• Cultural beliefs A P[preferred]-drug (generic treatment

DRUG USE
HOW WOULD YOU DESCRIBE THE
PROCESS OF RATIONAL
PRESCRIBING?
• Making sure that the diagnosis,
prescribed treatment and advice
given for every patient / individual /
community is correct.
• If a drug is needed, making sure
that you give the right…
- Drug
- Dose
- Route of administration
- Duration of treatment
- Advice
- Monitoring
…for that diagnosis in that
particular patient.
WHAT FACOTRS INFLUENCE
PRESCRIBING?
Prescriber:
Context:
• Unbiased information vs
pharmaceutical industry influence
• Authority, supervision, peer
pressure
• Workload
• Availability of medicines and other
resources
REQUIREMENTS FOR RATIONAL
DRUG USE
• Undergraduate therapeutics
teaching
• Unbiased drug information
• Drug regulation
• Essential drugs programme
• In service training (CPD) for health
care professionals
ESSENTIAL MEDICINES
What is the concept of essential
medicines?
• A limited range of carefully
selected essential drugs leads to…
- Better healthcare
THE ESSENTIAL MEDICINES
TARGET
WHO GUIDE TO GOOD
PRESCRIBING
• Step 1: Define the problem.
• Step 2: Set therapeutic objectives.
• Step 3: Select therapy:
- Non-drug therapy, vs
- Drug therapy
o P-drugs, vs
o Patient drugs
• Step 4: Practical aspects of
prescribing:
- Prescription writing
- Information, instructions, and
warnings
• Step 5: Monitor therapy:
plan) is the prescriber’s first line
therapy…
• Personal to the prescriber.
• Proven to be effective and safe
and affordable (this must be based
on evidence based appraisal of
risks and benefits).
• Process of selection is the perfect
pharmacotherapy learning tool.
Selecting your P-drug:
• Best evidence (RCT, meta-
analysis).
• Best value for money.
Once a definitive therapy is chosen
for a patient, one must be aware of…
• Drug name (generic, not trade
name)
• Dosage form
• Dosage
• Length of treatment
• Non-drug treatment
WHAT IS A PATIENT DRUG?
• These are adapted treatment
plans.
Why would an individual patient need
a treatment different to your P-drug?
• Comorbidities, cautions, &
contraindications.
• Concomitant medications and
drug-drug interactions.
• Convenience and compliance.
DRUG SAFETY
Adverse Drug Event:
• Medical occurrence temporally
associated with the sue of a
medicinal product, but not
necessarily causally related.
• Any new clinical experience that
occurs after commencing a
medicine, not necessarily a
response to a medicine, and is
recorded without judgement on its
causality.
Adverse Drug Reaction:
• A response to a drug which is
noxious and unintended, and which
occurs at doses normally used in
man for the prophylaxis, diagnosis,
or therapy of disease, or for the
modification of physiological
function.
Causality Assessment determines TYPES OF ADVERSE DRUG • Avoid unnecessary drugs.
whether it is an adverse drug event or REACTIONS • Avoid drug interactions.
an adverse drug reaction… • Use correct dose.
• Type A: Augmented • Conduct appropriate monitoring.
• How close is the relationship - Dose-dependent
between the medicine and the • Report suspected ADRs.
- Common, predictable
adverse event?
• Type B: Bizarre PHARMACOVIGILANCE
• Was the event caused by the
- Dose-independent (allergy
medicine? or idiosyncratic) The WHO defines pharmacovigilance
as “the science and activities relating
FREQUENCY OF ADVERSE DRUG - Rare, unpredictable
• Type C: Chronic to the detection, assessment,
REACTIONS (CIOMS) understanding, and prevention of
- Associated with chronic use
- Have a cumulative effect adverse effects or any other drug-
Very common >1/10
• Type D: Delayed related problems”. Ultimately these
Common < 1/10 to <
(frequent) 1/100 - These can occur even after activities are aimed at protecting
Uncommon < 1/100 to < the pt stops taking the drug patients and the public from drug-
(infrequent) 1/1000 - May have had a lasting effect related harms.
Rare < 1/1000 to < on pt’s physiology Pharmacovigilance includes a number
1/10 000 - Very rare
of approaches to monitor the safety of
Very rare < 1/10 0000 • Type E: End-of-use
licensed medicines:
- More commonly called
withdrawal reactions • Passive surveillance (spontaneous
SERIOUS ADVERSE EVENT
- These occur when pt reports).
A serious adverse event (experience) experiences withdrawal after • Stimulated reporting.
or reaction is any untoward medical medication is stopped • Active surveillance (sentinel sites,
occurrence that at any dose results in: • Type F: Failure of Treatment e.g. review of records/ interviewing
doctors/ patients at sample sites).
• Death Note: types A & B most NB! • Drug event (prescription event)
• Life threatening injury monitoring (patients identified from
• Disability
RISK MITIGATION
prescription data/health insurance
• Hospitalization, or claims – sent questionnaires).
• Take a full history, including
• Congenital malformation concomitant illnesses and • Electronic health records /
medications (including OCT, CAT, databases.
& SOA meds). • Registries (drug or disease).
• Heed contra-indications, cautions, • Comparative observational studies.
and warnings. • Targeted clinical investigations.

CARDIAC
FAILURE
• Cardiac failure is a very common
condition, affecting 1-3% of the
adult population.
• The incidence increase with age.
• It have a very poor prognosis (5 yr
mortality of about 50%) and is
debilitating.
• But, it is also detectable and
treatable.
• Cardiac failure is a complex clinical
syndrome which is symptomatically
characterized by exercise
intolerance. There is inadequate
systemic perfusion due to impaired
cardiac pump function and this
leads to a train of compensatory
mechanisms. However, some of
these compensatory mechanisms
are ultimately detrimental and
worsen the symptoms and reduce
the patient’s survival rate.
PHYSIOLOGIC RESPONSES TO
CARDIAC FAILURE (A VICIOUS
CYCLE!)
• RAAS is activated – causing
sodium and water retention, and
vasoconstriction.
• Norepinephrine is released –
resulting in tachycardia and
vasoconstriction.
• TNF is released – which is not
usually released in the normal
heart. There is a direct relationship
between the level of TNF released
and the disease severity.
• Endothelin is released by the
vascular endothelial cells – which
also has a potent vasoconstrictive
effect. The endothelin also has a
direct toxic myocardial effect (the
higher the levels of endothelin 1,
the greater the degree of
haemodynamic and functional
impairment, and the worse the
prognosis of the heart failure.
• Beta adrenergic desensitisation.
• Hypertrophy, ischaemia, and
arrhythmia.
• Necrosis, fibrosis, apoptosis, left
ventricular remodelling (dilatation).
Thus – therapy directed at non-
cardiac targets are more valuable in
long term treatment than inotropic
support.
_________
DEFINING THE PROBLEM
• De novo vs chronic HF.
• Clinical severity.
• Precipitants, e.g. coronary artery
disease, pericardial disease,
electrical abnormalities, valvular
disease, medical noncompliance.
• Heart rate and rhythm.
• Blood pressure, and
• Comorbidities (e.g. renal disease,
iron deficiency, lung disease, and
diabetes).
SET THERAPEUTIC OBJECTIVES
• Reduce mortality.
• Modify disease progression.
• Reduce symptoms to improve
quality of life.
• Reduce hospital admissions.
• Treat reversible conditions.
• Avoid / correct aggravating
factors.
• Avoid unwanted drug
interactions.
Causes of Cardiac Failure:
• Hypertension
• Coronary artery disease (IHD)
• Cardiomyopathy
• Valvular heart disease
• Thyrotoxicosis
• Alcohol excess
• Anaemia
NB: always look for reversible causes!
SELECT THERAPY
Examples of drugs which can
precipitate or aggravate cardiac
failure:
• Oestrogens
• Steroids
• (non-dihydropyridine) calcium
channel blockers [thus not used for
management of BP in HF]
• Beta-blockers (but some may be
beneficial)
• NSAIDs
• Excessive diuretics
• Tricyclic antidepressants
Non-drug Measures:
• Exercise training.
• Flu immunization.
• Reduction in alcohol consumption.
• Cessation of smoking.
• Correction of anaemia.
• Diet (sodium restriction).
• Review drug interactions.
• Consider possible risk factors
which can be controlled (e.g. DM,
HPT, Hypercholesterolaemia)
Drug Treatment (Aim is to reduce
mortality) – must try:
• The use of ACE inhibitors as
standard therapy (whatever the
ejection fraction). An alternative for
this if it is not tolerated is
Angiotensin Receptor Blockers
(ARBs).
• Inhibition of b-adrenergic response
by beta-blockers initially given in
low doses but up-titrated to
maximally tolerated doses.
• Inhibition of aldosterone effects by
spironolactone.
• Isosorbide-hydralazine is a useful ACE INHIBITORS
adjunct in select patients.
• These counteract the increased • Potential Adverse Effects:
STEP-WISE APPROACH FOR renin-angiotensin-aldosterone - Hyperkalaemia (due to
CHRONIC MANAGEMENT activity. decreased aldosterone release;
• This means that they prevent the thus important to take care when
• Step 1:
hypotension from causing giving ACE-inh in conjunction with
- ACE Inhibitor – if not tolerated,
discuss with specialist regarding
increased sympathetic activity, and a K-sparing diuretic!)
also prevent the decreased renal - Acute drop in BP (usually
using Angiotensin II receptor occurs with the first dose, then
perfusion from increasing renin
Antagonist.
release. settles)
- Diuretics (for fluid retention) –
• ACE-inhibitors Class Effect: - May cause worsening renal
thiazide (for mild CCF) and loop
- Reduce mortality function (GFR dependant of
diuretic (for significant fluid
- Reverse remodelling constriction of the efferent arteriole,
overload or abnormal renal
which is stimulated by angiotensin
- Decrease hospital admissions
function).
- Improved quality of life II)
• Step 2:
• Mechanism of action – ACE- - Chronic dry cough (due to
- Add Carvedilol
inhibitors inhibit the conversion of increased bradykinin which acts on
• Step 3: the larynx)
angiotensin I to angiotensin II by
- Add spironolactone - Acute angioedema in the
ACE. In addition, bradykinin would
• Step 4: also remain active, as you need larynx (rare but fatal, also due to
- Add digoxin (discuss with ACE in order to inactivate it. increased bradykinin)
specialist)
- This is a very dangerous drug
and should be added with caution.
When to move from one step to the
next?
• when the patient’s symptoms and
their condition is still at NYHA
Class 2 or 3 despite being on
optimal treatment from the
previous step.
• Contraindications:
- Renal artery stenosis
 - Pregnancy
- Previous angioedema
- Hyperkalaemia
• If not tolerated, consider
Angiotensin Receptor Blocker.
• Predictors of adverse ACE-inhibitor
Response:
- Hyponatraemia
- Hypotension (orthostatic
hypotension)
- Low output states
- Renal dysfunction
- NSAID therapy
Management of ACE-Inhibitor Related
Angioedema:
• Withdraw ACE-inhibitor!
• Supportive treatment –
corticosteroid, antihistamine,
adrenalin.
• Once resolved, discuss with
specialist regarding using ARB
instead.
• Note that this can occur even up to
6 month after starting on ACE-inh.
ANGIOTENSIN II RECEPTOR
BLOCKERS
• Alternative to ACE Inhibitors.
• Similar precautions / contra-
indications.
• Its advantage is that is causes less
coughing and angiotensin II
mediated vasoconstriction, but also
no beneficial bradykinin effects
(renal vasodilation, endothelial
protection)
• However, ACE-inhibitors are better
than ARBs as they have a 12%
lower risk of death, and a 20%
lower risk of lethal arrythmias
(particularly in patients with beta-
blockers).
BETA-BLOCKERS
• Cardiac failure causes an increase
in your CVS sympathetic activity.
This leads to the release of renin
and other vasoactive substances
that trigger vasoconstriction and
tachycardia. It also leads to
myocyte hypertrophy and death,
dilatation, ischaemia, and
arrhythmias. How do we prevent all
of this from happening?...Beta-
blockers.
• Examples of beta-blockers include
carvedilol, bisoprolol, and
metoprolol.
• Although beta-blockers can
aggravate CCF in the acute
setting, the few with proven
benefits can decrease mortality by
30% and improve the LV ejection
fraction in the long term.
• The exact mechanism of action is
unclear but we do know that it is
multifactorial.
Beta-blocker Effects:
• Decrease the heart rate (which
allows for a prolonged diastolic
filling time).
• Protect against the cardiotoxic
effects of catecholamines.
• Carvedilol specifically also has a
vasodilating and anti-oxidant effect,
which is also beneficial in these
patients.
• Anti-arrhythmic.
Long-term Effects of Beta-blockers:
• Mortality reduction (CHF and
sudden death).
• Improved LVEF.
• BUT not short-term
haemodynamic improvement, and
may even worsen symptoms.
Indication:
• Added to STABLE Grade II (or III)
patients.
• Important to first treat the
congestion before adding the beta-
blocker.
• Cautious introduction with upward
titration (‘start slow and go slow’)
Contra-indications:
• Heart rate <60bpm.
• Symptomatic hypotension.
• Second- or third-degree
atrioventricular block.
• History of asthma or reactive
airways (beta-blocker may worsen
bronchospasm).
• Peripheral artery disease with
resting limb ischaemia.
NB – never stop abruptly! This can
lead to ischaemia and infarction.
SPIRONOLACTONE
• Spironolactone is a competitive
inhibitor of aldosterone.
• Also known as a potassium sparing
diuretic.
• In HF, aldosterone levels increase
to about 20x their normal amount
due to the increased angiotensin II.
Effects of Aldosterone:
• Increases sodium and water
retention (which causes the
oedema).
• Causes left ventricular fibrosis and
hypertrophy (contributes to cardiac
remodelling).
• Reduces potassium and
magnesium (results in
arrhythmias).
• Reduces arterial compliance and
endothelial function (can result in
ischaemic heart disease).
Adding spironolactone to diuretics
and ACE-inhibitor in severe HF, you
are able to…
• Reduce mortality.
• Reduce hospital admissions.
• Improve symptoms.
Indication:
• NYHA III & IV despite treatment
with ACE-I & B-blocker.
Side-effects:
• Hyperkalaemia may occur (but is
uncommon). Do not give if K>5 or
GFR <30mL/min
• Because spironolactone is a
competitive inhibitor for
aldosterone, it also has an affinity
for other steroid receptors, thus
can lead to gynecomastia,
hirsutism, and sexual dysfunction.
ISOSORBIDE-HYDRALAZINE
• This drug can be used as an
adjunctive therapy to your standard
treatment.
• It is available in a fixed-dose
combination:
- Isosorbide dinitrate –
vasodilator of both arteries and
veins.
- Hydralazine hydrochloride –
predominantly arterial vasodilator.
• Indicated for treatment of heart
failure as an adjunct to standard
therapy, with greater benefits seen
in self-identified black patients in
terms of:
- Improved survival
- Prolonged time to
hospitalization for HF, and
- Improved patient-reported
functional status
• There is little experience with the
use of this drug in patients who
have a class IV heart failure.
DIURETICS
• Antagonise sodium retention.
• Relieve symptoms (especially in
congested patients).
• But:
- Wide range of side effects
which you must try to avoid
(especially electrolyte imbalances).
- Find a balance (minimum dose
to maintain “dry weight”).
• Consider combining different
classes to achieve optimal
balance.
• High ceiling diuretic – as you
increase the dosage, the effect of
the drug increases.
• Low ceiling diuretic – maximal
effective dose reached much
earlier.
• In the acute setting it is therefore
more beneficial to use a high
ceiling diuretic.
• Diuretics increase urine output by
altering how the kidney handles
sodium.
• Furosemide inhibits Na-K-Cl co-
transporter on the ascending loop
of Henle.
• Thiazides inhibit NaCl channel.
• Spironolactone antagonises
aldosterone.
Side-effects of Furosemide:
• Electrolyte disturbances (Na, K,
Ca, & Mg) – due to Na-K-Cl
transporter inhibition.
• Ototoxicity – reversible & dose
related.
• Hypovolaemia – due to fluid loss.
• Hyperuricaemia – active secretion
PCT.
• Hyperglycaemia – occurs because
K is involved in hormone secretion.
This is mostly a risk for pre-
diabetics.
• Hypersensitivity reaction –
sulfonamides.
Side-effects of Thiazides:
• Electrolyte disturbances – Na & Cl.
• Hyperuricaemia & gout – due to
the active secretions at the PCT.
• Hypercalcaemia
• Glucose intolerance – at high
doses.
• Hyperlipidaemia – at high doses.
DIGOXIN
• ‘drug with many problems that
needs to be used with great
caution!’.
• Requires a specialist to administer
and follow-up, but in-between
monitoring can be done by a
primary HCP.
Benefits of Digoxin:
• Reduces symptoms.
• Reduces hospital admissions.
• (BUT does NOT reduce
mortality!)
Problems Associated with Digoxin:
• Narrow therapeutic range.
•
Variable bio-availability.
• Toxic side-effects.
• Drug interactions.
Factors that Increased Digoxin
Toxicity:
• Elderly
• Myocardial infarction
• Hypoxaemia
• Hypokalaemia
• Hypomagnesaemia
• Hypercalcaemia
• Hypothyroidism
• Quinidine, verapamil, amiodarone
• Cardioversion
Contra-indications:
• Hypertrophic cardiomyopathy
• Hypokalaemia
• AV block, WPW syndrome
Features of Digitalis Toxicity:
• GIT – anorexia, nausea, vomiting,
diarrhoea.
• Neurologic – malaise, fatigue,
confusion, facial pain, insomnia,
depression, vertigo, coloured vision
(green or yellow halos around
lights).
• Cardiologic – palpitations,
arrhythmias, syncope.
• Blood – high digoxin
concentration
(digitalis is a drug prepared from the
dried leaves of foxgloves and
containing substances (notably
digoxin and digitoxin) that stimulate
the heart muscle)
MONITORING
• With regards to monitoring the
response, the first 2-3 months
post-discharge are a vulnerable
period and so it is very crucial to
monitor the patient closely during
this period.
• Review adherence before
considering moving to the next
step of management as this could
be a reason for their deterioration.
• Make timely decision to continue,
change, or stop the treatment.
• Reassess comorbidities.
MANAGING ACUTE HEART
FAILURE
• Acute HF has a rapid onset of
signs and symptoms (as opposed
to the more progressive
presentations of chronic HF).
• It may occur with or without
previous cardiac disease.
Therefore, it can either be an acute
decompensation of chronic HF, or
a new onset in patients without
previously known cardiac
dysfunction.
• Acute HF is mainly a systolic
dysfunction with a reduced CO and
significantly decreased ejection
fraction (<45%).
• Patients presenting with acute HF
is usually life threatening and one
of the pathognomonic
presentations is pulmonary
oedema. Therefore treatment of
the pulmonary oedema is an
important cornerstone in the
management of acute HF.
Symptoms & Signs of Fluid Overload
due to Acute HF:
• Dyspnoea, orthopnoea, PND,
oedema.
• Tachypnoea, cyanosis,
hypotension, raised JVP, displaced
apex, S3 gallop rhythm, tender
hepatomegaly, pulmonary oedema.
• Pulmonary Oedema Treatment –
patient needs to be placed in the
Fowler’s position and then
administered oxygen.
• Important parameters to monitor
when managing acute HF include:
- Oxygen saturation
- Blood pressure
- Urine output
• Because the pathognomonic
presentation of acute HF is fluid
overload, a loop diuretic is given
intravenously because it is a high
ceiling diuretic.
• Oxygen is only given is the
saturation drops below 90%.
• Because these patients are often
stressed and anxious, they tend to
hyperventilate which can further
decrease their oxygen saturation.
Therefore, these patients are also
given morphine for the anxiety and
stress.
• The blood pressure is controlled by
considering the use of a
vasodilator if the systolic BP is
high, or by adding a non-
vasodilating inotrope if it is low.
MORPHINE
• MOA – central sedative action with
a venodilatory effect (which causes
a decrease in the preload).
• The main side effect to be aware of
is the respiratory depression which
may be associated with opioid use.
• Naloxone – opioid antagonist.
NITRATES
• Venodilation predominates at the
therapeutic dose – decreases
preload.
• It also improves blood flow in
patients who have ischaemic heart
disease.
• Important to be aware of the
tolerance associated with the use
of nitrates. This tolerance can be
overcome by having nitrate-free
intervals.
• Be careful in patients who are on
phosphodiesterase inhibitors (e.g.
Viagra) as they may be excessively
sensitive to the effects of nitrates
which may lead to hypotension.
• For hypotensive patients, consider
rather using inotropic support with
Dobutamine, which is a selective
B1 agonist with inotropic effect but
no chronotropic effect.
• Very NB – use of Dobutamine must
be accompanied by constant ECG
monitoring (so can’t be given at
clinic level).
TAKE HOME MESSAGES
Heart failure is a complex, potentially
fatal condition and includes:
• Chronic HF, which requires neuro- Normal BP <130 <85 • Secondary HPT is elevated BP due
humoral antagonism by mortality Pre-HPT 130-139 85-89 to a specific and potentially
reducing ACE-inhibitors (or ARBs), Grade 1 140-159 90-99 treatable cause.
beta-blockers, aldosterone HPT
(mild) Renal Causes [>80%]:
blockers, and isosorbide-
Grade 2 160-179 100-109
hydralazine besides symptomatic • Diabetic nephropathy
treatment (e.g. diuretics). HPT
(moderate) • Polycystic disease
• Acute HF, often needs therapy by • Chronic GN
Grade 3 >180 >110
intravenous diuretics, vasodilators HPT • Cardiovascular risk doubles with • Chronic tubulointerstitial nephritis
(nitrates & possibly morphine) and (severe) each 20/10 mmHg increment. • Renovascular disease
possibly inotropes. Isolated 140-159 <90
systolic CAUSES OF PRIMARY

HYPER-
HPT (ESSENTIAL) HYPERTENSION Endocrine Causes:
(grade 1)
• Primary (essential) hypertension • Phaeochromocytoma
Isolated >160 <90
systolic makes up about 80-90% of all (catecholamine secreting tumour)

TENSION HPT hypertension cases. • Cushing’s syndrome

(grade 2) • Thyroid disease
Linked to…
• Conn’s syndrome
• Family Hx (genetic or shared • Acromegaly (GH excess)
• Definition – elevated BP measured MECHANISM OF HYPERTENSION environmental influences).
on 3 separate occasions, minimum Vascular Causes:
• Foetal factors (low birth weight).
of 2 days apart. • BP = CO x PVR
• Obesity. • Renal artery stenosis
• When severely elevated, minimum • [CO = SV x HR]
• Environmental factors (e.g., • Aortic coarctation
of 3 readings on same visit. • BP = SV x HR x PVR
alcohol, sodium intake, poor diet).
• Important to be cautious of ‘white Drug Causes:
Determinants of BP:
coat hypertension’. This can be What is Metabolic Syndrome?
minimised by automated BP cuffs • Volume overload / salt overload. DRUG CLASS EXAMPLES
• Hyperinsulinemia Oestrogens Oral
which take readings in the absence • Increased systemic vascular
of a HCP. • Glucose intolerance contraceptives
resistance.
• Dyslipidaemia Herbal Ephedra,
• Increased central drive to ginseng, ma
CLASSIFICATION
increased BP. • Central obesity
juang
HYPERTENSION (HPT) STAGES • Increased sympathetic nerve CAUSES OF SECONDARY Illicit Amphetamines,
Category Systolic Diastolic stimulation. HYPERTENSION cocaine
(mmHg) (mmHg) NSAIDs COX2-inh,
Frank Starling Law Graph: ibuprofen,
Optimal BP <120 <80
 naproxen Cardiac Effects: MANAGEMENT OF • Alcohol consumption reduction.
(Naprosyn) HYPERTENSION • Smoking cessation.
Psychiatric Buspirone • Atrial enlargement.
• Avoid use of stimulant drugs.
(Buspar), • Left ventricular hypertrophy. Therapeutic Objectives:
carbamazepine If there is no blood pressure reduction
Retinopathy: • Reduce cardiovascular and renal
(Tegretol), after 3 months, consider
clozapine • Grade 1 – tortuosity of the retinal morbidity and mortality. pharmacological therapy.
(Clozaril), arteries with increased • Obtain target BP goals of <140/90
fluoxetine mmHg with diabetes or renal PHARMACOLOGICAL
reflectiveness (silver wiring).
(Prozac), disease. MANAGEMENT OF HPT
lithium, TCAs • Grade 2 – grade 1 + arteriovenous
nipping (thickened retinal arteries • Manage co-morbid conditions and
Steroid Methyl Drugs used in Hypertension:
pass over the retinal veins). reduce contributory factors.
prednisone
(Depo-Medrol), • Grade 3 – grade 2 + flame shaped • Prevent disease progression and • Diuretics
prednisone haemorrhages and soft exudates improve quality of life. • ACE-inhibitors
Sympatho- Decongestants, [‘cotton wool’] (due to small cotton- General Approach to HPT • Angiotensin receptor blockers
mimetic diet pills wool spots. Management: (ARBs)
• Grade 4 – optic neuropathy, • Sympatholytic agents
papilledema (leads to blindness). • Non-pharmacological • Calcium channel blockers
• Another rare possible cause of
• Pharmacological
secondary hypertension is Renal Changes: Glomerular Filtration:
• Holistic approach (biopsychosocial)
glycyrrhiza glabra (which is also
found in liquorice). MOA – • Macroscopic… Keep the following principles in mind:
increases cortisol which leads to - Atrophic kidneys with scarring.
increased sodium reabsorption. • Microscopic… • Efficacy
- Focal sclerosis on glomeruli. • Safety
COMPLICATIONS OF - Changes in large and small • Suitability
UNCONTROLLED HPT arteries (atheroma, elastic re-
duplication). NON-PHARMACOLOGICAL
Blood Vessels: MANAGEMENT OF HPT
Brain Changes:
• Vascular smooth muscle Lifestyle modification:
hypertrophy. • Arterioles – sclerosis & aneurysm
• Small vessel leak (resulting in formation. • Exercise – >30 min/d at lease
proteinuria and retinopathy in • Basal ganglia – small infarcts & 3/week.
kidneys and eyes, respectively). haemorrhages. • Diet – low salt, low fat, vegetables,
• Atherosclerosis (peripheral artery • Dementia – likely due to small fruits.
occlusive disease). vessel complications. • Weight loss – ideal bodyweight
(BMI<25).
4 Sites of Sodium Reabsorption:
• PCT – Na+/HCO3—cotransporter
(65%).
• Thick ascending limb – Na/K/Cl-
symporter (25%).
• DCT – Na/Cl-symporter (5%).
• Collecting duct – Na reabsorption /
K/H excretion (2-4%).
LOOP DIURETICS
• MOA – inhibit Na/K/Cl-symporter in
ascending limb of loop of Henle by
competing for Cl binding site.
• Prevents Na, Cl, & K reabsorption,
thus decreasing fluid retention.
• BUT – short-lived duration of
action.
• Useful in treatment of hypertension
when renal impairment is present,
and for oedema.
Adverse Effects of Loop Diuretics:
• Hyponatraemia
• Hypokalaemia (increases risk of
ventricular arrhythmia)
• Gout (diuretics inhibit uric acid
excretion, resulting in
hyperuricaemia)
• Postural hypotension
• Dyslipidaemia
• Metabolic alkalosis
• Hearing impairment (can be
irreversible)
THIAZIDE DIURETICS
• MOA – block the NaCl
cotransporter in the DCT. This
prevents Na reabsorption, hence
increasing Na excretion.
• It results in a decrease in cardiac
output.
• Long-term effect maintained
through reduced vascular
resistance (opening of Ca activated
K channels).
Adverse Effects of Thiazide Diuretics:
• Hypokalaemia (due to stimulation
of aldosterone-sensitive Na pump
reabsorbing Na in exchange for K
and H; increases the risk of
ventricular arrhythmia).
• Hyponatraemia
• Gout (diuretics inhibit uric acid
excretion, resulting in
hyperuricaemia).
• Metabolic changes (lipid and
glucose intolerance).
• Erectile dysfunction (reduced flow
to penile structures, as well as
reduction in zinc levels, which is
necessary for formation of sex
hormones).
POTASSIUM SPARING DIURETICS
(SPIRONOLACTONE)
• MOA – inhibits epithelial Na
channel in DCT. This transporter is
responsible for reabsorption of Na
in exchange for K, therefore this
inhibition results in sparring K loss.
• Spironolactone is a
mineralocorticoid receptor
antagonist.
• Its action is delayed (~3days), but it
is long acting.
Adverse Effects of K Sparring
Diuretics:
• Hyperkalaemia
• Erectile dysfunction
• Gynecomastia (decreases
testosterone production &
increases peripheral conversion of
testosterone to oestradiol, resulting
in an imbalance between androgen
to oestrogen)
DIURETICS: LOW & HIGH CEILING
CONCEPT
High Ceiling Diuretics:
• Effect of diuresis increases with
increasing dose.
• Cause substantial diuresis.
• E.g., loop diuretics (furosemide).
Low Ceiling Diuretics:
• Effect of diuresis flattens with dose
increase.
• Increased risk of adverse effects.
• E.g., thiazide diuretics
(hydrochlorothiazide)
ACE INHIBITORS
Use in Sub-groups:
• Diabetes – shown to reduce
progression to diabetic
glomerulopathy.
• Renal disease – shown to slow
progression of renal disease (e.g.,
glomerulosclerosis).
• IHD & Post-MI – reduces
angiotensin II mediated effect of
unnecessary cardiac muscle
remodelling after MI.
Adverse Effects of ACE-Inhibitors:
• Dry cough
• Hyperkalaemia
• Angioedema
• First dose hypotension
Contraindications:
• Bilateral renal artery stenosis
(results in substantial reduction in
GFR)
• Pregnancy
• Previous Hx of angioedema
ARBs AS ALTERNATIVES FOR
ACE INHIBITORS
• ACE is involved in breakdown of
bradykinin & substance P.
• Inhibition of ACE by ACE-inhibitors
leads to accumulation of bradykinin
& substance P leading to the dry
cough and angioedema (rarely).
• Angiotensin Receptor Blockers
(ARBs) do not inhibit the ACE-
mediated breakdown of bradykinin
& substance P, therefore it is a
suitable alternative agent.
• With the exception of the cough &
angioedema, adverse effects &
contra-indications of ARBs and
ACE-inhibitors are similar.
CALCIUM CHANNEL BLOCKERS
• MOA – blocks voltage gated Ca
channels (L-type/slow channels).
• There are 2 types of CCBs,
dihydropyridine and non-
dihydropyridine.
• The dihydropyridines
- E.g., nifedipine, amlodipine.
- Have anti-hypertensive
properties.
- Can be used with beta-
blockers.
• The Non-dihydropyridines:
- E.g., verapamil, diltiazem.
- Have anti-arrhythmic
properties.
- Should not be used with beta-
blockers.
Adverse Effects of CCBs:
• Tachycardia
• Ankle oedema
• Headache
• Flushing
Contra-indications:
• Tachyarrhythmias
• Heart failure (especially with
reduced ejection fraction)
• Atrioventricular block (in the case
of non-dihydropyridine)
SYMPATHOLYTIC DRUGS: BETA-
BLOCKERS
• Initial effect – initially produce a fall
in BP by decreasing the CO (by
reducing the frequency of
spontaneous depolarisations in
pacemaker cells). Vagus and
sympathetic nerves affect heartrate
and CO.
• Beta-blockers prevent activation of
the Beta adrenoreceptors by NE
and EPI and block increased
sympathetic effects on the heart.
• With continued treatment, CO
returns to normal but BP remains
low, because by unknown
mechanisms, the PVR is reset at a
lower level.
• Beta-blockers vary in their lipid
solubility and cardioselectivity.
However they all block B1
receptors and are equally effective
in reducing BP and preventing
angina.
Cardioselectivity:
• Cardioselectivity is relative and
diminishes with higher doses.
• Cardioselective drugs may have
sufficient B2 activity to precipitate
severe bronchospasm in patients
with asthma.
• Side effects can be reduced by
using cardioselective hydrophilic
drugs (those without liver
metabolism or brain penetration)
such as atenolol.
• Cardioselective (B1 receptors)
beta-blockers include…
- Atenolol
• Non-cardioselective (B1 & B2
receptors) beta-blockers include…
- Propranolol
- Pindolol
- Carvedilol (has additional a-
blocking properties)
Beta-blockers used in cardiac
conditions:
• Heart failure
• Angina
• Atrial fibrillation (rate control)
Adverse Effects of Beta-blockers:
• Increased risk of hypoglycaemia in
diabetics on insulin (type 2
diabetes not a contraindication)
• Increase triglycerides and lower
HDL in plasma
• Rebound hypertension may occur
when stopped suddenly!
• Cold hands
Contra-indications:
• Asthma
• Atrioventricular block or SA node
dysfunction
SYMPATHOLYTIC DRUGS: ALPHA-
METHYLDOPA
• Alpha methyldopa is centrally
acting. It acts in the CNS to inhibit
adrenergic neuronal outflow,
reducing signals to peripheral
sympathetic nervous system.
• It is the preferred drug for
treatment of hypertension
during pregnancy.
Side-effects:
• Sedation
• Depression
• Diminished libido
• Parkinsonism
• Hyperprolactinemia
• Hepatotoxicity
BP CONTROL: INTENSIVE VS
STANDARD MANAGEMENT
• Conventional management is to
maintain blood pressure below
140/90mmHg for management of
BP.
• However, cardiovascular risk
increases with BP > 115mmHg.
• Alternative strategy – intensive BP
control – maintain systolic BP <
120mmHg (SPRINT trial, 2015).
Benefits of Intensive Management:
• Decreased rate of cardiovascular
events (e.g. MI, ACS, stroke, acute
decompensated HF, CV death).
• Decreased orthostatic hypotension.
Risks of Intensive Management:
• Hypotension
• Acute kidney injury
• Syncope
• Electrolyte abnormalities
• (falls not significantly increased)
PSYCHOSIS
• Definition – clinical state of mind
characterised by loss of contact
with reality.
• The patient might experience
perceptual disturbances, e.g.
hallucinations that are generally
auditory as well as disturbances of
though content, i.e. delusions.
• Delusions are fixed unshakeable
beliefs.
• Hallucinations are perceptions
without adequate stimuli, e.g.
hearing voices or seeing dead
people.
• Negative symptoms – blunting of
affect, avolition, alogia.
• Social or occupational dysfunction.
• NB! Clear sensorium!
DELIRIUM WITH ACUTE
CONFUSION & AGGRESSION
• Medical emergency.
• Impaired awareness, confusion,
and disorientation.
• Others – restlessness, agitation,
and hallucinations, ANS
symptoms, aggressiveness, etc.
• Always look for a cause – think
DIMTOP (drugs, infection,
metabolic, trauma, oxygen,
psychological).
PATHOGENESIS OF PSYCHOSIS
• UNKNOWN
• Dopamine hypothesis of
schizophrenia – excessive
dopaminergic activity.
CAUSES OF PSYCHOSIS
Functional Psychosis:
• Schizophrenia
• Bipolar mood disorder
Psychotic disorders due to medical
conditions:
• Medical conditions, e.g. epilepsy,
Alzheimer’s dementia, HIV,
neurosyphilis.
Drugs:
• Illicit drugs – cannabis, Mandrax,
cocaine, amphetamines.
• Prescription drugs – steroids,
antiparkinsonism drugs, atropine.
Other:
• E.g., postpartum psychosis
APPROACH TO MANAGEMENT
• Depends on aetiology and onset of
the psychosis.
• For acute management (i.e.
agitated or acutely disturbed pt),
the goal of therapy is to calm the pt
down and achieve containment.
Antipsychotics and/or
benzodiazepine are the drugs of
choice for this.
• For chronic management, the goal
of therapy is to prevent relapse of
acute psychotic symptoms (i.e.
delusions, hallucinations) so as to
maintain functionality.
Antipsychotics and supportive
psychotherapy for both the patient
and the family can help to achieve
this.
NEUROLEPTICS
• There are 2 groups of neuroleptics,
classical, and atypical.
• Classical neuroleptics are
dopamine 2 receptor antagonists,
and have a tendency to cause
extrapyramidal side effects.
• Atypical neuroleptics are D2 & D3
receptor antagonists. They can
also act as serotonin receptor
antagonists.
Primary Indications for Neuroleptics:
• Schizophrenia
• Mania
• Organic psychosis
Other Indications:
•
Nausea & vomiting
• Intractable hiccups
• Tourette’s syndrome
• Behaviour disorders
• Anaesthesia
Traditional Neuroleptics:
• Phenothiazines (side chain)
- Aliphatic, e.g. chlorpromazine
- Piperazine, e.g.,
prochlorperazine, fluphenazine
- Piperidine, e.g., thioridazine*,
periciazine
• Butyrophenones Contra-indications: HALOPERIDOL-BUTYROPHENONE CLOZAPINE-DIBENZODIAZEPINE
- Haloperidol, droperidol
• Coma • Very potent antipsychotic. • Atypical neuroleptic
• Thioxanthenes
• Severe mental depression • Indications similar to other - D2 and serotonin receptor
- Flupenthixol, zuclopenthixol
• Severe liver impairment neuroleptics. antagonist.
*discontinued due to cardiotoxicity • Significant cardiac disorders • Onset of action is 10 minutes after • Indicated for resistant psychosis.
• Glaucoma IM injection, Tmax 4-6hrs after oral • Contraindicated in history of drug
Formulations:
• Bone marrow depression ingestion. induced agranulocytosis.
• Oral • Half-life is 13-35hrs.
Adverse Effects: Adverse Effects:
• Injectables (usually IM) • Metabolised in the liver
- Short acting – acute • EPSEs extensively. • Weight gain
management • Sedation • Contraindicated in parkinson’s and • Agranulocytosis and neutropenia
- Long acting depot • Postural hypotension patients with a history of EPSEs • Sedation
preparations (preferred if • Anticholinergic side effects from neuroleptics. • Postural hypotension
compliance is a problem) • • Caution in special groups as there
Epileptogenic • Anticholinergic s/e.LESS EPSEs.
• Photosensitivity is an increased risk of side effects.
• Jaundice Adult Doses:
CHLORPROMAZINE- Adverse Effects:
PHENOTHIAZINE • Agranulocytosis • 12.5 – 25mg dly then increase to
• Less anticholinergic therapeutic levels in 2-3 weeks.
Drug Interactions:
• Oldest neuroleptic of low potency. • Hypotensive • NB!! WCC monitoring is essential.
• Anticholinergics • Least epileptogenic, BUT
Indications:
• Antiepileptics increased risk of EPSEs DIFFERENCES AMONG
• Schizophrenia • Antihypertensives ANTIPSYCHOTICS
Drug Interactions:
• Mania • Anti-parkinsonism drugs
• All effectively bind D2 receptors but
• Organic psychosis, etc. • CNS depressants • Lithium (neurotoxicity)
have different affinity for other
• Tranquillization in emergency • Enzyme inducers • As with other antipsychotic drugs
receptors viz..
aggressive behavioural
Doses: Adult Doses: - Muscarinic receptors –
disturbances
anticholinergic, urinary retention,
Onset: • Initially 25mg tds but maintenance • Initially 0.5-5.0mg 2-3X daily then blurred vision, orthostatic
range 75-300mg. reduce to LOWEST EFFECTIVE hypotension, erectile dysfunction.
• 30-60min after oral ingestion. • IM 25-50mg, can be repeated 3-4 DOSE. - Histamine receptors –
• 15 minutes after injection. times in 24hrs as necessary • Usual maintenance dose is 2-10mg sedation, antiemetic.
• USE THE LOWEST EFFECTIVE daily. - Alpha adrenergic receptor –
Half-life:
DOSE! • Advantage is that it is also orthostatic hypotension.
• 30 hours available in IV formulation.
 - Serotonin receptors – pseudo-
depression.
• Difference in lowering seizure
threshold.
• Difference in tendency to cause
metabolic and endocrine effects,
e.g. weight gain and
hyperprolactinaemia resp.
• Difference in tendency to cause
cardiac toxicity, e.g., ventricular
arrhythmia, QT prolongation.
COMPLICATIONS OF
NEUROLEPTICS
EPSEs:
• Acute dystonic reaction – spasm of
muscles of tongue, face, neck and
back.
• Onset – 24-48hrs.
• Risk factor – young male.
• Rx – biperiden 2mg IM/IV,
benzodiazepine if necessary, if c/o
pain analgesia.
• Stop neuroleptic until symptoms
full resolution.
Parkinsonism:
• Bradykinesia, rigidity, tremors.
• Onset – weeks or months.
• Common in older patients.
• Rx – reduce dose to lowest
effective dose; prescribe
anticholinergic orphenadrine 50-
150mg.
Akathisia:
• Akathisia-motor restlessness vs
anxiety.
• Onset – days to weeks.
• Rx – reduce dose; add
anticholinergic if necessary.
• Tardive dyskinesia – syndrome of
choreoathetoid and or other
involuntary movements, usually of
face, lips and tongue +/- arms, legs
and trunk.
• Onset – usually >6/12
• MOA - ?? Excess dopamine.
• Rx – prevention; lowest effective
dose for the shortest time;
gradually withdraw; consider
changing to atypical antipsychotic
(less tendency for EPSEs).
Neuroleptic Malignant Syndrome:
• Rare but has a mortality of more
than 10%.
• Aetiology is unknown (?dopamine
blockade in hypothalamus)
• Onset – usually weeks but can
occur after first dose.
• Risk factors – increased ambient
temperature, dehydration,
intercurrent mildly febrile illness,
catatonia.
ATYPICAL NEUROLEPTICS CAUSES OF TREATMENT FAILURE
• Newer and expensive. • Low efficacy rate!!!
• Less EPSEs (not devoid of • Inter and intraindividual variability.
EPSEs), prolactin effects, • Under dosing (lowest EFFECTIVE
increased weight gain. dose).
• Clozapine EDL – reserved for
• Malabsorption (change to depot
treatment resistant psychosis preparation).
(major s/e is agranulocytosis and • Drug interactions.
neutropenia). • Wrong diagnosis – Rx underlying
• Associated with QT prolongation. cause, e.g. brain tumours.
• Non-compliance.
SPECIAL POPULATIONS
TAKE HOME MESSAGE
Pregnancy:
• Neuroleptics are effective in
• No randomised controlled trials.
psychosis.
• All neuroleptics cross the placenta.
• They have numerous adverse
• Phenothiazines are excreted in
effects so use LOWEST
breastmilk (behavioural changes in
EFFECTIVE DOSE.
infants).
• Different classes have different
Children: pharmacological properties – risk
assess your patient before
• Use only if necessary as EPSEs
prescribing any.
can occur after first dose.
• Beware of special risk groups.
Elderly:
• More susceptible to cardiovascular
side effects and anticholinergic
side effects.
Hepatic Disease:
• Dose adjustment may be needed.
 know in advance the treatment known and unknown confounding the two percentages as that

CRITICAL group.
• Controlled – control group (no
treatment or standard of care
variables (i.e., controls for
confounding).
• If done correctly, randomisation
•
observed?”
What does P<0.05 mean in relation
to difference in two proportions of

APPRAISAL
group). yields groups that are balanced outcome between treatments A
with regard to prognostic variables and B?
SOURCES OF ERRORS IN (variables that have an impact or • If treatment A and B really are
EPIDEMIOLOGICAL STUDIES

OF MEDICAL
an influence on developing the equally effective the chances of
outcome under study). getting such a big difference as
• Random error
• If two (or more) groups are one observed (or even bigger) is
• Bias (systematic error)
prognostically balanced, with the less that 5 in 1000.

LITERATURE
LEVELS OF EVIDENCE
• Systematic reviews and meta-
analyses
• Randomised controlled double
blind studies
• Cohort studies
• Case control studies
• Case series
• Case reports
• Ideas, editorials, opinions
• Animal research
• In vitro research
RANDOMISED CONTROLLED
TRIAL
• Scientific experiment which tests
interventions in an unbiased way.
• Randomised – random allocation
of treatment between groups. Both
participant and researcher cannot
- Selection bias
- Information bias
(misclassification or measurement
error)
- Confounding
Bias (systematic error):
• Estimates of effects that deviate
from the truth and which are not
dependent on the sample size.
Confounding:
• Occurs when estimate of
association between exposure and
disease (outcome) is wholly or
partly due to effect of another
exposure on the same disease
(outcome), and the two exposures
are correlated.
WHY SHOULD WE RANDOMISE
INTERVENTIONS?
• Randomisation affords an
unbiased comparison between
groups as it controls for both
exception of the intervention, and
an investigator observes a
difference in outcomes, a sound
argument can be made attributing
the difference in results to the
intervention.
HYPOTHESIS TESTING IN
RESEARCH
• Hypothesis – a precise, testable
statement predicting the outcome
of the study.
• Null hypothesis – there is no
difference in outcome estimate
between two groups.
• Alternative hypothesis – there is a
difference (greater or less)
between the two groups.
P-VALUE
• “If the null hypothesis is true, what
are the chances of getting as big
(or bigger) a difference between
• Smaller chance (small p-value) =
strong evidence against null
hypothesis.
• Bigger chance (big p-value) = lack
of evidence against null
hypothesis.
PLACEBO, PLACEBO EFFECT, &
STANDARD OF CARE
Placebo:
• An intervention (substance or
treatment) of no intended
therapeutic value. It does not
contain the active substance to
affect health.
Placebo Effect:
• Beneficial effect produced by a
placebo drug or treatment, not
attributable to the properties of the
placebo, & therefore due to the
patient’s belief in that treatment.
Standard of Care:
• Treatment agreed by experts to be
appropriate, acceptable and widely
used.
ENDPOINTS: CLINICAL &
SERROGATE
• Primary endpoint – main result
measured at the end of a study to
see if a given treatment worked.
• Secondary endpoint – other
result(s) being measured at
different time points of the study to
assess impact of intervention.
• Clinical endpoint – occurrence of a
disease, symptom, sign, or
laboratory abnormality that
constitutes one of the target
outcomes of the trial.
• Surrogate endpoint – measure of
effect of treatment that may
correlate with a real clinical
endpoint but does not have a
guaranteed relationship.
MEASURES OF EFFECT
Ratio Measures of Effect:
• Demonstrate strength of
association between exposure and
outcome.
• Confusingly all referred to as risks.
• Derived from different study
designs.
• Includes – risk ratio, rate ratio,
odds ratio, and hazard ratio
• A values less <1 indicate people
defined as exposed are less likely
to have the outcome of interest.
Difference Measures of Effect:
• Estimates excess risk caused by
exposure in the exposed compared
to unexposed group.
• Includes – rate difference, rate
difference percent, risk difference,
and risk difference percent.
AR, OR, RR, HR, ARR, & NNT
• Risk (absolute risk, AR) – is the
probability of occurrence of
disease.
• Odds – ratio of probability of
outcome in exposed group to
probability in outcome in
unexposed group.
• Odds ratio (OR) – comparison of
odds in unexposed and exposed
groups.
• Hazard ratio (HR) – comparison
between the probability of events in
a treatment group, compared to
probability of events in a control
group. Used to see if patients
receiving a treatment progress
faster (or slower) than those not
receiving treatment.
• Absolute risk reduction (ARR) –
amount by which therapy /
intervention reduces risk of bad
outcome. Difference in AR
between two groups.
• Number needed to treat (NNT) –
number needed to treat in order to
prevent one additional bad
outcome.??. NNT = 1/ARR.
CONFIDENCE INTERVAL
• Clinical trials / experiments are
conducted by drawing a sample
from a population.
• A confidence interval gives a range
of values within which you can be
reasonably confident that the
population value lies.
• When estimating a proportion base
on a random sample, it is useful to
quantify the statistical uncertainty
of the estimate. You can calculate
an interval within which the true
population proportion is expected
to lie.
• A 95% confidence interval implies
that if we repeated the experiment
100 times, on 95 occasions, out of
the 100 the confidence interaval
would contain the true population
estimate.
TYPE 1 & TYPE 2 ERROR
4 Scenarios:
1. We reject he null hypothesis
when we should reject it.
Correct decision
 2. We do not reject the null
hypothesis when we should
not reject it. Correct decision
3. We reject the null hypothesis
when we should not reject it.
Type I error
4. We do not reject the null
hypothesis when we should
reject it. Type II error
STUDY POWER
• Ability of a study to detect a
difference between two treatment
groups if one really exists.
• Also known as ability of a study to
not commit type II error.
INTENTION TO TREAT (ITT) VS representation of the general
PER-PROTOCOL (PP) ANALYSES population?
• How ere participants selected? Any
ITT Analysis: bias?
• Clinically significant – a change in
• Method for analysing results in a
patient’s life or disease status that
prospective randomized study
is considered/regarded as
where all participants who are
important.
randomized are included in the
statistical analysis and analysed
according to the group they were
originally assigned, regardless of
what treatment (if any) they
received.
• Gives information about
effectiveness of an intervention.
PP Analysis:
• Method of data analysis and
interpretation of randomised
clinical trial results that removes
data from patients who didn’t
comply with the protocol.
• Provides information about
efficacy.
• Creates some form of selection
bias.
• Undermines randomisation.
GENERALISABILITY
• Generalisability – applicability of
research findings and conclusions
from the sample population to the
population at large.
• Are the populations under the
study too selective to not be a

ANTI-
MICROBIAL
THERAPY
: • Another mechanism which is very
OVERVIEW & PRINCIPLES
TERMS
• Antimicrobials – drugs that act on
micro-organisms (acts on fungus,
bacteria, or virus).
• Antibiotics – antimicrobials
derived from micro-organisms (but,
clinicians use this term when they
mean antimicrobials used for
bacteria).
• Chemotherapeutic – synthetic
antimicrobial.
ANTIMICROBIALS: SITES OF
ACTION
• Beta-lactams and glycopeptides
act on the cell wall.
• Quinolones, sulphonamides (via
folate), and rifampicin, act on DNA
synthesis.
• Macrolides, tetracyclines, and
aminoglycosides, act on protein
synthesis.
MECHANISMS OF ANTIMICROBIAL
RESISTANCE
• One of the most common
examples is when the antimicrobial
simply cannot enter the cell. This is
particularly the case for gram
negative bacilli (especially
pseudomonas).
common is where the drug can
enter, but it is destroyed by an
enzyme produced by the bacteria
before it can reach its target. This
is the main mechanism of
resistance to beta-lactams and
aminoglycoside enzymes.
• Another mechanism is where the is
a mutation at the target site, so the
antimicrobial can no longer bind to
it. Resistance to quinolones,
macrolides, and penicillin Binding
Protein is primarily through this
mechanism.
HOW DOES RESISTANCE ARISE?
• It might be that the resistance was
always intrinsic (e.g., enterococci &
cephalosporins, etc.).
• Or it may be due to mutation where
the target site is altered.
• Or it can be due to transferable
DNA. The two transferable
elements of DNA are plasmids &
transposons. This is the most
common method and often leads to
resistance to multiple
agents/drugs.
NB! Selection pressure drives
resistance.
GRAM -VE VS. GRAM +VE
• The gram-positive cell wall is
actually thicker than the gram-
negative cell wall, but it is very
simple.
• The gram-negative cell wall is
much more complex and has an
outer membrane. This outer
membrane is very good at blocking
out / removing small molecules,
hence why gram-negative
organisms are harder treat.
CLINICAL QUESTIONS FOR
ANTIMICROBIAL SELECTION
• Is there an indication?
• What is the likely organism/s?
• Community or hospital acquired?
• Important host factors present?
• Oral or parenteral?
• Dose?
• What is the optimal duration?
• Narrowest spectrum agent?
• Cost?
IS THERE AN INDICATION?
• In primary care the majority of
antibiotics are used for respiratory
tract infections, most of which are
viral.
• Urgent indications:
- Severe sepsis
- Bacterial meningitis
• Clear cut indications:
- Obvious infection
Antimicrobial Adverse Drug
Reactions:
• Minor ADRs are very common,
including consequences of
antimicrobial action such as
diarrhoea and vaginal candidiasis.
• Life threatening ADRs include:
- Stevens-Johnson
syndrome/TEN
- Angioedema, anaphylaxis,
bronchospasm
- Hepatitis
- Interstitial nephritis
- Thrombocytopenia,
neutropenia
WHAT IS THE LIKELY
ORGANISM(S)?
• Need an accurate clinical problem.
• Need knowledge of the likely
organisms in a given clinical
setting.
COMMUNITY/HOSPITAL
AQUIRED?
• Hospital >/=48hrs – high risk of
antibiotic resistance:
- Staphylococci resistant to
cloxacillin.
- Gram negative resistant to
most beta-lactams, gentamicin,
etc.
- Need microbiology input.
• Community resistance is also
increasing:
- Streptococcus pneumonia
(vaccination is decreasing this)
- Gram negative bacilli
- Neisseria gonorrhoea
IMPORTANT HOST FACTORS?
• Compromised host = broader
range of possible pathogens.
• Host factors for drug selection –
e.g., extremes of age, renal/hepatic
failure.
ORAL OR PARENTERAL?
• Parenteral essential:
- In severe sepsis (GIT function
impaired).
- When you need very high
doses (e.g., bacterial meningitis,
endocarditis).
• An early switch from IV to oral
therapy is often possible, which
you may want to do because then
you get rid of the drip and there is
one less source of infection. But
switching to oral is not an option for
meningitis or endocarditis.
DOSING
• Doses that are too low increase the
risk of carriage of resistant strains.
• The science behind dose and dose
intervals depends on serum/tissue
levels and mode of action (e.g.,
post-antibiotic effect) [time vs.
concentration dependant action].
• With concentration dependent
antimicrobials (e.g.,
aminoglycosides/quinolones), it is
important not to underdose.
• With time dependent antimicrobials
(beta-lactams) it is important not to
skip doses (e.g., for bacterial
meningitis).
WHAT IS THE OPTIMAL
DURATION?
• There are limited studies on
duration of therapies.
• Prolonged therapy (>/=4 weeks)
may sometimes be required for
difficult sites (e.g., endocarditis,
bone).
• In practice however, most
infections are treated for short (5-7
days) or intermediate (10-14 days)
duration.
• Longer courses increase the risk of • To prevent disease in close
carriage of resistant strains. contacts (meningococcal infection).
• Too short of a course could lead to
ANTIBIOTIC
failure to eradicate, especially at
difficult sites.
NARROWEST SPECTRUM AGENT
• Broader spectrum means more
alteration of normal flora with
CLASSES
higher risk of antibiotic-associated
diarrhoea, mucosal candidiasis, OVERVIEW
and carriage of resistant
• Antibiotics are derived from living
organisms.
organisms (e.g. penicillin) and
• Gut microbiome altered for
chemotherapeutic agents were
months/years after a course of
synthesised; but in this lecture
antibiotics. Long term health
antibiotic will be used to mean
consequences are unclear.
antibacterial drugs.
• Therefore, it is very important that
• Emphasis is on drugs for
once the culture has revealed the
community-acquired infections.
exact causative organism, the
patient should be switched to a • Drugs for nosocomial infections
narrower spectrum. included for completeness only.
INDICATIONS FOR BETA-LACTAMS
ANTIMICROBIAL PROPHYLAXIS
• There are 4 different classes of
• To prevent surgical infections beta-lactams:
- Penicillins
(single dose at induction!).
- Cephalosporins
• To reduce infections in immune
- Clavulanic acid (b-lactamase
compromised patients (e.g.
inhibitor)
cotrimoxazole in advanced HIV
- Carbapenems
infection).
• Act on cell wall.
• To prevent endocarditis in valvular
heart disease (?value). • MOA of Beta-lactams: penicillins
inhibit the formation of
• To prevent recurrences of
peptidoglycan cross-links,
rheumatic fever.
 hindering bacterial cell-wall
synthesis.
• Time dependent bactericidal
action.
• Wide therapeutic index (CNS toxic
at maximal doses).
• Main adverse effect is
hypersensitivity.
• Most eliminated by renal tubular
secretion.
• IVI, pen V oral (poorly absorbed –
Commonest mechanism of
resistance is mediated by beta-
lactamases…
- Cannot be overcome by using
higher doses.
- In community most aerobic
gram-negatives, anaerobes, and
staphylococci produce beta-
lactamases.
- Extended spectrum beta-
lactamases in aerobic gram
negatives in hospitals, which
results in high level resistance to
all penicillins and cephalosporins.
• Second resistance mechanism is
mutations in the Penicillin Binding
Proteins (e.g. S. pneumoniae) –
usually low level resistance, which
can be overcome by using higher
doses.
PENICILLINS
• Penicillin is active against gram
positives, and spirochaetes.
• It is the drug of choice for…
- Streptococci (few S.
pneumoniae highly resistant)
- Syphilis & other spirochaetes
- Enterococci
- Listeria
- Actinomyces
• Susceptible to beta—lactamases.
• Different formulations: Penicillin G
concentrations inadequate for S.
pneumoniae).
• Long-acting injectable benzathine
penicillin (IMI) lasts for 21 days.
This is helpful for treating
streptococcal tonsillar pharyngitis,
and for prophylaxis for rheumatic
fever and syphilis.
Penicillins 2 – Aminopenicillins:
• e.g. ampicillin & amoxicillin
• Were developed to treat gram
negative infections, but
unfortunately resistance has now
become widespread.
• Ampicillin is only used
intravenously.
• Amoxycillin is an oral agent and is
well absorbed.
• Initially were broad spectrum
agents, but resistance has become
widespread.
• Their spectrum of action is similar
to penicillin, but they do have
reasonable cover against
Haemophilus (except those 15%
that have b-lactamase).
• They have excellent activity
against S. pneumoniae, therefore
recommended for respiratory
infections.
Penicillins 3 – Cloxacillin:
• Resists b-lactamase from
staphylococci.
• Flucloxacillin specifically, is better
absorbed orally.
• Both are only used for gram
positive bacteria.
• Widely used for skin and soft tissue
infections.
Beta-lactamase Inhibitors:
• These are irreversible inhibitors of
b-lactamases.
• E.g., clavulanate, tazobactam
• When combined with b-lactams,
they can reverse resistance…
- Amoxicillin-clavulanate –
broad spectrum community-
acquired gram positive, gram
negative, and anaerobe infections.
- Piperacillin-tazobactam – for
nosocomial infections.
Summary of Must-Know Penicillins:
• Penicillin (IV, oral, and depot IM)
• Cloxacillin/flucloxacillin
• Amoxicillin
• Amoxicillin-clavulanate
CEPHALOSPORINS
• Developed in successive waves or
generations.
1st Generation:
• Spectrum largely limited to
Streptococci & Staphylococci).
• E.g. Cefazolin IV, Cephalexin PO
2nd generation:
• Spectrum as for 1st generation
PLUS Haemophilus, & community-
acquired gram negatives).
• E.g. Cefuroxime PO & IVI.
3rd Generation:
• Spectrum as for 2nd generation
PLUS typhoid & spirochetes.
• Good CSF penetration.
• Examples…
- Cefotaxime/ceftriaxone
- Ceftazidime (for nosocomial
infections; pseudomonas; poor for
streptococci)
4th Generation:
• Cefepime (for nosocomial
infections; similar to ceftazidime +
cefotaxime)
____________________
Cefazolin (1st Gen):
• Used at induction for surgical
prophylaxis.
• Also for serious staphylococcal
infections.
Ceftriaxone IVI/IMI daily (3rd Gen):
• Excreted mainly bile.
• Spectrum community-acquired
gram+ (including most S.
pneumoniae, not ideal for S.
aureus) & gram-.
• Good CSF penetration & empiric
drug of choice for bacterial
meningitis.
• Drug of choice for typhoid.
• Drug of choice for gonorrhoea
(IMI).
• Useful broad-spectrum agent for
serious community acquired
infections.
CARBAPENEMS
• Extremely broad spectrum
covering most hospital-acquired
gram+, gram-, and anaerobes.
• Only used for nosocomial
infections, or for confirmed multi-
drug resistance.
• Not active against cloxacillin-
resistant Staphylococci.
• Very expensive.
BETA-LACTAM
HYPERSENSITIVITY REACTIONS
• Incidence highest with penicillins (1
to 6%).
• By far the commonest
hypersensitivity reaction to b-
lactams is a maculopapular rash,
which is usually due to amoxicillin
and appears after 72 hours.
• The more serious reactions are
mediated by IgE (thus type 1
hypersensitivity reaction). These
include anaphylaxis (within 1 hour),
angioedema, urticaria, and
bronchospasm (last 3 within 72
hours).
There is a potential for cross reactions
for beta-lactams:
• Cross reaction between
cephalosporins & penicillins <5%,
lowest with 3rd generation (<1%)
- Therefore, it is okay to use in
penicillin allergy if hypersensitivity
reactions was not IgE mediated.
• Avoid entire class if IgE-mediated
reaction…
- Desensitise in exceptional
cases.
• Cross reactions with carbapenems
are rare.
GLYCOPEPTIDES
• Only used for nosocomial
infections.
• Active against cell walls.
• Time dependent killing.
• Not absorbed orally.
• Only covers gram positives,
especially cloxacillin-resistant
Staphylococci.
• E.g. vancomycin
Vancomycin:
• Slow IV infusion essential (red man
syndrome).
• Mildly neprho-/oto-toxic.
• Measure concentration in renal
failure & selected organisms.
AMINOGLYCOSIDES
• Potent against aerobic gram
negative bacilli.
• Bactericidal inhibitors of protein
synthesis and are bactericidal.
• Concentration dependent killing.
• Synergy with beta-lactams (seldom
necessary).
• Polar compounds (thus poor tissue
penetration).
• Must be given parenterally.
• Concentrated in urine.
• Single daily dosing best (because it
has post-antibiotic effect).
• Measure concentrations if >3 days
or renal failure.
• E.g. gentamicin, amikacin
Gentamicin:
• For serious community infections
such as pyelonephritis.
• Combined with beta-lactams for
polymicrobial infections or synergy
(enterococci, streptococcal
endocarditis).
Amikacin:
• Used for nosocomial infections.
Aminoglycoside Toxicity:
• Related to prolonged elevated
trough concentrations.
• May cause ototoxicity (irreversible
in many cases) or nephrotoxicity
(reversible).
QUINOLONES
• Targets DNA enzymes (gyrase &
topoisomerase IV).
• Concentration dependent killing.
• Older agents (first generation)
poorly absorbed, limited spectrum
gram negative aerobes, resistance
arises readily (nalidixic acid).
• Second generation
fluoroquinolones well absorbed,
spectrum gram negative aerobes
(including pseudomonas); poor for
gram positive.
• Third generation
fluoroquinolones well absorbed,
spectrum includes gram positives
(especially streptococci) and gram
negatives (except pseudomonas).
• Toxicity – rashes, CNS (headache,
dizziness, excitation, seizures),
tendonitis.
• Use in children limited to animal
toxicity, but okay for restricted
indications.
• Resistance generally by mutations
in the target genes.
Therapeutic Use of Quinolones:
• Recent toxicity concerns, therefore
only for serious infections.
• 2nd generation (ciprofloxacin) is
drug of choice for…
- Bacterial dysentery
- Pyelonephritis
- Prostatitis
- Alternative to aminoglycosides
- Typhoid (resistance is
increasing)
• 3rd generation (moxifloxacin) is
drug of choice for…
• MDR TB
• Alternative for RTIs (only if severe
beta lactam allergy), cover atypical
pneumonia agents as well as
conventional bacterial causes of
community-acquired pneumonia.
MACROLIDES
• Inhibit protein synthesis (50 S
ribosome).
• Bacteriostatic.
• Active against gram positives, but
increasing S. pneumoniae
resistance.
• Erythromycin has fair
bioavailability.
• Newer agents better absorbed,
longer half-life (clarithromycin &
azithromycin).
• Toxicity – common GIT
(nausea/vomiting, diarrhoea).
• Inhibit CYP450 metabolism (except
azithromycin).
Therapeutic Uses for Macrolides:
• Alternative to penicillin (for allergic
patients) for mild streptococcal &
staphylococcal infectinos.
• Active against “atypical”
pneumonia agents (legionella,
mycoplasma, Chlamydophila).
• Drug of choice for…
- H. pylori
(clarithromycin/azithromycin)
- Chlamydia
urethritis/cervicitis (single dose
azithromycin)
- Pertussis
- Chancroid
- M. avium complex infections
in AIDS (clarithromycin /
azithromycin)
TETRACYCLINES
• Inhibit protein synthesis (30 S
ribosome).
• Bacteriostatic.
• Resistance by efflux or enzymatic
breakdown.
• Absorption varies – excellent for
doxycycline (impaired by divalent
cations).
• Good intracellular penetration.
• Toxicity – nausea/vomiting,
photosensitivity, and teeth
discolouration (avoid <8 years /
pregnancy).
Therapeutic Uses of Tetracyclines:
• Drug of choice for…
- Rickettsia
- Brucellosis
- Acne (low dose)
• Prophylaxis of falciparum malaria.
• Chlamydia STI (urethritis, PID) –
superseded by azithromycin.
• Limited usefulness as single agent
for respiratory infections as
Streptococcus pneumoniae often
resistant.
COTRIMOXAZOLE
• This drug is a combination of
Sulfamethoxazole (sulphonamide)
+ trimethoprim.
• It blocks successive steps in
bacterial folate pathway and
prevents nucleic acid synthesis.
• Well absorbed orally.
• Main side effect is sulphonamide
hypersensitivity - skin rashes,
which may be severe (Stevens-
Johnson syndrome/Toxic
Epidermal Necrolysis)
• Minimal value outside of HIV due
to toxicity and high prevalence of
resistance in community-acquired
gram negatives and S.
pneumoniae.
Therapeutic Uses of Cotrimoxazole:
• In HIV infection, drug of choice
for…
 - Pneumocystis jirovecci
pneumonia
- Toxoplasmosis
- Cystoisopora belli diarrhoea
• In HIV also primary prophylaxis –
to prevent above and reduce
bacterial infections.
• Also effective for protozoans
lacking mitochondria…
- Entamoeba histolytica
- Trichomonas vaginalis
- Giardia lamblia
• Primary care disease.
• Lifestyle changes essential, i.e.
diet, exercise, ideal body weight,
etc.
Pathogenesis of Atherosclerosis:
• Endothelial damage occurs.
Investigations:
• Resting ECG (NB!)
• Stress ECG if indicated
• CXR (?useful)
• Bloods (cholesterol, glucose, renal
function if required)

ISCHAEMIC
• HIV+ patients have a much higher • Leads to inflammation with plaque Risk Factors:
frequency of getting a deposition.
hypersensitivity rash, especially • Hypertension
• Cholesterol, fibrin, etc.
• Diabetes

HEART
with higher doses. • Fibrous cap stability determines
Rechallenge/dose reduction often rupture, not size. • Smoking
successful (not if reaction was • Obesity
severe). Prognosis of Angina Depends On: • Age (male greater than 40;
METRONIDAZOLE

• Toxic to DNA (forms highly reactive

nitro radical with anaerobic
metabolism Fe:S proteins).
• Good oral absorption. But also
available PR and IVI.
• Well tolerated in short courses,
but…
- Has metallic taste.
- Has a disulfiram-like effect
(avoid alcohol).
- Long-term use can lead to
neurotoxicity and neutropenia.
Therapeutic Uses of Metronidazole:
• Broad spectrum anaerobe
agent…
- Cocci
- Gram negative bacilli
- Gram positive spore-forming
bacilli
DISEASE
ANGINA
• Clinical syndrome characterised by
discomfort in the chest, jaw,
shoulder, back or arm.
• Aggravated by exertion or
emotional stress.
• Relieved by rest.
• Usually lasts less than 20 minutes.
• Most common cause is
atherosclerosis.
• Incidence increasing in all
population groups.
• Large increase in number of young
women.
• Western diet and lifestyle a
problem.
• Good prognosis.
• Left ventricular function.
• Number of coronary arteries with
significant stenosis.
• Extent of jeopardized myocardium.
Diagnosis of Angina:
• Often little on examination.
• Need to look for macrovascular
disease – diminished peripheral
pulses, bruits, etc.
• Risk factors?
• Precipitating factors:
- Anaemia
- Thyrotoxicosis
- Tachyarrhythmias
• Evidence of ischaemic changes to
the heart:
- Enlarged heart
- Signs of heart failure
- S3/S4
postmenopausal women)
• Family history
• Previous MI
Risk Stratification:
• Clinical
- Hypertension
- Diabetes
• ECG – abnormal resting ECG.
• LV dysfunction
MANAGEMENT OF ANGINA
Primary Objectives:
• To prevent MI
• To reduce symptoms in order to
improve quality of life.
Mnemonic: [ABCDEF]
• Aspirin and Anti-anginals
• Beta-blockers and BP
• Cholesterol and Cigarettes
• Diet & Diabetes
• Education & Exercise
• Follow up
ASPIRIN (75-150mg/day)
• COX inhibitor.
• Prevents platelet thromboxane
formation.
• Inhibits platelet aggregation.
• Important in preventing
atherosclerotic plaque formation.
• Helps preserve endothelial
function.
• Controlled studies make a
persuasive argument for its use in
ALL patients with stable angina,
provided there are no
contraindications (usually GIT).
NITRATES
• Potent vasodilators.
• Venodilation results in decreased
preload and venous return.
• Less myocardial oxygen required.
• Best option is sub-lingual for
angina.
• Can be used prophylactically!
• Remember postural hypotension.
• Headache common, spit out when
pain subsides.
• Paracetamol has role in some
patients for headache.
Adverse Effects: Adverse Effects: Diabetes:
• Postural hypotension (BEWARE • Impotence • Strict control prevents
VIAGRA & others) • Bronchospasm microvascular complications as
• Headache • Lethargy / decreased exercise well as accelerated
• Flushing ability atherosclerosis.
• Bradycardia / heart block
Contraindications: Obesity:
• Cold peripheries
• Hypotension • Commonly associated with angina.
RISK MODIFICATION • Contributes to other risk factors,
• Fixe output states
• Previous Viagra use, etc. e.g. hypertension, diabetes, &
Lipid Lowering:
hypercholesterolaemia.
BETA BLOCKERS • Highly beneficial role for statins. • Weight reduction improves these
• Reduces risk of MI and the need risks and reduces oxygen demand.
• All appear to be equally effective in
for revascularisation.
angina. Exercise:
• Diet must not be overlooked.
• They decrease the heart rate and
• Good trial data to support exercise.
myocardial contraction. Smoking Cessation:
• BP lowering lipid improvement
• Thereby decreasing myocardial
• Few randomised trials. occurs as a bonus!
oxygen requirements.
• However, in primary prevention
• Angina onset is delayed or FOLLOW UP
setting, smoking cessation
avoided.
decreases risk of cardiac event by
• Keep resting heart rate at 55- • Has patient’s activity decreased?
45%.
60bpm. • Have anginal symptoms changed?
• Use other healthcare workers to
• HR can be further decreased in • Is therapy tolerated?
increase rate cessation.
symptomatic patients providing no • Are modifiable risks treated?
symptoms of bradycardia. Hypertension: • Has co-morbid illness developed?
• Should be used first line if no
contraindications are present. • Beneficial effects on cardiac REFER
mortality confirmed in many trials.
Contraindications: • Poorly controlled hypertension Must refer patient if…
aggravates angina.
• Asthma • There is failure of medical therapy.
• Rational prescribing (beta
• COPD with reversibility • The diagnosis is unclear.
blockers) facilitates control of both.
• CCF? • UAP/MI.
• Heart block • CCF symptoms or sigs are
• Bradycardia (<50) present.
• Dizziness or syncopal signs.
• Poor quality of life.
• Very positive stress test.
DEPRESSION
& ANXIETY
DEPRESSION – WHO
PREVALENCE
• Globally >300 million people of all
ages suffer from depression (9%
African region vs 12% European
region).
• Higher prevalence in females than
males.
• Peak prevalence in age group 60-
64.
• Single largest contributor to global
disability, anxiety disorders ranked
6th.
• Estimated 800 000 deaths to
suicide annually.
• Suicide is 2nd leading cause of
death in 15–29-year-olds.
• Issues such as environmental
stressors (social media, stress-
related), genetic predisposition and
stigmatisation contribute.
DSM-5 DIAGNOSTIC CRITERIA
FOR DEPRESSION
• At least 5 symptoms for 2 weeks;
change from previous functioning;
at least depressed mood/loss of
interest must be present.
- Weight loss/-gain;
insomnia/hypersomnia;
psychomotor agitation/retardation;
fatigue; worthlessness/guilt;
impaired thinking/indecisiveness;
suicidal ideation.
• Symptoms cause significant clinical
impairment in functioning.
• Episode not attributed to direct
physiological effects of a
substance or underlying general
medical condition.
• The occurrence of the major
depressive episode is not better
explained by presence of
schizophrenia, delusional disorder,
or any other psychotic disorder.
• There has never been a manic or
hypomanic episode.
IDEAS FOR PATHOGENESIS OF
DEPRESSION
Normally, when a nerve impulse
arrives at a 5-HT or noradrenaline
nerve terminal the neurotransmitter is
released from the synaptic vesicle into
the synaptic cleft. Neurotransmitter
molecules bind to their specific
receptors on the post-synaptic
membrane and the nerve impulse is
propagated or inhibited, depending on
the receptor type. 5-HT and
noradrenaline molecules are then
released from their receptors and
taken back into the nerve terminal via
either the 5-HT or noradrenaline re-
uptake transporters. 5-HT and
noradrenaline are degraded by MAO
and COMT, these enzymes are found
in both the synaptic cleft and in the
nerve terminal.
Depression is a biochemically
mediated state with genetic
predisposition and is most likely
based on abnormalities in the
metabolism of 5-HT (serotonin) and
norepinephrine. The neurobiological
basis of depression is thought to
involve underactivity of central
neuronal pathways where
noradrenaline or serotonin act as
transmitters.
Monoamine Theory of Depression:
It is currently thought that
monoaminergic change is the
beginning of a molecular cascade in
depression. According to the ‘classic’
monoamine hypothesis of depression,
when there is a ‘normal’ amount of
monoamine neurotransmitter activity,
there is no depression present.
• Monoamine = an amine containing
one amino group (also called
catecholamines because they
contain a catechol group) e.g.
serotonin, dopamine, epinephrine
and norepinephrine.
• MAO = monoamine oxidase, a
copper-containing enzyme that
deaminates monoamines
• COMT = catechol-O-
methyltransferase, enzyme that
degrades catecholamines
If the amount of monoamine
neurotransmitter activity becomes
reduced/depleted/dysfunctional,
depression may ensue.
The hypothesis is that deficient
activity of monoamine NTs causes
compensatory upregulation of
postsynaptic monoamine
neurotransmitter receptors which
leads to depression.
Direct clear evidence for this
hypothesis is lacking, i.e. there is no
‘real’ monoamine deficit, and it is an
oversimplified notion about
depression. This hypothesis has
assisted however, with focusing
attention on the physiological
functioning of the 3 monoamine
neurotransmitter systems; as well as
the various mechanisms by which
antidepressants act to boost
neurotransmission.
Instead, it is now hypothesized that
molecular problem could lie within
molecular events distal to the
receptor, in the signal transduction
cascade system, and in inappropriate
gene expression (e.g. stress –
repressed gene for BDNF – atrophy
and apoptosis of vulnerable
hippocampal neurons; hippocampus
and amygdala regulates guilt,
suicidality, worthlessness, mood).
ANTIDEPRESSANT COURSE OF
ACTION
ANTIDEPRESSANTS MECHANISM
OF ACTION
There are 2 main mechanisms of
action of antidepressants:
• Blocking degradation of
neurotransmitters – monoamine
oxidase inhibitors (MAOI).
• Blocking neurotransmitter reuptake
– SSRIs, SNRIs.
ANTIDEPRESSANT DRUG
CLASSES
controversial; weak reuptake blocking TCAs
properties; metabolised to a number
of active metabolites; has no effect
on 5-HT, thus no serotonergic effect;
Effective for smoking cessation and
low weight gain potential, yet highly
epileptogenic.
MECHANISM OF POTENTIATION
OF CARDIOVASCULAR EFFECTS
OF TYRAMINE: THE CHEESE
EFFECT

Tricyclic Antidepressants (TCA): MAOI (older class of antidepressants)

Generally, patients respond within 6-8
weeks of antidepressant initiation.
This figure depicts the different time
courses for three effects of
antidepressant drugs – namely clinical
changes, NT changes and receptor
sensitivity changes. Specifically, the
amount of NT changes relatively
rapidly after antidepressant
introduction. However, clinical effect is
delayed; as is the
desensitization/downregulation of NT
receptors. Temporal correlation of
clinical effects with changes in NT
receptor sensitivity may mediate the
clinical effects of antidepressant
drugs.
use declined due to interaction with • Oldest TCA was developed in
• Amitriptyline foodstuffs and/medicines. MAO Type 1957.
• Imipramine A normally metabolises NE after re- • Effective in severe depression.
SSRIs: uptake of NE by the NET (NE
reuptake transporter) back into Mechanism of Action:
• Fluoxetine synaptic terminal. MAOI however,
All TCAs block reuptake of NE and
• Citalopram which irreversibly inhibits MAO Type
are antagonists at histamine 1, alpha
A, results in prevention of NE
SNRIs: 1 adrenergic, and muscarinic
breakdown/degradation, hence
cholinergic receptors; they also block
• Venlafaxine accumulation of NE. MAO-A inhibition
voltage-sensitive sodium channels.
• Duloxetine also prevents breakdown of tyramine
Some TCAs are also potent inhibitors
(tyramine ingested in forms of
Monoamine Oxidase Inhibitors: of the serotonin reuptake pump and
cheese). Tyramine (sympathomimetic
some may additionally be antagonists
agent) increases the release of NE.
• Selegiline at serotonin 2A and 2C receptors.
The combination can result in large
Atypical Antidepressants: accumulation of NE release with Hence, TCAs can present with
vasoconstriction and BP elevation, marked anti-cholinergic (confusion,
• Bupropion presenting with hypertensive crisis. urinary retention, blurred vision, dry
Stop MAOI, treat with IV nitrates and mouth, constipation, tachycardia);
Bupropion – NDRI – norepinephrine
beta-blocker (labetalol). anti-histaminic (sedation, weight
and dopamine reuptake inhibitor –
mechanism of action still
gain), and alpha-blocking (postural
hypotension) side-effects.
Contra-indications:
• Closed-angle glaucoma
• BPH
• MI
• Arrythmia.
Amitriptyline considered safest in
early pregnancy and can be used in
elderly.
Imipramine used for enuresis.
In Overdose:
Cardiac toxicity – sinus tachycardia
(due to anticholinergic effect,
worsened by hypotension); refractory
hypotension (alpha-1 adrenergic
receptor blockade with decreased
peripheral resistance, impaired
sodium input resulting in impaired
myocardial contractility thus
contributing to hypotension and
decreased cardiac output); cardiac
conduction abnormalities (due to
inhibition of fast sodium channels,
delayed AV conduction, risk of
arrythmias).
CNS toxicity – delirium, lethargy,
seizures, coma (inhibition of fast
sodium channels in the CNS,
antagonism of GABA A receptors,
antihistaminic effects).
SSRIs
• Discovered 1987 – thought to be
the miracle drug – fluoxetine
(prozac).
• Effective, yet no better than older
antidepressants, just slightly better
side-effect profile.
• Nowadays, citalopram and
sertraline are SSRIs of choice.
• MOA – In addition to serotonin
reuptake inhibition, fluoxetine has
NE reuptake inhibition (clinically
relevant at high doses), CYP450
2D6 and 3A4 inhibition, and
serotonin 2C antagonist actions
(activating effects).
Side Effects:
• No cardiac, no anti-cholinergic and
no antihistaminic side-effects. Yet,
sexual dysfunction (ejaculatory
dysfunction, anorgasmia) is a class
effect.
• Nausea and vomiting; energising
(not sedation) and initially
anxiogenic (start low, go slow).
• Can cause weight gain / weight
loss.
In younger age groups, TCAs used
rather than SSRIs.
Contra-indicated in
adolescents/children – may
potentiate suicidality.
SSRIs relatively safe in early
pregnancy (late pregnancy risk of
neonatal pulmonary hypertension,
apnoea, floppy syndrome).
5-HT in brain, gut and platelets –
SSRIs block serotonin uptake in
platelets, thus increased risk of
bleeding; warfarin and SSRI’s contra-
indicated.
Fluoxetine potent inhibitor of CYP2D6
– DDI’s; long t1/2 (7-10 days); taper
gradually.
SEROTONIN SYNDROME
• Syndrome due to excess serotonin.
• Very rare but can be fatal.
• Often occurs when patient on
multiple drugs that can increase
serotonin levels.
• Tx – stop all serotoninergic agents
and give benzodiazepine; also
treat symptomatically.
Signs & Symptoms:
• Neuromuscular hyperactivity:
- Tremor, sustained clonus
(pathognomonic; mostly if high
doses of SSRI’s used, if other
serotonergic agents used),
hyperreflexia, rigidity
• Altered mental state:
- Agitation, confusion
• Autonomic hyperactivity:
- Fever, sweating, tachycardia,
tachypnoea, diarrhea
Examples of serotonergic agents
include – tramadol; linezolid, St.
John’s Wort.
CHOICE OF ANTIDEPRESSANT
One anti-depressant not necessarily
better than the other, depends on –
comorbidities, age of patient,
pregnancy, etc.
Polypharmacy in the patient with
depression only, is not advocated;
monopharmacy just as effective.
Mianserin and mirtazapine:
• Tetracyclic antidepressants
• Alpha 2 antagonists.
• Not a SSRI, not a TCA.
• Unlike the tricyclic antidepressants,
it does not prevent peripheral
reuptake of NE, but releases 5-HT
and NE into the synaptic cleft.
• Free of anticholinergic side-effects
(useful in patients with prostatic
enlargement; closed-angle
glaucoma).
• Not cardiotoxic.
• No risk of OD.
• Potentially anti-histaminic side-
effect with sedation; and weight
gain.
• Serious risk of neutropenia and
agranulocytosis – do baseline and
follow-up WCC.
Venlafaxine:
• At lower doses only has serotonin
reuptake inhibition.
• At higher doses has NE reuptake
inhibition (not the case with
duloxetine, which has uptake
inhibition of both at low and high
doses).
• Thus, at lower doses, acts as
SSRI.
• Problem with venlafaxine –
discontinuation/withdrawal
syndrome; follows
interruption/reduction/discontinuati
on of drug.
• Can present with paraesthesia,
ataxia/dizziness, lethargy,
insomnia, anxiety, agitation.
• Consider drug only when patient
poorly responsive to others.
DEPRESSION VS BIPOLAR MOOD
DISORDER
Although both patients in this mood
chart are presenting with identical
current symptoms of a major
depressive episode over the past
several days, patient 1 has unipolar
depression whereas patient 2 has
bipolar depression.
So, what is the difference?
The pattern of past symptoms is quite
different; for example, patient 1 has
experienced a prior depressive
episode whereas patient 2 has
experienced a prior hypomanic
episode.
Gaining a complete picture may often
require additional interviews with
family members or close friends of the
patient.
Who’s your daddy approach – family
history of mood disorders, psychiatric
hospitalisation, suicide, use of lithium,
mood stabilisers, antipsychotics,
antidepressants with poor response.
Where’s your mama – additional
history from collateral close to you,
patients may especially lack insight
about their manic symptoms and
underreport them.
Strong genetic link, if both parents
have bipolar, 50-75% risk child could
inherit it. One parent with bipolar, 25%
risk.
BIPOLAR MOOD DISORDER
Treatment-response history,
particularly prior response to
antidepressants, may provide insight
into whether depression is unipolar or
bipolar. Prior responses that suggest
bipolar depression may include
multiple antidepressant failures, rapid
responses to an antidepressant, and
activating side-effects such as
insomnia, agitation, and anxiety.
Bipolar type 1 is defined as the
occurrence of at least one manic or
mixed (full mania and full depression
simultaneously) episode. Patients with
bipolar disorder 1 typically experience
major depressive episodes as well,
although this is not necessary for
bipolar 1 diagnosis.
Bipolar type 2 disorder is defined as
an illness course consisting of one of
more major depressive episodes and
at least one hypomanic episode.
SYMPTOM DIMENSIONS OF MANIC
EPISODE
Symptoms Necessary for Diagnosis:
• Elevated/expansive mood.
• Irritable mood.
Plus three or more of these (4 if mood
is only irritable):
• Inflated self-esteem / grandiosity.
• Increased goal-directed activity or
agitation.
• Risk taking.
• Decreased need for sleep.
• Distractible / concentration.
• More talkative pressured speech.
• Flight of ideas / racing thoughts.
These are the symptoms of mania as
designated by the DSM-IV.
According to these criteria, diagnosis
of a manic episode requires at least
one of the symptoms in the top row as
well as at least three of the symptoms
in the bottom two rows. Four of the
symptoms in the bottom two rows are
required if the mood is only irritable.
Mania which occurs in lesser degrees,
referred to as hypomania.
APPROACH TO MANAGEMENT OF
BMD
• Advocate for polypharmacy in
BMD…
- Mood stabiliser +
antidepressant.
- Treat frequency and
amplitude.
- Monotherapy with
antidepressant may precipitate
manic episode.
• Lithium – Drug of Choice!
• Anticonvulsants (sodium valproate
and carbamazepine) are less
effective.
• Sodium valproate is also
teratogenic (contraindicated in
pregnancy).
• Lamotrigine is effective in bipolar
depression, BUT! Caution with
lamotrigine – if dose-escalation
exceeded, risk of life-threatening
rash (SJS, TEN). Start low and go
slow, follow dosing
recommendations.
LITHIUM – MOOD STABILISER
• Specific mechanism of action in
mania is unknown.
• Has a narrow therapeutic index.
Therefore requires TDM (6
monthly), and annual serum
creatinine and TSH monitoring.
• Lithium usually required lifelong.
• TDM is essential when using
lithium.
• Clinical toxicity may occur even
within therapeutic range.
• Depression may mask
hypothyroidism and unnecessary
addition of thyroxin)
• Pregnancy – not teratogenic, yet
early U/S required at 16 weeks,
controversial issue of ebstein’s
anomaly (heart defect affecting
tricuspid valve).
• Concomitant use of medicines, e.g.
NSAIDS (anti-prostaglandins
reduce blood supply to the kidneys,
lithium is renally excreted), thiazide
diuretics, ACE-I, may increase the
risk of toxicity.
Lithium Toxicity:
• Neurotoxic (convulsions, ataxia),
nephrotoxic (80% renal
elimination), thyrotoxic.
Adverse Effects:
• Neutrophilia, weight gain,
polydipsia and polyuria.
• Not teratogenic.
Be aware of drug-drug interactions.
REFERRAL TO PSYCHIATRY
Necessary if…
• Suicidal ideation.
• Severe depression.
• Impairment of daily function.
• If poor response to intervention.
OVERLAP OF MMD & ANXIETY
DISORDERS
Anxiety and depression often co-exist.
Anxiety is debilitating.
Although the core symptoms of
anxiety disorders (anxiety and worry)
differ from the core symptoms of
major depression (loss of interest and
depressed mood), there is
considerable overlap among the rest
of the symptoms associated with
these disorders (compare the “anxiety
disorders” puzzle on the right to the
“MDD” puzzle on the left). For
example, fatigue, sleep difficulties,
and problems concentrating are
common to both types of disorders.
ANXIETY
Common Anxiety Signs & Symptoms:
• Feeling nervous
• Having a sense of impending
danger, panic, or doom.
• Palpitations.
• Hyperventilation
• Sweating
• Tremor
• Feeling weak or tired
• Trouble concentrating or thinking
about anything other than the
present worry/overthinking.
Anxiety may be secondary to an
organic disease (e.g. acute MI), or
may be situational (e.g. family death).
DSM V Disorders:
• GAD
• PTSD
• OCD
• Panic disorder
TYPES OF ANXIETY DISORDERS
• Separation anxiety disorder
is a childhood disorder
characterized by anxiety that
is excessive for the
developmental level and
related to separation from
parents or others who have
parental roles.
• Selective mutism is a
consistent failure to speak in
certain situations, such as
school, even when you can
speak in other situations, such
as at home with close family
members. This can interfere
with school, work and social
functioning.
• Specific phobias are
characterized by major anxiety
when you're exposed to a
specific object or situation and
a desire to avoid it. Phobias
provoke panic attacks in some
people.
• Social anxiety disorder
(social phobia) involves high
levels of anxiety, fear and
avoidance of social situations
due to feelings of
embarrassment, self-
consciousness and concern
about being judged or viewed
negatively by others.
• Panic disorder involves
repeated episodes of sudden
feelings of intense anxiety and
fear or terror that reach a peak
within minutes (panic attacks).
You may have feelings of
impending doom, shortness of
breath, heart palpitations or
chest pain.
• Agoraphobia is anxiety about,
and often avoidance of, places
or situations where you might
feel trapped or helpless if you
start to feel panicky or
experience embarrassing
symptoms, such as losing
control.
• Generalized anxiety disorder
includes persistent and
excessive anxiety and worry
about activities or events —
even ordinary, routine issues.
The worry is usually out of
proportion to the actual
circumstance, is difficult to
control and interferes with your
ability to focus on current
tasks. It often occurs along
with other anxiety disorders or
depression.
• Substance-induced anxiety
disorder is characterized by
prominent symptoms of
anxiety or panic that are a
direct result of abusing drugs,
taking medications, being
exposed to a toxic substance
or withdrawal from drugs.
• Anxiety disorder due to a
medical condition includes
prominent symptoms of
anxiety or panic that are
directly caused by a physical
health problem.
• Specified anxiety disorder
and unspecified anxiety
disorder are terms for anxiety
or phobias that don't meet the
exact criteria for any other
anxiety disorders but are
significant enough to be
distressing and disruptive.
APPROACH TO MANAGEMENT OF
ANXIETY
• Aim to treat – first try with
psychotherapy, not
pharmacotherapy.
Benzodiazepines:
• Mainstay in the past, yet high
dependency rate.
• Role in acute setting, not chronic.
• Relatively safe in overdose.
• Causes CNS depression.
• Contra-indicated with alcohol use.
BENZODIAZEPINES
Gamma-amino butyric acid (GABA):
• Key neurotransmitter involved in
anxiety and anxiolytic action of
drugs.
• Principal inhibitory neurotransmitter
in the brain.
• Serves regulatory role in reducing
activity of neurons in amygdala.
MOA – Benzodiazepines enhance
action of GABA:
• Reduce neuronal depolarization,
resulting in decreased action
potentials.
• Bind to A-type GABA receptors
with opening of membrane
channels and allowing entry of
chloride ions.
All will terminate seizures (status
epilepticus).
Other indications (other than anxiety
and seizures) include:
• Treatment of alcohol withdrawal
states / delirium tremens.
• Muscle spasms
• Tetanus
• Acute psychotic states
• Serotonin syndrome
In Overdose:
• Respiratory depression
• Coma
Flumazenil:
• Antidote
• Shorter half life than
benzodiazepines.
• Can be used for diagnosis of
benzodiazepine overdose.
CHOICE OF BENZODIAZEPINES
Psychiatry patients more prone to
develop dependency versus patients
on benzodiazepines for pain/muscle
spasms.
Tolerance – increasing
ineffectiveness of therapy. The longer
the duration of action, the more
tolerance is likely to develop. Thus
effectively turns into balancing act
between duration of action and
avoidance of tolerance.
Possible that NMDA receptors are
• WHO - There are effective
involved in tolerance to effects of
benzodiazepines. Continued use
seems to be associated with
avoidance of unpleasant withdrawal
reaction rather than from the
pleasurable effects of the drug.
NON-DRUG MEASURES ARE
IMPORTANT
• Psychotherapy / counselling before
drugs.
• If long term treatment needed,
consider SSRI/TCA…
- Not benzodiazepines
- OCD
- Panic disorders
- PTSD
• Long duration drugs better than
short acting drugs due to the issue
of tolerance.
• Pharmacotherapy not always first
option. Response rate to
medication 60-70 %. Remission
rate about 30-40%. Placebo rate
about 40-50% - enhance placebo
effect (beneficial effect of treatment
produced by the placebo drug, due
to the patient’s belief in the
treatment; effect cannot be
attributed to the properties of the
drug itself). ECT best
antidepressant, not sustainable.
When to stop? At least to treat for
6 months, then gradual cessation.
treatments for moderate and
severe depression. Health-care
providers may offer psychological
treatments (such as behavioural
activation, cognitive behavioural
therapy [CBT], and interpersonal
psychotherapy [IPT]) or
antidepressant medication (such
as selective serotonin reuptake
inhibitors [SSRIs] and tricyclic
antidepressants [TCAs]). Health-
care providers should keep in mind
the possible adverse effects
associated with antidepressant
medication, the ability to deliver
either intervention (in terms of
expertise, and/or treatment
availability), and individual
preferences. Different
psychological treatment formats for
consideration include individual
and/or group face-to-face
psychological treatments delivered
by professionals and supervised
lay therapists.
• Psychosocial treatments are also
effective for mild depression.
Antidepressants can be an
effective form of treatment for
moderate-severe depression but
are not the first line of treatment for
cases of mild depression. They
should not be used for treating
depression in children and are not
the first line of treatment in
adolescents, among whom they
should be used with extra caution.
AUTONOMIC
NERVOUS
SYSTEM
ORGANISATION OF THE ANS
The nervous system is divided into
two anatomical divisions: the central
nervous system (CNS), which is
composed of the brain and spinal
cord, and the peripheral nervous
system, which includes neurons
located outside the brain and spinal
cord—that is, any nerves that enter or
leave the CNS.
The peripheral nervous system is
subdivided into the efferent (E for
Exit) and afferent divisions. The
efferent neurons carry signals away
from the brain and spinal cord to the
peripheral tissues, and the afferent
neurons bring information from the
periphery to the CNS.
Afferent neurons provide sensory
input to modulate the function of the
efferent division through reflex arcs or
neural pathways that mediate a reflex
action.
The efferent portion of the
peripheral nervous system is
further divided into two major
functional subdivisions: the somatic
and the ANS. The somatic efferent
neurons are involved in the voluntary
control of functions such as
contraction of the skeletal muscles
essential for locomotion.
The ANS, conversely, regulates the
everyday requirements of vital bodily
functions without the conscious
participation of the mind.
Because of the involuntary nature of
the ANS as well as its functions, it is
also known as the visceral,
vegetative, or involuntary nervous
system. It is composed of efferent
neurons that innervate smooth muscle
of the viscera, cardiac muscle,
vasculature, and the exocrine glands,
thereby controlling digestion, cardiac
output, blood flow, and glandular
secretions.
DIVISIONS OF THE ANS
Anatomically, the sympathetic and the
parasympathetic neurons originate in
the CNS and emerge from two
different spinal cord regions.
The changes experienced by the body
during emergencies are referred to as
the “fight or flight” response.
The parasympathetic preganglionic
motor fibres originate from cranial
nerve nuclei 111, VII,IX and X AND
sacral segment of the spinal cord
The sympathetic preganglionic fibres
originate in the thoracic ( T1 to T12)
and Lumbar ( L1-L5) segments of the
spinal cord.
ANATOMY OF THE ANS
1. Efferent neurons: The ANS carries
nerve impulses from the CNS to the
effector organs by way of two types of
efferent neurons: the preganglionic
neurons and the postganglionic
neurons. The cell body of the first
nerve cell, the preganglionic neuron,
is located within the CNS. The
preganglionic neurons emerge from
the brainstem or spinal cord and
make a synaptic connection in
ganglia (an aggregation of nerve cell
bodies located in the peripheral
nervous system). The ganglia function
as relay stations between the
preganglionic neuron and the second
nerve cell, the postganglionic neuron.
The cell body of the postganglionic
neuron originates in the ganglion. It is
generally nonmyelinated and
terminates on effector organs, such
as smooth muscles of the viscera,
cardiac muscle, and the exocrine
glands.
2. Afferent neurons: The afferent
neurons (fibers) of the ANS are
important in the reflex regulation of
this system (for example, by sensing
pressure in the carotid sinus and
aortic arch) and in signaling the CNS
to influence the efferent branch of the
system to respond.
TRANSMISSION IN THE ANS
Basic steps and site of drug actions:
• Synthesis of a transmitter.
• Storage of a transmitter.
• Release of a transmitter.
• Interaction of a transmitter with
receptor on the effector cells.
• Removal/degradation/recycling
transmitters.
Neurotransmission in the ANS is an
example of the more general process
of chemical signalling between cells.
In addition to neurotransmission,
other types of chemical signalling
include the secretion of hormones
and the release of local mediators.
A. Hormones
Specialized endocrine cells secrete
hormones into the bloodstream,
where they travel throughout the
body, exerting effects on broadly
distributed target cells.
B. Local mediators
Most cells in the body secrete
chemicals that act locally on cells in
the immediate environment. Because
these chemical signals are rapidly
destroyed or removed, they do not
enter the blood and are not distributed
throughout the body. Histamine and
the prostaglandins are examples of
local mediators.
The synthesis, storage, release,
receptor interactions, and termination
of action of the neurotransmitters all
contribute to the action of autonomic
drugs.
NEUROTRANSMITTERS
1. Acetylcholine
• Preganglionic
• Postganglionic parasympathetic
• (Postganglionic Sympathetic in
arterioles and sweat glands)
2. Noradrenaline / adrenaline
• Postganglionic sympathetic
3. Non-ACh/Non-Adrenergic
• e.g. serotonin, dopamine, GABA,
histamine, nitric oxide.
Types of neurotransmitters:
Although over 50 signal molecules in
the nervous system have been
identified, norepinephrine (and the
closely related epinephrine),
dopamine, (most common examples
of catecholamines functioning as
neurotransmitters in a stress
response)acetylcholine, serotonin,
histamine, glutamate, and γ-
aminobutyric acid are most commonly
involved in the actions of
therapeutically useful drugs. Each of
these chemical signals binds to a
specific family of receptors.
Acetylcholine and norepinephrine are
the primary chemical signals in the
ANS, whereas a wide variety of
neurotransmitters function in the CNS.
a. Acetylcholine:
The autonomic nerve fibres can be
divided into two groups based on the
type of neurotransmitter released. If
transmission is mediated by
acetylcholine, the neuron is termed
Cholinergic.
Acetylcholine mediates the
transmission of nerve impulses across
autonomic ganglia in both the
sympathetic and parasympathetic
nervous systems. It is the
neurotransmitter at the adrenal
medulla.
Transmission from the autonomic
postganglionic nerves to the effector
organs in the parasympathetic
system, and a few sympathetic
system organs, also involves the
release of acetylcholine. In the
somatic nervous system, transmission
at the neuromuscular junction (the
junction of nerve fibres and voluntary
muscles) is also cholinergic.
b. Norepinephrine and epinephrine:
When norepinephrine and
epinephrine are the neurotransmitters,
the fiber is termed Adrenergic.
In the sympathetic system,
norepinephrine mediates the
transmission of nerve impulses from
autonomic postganglionic nerves to
effector organs.
So knowing the identity and synaptic
distribution of neurotransmitters can
offer insight into the therapeutic action
or adverse effects of a drug, which
can often be predicted.
To summarise – ACh is the
neurotransmitter at NMJ,
preganglionic synapses (sympathetic
and para), and postganglionic
parasympathetic synapses. NE/NA, is
the neurotransmitter at most
postganglionic sympathetic synapses.
Drugs that mimic or potentiate NE,
produce sympathetic effects that
resemble fight or flight responses
such as increased heart rate.
Drugs that mimic or potentiate Ach,
produce parasympathetic effects such
as decreased heartrate.
ACETYLCHOLINE
Synthesis of acetylcholine:
ACh is synthesised from a precursor,
Choline and acetyl-CoA by the
enzyme acetyltransferase. Choline is
derived from the diet. ACh breakdown
or synthesised by the liver and
transported into nerve terminal by a
high affinity Na- choline co-
transporter. Acetylcholine synthesis
may be reduced by hemicholinium, a
neuronal choline transporter inhibitor.
Storage of acetylcholine:
Once synthesised, ACh is transported
by vesicle transporter to be stored in
vesicles. The Ach vesicular
transporter can be inhibited by
vesamicol.
Acetylcholine in vesicles is released
into synaptic cleft by Ca- dependent
exocytosis.
The action of acetylcholine in the
synapse is normally terminated by
metabolism to acetate and choline by
the enzyme acetylcholinesterase in
the synaptic cleft.
Blockade of cholinesterase enzymes
result in increased autonomic activity
but primary with increased cholinergic
effects.
At postganglionic nerve terminal with
increased stimulation of muscarinic
receptors, enhancing synaptic
cholinergic activity, causing excessive
salivation, bradycardia,
bronchospasm and hypotension.
By increasing NMJ activity with
muscle fasciculation and twitching
and may result in a depolarisation
block and paralysis.
Effects of Inhibiting ACh Vesicular
Release Into the Synapse:
• inhibition of sweating, giving
symptoms of a dry, warm skin.
• Inhibition of salivation with Dopa is rapidly converted to
symptoms of dry mouth. dopamine by the enzyme dopa
• Pupillary dilatation. decarboxylase.
• Inhibition of vesicular release at the
In dopaminergic neurons this is the
neuromuscular junction would lead
end of the synthetic pathway.
to muscle paralysis, e.g.
streptomycin, neomycin. In sympathetic neurons dopamine is
• Botulinum poisoning causes formed in the cytoplasm of the nerve
parasympathetic paralysis with terminal is actively transported by
symptoms of a dry mouth and vesicle transporter into the storage
blurring of vision. vesicle, where it is converted to
• Beta-bungarotoxin is contained in norepinephrine by the enzyme
venoms of variety of cobras and dopamine beta-hydroxylase.
black window spider has similar
Norepinephrine storage:
effects to botulism.
Cytoplasmic dopamine is actively
NOREPINEPHRINE taken into vesicles by a vesicular
transporter and converted to
Norepinephrine is the primary
norepinephrine. Inhibition of the
transmitter at the sympathetic
vesicular transporter leads to the
postganglionic neuron-effector cell
depletion of NE stores.
synapses in most tissues.
Reserpine binds to the vesicular
Norepinephrine is synthesised from L-
transporter with a slow rate of
tyrosine in adrenergic neurons.
dissociation and prolonged duration of
Tyrosine is converted to dopa action.
(levodopa) by the enzyme tyrosine
hydrolase.
The activity of tyrosine hydrolase is
rate limiting for catecholamine
synthesis. These changes in the
synthesis and function of tyrosine
hydrolase, in response to the neural
activity serves to maintain the rate of
synthesis of norepinephrine relative to
the requirement for the transmitter.

RECEPTORS IN THE ANS
All neurotransmitters, and most
hormones and local mediators, are
too hydrophilic to penetrate the lipid
bilayers of target cell plasma
membranes. Instead, their signal is
mediated by binding to specific
receptors on the cell surface of target
organs.
Acetylcholine receptors
(cholinoreceptors) are divided into two
major types - nicotinic and
muscarinic subtypes, each having
several subtypes. nAChRs are
ligand-gated ion channels and
mAChRs are GPCRs. The receptors
were named on the basis of selective
actions of nicotine and muscarine
(from the mushroom Amanita
muscaria).
Adrenergic receptors (adrenoceptors)
are classified into two major types,
alfa and beta, each with multiple
subtypes that differ in terms of
their mechanism of signal
transduction (e.g. increased or
decreased cAMP).
All adrenoceptors are 7-
transmembrane GPCRs: they cross
the cell membrane 7 times and are
coupled to a G protein (guanine
nucleotide-binding protein). When an
agonist binds to a GPCR, it enhances
the association of a receptor with a G-
protein, which then stimulates (e.g.
Gs) or inhibits (e.g. Gi), a step in the
2nd messenger pathway, such as
adenylyl cyclase, phospholipase C, or
an ion channel. The same adrenergic
agonist (e.g. epinephrine/NE or a
drug) can produce various effects
depending on the G protein coupling
in a cell. Effects of receptor activation
include muscle contraction (alfa1,
alfa2), and muscle relaxation (alfa1,
alfa2, beta2), increased heartrate and
force (beta1) and lipolysis and
thermogenesis (beta3).
With drug agonists mimicking the
actions of the neurotransmitters at the
synapses/NMJ and antagonists
inhibiting these actions.
Cholinergic Receptors:
M1: gastric parietal cells
M2: heart
M3: glands, smooth muscle
N: autonomic ganglia, adrenal
medulla, NMJunction
Adrenergic Receptors:
α1: postsynaptic neurons
α2: mainly presynaptic neurons
(autoceptors)
β1: heart; intestinal smooth muscle
β2: bronchial, vascular and uterine CHOLINERGIC DRUGS
smooth muscle
DIRECT ACTING
Β3: Fat cells
Choline Esters:
THE PARASYMPATHETIC SYSTEM • Acetylcholine
• Methacholine
The parasympathetic preganglionic
• Bethanechol
fibres arise from cranial nerves III
(oculomotor), VII (facial), IX Natural Alkaloids:
(glossopharyngeal), and X (vagus), as • Muscarine
well as from the sacral region (S2 to • Pilocarpine
S4) of the spinal cord and synapse in • Arecoline
ganglia near or on the effector organs.
[Note: The vagus nerve accounts for
90% of preganglionic parasympathetic
fibres in the body. Postganglionic
neurons from this nerve innervate
most of the organs in the thoracic and
abdominal cavity.]
 INDIRECT ACTING Choline Esters: • Carbamate esters Neostigmine Pilocarpine reduce IOP by
(anticholinesterase agents) and pyridostigmine undergo two contracting the ciliary muscle. This
• Bethanechol is a quaternary pulls the sclera spur and result in the
step process.
Irreversible Anticholinesterase compound that does not penetrate trabecular meshwork being stretched
Agents: the blood brain barrier. Its action GLAUCOMA and separated. The fluid pathways
• Organo-phosphorus compounds are much more prolonged than that are opened up and aqueous outflow is
- Disopropyl of ACH because it is not Glaucoma occurs in about 1 % of increased.
phosphorofluoridate (DFP) hydrolysed by cholinesterase people over 40 years of age. Viewed
- Malathion through an ophthalmoscope, the optic All parasympathomimetic causes
- Parathion Natural Alkaloid: disc appears depressed (cupping) miosis.
- Tabun because of the loss of nerve fibres.
• Pilocarpine used in closed-angle Drugs that reduce IOP by decreasing
- Sarin The mechanism by which the nerve
glaucoma.
• Carbamates fibres are destroyed in glaucoma is
aqueous secretion.
- Carbaryl (Sevin®) Anticholinesterases:
- Propoxur (Baygon®)
still unclear. • Timolol a beta blocker, it block B-2
• These are indirectly acting Open angle glaucoma is the most receptors on the ciliary processes
cholinomimetics common form of the disease. At and reduce aqueous production.
Reversible Anticholinesterase • The commonly used present lowering the intra-ocular They may block vessels supplying
Agents: anticholinesterases are quaternary pressure is the only treatment. the ciliary processes. The resulting
• Neostigmine compounds that do not pass the vasoconstriction produces reduced
• Physostigmine (eserine) blood-brain barrier and have Generally, the aim is to use topical ultrafiltration and aqueous
• Pyridostigmine negligible central effects. drugs or if they fail, surgery to reduce formation.
• Edrophonium IOP. • Brimonidine alpha 2 adrenoceptor
• Demecarium Mechanism of action: agonists, they decrease aqueous
• Ambenonium In closed-angle glaucoma, the angle
by stimulating alpha 2
• Initially, acetylcholine binds to the between cornea and Iris is abnormally
adrenoceptors on the adrenergic
active site of the esterase and is small. Occasionally the angle closes
nerve terminal innervating the
hydrolysed, producing free choline completely, preventing aqueous flow
Drugs with acetylcholine-like effects ciliary body.
and acetylated enzyme. In second and the IOP rises. Because
(Cholinomimetics) consists of two step the covalent acetyl-enzyme permanent damage can occur during
groups: bond split with the addition of these attacks, pressure must be
water. reduced as quickly as possible.
• Acetylcholine may be considered
• Edrophonium is the main example
a prototype that acts directly at The heavy blue line illustrates the flow
of a reversible anticholinesterase.
both muscarinic and nicotinic of aqueous humor from its secretion
It binds by electrostatic forces to
receptors. by the ciliary epithelium to its drainage
the active site of the enzyme. It
• Neostigmine is a prototype for the though chanel of Schlemm.
does not form covalent bonds with
indirect-acting cholinesterase
the enzyme.
inhibitors.

MYASTHENIA GRAVIS
Myasthenia Gravis is characterized
by progressive weakening of skeletal
muscles. It preferentially affects
women and can be lethal if untreated.
Symptoms are caused by an
autoimmune-induced decrease (70-
90%) in the number of nAChRs at the
NMJ. Ptosis and weakness of smile
are common early signs.
In early stages of disease, AChE
inhibitors such as edrophonium
produce a rapid recovery of
function, which is diagnostic and
can be continued for therapy. Adverse
effects of AChE inhibitors are those of
excess ACh, known as DUMBELS:
diarrhea, urination, miosis,
bronchoconstriction, excitation,
lacrimation, salivation and sweating.
Neostigmine and Pyridostigmine
tend to affect neuromuscular
transmission more than autonomic
system. They are used to treat
Myasthenia gravis.
?Cholinesterase Inhibitors
CHOLINOCEPTOR BLOCKERS &
CHOLINESTERASE
REGENERATORS
ANTICHOLINERGIC DRUGS
Antimuscarinic:
• Pirenzepine (M1-selective)
• Atropine (nonselective)
Antinicotinic:
• Hexamethonium (ganglion
blocker)
• Tubocurarine (neuromuscular
blocker)
CHOLINESTERASE
REGENERATORS
• Oximes (e.g. pralidoxime)
CHOLINERGIC ANTAGONISTS
Atropine:
• Muscarinic antagonist.
• Tertiary amine with competitive
binding to muscarinic receptors.
• Treatment of organophosphate
poisoning.
• Antispasmodic, antisecretory, The preganglionic neurons of the
mydriasis and cycloplegic. sympathetic system come from the
thoracic and lumbar regions (T1 to
Glycopyrrolate: L2) of the spinal cord, and they
• Antimuscarinic/bronchodilator. synapse in two cord-like chains of
• Used for reversal of neuromuscular ganglia that run close to and in
blockade. parallel on each side of the spinal
• Quaternary amine, preoperative cord.
medication. Nerves arising from the lateral horn of
• Ophthalmology to produce the spinal cord are those of the
mydriasis and cycloplegia. autonomic nervous system. They exit
through the ventral root of the spinal
Ipratropium:
cord, and continue through the ventral
• Used in Asthma/COPD. rami. At that point, they sharply
• Anticholinergic/bronchodilator/ branch to go through the white ramus
nasal agent. communicans of the paravertebral
body.
Oxybutynin:
• Antimuscarinic/ urinary
antispasmodic.
• Urge incontinence.
• Post-operative urinary spasms.
Muscarinic antagonists such as
Atropine (derived from Atropa
Belladonna) and Scopolamine, have
the opposite effects, i.e. increase
heartrate, mydriasis.
Nicotinic agonists such as
succinylcholine stimulate, and
Nicotine receptor antagonists such as
Pancuronium, inhibit skeletal muscle
contraction.
SYMPATHETIC SYSTEM
SYMPATHOMIMETIC DRUGS SOME USES FOR INDIRECTLY ACTING
Others: SYMPATHOMIMETICS SYMPATHOMIMETICS:
• Oxymetazoline AMPHETAMINE
• Xylometazoline • Phenylephrine (a1 agonist) –
DIRECT ACTING: • Naphazoline Amphetamine is a CNS Stimulant and
topical to eye for mydriasis and
CATECHOLAMINES
nasal decongestant. indirectly acting sympathomimetic.
Endogenous: Sympathomimetics constitute a very • Clonidine (a2 agonist) – anxiolytic,
Amphetamine increases the release
• DA, E, NE important group of drugs used for sedation, antihypertensive.
of norepinephrine, dopamine and
cardiovascular, respiratory and other • Methyldopa (a2 agonist) –
serotonin from the nerve terminal.
Synthetic: conditions. hypertension (for pregnant
• Isoprenaline (b1, b2) women). Primary mechanism:
• Dobutamine (b1) They are divided into sub-groups on • Oxymetazoline (a2 agonist) – nasal
Amphetamines bind to presynaptic
• Isoetharine the basis of their spectrum of action ( decongestant.
membrane transporters responsible
• Prenalterol ALPHA or Beta receptors) or mode of • Dobutamine (b1 agonist) – mild a1
action ( direct or indirect).. for the reuptake of norepinephrine (
properties and greater inotropic
NET), dopamine ( DAT) and serotonin
Sympathomimetics agonists may than chronotropic effect; augment
( SERT).
directly activate their adrenoceptors sympathetic innervation of the
DIRECT ACTING: NON-
CATECHOLAMINES OR they may act indirectly to increase heart and are used as cardiac Uptake of amphetamine resulting in
concentration of endogenous stimulants. efflux of these monoamines from the
a1 Agonists: catecholamine transmitter in the • Salbutamol,, formoterol, salmeterol cytoplasmic pool into extracellular
• Methoxamine synapse. (LABA) – asthma, pre-term labour. space.
• Phenylephrine
Amphetamine derivatives and Epinephrine uses: Amphetamine causes the intracellular
tyramine causes the release of the vesicular release of catecholamines
a2 Agonists: • Adjuvant of local anaesthesia within the nerve terminal causing
• Clonidine stored catecholamines indirect mode (topical)
• Methyldopa of action. redistribution of monoamines from the
• Bleeding (topical) storage vesicles into the cytoplasmic
• Apraclonidine • Glaucoma (topical)
Cocaine and tricyclic antidepressants pool.
• Guanfacine
exhibit another form of indirect action. • Cardiac arrest (systematic use)
• Guanabenz The will be release of NE in the
• Anaphylactic shock (systematic
These drugs inhibit the reuptake of use) synaptic junction.
b2 Agonists: catecholamines by the NET, THUS
• Terbutaline • Acute bronchial asthma
increases synaptic activity of the (systematic use)
• Albuterol released transmitter.
• Fenoterol
• Pirbuterol
• Procaterol (long acting)
• Salmeterol (long acting)
 expression of MAO in the GUT tract A2-selective: SOME USES FOR ADRENERGIC
and liver. When MAO is inhibited, high • Yohimbine ANTAGONISTS
level of tyramine is absorbed,
resulting in a “Hypertensive crisis” due • Doxazosin (selective a1 blocker) –
to the release of NE from nerve BETA RECEPTOR
hypertension, BPH).
ANTAGONISTS
terminals. • Propranolol (non-selective &
Non-selective [first generation]: lipophilic b-blocker) – hypertension,
• Nadolol migraine, hyperthyroidism, angina
• Penbutolol pectoris, MI.
• Pindolol • Atenolol (selective b1 blocker) –
• Propranolol IHD & hypertension.
INDIRECTLY ACTING • Timolol • Carvedilol (blocks both a & b) –
SYMPATHOMIMETICS: TYRAMINE • Sotalol hypertension, congestive HF.
• Levobunolol • Labetalol (blocks both a & b) –
Tyramine is an indirectly acting • Metipranolol hypertensive crisis. Adverse effects
sympathomimetic ( a by-product of include vasoconstriction,
tyrosine metabolism). B1-selective [second vasodilatation, and tachycardia.
generation]: • Timolol – glaucoma, hypertension.
Mechanism of action: ADRENERGIC RECEPTOR • Acebutolol
ANTAGONISTS • Atenolol

MALARIA
Tyramine is taken up into nerve
terminals by NET ( the norepinephrine • Bisoprolol
ALPHA RECEPTOR
reuptake transporter) and causes the • Esmolol
ANTAGONISTS
release of catecholamines. It is • Metoprolol
because of the reverse transport of
NET.
Non-selective:
• Phenoxybenzamine
• Phentolamine
Non-selective [third generation]:
• Carteolol
PREVENTION
The effects of tyramine are increased • Carvedilol
in the presence of MAO inhibitors.
A1-selective: • Bucindolol THE ABCs OF MALARIA
MAO present in the nerve terminals
• Prazosin • Labetalol PREVENTION
metabolises both cytosolic amines
• Terazosin A – Awareness & Assessment of
such as NE as well as Tyramine B1-selective [third generation]:
• Doxazosin
converting them into inactive • Betaxolol malaria risk.
• Alfuzosin
metabolites. • Celiprolol
• Tamsulosin B – avoid mosquito Bites.
• Nebivolol
Normally the bioavailability of dietary • Indoramin
• Urapidil C – Compliance with
tyramine (present in red wine and
• Bunazosin Chemoprophylaxis, if indicated.
cheese) is relatively low due to the
D – Don’t Delay malaria Diagnosis. doxycycline, should be used; in CHEMOPROPHYLAXIS OPTIONS (potential DI);
addition to non-drug measure from epilepsy pts;
Early, Effective treatment. High P. falciparum protective efficacy psychiatric
September to May.
(if adherent)… conditions
AWAREMESS & ASSESSMENT OF RISK:BENEFIT ASSESSMENT
MALARIA RISK • Atovaquone-proguanil
Always use non-drug measures: • Doxycycline DOXYCYCLINE
• How?
• Mefloquine
• Where? • Remain indoors between dusk and
dawn. NB! Always use non-drug measures
• Wear long, light coloured clothing. to avoid mosquito bites. Examples Doxymal ®
Cyclidox ®
• Screen doorways and windows.
ATOVAQUONE-PROGUANIL Doxytab ®
• Apply a DEET-containing repellent Doxycycl ®
(repeat every 4-6 hours if Frequency Daily
outdoors). Start 1-2 days before
• Use mosquito mats and coils. Examples Malanil ® travel
• Use (long-lasting) insecticide- Malateq ® Continue 4 weeks after
• When? treated bed nets & IRS sprayed Mozitec ® until leaving malaria area
• Who? accommodation. Frequency Daily ADRs Photosensitivity;
• Spray aerosol insecticide. Start 1-2 days before oesophageal
- Travelers – 80% took no
travel ulceration; GIT
prophylaxis, and of those that took • Use ceiling fans / air conditioner.
Continue 7 days after leaving symptoms; candida
prophylaxis, only 25% took it • Do not apply insect repellent to
until malaria area super-infection
appropriately; most common travel face, lips, eyes, sun-burnt, or ADRs Well tolerated; (GIT/vaginal)
destination = Mozambique. damaged skin. headache; Special Take with water /
- People living in endemic areas abdominal pain precautions food for better
DEET-Containing Products:
– in SA, mainly Limpopo and Special Take with water / absorption
Mpumalanga (northern KZN) • Recommended strength – 20-50%. precautions food for better Contra- Pregnancy; diabetics
- NB to be aware of high risk absorption indications (incr. insulin-related
groups. Contra- Pregnancy; hypoglyc.)
indications renal/hepatic Safe to use Breastfeeding moms
impairment for… (?if short trip);
(GFR<30) children over 8;
• Only non-drug measures
Safe to use Diabetics; HIV+; epilepsy pts;
recommended from September to
for… breastfeeding moms psychiatric
May. (?CDC if >5kg conditions (some
• Where malaria chemoprophylaxis baby); children DI); renal/hepatic
is indicated; mefloquine, OR (>11kg); HIV+ impairment
atovaquone-proguanil, OR
MEFLOQUINE • Activities – e.g. scuba diving, PATIENT COUNSELLING Adequate pharmacological treatment:
flying. (GENERAL)
• Dyslipidaemia
• Concomitant medication, e.g.
• Take measure to prevent being • Hypertension
ARVs, rifampicin, chloroquine,
Examples Lariam ®
doxycycline (e.g. for acne), bitten by mosquitos. • Primary cardiovascular prevention
Mefliam ® in higher risk patients
anticoagulants, antimalarial allergy. • Take dose at same time every day
Frequency Weekly • Pharmacological treatment of
Start 1-2 weeks before • Other medical conditions, e.g. / same day every week.
epilepsy, mental health problems, • If you miss a dose, take it as soon hyperglycaemia
travel
Continue 4 weeks after diabetes, cardiac patients, as possible and carry on as before.
TYPE 1 DIABETES – INSULIN
until leaving malaria area myasthenia gravis, renal / hepatic • If vomiting occurs within one hour THERAPY
ADRs Nausea; strange impairment. of taking the dose, repeat it.
dreams; dizziness; • Report any adverse effects that Insulin is the sole therapy for type 1
mood changes; CHEMOPROPHYLAXIS OPTIONS occur. DM. It is also used (combination
insomnia; headache; THAT ARE NOT !!! • Get a malaria test within 24 hours if therapy or monotherapy) in type 2 DM
diarrhoea RECOMMENDED you develop fever / flu-like poorly controlled with diet and oral
Special Avoid if requires fine
symptoms. agents. Exogenous insulin stimulates
precautions motor coordination • Complementary preparations – no
carbohydrate metabolism and helps
Contra- Epilepsy pts; proven efficacy.

DIABETES
with transfer of glucose into cardiac
indications past/present • Dapsone-pyrimethamine –
psychiatric condition; and skeletal muscle and adipose
widespread resistance, adverse
severe hepatic tissue. Insulin also aids in conversion
effects.

impairment
Safe to use Pregnancy;
for… breastfeeding mom;
children over 5kg;
HIV+ (potential DI);
diabetics
INDIVIDUALISE PROPHYLAXIS
CHOICE FOR EACH TRAVELER
Take into account / consider….
• Age and weight.
• Pregnancy / breastfeeding
(contraception; infants).
• Chloroquine + proguanil –
widespread resistance, poor
compliance.
• Artemisinin derivatives – use as
combination therapy only; to
preserve sensitivity.
Note: Citronella oil is the most
effective of alternative insect
repellents – but less effective than
DEET and need to be re-applied
every 40 – 90min; it has been
withdrawn as insect repellent in EU.
MELLITUS
of glucose to glycogen, stimulates
lipogenesis and protein synthesis, and
reduces serum potassium and
magnesium levels. Insulin, a protein,
PREVENTION IS BETTER THAN is degraded in the GI system if used
CURE! orally, so it is given subcutaneously,
or, in emergencies, intravenously.
Lifestyle changes:
• The goal of therapy is to improve
• Obesity, diet glycaemic control.
• Smoking • Too much insulin can cause
• Lack of physical exercise hypoglycaemia, which is the most
• Stress common side effect of insulin
therapy.
Metabolic syndrome
• An insulin regimen should seek to
closely mimic normal physiologic
insulin secretion patterns.
Absorption of an insulin product may
vary in a patient from one injection to
the next, absorption being affected by
site of injection, temperature, physical
activity, and dose. Insulin
preparations differ in dose, onset,
duration, and sources of origin,
including biosynthetic and
semisynthetic human (therapeutically
equal), human insulin (least antigenic
and most soluble), and beef and pork
(replaced by human).
Types of Insulin for Type 1 Diabetics:
INSULIN, SHORT ACTING, SC
Type of insulin Regular human
insulin
Administration 3x daily, 30 mins
before meals
Onset of 30 mins
action
Peak action 2-5 hrs
Duration of 5-8 hrs
action
INSULIN, INTERMEDIATE
ACTING, SC
Type of insulin Neutral
Protamine
Hagedorn (NPH)
insulin
Administration 1x / 2x daily,
usually at night,
not later than later than 10pm) intermediate- • Insulin injection may also cause
10pm acting insulin. lipohypertrophy, which occurs in
Onset of 1-3 hrs • The initial total daily insulin dose is patients who use only 1 site rather
action 0.6 units/kg body weight. than rotating sites. Rotating sites
Peak action 6-12 hrs • The total dose is divided into 40- solves the problem. Lipoatrophy,
Duration of 16-24 hrs 50% basal insulin and rest as bolus an immunologic reaction to insulin,
action
insulin, split equally before each is treated by changing to human
meal. insulin and injecting it into the
INSULIN, BIPHASIC, SC affected area.
Pre-mixed Insulin:
Type of insulin Mixture of • Insulin storage – stock in fridge;
regular human • Twice daily pre-mixed insulin, i.e. a room temperature if in use.
insulin and NPH mixture of intermediate- or short- • Recognition and treatment of acute
insulin in acting insulin. complications, e.g. hypoglycaemia.
different
• At least daily blood glucose • Self-monitoring and how to self-
proportions
monitoring (practical option for adjust insulin doses – basal bolus
Administration 1x / 2x daily
patients who cannot monitor blood at least 2x daily initially.
Onset of 30 mins
glucose frequently). • In visually impaired patients and
action
arthritic patients, prefilled pens and
Peak action 2-12 hrs
EDUCATION RELATED TO INSULIN cartridges.
Duration of 16-24 hrs
THERAPY
action
TYPE 1 DIABETIC MONITORING
• Injection technique – should not be
Monitoring following down referral:
• Insulin, a protein, is degraded in painful, inject at 90 degrees angle
the GI system if used orally, so it is if needle is short enough, into fat
• At every visit – finger-prick blood
given subcutaneously, or, in layer underneath skin (not
glucose, weight, and BP.
emergencies, intravenously. intramuscular); shorter needles are
• Annually – HbA1c, one month
• Short-acting – actrapid; better; if patient not overweight, lift
before next hospital appointment.
intermediate acting – protophane. skinfold with 2 fingers and inject at
45-degree angle. Treatment Targets:
REGIMENS FOR T1 DIABETICS • Major predisposing factors to
hypoglycaemia (the most common Finger-prick Blood Glucose
Basal Bolus Regimen: Values
and serious adverse reaction to
(mmol/L)
• Preferred management with “basal insulin) include inadequate food
Optimal 4-7 (fasting)
bolus regimen”. intake, poor timing of injections,
5-8 (2h post-prandial)
exercise, and use of
• Combined pre-meal short-acting Acceptable <8 (fasting)
hypoglycaemic drugs. 8-10 (2h pp)
insulin (bolus) and bedtime (not
 Additional >8 (fasting) METFORMIN - Less severe for extended- are regulated by intracellular
action >10 (2h pp) release formulation. adenosine triphosphate (ATP) (KATP
suggested Mechanism of Action: • Lactic acidosis (0.05 cases/1000- channels.) When the blood glucose
patient-years) increases, more glucose enters the ß-
• Reduces hepatic gluconeogenesis
- Due to inhibited conversion of cells and its metabolism results in an
HbA1c (%) and glycogen metabolism.
lactate to glucose. increase in intracellular ATP, which
Optimal <7 • Improves insulin resistance via
Acceptable 7-8 • Reduced vitamin B12 absorption. closes KATP channels. The resulting
enhancing insulin-mediated depolarization of the ß-cell initiates an
Additional >8 glucose uptake by skeletal muscle. SULPHONYLUREA influx of Ca 2+ ions through voltage-
action
• Decrease carbohydrate absorption sensitive Ca 2+ channels and this
suggested
from GIT. 2nd Generation: triggers insulin release.
• Lowers triglyceride and total
• Glibenclamide
Blood Pressure (mmHg) cholesterol levels, raises HDL.
• Gliclazide (lowest risk of
Systolic <140 • Weight neutral and does not
Diastolic <90 hypoglycaemia)
cause hypoglycaemia.
• Glimepride
• Indicated alone in obese, mild
• Glipizide
diabetics as it does not enhance
The increased risk of hypoglycaemia
lipogenesis (unlike insulin). Mechanism of Action:
must always be weighed against the
potential benefit of reducing Dosing: • Historical mainstay of treatment for
microvascular and macrovascular Type 2 DM.
complications. • Initially 500mg once or twice daily;
or 850mg once or twice daily, with • Requires residual beta cell
TYPE 2 DIABETES NON-INSULIN meals. functioning.
THERAPY • After 5-7 days, up-titration, • Stimulates insulin secretion from
pancreatic beta cells, beta cells Dosing:
maximum 2000mg/day (based on
• Biguanides (Metformin) GIT side effects). growth promoted. Glimepride
• Sulfonylureas • Extended-release formulation • Enhances beta cell sensitivity to • Initially 1mg daily, adjusted
• Thiazolidinediones (Glitazones) preferred in patients with severe glucose. according to response in 1mg
• SGLT-2 inhibitors (Dapagliflozin) GIT side effects. • Reduces glucagon release. increments at 1-2 week intervals
• a-Glucosidase inhibitors • Consider risk-benefit if eGFR<45. SU (stimulant of insulin secretion);
(max dose of 4mg daily).
• Incretin (GLP-1) based drugs • Contraindicated if eGFR<30. • Preferred in the elderly.
requires some residual beta cell
(DPP-4 inhibitors; GLP-1 receptor function.
agonists) Side Effects:
Glucose is the most potent stimulus
• GIT disturbances (10-50%)
for insulin release from the ß-cells.
- Loss of appetite, nausea,
These cells possess K+ channels that
diarrhoea.
 Glibenclamide Treatment Targets [same as for T1]: Step 3 – for persisting HbA1c above First increment is
• 2.5mg daily and titrate slowly to acceptable levels and despite added to dose before
maximum of 15mg daily. Finger-prick Blood Glucose adequate adherence to oral agents; breakfast.
Values
• When 7.5mg or more per day is add insulin and withdraw sulphonyl
(mmol/L)
needed – 2/3 of the total dose in urea. Continue lifestyle modification. Second increment is
the morning and 1/3 at night. Optimal 4-7 (fasting) added to dose before
5-8 (2h post-prandial)
• Avoid in the elderly. Note: ensure patient is adherent. supper.
Acceptable <8 (fasting)
8-10 (2h pp) Note: oral agents should not be used
• Avoid in renal impairment if Additional >8 (fasting) in type 1 diabetes. TREATMENT FOR
eGFR<60mL/min. action >10 (2h pp) HYPOGLYCAEMIA
suggested Insulin Regimen for Type 2 Diabetes:
• Contraindicated in severe hepatic
impairment (hepatic metabolism Add On Therapy For Mild Hypoglycaemia:
CYP2C9, CYP2C19) and Insulin Intermediate to long-
HbA1c (%) • Fast acting oral carbohydrates (at
pregnancy. Optimal <7 type acting
least 15g).
Starting 10units in the evening
Side Effects:
Acceptable 7-8
dose before bedtime, but • Sources include…
Additional >8 - 3 glucose tablets (5g each)
not after 10pm
• Hypoglycaemia (risk factors action
Increment If 10units not effective; - 2,5 cups of fruit juice
include renal impairment, elderly suggested
increase gradually to - ½ to ¾ cup of regular soda
pt, & irregular meal schedule) 20units (2-4units incr. - 1 cup of milk
• Weight gain (5kg over first 6 years) Blood Pressure (mmHg) each week) • If patient is unable to take orally,
Systolic <140 give IV dextrose.
TYPE 2 DIABETES MONITORING
Diastolic <90
Substitution Therapy For Moderate to Severe
• At every visit – weight and finger Insulin Biphasic Hypoglycaemia:
prick blood glucose. TYPE 2 DIABETES – STEPWISE type
• Baseline – serum creatinine, serum Starting 2x daily. • Dextrose – 50mL of 50% dextrose
APPROACH TO MANAGEMENT
K if on ACE-inhibitor or eGFR<30, dose 15units divided as IV bolus after blood drawn,
urine protein by dipstick, blood lipid Step 1 – add metformin to the follows: followed by 10% dextrose.
profile, food examination, eye combination of dietary modifications • 2/3 of total daily • Glucagon – 1mg IM or SC can be
examination, abdominal and physical activity / exercise. dose (i.e. 10units) given (family/friend); effective in
30 mins before treating hypoglycaemia only if
circumference.
Step 2 – combination therapy with breakfast sufficient liver glycogen present.
• Annually – same as baseline and
metformin plus a sulphonyl urea is • 1/3 of total daily • These measures raise blood
HbA1c, in patients who meet dose (i.e. 5units) 30
indicated if therapy with metformin glucose only transiently!
treatment goals. mins before supper
alone (together with lifestyle changes) • Patient should be urged to eat as
has not achieved the HbA1c target. Increment 4units weekly.
soon as possible, once fully awake.
Prevention of Hypoglycaemia:
• Patient education.
• Knowing signs and symptoms.
• Take meals on a regular schedule.
• Carry a source of carbohydrate.
• Self-monitoring of blood glucose.
• Take regular insulin at least 30
mins before eating.
TREATMENT FOR DIABETIC
KETOACIDOSIS
IV Fluids:
• Average fluid deficit 6L, may be up
to 12L..
• 0.9% NaCl IV 15-20mL/kg in first
hour.
• Subsequent infusion varies from 5-
15mL/kg/hr depending on clinical
condition.
• Volume infused in first 4hrs should
not exceed 50mL/kg.
• Thereafter, fluid replaced over
48hrs (about 50mL/kg/hr).
• 0.45% NaCl if Na > 140mmol/L.
• Change to 5% dextrose or 5%
dextrose in NaCl 0.9% when
plasma glucose <15mmol/L and
ketones still present.
Always admission to hospital., as
significant mortality.
Place NGT is suppressed LOC, as
gastric dilatation can cause increased
risk of aspiration.
Urinary catheter to monitor output, is
patient is unstable.
Insulin:
• Ketonaemia takes longer to clear
than hyperglycaemia, and
combined insulin and glucose are
needed.
• If initial K is <3.5mmol/L give
IV40mmol KCl with each litre of
replacement fluid, if 3.5-5.5mmol//L
give 20mmol KCl.
• Maximum KCl dose is 40mmol/hr
and monitor K hourly.
• Short acting insulin, IV infusion,
50units in 200ml 0,9% NaCl (4mL
= 1unit insulin).
• Initial infusion – 0.1units/kg/hr
- If glucose does not fall by
3mmol/L in first hour, double the
infusion rate hourly, until a steady
reduction (3-4mmol/L per hour).
- If glucose <14mmol/L reduce
infusion rate 1-2units/hr.
Progress:
• Avoid focusing on glucose control
alone.
• Continue IV insulin until ketosis
and acidosis has resolved and
patient can eat.
• Intermediate or long-acting insulin,
in combination with SC short-acting
insulin (insulin infusion should
overlap SC regimen for 1-2 hrs).
• Bicarbonate – no proven role for IV • Night-time symptoms –
sodium bicarb and could cause </=1/month.
• PEF of 80% or above.
harm.
Note – treatment and management for
Hyperosmolar Hyperglycaemic State CHRONIC PERSISTENT
(HHS) similar as for DKA.
Mild (II):
• Daytime symptoms; 3-4/week.
ASTHMA &
• Night-time symptoms; 2-
4/month.
• PEF of 80% or above.
COPD
Moderate (III):
• Daytime symptoms - >4/week.
• Night symptoms - >4/month.
GOALS OF MANAGEMENT • PEF between 60-80%.
• Abolish symptoms and achieve a Severe (IV):
normal lifestyle. • Daytime symptoms –
• Optimize treatment and minimize continuous.
medication adverse effects. • Night symptoms – frequent.
• Avoid causative and trigger factors. • PEF <60%.
• Restore normal / best possible lung
function.
• Reduce the risk of severe attack.
ASTHMA PHARMACOTHERAPY
ASSESSMENT OF ASTHMA
Relievers:
SEVERITY
• These are short-acting
…using symptoms and PEF in bronchodilators with rapid onset of
patients presenting for the first time action providing acute symptomatic
on no treatment: relief.
• Short-acting b2 agonists:
INTERMITTENT
- Salbutamol
Mild (I):
• Daytime symptoms – 2 or less - Fenoterol
per week. - Terbutaline
• Anti-cholinergics:
- Ipratropium bromide
Controllers:
• These are drugs with anti-
inflammatory and/or a sustained
bronchodilator action.
• Inhaled corticosteroids…
- These have anti-inflammatory
action to prevent asthma attacks.
- Include – beclomethasone,
budesonide, fluticasone,
Ciclesonide
• Leukotriene modifiers…
- These have anti-inflammatory
action to prevent asthma attacks.
- E.g. montelukast, zafirlukast.
• Oral corticosteroids…
- These have anti-inflammatory
action to prevent asthma attacks.
- E.g. prednisone, prednisolone,
methylprednisone,
methylprednisolone.
• Long-acting b2 agonists…
- These have sustained
bronchodilator action but weak or
unproven anti-inflammatory effects.
- E.g. salmeterol, formoterol.
• Sustained-release theophylline
preparations…
- These have sustained
bronchodilator action but weak or
unproven anti-inflammatory effects.
CHRONIC ASTHMA MANAGEMENT
• Inhaled corticosteroids are the
mainstay of asthma management.
• Space device.
• All patients get reliever –
salbutamol. [check inhaler
technique].
• Start beclomethasone 200mcg 12
hourly.
• If not controlled increase dose to
beclomethasone 400mcg 12
hourly.
• If still not controlled, add LABA,
e.g. switch to salmeterol +
fluticasone 50/250 1 puff 12 hourly.
• If still not controlled, referral to
specialist – leukotriene receptor
antagonist, tiotropium bromide,
theophylline.
INHALER FORMULATIONS
• Dry powder inhaler.
• Pressured metered-dose inhaler.
• Nebuliser.
SHORT ACTING B2-AGONSTS
• Drug of choice for the relief of
bronchospasm during acute
exacerbations – either metered
dose inhaler with spacer, or
nebuliser.
• frequency of use is measure of
control.
• Increased use is an indication of
deterioration of asthma control.
• May only be used as the sole
therapy for MILD INTERMITTENT
ASTHMA.
• In chronic persistent asthma, they
should only be used as needed.
• Oral b2-agonists have a slower
onset of action and risk of systemic
side-effects is higher – not
recommended.
ANTICHOLINERGICS
• Ipratropium bromide.
• Antagonists of muscarinic
receptors – inhibit
bronchoconstriction.
• Less effective reliever in asthma
than inhaled b2-agonist.
• Onset of action – 30 minutes.
• Additive effect with b2 agonist.
INHALED CORTICOSTEROIDS
• Bind to glucocorticoid receptors –
alter gene expression – anti-
inflammatory action.
• Most effective anti-inflammatory
medication.
• DOES NOT CURE ASTHMA –
when discontinued, deterioration of
control follows.
• Targeted directly at the site of
inflammation (fewer side effects).
• Side effects include –
oropharyngeal candidiasis &
hoarseness.
LONG-ACTING B2-AGONISTS
• Bind to beta 2 receptors –
stimulate adenylyl cyclase – incr.
cAMP – bronchodilation.
• No anti-inflammatory effect.
• Should never be used as
monotherapy for asthma, use as
add-on therapy to inhaled
glococorticosteroids.
• Inhaled.
• May cause tremor and palpitations.
LEUKOTRINE RECEPTOR
ANTAGONISTS
• Not effective as monotherapy.
• Less effective than long-acting b2-
agonist when added to
corticosteroids.
• Useful as add on therapy when still
symptomatic despite already on
corticosteroids and long-acting b2-
agonist or patient cannot tolerate
long-acting b2-agonist.
• Not all patients respond.
• Withdraw if no improvement after 4
weeks.
• Very few side effects.
THEOPHYLLINE
• MOA – non-selective inhibition of
phosphodiesterases – may result
in bronchodilation and anti-
inflammatory effect (inhibits
release of mediators).
• Complementary mode of action to
other bronchodilators.
• Only used as add-on therapy.
• Narrow therapeutic index with a
high potential for side-effects.
Side Effects:
• GIT symptoms (nausea, vomiting).
• Cardiac arrhythmias and CNS
symptoms (tremor, confusion,
seizures)
ORAL CORTICOSTEROIDS
• Sort course after acute
exacerbation.
• Severe and poorly controlled
asthma.
• Risk of significant side effects -
suppress HPA axis-adrenal
atrophy and inadequate stress
response. Hypertension, fluid and
electrolyte disturbances,
hyperglycaemia, inhibits
inflammatory response, peptic
ulcer disease, muscle weakness,
cataracts, osteoporosis,
osteonecrosis, growth retardation,
Cushing’s syndrome, diabetogenic,
dyslipidaemia. Psychiatric-
euphoria, behavioural changes,
depression.
MANAGEMENT OF ACUTE
SEVERE ASTHMA
• Oxygen by face mask.
• Beta2-agonist by MDI with
spacer/nebuliser.
• Early systemic corticosteroids –
oral prednisone or IV
corticosteroids.
• Ipratropium bromide if response to
salbutamol poor.
• IV magnesium sulphate.
• Intubation and ventilation.
DO NOT use IV aminophylline –
increased adverse effects (vomiting
and dysrhythmias), does not improve
bronchodilation and outcome.
Intravenous beta2 stimulants – side
effects.
HOME ACTION PLAN
• Discharge with oral prednisone for
7-14 days.
• Patient education in a
structured/written form,
concerning…
- Chronic nature of disease.
- Drug education (relievers and
controllers, use of SPACER).
- Correct techniques.
- Monitoring peak-flow.
- Warning signs.
- Triggers and avoidance plans.
PREVENTATIVE MEASURES
• Avoid exposure to personal and
second-hand tobacco smoke.
• Avoid contact with furry animals.
• Reduce pollen exposure.
• Reduce exposure to house dust
mite.
• Avoid irritants (dust and fumes).
• Avoid food and beverages
containing preservatives.
• Avoid beta blockers, NSAIDs, and
aspirin.
POORLY CONTROLLED,
CONSIDER…
• Wrong Dx – would be HF, COPD,
gastro-oesophageal reflux disease,
foreign body aspiration in kids.
• Poor adherence.
• Confusion about when to use
controller and reliever drugs.
• Concomitant medications such as
aspirin, NSAIDs & beta-blockers
that aggravate asthma.
• Inhaler technique.
• Exposure to trigger factors.
• Rhinitis or sinusitis.
GOALS FOR MANAGEMENT OF
COPD
1. Recognition of disease (early
Dx and staging of severity).
2. Prevention of disease
progression (including
smoking cessation).
3. Alleviation of breathlessness
and improvement in effort
tolerance (treatment of airflow
obstruction).
4. Pulmonary rehabilitation and
education (improving quality of
life.
5. Prevention and treatment of
exacerbations.
6. Prevention and treatment of
complications.
7. Reduction in mortality.
ACUTE EXACERBATION OF COPD
• Worsening of dyspnoea, increased
cough, increased sputum
production or purulence, increase
in symptom variability.
• Exclude other causes, e.g. cardiac
failure, pulmonary embolism,
pneumonia.
Management:
• Nebulised salbutamol.
• Add ipratropium bromide if poor
response.
• Start prednisone (hydrocortisone if
cannot take oral therapy).
• Discharge with prednisone 40mg
for 5 days.
• Amoxicillin 500mg y hourly for 5
days.
• If recent amoxicillin exposure;
amoxicillin + clavulanic acid for 5
days.
CHRONIC MANAGEMENT OF
COPD
• Short acting beta 2 agonists, e.g.
salbutamol with spacer.
• If no response, replace with LABA,
e.g. formoterol, salmeterol.
• If frequent exacerbations (2 or
more per year) replace with LABA
+ ICS combination.
• If inadequate control add
theophylline slow release 200mg at
night.
• Oral corticosteroids NOT
recommended for stable COPD.
PRE-
SCRIPTION
WRITING
Why are substances scheduled?
• Drugs are scheduled from 0-7.
• Scheduling governs medicine use.
• Schedules 0, 1, & 2 are medicines
that can be accessed over the
counter (OTC).
• Schedules 3-6 can only be
obtained on prescription.
• Schedule 7 are drugs that are very
strictly controlled and difficult to
access.
• Scheduling is based on…
- Potential for abuse
- Potential for dependence
- Safety
- Clinical indication (schedule
may vary accordingly)
• Sometimes the same substance
might be found in several different
schedules depending on the
specific uses.
• Schedule 3 contains most of the
chronic medications, e.g.
antihypertensives.
• Schedule 4 contains most
antibiotics.
• Schedule 5 & 6 have substances
that have high abuse potentials.
Schedule 0 – possessing & selling:
• Can be sold anywhere, e.g.,
grocery stores, corner café,
pharmacies, health shops, etc.
• Example – paracetamol.
Schedule 1-6 – possessing & selling:
• These can be prescribed by a
medical practitioner, and if that
medical practitioner has a
dispensing license, they may also
compound and dispense
medication.
• Pharmacists, interns or
pharmacist’s assistants may also
dispense these, but with S3-S6
only on valid prescription.
• Pharmaceutical
manufacturers/wholesalers can
also be in possession of these
drugs.
• Other authorised prescribers, e.g.
vets, nurses, first responders, etc.,
although this is limited to only the
drugs that are relevant for their
work.
Schedule 7 – possessing & selling:
• Only if issued a permit by the
director general.
• Examples – amphetamines,
nabilone (anabolic steroid),
phencyclidine (PCP)
• Permit valid for 12 months.
In summary…who may possess
what??
• Schedule 0-2 – any person for
medicinal use.
• Schedule 3-7 – any person if in
possession of a valid script.
• Medical practitioner – any
medicine for the purposes of
administering in accordance with
scope of practice; and if licensed
and registered as a dispenser.
• Persons entering SA – 6 months
of medicines for personal use for
S3-S5; 30 days supply for S6; valid
prescription required.
• Person leaving SA – quantity of
meds no longer specified; will
depend on which country patient is
travelling to; maximum amount on
a valid prescription in SA is 6
months; valid prescription required.
VERBAL PRESCRIPTIONS
Non-emergencies:
• Verbal prescriptions can be issues
for S2-S4 for non-emergencies.
• Maximum treatment period 7 days.
• Has to be followed up with a
written prescription within 7 days.
Emergencies:
• S5-S6.
• Supply quantity for continuous use
for up to 48 hours.
• Prescriber to supply written
prescription within 72 hours.
REPEAT PRESCRIPTIONS
• Schedules 2-5:
- Number of repeats indicated
on Rx.
- Maximum 6 months.
- S5 specify repeat intervals as
well.
• Schedule 6:
- No repeats.
- New prescription required
every time.
- Maximum 30 days supply.
• Anxiolytics, tranquilisers,
antidepressants max 6 months;
unless prescriber has a record of
consulting with registered
psychiatrist in which case may
continue to issue.
• S5 analgesics max 6 months;
unless prescrber has a record of
consulting another medical
practitionier.
LATEST CHANGES
• Fexofenadine is now S1.
• Budesonide is now S2, “when
intended for the prophylaxis and
treatment of seasonal and
perennial allergic rhinitis in adults
and children aged 12 years and
older”.
• Fusidic acid is now S2, “when
intended for topical application”.
• Cannabidiol is now S4, without
mention of “when intended for
therapeutic purposes” and without
the cross-reference to S7.
• Carfentanil is S6 “when intended
for veterinary use”, but is otherwise
S7.
• A number of fentanyl analogues
are listed in S7.
WHAT IS A PRESCRIPTION?
• An order or set of instructions
wither written or transmitted
electronically/verbally, by an
authorised prescriber to a
dispenser, for the preparation and
use of a medicine(s) by a specified
patient.
• A prescription expires after 30
days and may no longer be
dispensed.
• Precede decimal by a zero if a
decimal is necessary (0.5ml rather
than .5ml).
• Avoid using I for litre.
• Write the words “units” in full rather
than U.
• Avoid vague directions (“take as
directed; use as before”).
• Write instructions for repeats
clearly.
• Generic substitution.
• Also worth bearing in mind costs,
and rational prescribing.
Prescribing Tips:
• Indelible ink – no pencils, etc. or
printed.
• Clear handwriting.
• Directions in plain
English/isiXhosa/Afrikaans, etc.
• Latin abbreviations may result in
confusion.
• Avoid unnecessary decimal points
(5 mg, not 5.0 mg).
• For quantities less than 1g, rather
use mg (500mg, not 0.5g).
• For micrograms use full work or
mcg, not ug.