ALCOHOL 1

Chronic effects of heavy drinking

Ethanol (ethyl alcohol: CH3CH2OH)
Fermentation: organism converts carb into alcohol or acid
Peripheral neuropathies
Yeast perform fermentation to obtain energy
Cerebellar degeneration
They convert sugar into alcohol (and CO2)
Dementia
Max conc: 12-14%
Wernicke-Korsakoffs syndrome (thiamine deficiency)
Concentrations >12% are toxic to yeast get by distillation
EFFECTS ON THE CVS
Vasodilation due to central vasomotor depression
Impact and cost
o sense of warmth but loss of body heat
Second to tobacco as cause of drug-related deaths
Hypertension (withdrawal increases sympathetic activity)
>80% of Australians consumer alcohol last year
Myocardial problems conduct defects, rhythm disturbances
Stages of intoxication
2-3 drinks/day prevents coronary heart disease
1) Sobriety
2) Euphoria
EFFECTS ON LIPIDS, PLATELETS, BLOOD VESSELS
3) Excitement
Decreases atheroma (fatty deposit in artery) formation
4) Confusion
o good cholesterol (HDL) bad cholesterol (LDL)
5) Stupor
Decreases clotting
6) Death
o Increases production of t-PA breaks down clots
Decreases platelet aggregation
EFFECTS ON THE CNS
o Decreases production of arachidonic acid by PLA2
CNS depressant (not stimulant)
NB: good effect offset by increased risk of haemorrhagic stroke
1) Initial stimulation (due to disinhibition)
2) Relaxation
EFFECTS ON LIVER
3) Generalised CNS depression
Increased fat accumulation (fatty liver)
Characteristic response:
Hepatitis (inflammation of liver)
o euphoria
Irreversible liver necrosis & fibrosis liver failure
o impaired thought processes
Metabolites are toxic
o decreased motor control
Mechanism of action
Similar to volatile general anaesthetics
Inhibit APs
o Potentiate inhibitory GABAA receptors
o Inhibit neurotransmitter release (block Ca2+ channels)
o Block action of glutamate at NMDA receptors
o Inhibit adenosine uptake
(adenosine acts on A1 receptors to inhibit transmission)
Acute effects
Common effects:
o Euphoria
o Slurred speech
o Ataxia (unsteady gait)
o Increased self-confidence
o Decreased mental acuity & physical coordination
Thought and motor processes dependent on training,
judgement and previous experience are first affected
High conc. causes respiratory depression death
Effects on driving
Probability of having accident:
Legal limit in NSW: 0.05%
(0.05 g/100mL blood)
M: ~2 drinks/hr F: ~1 drink/hr
What is a standard drink?
1 middy of beer (285ml)
1 glass wine (100ml)
1 nip of spirits (30ml)
NB: Alcohol interacts with other drugs to impair driving
Chronic toxicity
Irreversible neurological abnormalities
Loss or damage to neurons and glia (seen in pathology)
Tissue shrinkage, CSF increases
Lower glucose metabolism
Reduced blood flow and neuronal viability

EFFECTS ON KIDNEY
Diuretic (increases weeing)
o Decreases release of ADH from pituitary
o Decreased reabsorption of water in renal tubules
EFFECTS ON GIT
Mucosal irritation
Inflammation of stomach (gastritis), pancreas, gall bladder
Duodenal/oesophageal varices (dilated veins that bleed)
FOETAL ALCOHOL SYNDROME (FAS)
Due to placental transfer
1 in 3 children born to alcoholic mothers get FAS
o microcephaly (small head)
o abnormal facial structure
o retarded growth
o cardiac defects
o mental retardation
o impaired immune system
Risk when >4 drinks/day
PHARMACOKINETICS OF ALCOHOL
Absorption
Rapidly absorbed from duodenum
Peak levels reached in 30-90 mins
BAC depends on:
o rate of drinking
o first pass metabolism (in stomach & liver)
o alcohol concentration
- high conc. delays gastric emptying slow absorption
o carbonation of beverages
- increases gastric emptying rate fast absorption
o food consumption (lowers BAC)
- NB: BAC (IV) > BAC (fasting)

ALCOHOL 2
Acute alcohol withdrawal
Distribution
BAC depends on:
o gender
Stage
Phase/symptoms
- distributes into body water not fat
1
Early withdrawal
- males have more water (bigger Vd) lower BAC
(6-48 hrs)
- tremor
o weight
- anxiety
- heaver people have lower BAC
- nausea
- obese people (BMI > 30) have low Vd high BAC
- headache
2
Withdrawal seizures (rum fits)
Metabolism
(48-72 hrs)
90-95% metabolised in liver
3
Delirium tremens
Ethanol acetaldehyde acetic acid
(72-96 hrs)
- tremors
1) Ethanol oxidised to acetaldehyde by alcohol
- hallucinations
dehydrogenase
- disorientation
- rate-limiting step (slowest rate of reaction)
- confusion
- zero order (rate of reaction is constant)
- fever
2) Acetaldehyde oxidised to acetic acid by aldehyde
- tachycardia
dehydrogenase
4
- protracted withdrawal
Depends on availability of cofactor: NAD+
(>7 days)
o fructose and amino acids increase availability
Normal rate of metabolism: 100/mg/kg/hr (8g/hr) in 80kg
TREATMENT & MANAGEMENT
Takes 1-1.5 hrs to eliminate 1 std drink (8g)
Treatment of acute alcohol withdrawal
Accumulation of acetaldehyde causes hangover effects
Benzodiazepines (e.g. diazepam) are first line agents
5-10% excreted unchanged in urine, faeces, breath, sweat
o increase GABAA receptor function
At high conc. more metabolism by mixed function oxidase
o decrease seizures
H2 histamine receptor blockers (e.g. ranitidine) inhibit gastric
o decrease delirium
ADH to increase BAC
Genetic factors
50% Asians have inactive variant of aldehyde dehydrogenase
o alcoholism is low
Sex differences
Women achieve higher BAC given same dose
50% less first-pass metabolism (low alcohol dehydrogenase)
Smaller Vd
Excretion
Most ethanol is metabolised - very little excreted by kidney
o Cant hasten excretion with diuretics
Some alcohol goes to lungs
o basis for breathalyser
o breath to blood ratio is 1:2100
ACUTE OVERDOSE
Potentially fatal
Average lethal BAC is 0.3%
o lower if other drugs (e.g. sedatives) taken
Death is the result of respiratory failure
Generally self-limiting process
o pass out before lethal conc. reached
o unconscious patient may aspirate vomitus & suffocate

For Wernicke-Korsikoff Syndrome

Alcoholics usually deficient in Vit B1 give thiamine
For psychiatric symptoms
Use antipsychotics (e.g. haloperidol, droperidol)
NOT phenothiazines can precipitate seizures
Long-term management of alcohol dependence
To reduce craving after withdrawal
Acamprosate
o NMDA receptor antagonist
o GABA agonist
To reduce alcohol-induced reward
Naltrexone
o opioid receptor antagonist
o precipitates opioid withdrawal in addicts
To render alcohol consumption unpleasant
Disulfiram (antabuse)
o if patient drinks, they will feel very sick
o interferes with aldehyde dehydrogenase
o leads to excessive acetaldehyde levels hangover

TOLERANCE & DEPENDENCE

No 2 people respond the same to equal amounts of alcohol
Tolerance
Tolerance develops with chronic use
2-3 fold loss of potency develops over 1-3 weeks due to:
1) tissue tolerance
- proliferation of Ca2+ channels
- proliferation of NMDA receptors
- reduction in density of GABA receptors
2) more rapid elimination
Dependence (alcoholism)
Common: 4-5% of population
Strong physical dependence (withdrawal symptoms)
Strong psychological dependence (cravings)

ANTIMALARIALS 1
Malaria
SITE OF ACTION OF ANTIMALARIAL DRUGS
Serious disease that causes chills and fever
Drugs to treat acute attack - kill parasites in blood
Passed from one person to another by bite of mosquitos
Drugs for radical cure - kill parasites in liver
Drugs for prophylaxis - kill merozoites emerging from liver
Morbidity and mortality
Drugs preventing transmission - kill gametocytes
Endemic in >90 countries
3.3 billion people (50% world) at risk
Quinolines (for acute attack)
Decreasing in most countries (few exceptions e.g. Rwanda)
Include: quinine, chloroquinine, mefloquine, primaquine
8 countries are in pre-elimination stage
Mechanism of action
Leads to nearly 1 million deaths every year
Accumulate in parasite food vacuole (acidic)
Serious problem in Africa 1 in 5 deaths is due to malaria
Bind to heme released after parasites digestion of Hb
Prevent conversion of heme to non-toxic haemozoin
MALARIA TRANSMISSION
Toxic heme accumulates and kills parasite
What is the cause of malaria?
4 species of protozoal parasite Plasmodium:
Adverse effects (quinine)
o P. vivax
Quinine is a derivative from the bark of the Cinchona tree
o P. malariae
Adverse effects (cinchonism):
o P. ovale
o dizziness
o P. falciparum (most severe and prevalent)
o GIT upset
o rashes
How is it transmitted?
o blurred vision
Insect vector
o tinnitus
o Female anopheles mosquito
o Breeds in stagnant (still) water
Antifolates
o Active from dusk to dawn
Include: sulfadoxine, pyrimethamine, proguanil
o Once considered to arise from marshes
Target enzymes involved in folate synthesis
Placental transfer
(required for parasite DNA synthesis)
Blood transfusion - survives up to 5 days in stored blood
Contaminated needles - IV drug addicts
Sulfadoxine-pyrimethamine (acute attack)
Used together
PARASITE LIFE CYCLE
In folate synthesis pathway:
1) During blood meal, mosquito injects sporozoites into human
o sulfadoxine targets DHPS
2) Sporozoites infect liver cells and mature into schizonts
o pyrimethamine targets DHFR
3) Schizonts rupture and release merozoites
o in P. vivax & P. ovale a dormant stage (hypnozoites)
Atovaquone-proguanil (radical cure, preventing transmission)
can persist in liver cause relapses
Interferes with pyrimidine synthesis pathways
4) Merozoites infect red blood cells and replicate
(essential for nucleic acid replication)
5) Some merozoites develop into male & female gametocytes
Atovaquone blocks mitochondrial electron transport chain
6) Gametocytes ingested by mosquito during blood meal
Proguanil inhibits DHFR
7) Sporozoites develop & go to salivary glands of mosquito
Poorly absorbed, must be taken with fatty foods
Artemisinins (acute attack)
Derived from leaves of sweet wormwood plant
Include: artemether, dihydroartemisinin, artesunate
Activate against chloroquine-resistant malaria
Mechanism of action
Bind iron break down peroxide bridges
Forms free radicals damage parasite proteins
Administration:
Oral, intramuscular, IV, rectal
Must be used in combination with other antimalarials:
artemisinin combination therapy (ACT)
Use of artemisinin monotherapies spreads resistance
CLINICAL PRESENTATION
Acute illness
Acute, febrile illness
Incubation period of 7-9 days
Fever, chills, headache, muscle weakness

Antimicrobials
E.g. doxycycline
Target parasite protein synthesis
Slow anti-malarial activity
Paired with fast-acting antimalarials
Long half life (once daily dosing)

Capillary blockade
RBC aggregates form and adhere to capillary walls
Cause renal failure & encephalopathy (loss of brain function)
Rupture of RBC schizont release
Pyrogenic toxins released

ANTIMALARIALS 2
ANTIMALARIAL DRUG RESISTANCE
Pregnant women living in areas of high transmission
Widespread:
Intermittent preventative treatment (IPT) with sulfadoxineo drug-resistance in parasite
pyrimethamine (SP) twice during 2nd & 3rd trimesters
o insecticide-resistance in mosquitos
PREVENTING MALARIA
Widespread resistance by P. falciparum to chloroquine
How resistance develops
Spontaneous mutations confer reduced sensitivity to drug
Over time resistance becomes established
Chloroquine: parasite expels drug from food vacuole
Antifolates: gene mutations confer resistance to enzymes
Atovaquone: mutation in cytochrome-b gene (mitochondria)
TREATMENT
Treating an uncomplicated acute attack
First line: artemisinin combination therapy (ACT)
E.g. artesunate + amodiaquinine
Treating a complicated (severe) acute attack
Diagnosed by:
o hyperparasitemia: parasite count >100,000/mm3
o hypoglycaemia (<60 mg/dl)
o severe anemia
o oligouria (not enough urine) or renal failure
o altered consciousness (cerebral malaria)
o lots of vomiting, diarrhea
If chloroquine-resistant:
o First line: IV artesunate
o Second line: IV quinine
Radical cure with primaquinine (an 8-aminoquinoline)
Prevents relapses
Eliminates latent liver hypnozoites of P. vivax & P. ovale
Also kills gametocytes to prevent transmission
Contraindicated for:
o G6PD-deficient persons (3% of world, Africa)
- can cause hemolysis
o pregnant women

4 principles of malaria protection (ABCD)

1) Be aware
2) Avoid being bitten
o insect repellent and insecticide
o light-coloured trousers & long-sleeved shirts in evening
o sleep in screened accommodation
o use mosquito nets
o avoid outside activities between dusk and dawn
o avoid perfume and aftershave
3) Take chemoprophylaxis
4) Seek immediate diagnosis if fever develops:
o more than 1 week after entering
o up to 3 months after departure
WHO methods to combat malaria
Vector-control methods:
o insecticide treated nets
o indoor spraying of insecticides (DDT)
Parasite-control methods
o artemisinin-based combination therapy (ACT) reduces
resistance
o intermittent preventive treatment in pregnancy (IPT)
reduces transmission
MALARIA VACCINE
Developing a vaccine is difficult because:
o parasite is complex (>5,000 genes, 4 stage life cycle)
o parasite replicates rapidly
o many parasite proteins exhibit polymorphism
o protective antigens from vector not identified

Chemoprophylaxis
Prior to travel, start chemoprophylaxis medication
Areas with chloroquine-sensitive malaria (C. America):
o chloroquine weekly
- unpleasant taste, pruritis (itching)
Areas with chloroquine-resistant bacteria either:
o atovquone/proguanil daily
- skin rashes, fever, insomnia, nausea
o mefloquine weekly
- contraindicated in patients with neuropsychiatric
disorders, epilepsy, or cardiac conduction defects
o deoxycycline daily
- oesophagitis (inflammation), photosensitivity, thrush
Start early to allow adverse effects to be identified
PREGNANCY AND MALARIA
Malaria infection more severe
Increased risk of miscarriage, stillbirth, low birth weight
Pregnant women should avoid malarious areas
Chemoprophylaxis for pregnant women
Safe
Not safe
Chloroquine
Primaquine
Mefloquine
Doxycycline
Atovaquone-proguanil

ILLICIT DRUGS
Most prevalent in 18-29 years
38% of people over the age of 14 have used illicit drugs
Marijuana: most common illicit drug used

CNS STIMULANTS
CNS STIMULANTS
Have effect on mental function and behaviour:
o excitement and euphoria
o reduced sensation of fatigue
o increase in motor activity

INCLUDES
Amphetamines
Cocaine
Methylxanthines caffeine, theophylline (Rx asthma)

Drug

Mechanism of action

Pharmacological effects

Chronic use, tolerance, dependence

Pharmacokinetics

Clinical use &

unwanted effects

AMPETHAMINES
Amphetamine
(speed)
Dextroamphetamine
(dexies)
Methamphetamine
(ice)
Methylphenidate
(Ritalin)

Releases dopamine
& noradrenaline
from nerve terminals
in brain
Inhibits reuptake of
dopamine &
noradrenaline
Blocks degradation
of dopamine by
MAO

Increased motor activity

Euphoria and excitement
(especially with IV)
Reduced sense of fatigue
- used by truckers &
students to pay attention
Improved mental
performance - simple tasks
Anorexia (no appetite)

Dependence
Stimulant effects last for a few hours
Extended runs to maintain high
Depressants used to counteract anxiety
and insomnia uppers & downers
Withdrawal
When drug is stopped, period of sleep
Wake up depressed, anxious, hungry

Routes of administration
Mostly oral, some IV
Inhaled methamphetamine (ice) used
like crack cocaine
Cant be taken topically by snorting

Clinical use
ADHD
Narcolepsy
Fatigue
Weight loss

Absorption
Readily absorbed in GIT from nasal
mucosa
Penetrates BBB

Unwanted effects
Headaches
Arrhythmias
Anginal (chest) pain
Hyperthermia
Insomnia
Anorexia
Tremors
Exacerbates
schizophrenia

Tolerance
Tolerance develops rapidly

Dopamine = euphoria
Noradrenaline = SNS

COCAINE
From leaves of coca
Street form - HCl
HCl salt
Snorted or injected
Crack cocaine
Free-base form
Made from HCl form
Can be smoked

Inhibits reuptake of
dopamine and
noradrenaline into
nerve terminals
Dopamine = euphoria
Noradrenaline = SNS

Chronic use
Degeneration of amine-containing
terminals cell death
Personality changes
Psychosis - hallucinations, paranoia
Repetitive stereotyped behaviour
e.g. polishing shoes
Similar to schizophrenia
- antipsychotics help
Similar to amphetamine
Psychotomimetic effects
rarer:
- stereotyped behaviour
- delusions
- hallucinations
- paranoia
IV of free-base cocaine
produces intense
pleasurable sensation
known as a rush/flash

Dependence
Strong psychological dependence
Tolerance
Not clear whether tolerance develops
Can take same dose every day and get
same effect

Metabolism
Deamination
Excretion
Excreted unchanged in urine
Rate of excretion increased when
urine made more acidic

Routes of administration
Inhalation (absorbed by nasal
mucosa)
IV

Unwanted effects
Serious
cardiovascular
events (e.g.
dysrhythmias)

Onset and duration of effect

Rapid onset
Short duration of action
(shorter than amphetamine)

PSYCHOTOMIMETIC DRUGS
Psychedelic or hallucinogenic drugs
Affect thought, perception and mood
Cause sensory distortion and hallucination (tripping)

PSYCHOTOMIMETIC DRUGS 1
MAIN EFFECTS
Heightened awareness of sensory input
Feeling that self is divided: spectator & participating
View of environment as novel & beautiful
Everything takes on great meaning, sense or truth
Reduced ability to determine boundaries between people & objects

MAIN TYPES
Cannabis
Lysergic acid diethylamine (LSD)
Methylenedioxymethamphetamine (MDMA, ecstasy)

Drug

Mechanism of action

Pharmacological effects

Tolerance & dependence

Pharmacokinetics

CANNABIS
Plant
Active ingredient
(cannabinoid):
9-tetrahydro-cannabinol
(THC)

Partial agonist of CB1 & CB2

receptors
THC binds to CB1 & CB2 in
neurons
Inhibits adenylyl cyclase and
cAMP production
Inhibits Ca2+ channels
Activates K+ channels

Central effects
Decrease in short-term memory
Impaired motor coordination
Analgesia
Antiemetic (stops vomiting)
Increased appetite

Tolerance
At daily low doses, no tolerance

Routes of administration
Smoking
Oral ingestion
Vaporiser

Peripheral effects
Tachycardia
Vasodilation (blood shot eyes)
Decreased IOP
Bronchodilation

Response to discontinuation
Irritability
Restlessness
Nervousness
Decreased appetite
Insomnia
Weight loss
lasts 4-5 days

Marijuana
Most common, least powerful
Dried leaves & flowers of plant
2-6% 9-THC
Hashish
Dried cannabis resin
Small light brown/black blocks
12% 9-THC

CB1 receptors
In brain
Psychoactive effects
CB1 receptors
In PNS
Peripheral effects
Action on dopamine receptors
Activate D1 receptors
Inhibit D2 receptors

SYNTHETIC CANNABINOIDS
Spice drugs legal
Do not contain THC
Available on internet
Not detected by drug tests
Variable potency
Higher affinity for & full
agonists at CB1 & CB2

Moderate to high doses

Hallucinations
Paranoia
Flashbacks

Dependence
Physical: mild withdrawal
Psychological: mild

Absorption
Rapid
Very lipophilic 60% absorbed
Peak plama levels in <10 min
Duration of action: 2-3 hrs

Chronic effects
Apathy
Impaired judgement
Impaired concentration
Impaired short-term memory
Endocrine effects
Lowered fertility
Reduced sex drive
Offspring: impaired learning
Other effects
Respiratory illness worse than smoking
Amotivational syndrome
Depressed immune system

Drug

Mechanism of action

PSYCHOTOMIMETIC DRUGS 2
Pharmacological effects

LSD
Lysergic acid diethylamide
Derivative of lysergic acid from
rye fungus Claviceps purpurea

Action on serotonin receptors

Partial agonist at 5-HT2A receptors
Agonist at 5-HT1A receptors
High affinity for 5-HT1-5 receptors

LSD is very potent

Dissociation & disordered thought
Frightening hallucinations violence
(bad trip)

Structure
Indole (6-ring + 5-ring)
Tetracyclic (4 rings)
D-LSD isomer has
psychoactive properties

Action on dopamine receptors

Agonist at D1 & D2 receptors

Physiological effects
Increased BP & HR
Loss of appetite
Sweating
Dizziness
Tremors
Dry mouth
Nausea

Action on neurons
Inhibits firing of 5-HT containing
neurons in the raphe nuclei

Potency of derivatives
Only derivatives at N-6 have
similar potency to LSD

Tolerance & dependence

Pharmacokinetics

Tolerance
Rapidly develops
Dissipates after about a week
Cross-tolerance among
hallucinogens

Long-term effects
Persistent psychosis
- similar to paranoid schizophrenia
- mood swings with hallucinations
- can trigger underlying condition or be
the cause psychosis
Hallucinations weeks/months/years later
(flashbacks)

MDMA (ecstasy)
Amphetamine analogue
Stimulant + psychotomimetic
Sold as small tablets

Initial euphoria
Releases dopamine & noradrenaline
from nerve terminals in brain
Inhibits reuptake of dopamine &
noradrenaline
Psychotomimetic effects:
Releases 5-HT
Inhibits reuptake of 5-HT
large increase in 5-HT in brain
areas, followed by depletion
NB: greater affinity for 5-HT receptors
than amphetamine

Toxicity
No reported deaths no lethal dose
CNS effects
Increase in locomotor activity
Increase in body temp hyperthermia
Serotonin syndrome (too much serotonin)
General effects
Euphoria
Closeness to others (love drug)
Intense awareness of sounds/colours
Dilated pupils
Teeth grinding
Increase in HR & BP
Nausea, loss of appetite

Tolerance
Develops leading to
amphetamine binges
Withdrawal effects
Anxiety
Irritability
Aggression
Depression
Lack of appetite
Decreased libido
Decreased cognitive ability
Insomnia

Well absorbed orally

Onset of action: 20-60 mins
Peak effect: 60-90 mins
Duration of action: 5 hrs

CANDY FLIPPING
MDMA + LSD
Enhance effects
Reduce bad trips
Both potentially neurotoxic
Both increase release of
excitatory glutamate

Possible long-lasting effects

Degeneration of 5-HT & dopamine
neurons

PHARMACOLOGY OF ADDICTION 1
Problems with theory
WHY PEOPLE ABUSE DRUGS
To feel good to have novel feels, sensations & experiences No relationship between strength of withdrawal & addiction
o Withdrawal: worse with alcohol than heroin
To feel better to lessen anxiety, worries, fears, depression
o Addiction: worse with heroin than alcohol
Route of admin affects addiction but not phys. dependence
LICIT vs ILLICIT DRUGS
3 most commonly used non-therapeutic drugs:
Can treat withdrawal but not addiction (cause of relapse)
1) caffeine
Only high doses of drugs produce dependence
2) nicotine
3) ethanol
Positive reinforcement models
These are all licit drugs: legal, freely available
Positive incentive (reward) model
Many other drugs are used, but their manufacture, sale and
Drive by cocaine, amphetamine, nicotine (stimulants)
consumption is illegal (illicit) except under medical direction Based on reward and reinforcement
Global annual sales of illegal drugs: $800 billion
Most to least rewarding drugs:
(8% of all international trade, 3x that of prescription drugs)
1) amphetamine
2) heroin, cocaine
TERMS USED IN DRUG ADDICTION
3) nicotine
Drug misuse: use for purpose not consistent with guidelines
4) alcohol
Drug abuse: recurrent use of illegal/harmful substances
Reward related to onset of action
o includes banned drugs in sport
Heroin more rewarding than morphine - gets to brain faster
Drug addiction: disease process characterised by continued
use of psychoactive substance despite harm
Route of administration determines onset of action:
1) IV
Tolerance: need for higher dose to achieve desired effect
2) Inhale
Cross-tolerance: tolerance to one drug confers tolerance to
3) Oral
another
Many non-addictive versions of drugs are ones where drug
Physical dependency: drug needed for therapeutic reasons
onset is slow (e.g. crystal meth vs DESOXYN oral)
Withdrawal syndrome: adverse effects that last days/weeks
after stopping taking a drug
REWARD PATHWAYS MESOLIMBIC SYSTEM
Dependence-producing drugs activate reward pathway
SUBSTANCE USE DEPENDENCE
(mesolimbic dopaminergic pathway)
From ventral tegmental area (VTA) of midbrain to nucleus
Criteria for substance abuse
accumbens (NAc) and limbic region
(from International Classification of Disease-10: ICD-10)
3 or more of the following during previous year:
1) strong desire or sense of compulsion to take substance
2) difficulties controlling substance-taking behaviour
3) physiological withdrawal when substance use is reduced
4) evidence of tolerance to substance
5) preoccupation with substance use
6) persisting with substance despite evidence of harm
Dependence liability - main drugs of abuse
Very strong
Strong
Moderate
- morphine - ethanol
- anaesthetic
- cocaine
- barbiturates
- benzos
- nicotine
- amphetamine

Dopamine
Weak
Dopamine is involved in:
- caffeine
o Movement
- LSD
o Motivation
- cannabis
o Reward
o Addiction
THEORIES OF ADDICTION
Natural rewards (e.g. food, sex) elevate dopamine levels
Drugs elevate dopamine levels
Negative reinforcement models
o Amphetamine
Physical dependence (withdrawal) theory
o Cocaine
Driven by opiates, barbiturates, alcohol
o MDMA
(pain relievers and CNS depressants)
o Alcohol
Based on tolerance and physical dependence
o Nicotine
o Heroin, morphine
Mechanisms of tolerance & dependence: morphine
hedonic/euphoric effects linked to increased dopamine
1) Morphine inhibits adenylyl cyclase - less cAMP produced
2) Secondary rise in enzyme expression occurs (tolerance)
Other neurotransmitters involved in reward
3) Cease morphine excessive cAMP production
Serotonin regulates mood, sleep, cognition, memory
(withdrawal)
Glutamate regulates learning & memory
Intensity of withdrawal
Varies form one drug class to another
Life-threatening Moderate
Mild
- alcohol
- opioids
- nicotine
- benzos
- barbiturates

DRUG DEPENDENCE CONDITIONING

Long-term drug dependence
Physical dependence NOT major factor
Psychological dependence (craving) more important
Conditioning
Plays role in sustaining drug dependence
Cues associated with drug taking/withdrawal cause craving
o e.g. social situation, location, site of syringe/spoon

PHARMACOLOGY OF ADDICTION 2
CO-MORBIDITIES MENTAL ILLNESS
Addiction co-exists with or predisposes to mental disorders
Risk factors
Protective factors
50% of addicts have mental disorder
Environmental
Environmental
Most prevalent mental disorders:
- availability of drugs
- economic situation
o affective
- poverty
- social support
o anxiety
- peer culture of drug use
- positive life events
o personality
o psychotic
Individual
Individual
- genetic disposition
- good coping skills
Drugs of abuse can cause symptoms of mental disorders
- victim of abuse
- optimism
o cocaine, methamphetamine schizophrenia
- poor school performance
- health-related behaviour
o alcohol depression
- depression/suicide
- ability to resist pressure
Why do mental illnesses and substance abuse go together
Self-medication:
Genetics
o use drug to alleviate symptoms of mental distress/illness
Genetics contributes to risk of addiction
Causal effects
Inheritability for drug abuse: 40-60%
o substance abuse increases risk for mental illness
Variability between drugs, genders
Common or correlated causes
o similar risk factors
Contribution of genetic factors to nicotine addiction
Liability to initiate: 56%
Transition to dependence: 70%
Smoking persistence = >50%
RISK OF ADDICTION

nAChR genes increase risk for addiction

TREATMENT OF ADDICTION
Why cant addicts just quit?
Addiction changes the brain
Decreases dopamine D2 receptors (due to over-stimulation)
Treatment approaches
Need to treat whole person:
o pharmacological treatments (medication)
o medical services
o behavioural therapies
o social services
Pharmacological approaches
Substitute to alleviate withdrawal symptoms
o methadone used to blunt opiate withdrawal
o benzos used to blunt alcohol withdrawal
Long-term substitution
o methadone substitution for opiate addiction
o nicotine patches/gum instead of cigarettes
Block desired effects of drug
o naltrexone blocks opiate effects
Aversive therapies induce unpleasant response to drug
o disulfiram induces unpleasant response to acohol
Reduce craving
o bupropion (anti-depressant)
Potential medications for addiction
Research
Medication
Opiate agonists stabilise brain
Opioid agonists:
function in heroin addicts
methadone, buprenorphine
CB1 KO mice have decreased
CB1 Antagonists
responses to drugs of abuse
Smokers who are poor nicotine
Inhibitors of
metabolisers smoke less
metabolising enzymes
Stress triggers relapse in addicts CRF antagonists
CRF antagonists interfere with
response to stress

ANTIPSYCHOTICS 1
First generation antipsychotics (conventional, typical)
SYMPTOMS OF PSYCHOSIS
Psychosis is severe psychiatric disturbance characterised by:
Phenothiazines (end in -azine)
Butyrophenones (end in -operidol)
Positive symptoms
Negative symptoms
Thioxanthenes (end in -penthixol)
- delusions
- blunted affect
- hallucinations
(flattening of emotions)
Second generation antipsychotics (atypical, clozapine-like)
- thought disorder
- poverty of speech
End in -apine, -idone + amisulpiride, aripiprazole
- bizarre behaviour
- anhedonia
As effective
(cant experience
pleasure)
Better tolerated - less likely to cause:
- asociality
o extrapyramidal effects (motor disturbances)
- lack of motivation
o prolactin elevation
Better control negative symptoms
SCHIZOPHRENIA
Schizophrenia diagnosis DSM-IV criteria
2 or more of the following each present for a 1-month period
o delusions
o hallucinations
o disorganised speech
o grossly disorganised behaviour
o negative symptoms
Only 1 if bizarre delusions or hearing voices
Social/occupational dysfunction
Schizophrenia
Characterised by psychosis
Affects 2/1000 Australians
Peak age of onset: late teens, early twenties (more males)
Due to changes in brain maturation/development
Risk factors
Genetic component, but no single gene
o risk if close relative has it: 10%
o risk of identical twin has it: 50%
Urban birth and rearing
Social adversity and trauma
Heavy cannabis use
Migration
Stressful life events
CURRENT THEORIES OF SCHIZOPHRENIA
Dopamine theory (too much dopamine)
Traditional antipsychotic drugs are D2 receptor antagonists
Positive symptoms brought about by drugs that:
o are DA receptor agonists (e.g. apomorphine)
o increase DA release (e.g. amphetamine)
o increase DA synthesis (e.g. levodopa)
Post-mortems show increased D2 receptor densities
Limitations of theory
1/3 of schizophrenics dont respond to 1st gen antipsychotics
Unlikely DA is the only neurotransmitter involved
Glutamate theory (not enough glutamate)
Post-mortems show reduced glutamate and its receptors
Psychotic symptoms brought about by NMDA receptor
antagonists (block action of glutamate)
o e.g. phencyclidine (PCP), ketamine
Serotonin theory (too much serotonin)
Many antipsychotics are 5-HT receptor antagonists
o serotonin modulates dopamine pathways
ANTIPSYCHOTICS (tranquilisers, neuroleptics)
Control (not cure) symptoms in 70% of cases
Have more effect on positive than negative symptoms

Dosage
Given orally, enter CNS readily (very lipid soluble)
Depot forms (IM) available for maintenance therapy
o e.g. fluphenazine decanoate
Mechanism of action block dopamine D2 receptors
Block dopamine D2 receptors (reduce effect of dopamine)
o antagonists or partial agonists
Mesolimbic system (pleasure, reward)
o Too much dopamine = positive symptoms
o Blockade reduces positive symptoms
Mesocortical system (cognition, motivation, emotion)
o Too little dopamine = negative symptoms
o Blockade worsens negative symptoms
Nigrostriatal pathway (coordination of movement)
o Too little dopamine = extrapyramidal disorders
Tuberoinfundibular system (neuroendocrine control)
o Too little dopamine = prolactin secretion
Activity at other receptors
Antipsychotics may have activity at other receptors
Can reduce extrapyramidal side effects
Presence of unwanted side effects determined by activity at:
muscarinic, H1 and receptors
Pharmacokinetics
Administered orally, IM or depot (sustained-release)
Erratically absorbed after oral administration
Variable peak plasma concentrations
Variable relationship between plasma conc. & effect
Plasma half life: 15-30 hrs
Metabolism in liver by oxidation or conjugation
TYPICAL SIDE EFFECTS
Typical side effects
Endocrine abnormalities
o e.g. diabetes
o hyperprolactinemia
- gynecomastia (man boobs) in males
- galactorrhoea (lactation) in females
- infertility
Neurological disorders
o e.g. tardive dyskinesia
Metabolic abnormalities
o e.g. lipid abnormalities, weight gain
Cardiovascular side effects
o e.g. long QT interval
Side effects when antipsychotics act on non-DA receptors
Anti-muscarinic effects
o atropine-like (sympathetic) effects: dry mouth & eyes,
constipation, urinary retention, blurred vision
-receptor blockade postural hypotension and impotence
Histamine H1 receptor blockade sedation
5-HT2 receptor blockade weight gain
Tolerance develops to sedation (days) and hypotension (weeks)

10

ANTIPSYCHOTICS 2
Idiosyncratic (individual) reactions
CLOZAPINE
Jaundice
Withdrawn soon after release
o common with old phenothiazines e.g. chlorpromazine
Potentially fatal agranulocytosis (reduced WBCs)
o disappears upon drug cessation
Found to treat resistant schizophrenia reintroduced
Leukopenia (low WBC) and agranulocytosis
o rare (with clozapine) but fatal
Novel mode of action
o reversible
Low affinity for D2 receptors
o occurs in first few weeks
High affinity for D4 receptors
Urticarial skin reactions
o common but mild
MOST TROUBLESOME ADVERSE EFFECTS
o excessive sensitivity to sun
Schizophrenics consider most troublesome effects to be:
Antipsychotic malignant syndrome
o EP effects
o rare but fatal
o weight gain
o reversible
o sexual dysfunction
o muscle rigidity + hyperthermia + confusion
o sedation
ADVERSE EFFECTS
Antipsychotics decrease DA activity in the:
o limbic system normal behaviour
o striatum extrapyramidal side effects

CLINICAL PRACTICE GUIDELINES

Use 2nd gen (atypical) antipsychotics
Use clozapine for treatment-resistant schizophrenia
Multiple antipsychotics should be avoided

Extrapyramidal (EP) effects

Potent antipsychotics e.g. haloperidol, fluphenazine
Reduced by antimuscarinic drugs (e.g. benztropine)
Capacity to produce EP effects inversely related to ability to
block cholinergic receptors
o thioridazine high anti-ACh low EP
o fluphenazine low anti-ACh high EP
Parkinsonian syndrome (early)
Low DA (inhibitory), high ACh (excitatory)
o tremor
o rigidity
o slowness of movement
o impaired balance
o shuffling gait
Akathisia (early)
Restlessness of feet & legs
Acute dystonias (early)
Abnormal postures
Spasms of face, neck, back muscles
Tardive dyskinesia (late months to years)
Involuntary uncontrollable movements
(especially mouth, tongue, trunk and limbs)
D2 RECEPTOR OCCUPANCY
60-70%: therapeutic effects
>72%: elevation of prolactin
>78-80%: extrapyramidal effects
o clozapine, quetiapine never exceed
o other 2nd gens do
Drugs that rapidly dissociate from receptor (clozapine)
Cause less severe EP effects
Drugs that are partial agonists (aripiprazole)
Reduce DA in mesolimbic pathway
alleviate +ve symptoms
Dont reduce DA too much in mesocortical pathway
prevent negative symptoms
Dont reduce DA too much in nigrostriatal pathway
prevent EP symptoms

11

NICOTINE & TOBACCO 1

BURDEN OF DISEASE
HARMFUL EFFECTS OF SMOKING
Reduces life expectancy
Greatest preventable cause of premature death/disease
Through increased risk of:
15% total deaths due to smoking
o ischaemic heart disease
Only major cause of death (+ AIDS) thats increasing rapidly
o cancer lung & bladder
o COPD
Tobacco related deaths
o peripheral vascular disease
40% cancer
o stroke
60% ischemic heart disease, COPD and other (e.g. stroke)
Number of smokers
23% of Australians
>1 billion in the world
SOURCE OF TOBACCO
From 2 plants: Nicotiana tabacum and Nicotiana rustica
Nicotiana rustica used most
o leaves contain higher nicotine content
Nicotine
Plant alkaloid
Derived from nicotinic acid
Mimics ACh (nicotinic ACH receptor (nAChR) agonist)
Not the only pharmacologically active substance in tobacco
o 4,000 chemical substances
o 200 toxicants (e.g. carbon monoxide)
o 50 carcinogens (e.g. benzene)
70-80% metabolised in liver to cotinine
o similar effect to nicotine
o lower potency
o longer half life
EFFECT OF NICOTINE ON CNS
Activates brain nAChRs
o (4)2 (2)3 subunit composition
o excitation but also desensitisation
Effects blocked by mecamylamine
o neuronal nicotinic receptor antagonist
Adaptive response to chronic nicotinic stimulation
Increase in number of nAChR (due to desensitisation)
There is balance between excitation and desensitisation
o increased arousal, relaxation, attention
o increased learning ability (particularly under stress)
Reinforcing properties
Increased activity in mesolimbic reward pathway
Increased dopamine release in nucleus accumbens
PERIPHERAL EFFECTS OF NICOTINE
Due to stimulation of autonomic ganglia (ANS nerves) and
peripheral sensory receptors (primarily heart and lungs)
Sympathetic effects:
o Increased cardiac output and BP
o Reduced GIT motility
o Sweating
o Secretion of Ad, NAd, ADH (decreased urine flow)
First timers get nauseous
o due to stimulation of stomach sensory receptors
Tolerance develops rapidly to these effects (but not CNS)
Can promote angiogenesis
Aids formation of atherosclerotic plaques & tumours
PHARMACOKINETICS
Cigarette has: 0.8g tobacco, 9-17mg nicotine
Amount of nicotine absorbed: 1.5mg
Rapidly absorbed from lungs (poorly from mouth/nose)
Plasma concentration falls:
o to half within 10 mins (distribution)
o more slowly over next 1-2 hrs (hepatic metabolism)

Ischemic heart disease

60% greater risk of coronary thrombosis
Total number of deaths higher than lung cancer
(this disease is more common)
Both nicotine and carbon monoxide may be responsible
Cancer
90% lung cancers are smoking related
Carcinogenic tars are responsible
20/day increase lung cancer risk 10-fold
Respiratory disease
Acute respiratory disease (e.g. pneumonia)
Chronic respiratory disease (e.g. COPD, chronic bronchitis)
o Tar mainly responsible
o However nicotine impairs cleansing by cilia
Effects in pregnancy
> 25/day (particularly late in pregnancy) causes:
o increased abortion rate
o premature delivery
o perinatal mortality
o placenta praevia (baby cant be born vaginally)
o low birth weight
Nicotine and carbon monoxide responsible
CO has high affinity for Hb carboxyhaemoglobin
o retards foetal development in rats
Quitting before baby due
Women who quit in early months of pregnancy have same
risk of having a low birthweight baby as non-smoker women
Other effects
Macular degeneration in eyes
Hair loss
Aging of skin
Impotence in men
Osteoporosis
BENEFICIAL EFFECTS
2-fold reduction in risk of Parkinsons (increases DA)
Lowers risk of Alzheimers (reverses cholinergic deficit)
BENEFITS OF QUITTING
Tissue damage due to smoking may repair
Airways cleared of mucous
Circulation improves
Sense of smell & taste restored
After 10 years, may live normal life span
TOLERANCE & DEPENDENCE
Nicotine gives rise to:
o tolerance
o physical dependence (withdrawl syndrome)
o psychological dependence (craiving)
Nicotine is highly addictive

12

NICOTINE & TOBACCO 2

Withdrawal symptoms:
Depressed mood
Anxiety
Restlessness
Insomnia
Difficulty concentrating
Decreased HR
Increased appetite & weight gain
withdrawal lasts 2-3 weeks, but craving lasts much longer
How to assess dependence
Minutes after waking to first cig (<30 mins)
Number of cigarettes per day (>15)
Craving or withdrawal symptoms in quit attempts
CESSATION THERAPY
Nicotine replacement therapy (NRT)
Gum, inhaler, patch, lozenge, tablet
Attempt to reduce withdrawal symptoms
Side effects: nausea, cramps, cough, insomnia, muscle pain
Advantages:
o do not contain toxic substances like CO and tar
o do not produce dramatic surge in blood nicotine levels
o do not produce strong dependence
More effective if combined with counselling
(doubles changes of quitting)
Success rate only 25%
Bupropion
DA and NAd reuptake inhibitor increases levels
Antidepressant
But mode of action unknown
Effective short-term therapy alone or with NRT
Adverse effects
Lowers seizure threshold
Worsens depression in bipolar disorder

13

DRUGS IN AFFECTIVE DISORDERS 1

CHARACTERISTICS OF AFFECTIVE DISORDERS
Tricyclic antidepressants (TCAs)
Changes in mood NOT thought disturbances (psychoses)
2nd line therapy
Includes major depression and bipolar disorder
3-ring structure (related to phenothiazines)
More prevalent in females (except bipolar)
Used in:
o unipolar depression
o bipolar depression
Major depression DSM-IV criteria
o anxiety disorders
At least 5 of the following for 2 weeks and incl. 1 & 2
1) depressed mood
Unwanted effects
2) loss of interest or pleasure
Sedative and anticholinergic effects
3) appetite or weight loss or gain
4) insomnia or hypersomnia
Combining with MAO inhibitors can be fatal
5) fatigue or loss of energy
Muscarinic blockade
6) feelings of worthlessness or guilt
o anti-muscaranic (atropine-like) effects: dry mouth,
7) impaired thinking or concentration; indecisiveness
blurred vision, constipation
Incidence of suicide: 15%
-receptor blockade postural hypotension, impotence
6% of Australians
Histamine (H1) receptor blockade sedation
Depression in Australia & NZ
Can occur in children but more common in teenagers
Major depression begins in late 20s
Untreated moderate episodes last 9 months
50% with moderate episodes respond to therapy in 6-8 wks
Depression recurs in 40% of people

MAO inhibitors
MAO degrades monoamines in brain and other tissues
Preferentially degrade certain monoamines:
o MAOA: 5HT > NAd > DA
o MAOB: DA
Inhibitors lead to elevated levels of monoamines

Bipolar disorder (manic-depressive illness)

Distinct episodes of mania and depression
Occurs in 1-2% of population
Peak onset in early adulthood
10% of patients only have manic episodes

Irreversible non-selective MAO inhibitors

Older agents used as 2nd line therapy
o structurally related to amphetamine
o used for atypical depression (when SSRIs not effective)
Unwanted effects:
o insomnia, weight gain, peripheral oedema
o interaction with foods containing tyramine
- MAO normally breaks down tyramine
- tyramine enhances release of catecholamines
- result: adrenergic stimulation hypertensive crisis

MONOAMINE THEORY OF AFFECTIVE DISORDERS

Proposed by Joseph Schildkraut
Certain levels of monoamine neurotransmitters (NAd, 5-HT)
and receptor sensitivity are necessary for normal mood
Depression occurs if:
o Deficit of monoamines
o Receptors insensitive
Mania occurs if:
o Excess of monoamines
Antidepressants facilitate monoaminergic transmission

Reversible selective MAOA inhibitors

Can be 1st line therapy
Interactions with food minimal
(tryamine can be broken down by MAOB)
Used for major depression unresponsive to other drugs
Unwanted effects: nausea, dizziness, insomnia, headache

TYPES OF ANTIDEPRESSANTS
Inhibitors of monoamine uptake
Tricyclic antidepressants
o end in: -ipramine, -triptyline
Selective 5-H uptake inhibitors
o e.g. fluoxetine
Selective NAd uptake inhibitors
o e.g. bupropion
Mixed 5-HT & NAd uptake inhibitors
o e.g. venlafaxine
St Johns Wort (hyperforin) weak uptake inhibitor
Monoamine receptor antagonists
Inhibit 2 adrenoreceptors and 5-HT2 receptors
o e.g. mirtazapine
Monoamine oxidase (MAO) inhibitors
Inhibit MAO, increasing stores of NAd & 5-HT
Irreversible, non-selective (MAOA & B) inhibitors
o e.g. phenelzine
Reversible, MAOA selective inhibitors
o e.g. moclobemide

Selective 5-HT reuptake inhibitors (SRRIs)

Onset of action is no more rapid than TCAs or MAOIs
Most commonly prescribed antidepressants - 1st line therapy
o used for patients with CV disease (avoids sedation)
Less effective than TCAs in treating severe depression
Unwanted effects:
o nausea, diarrhoea, weight loss
o increased aggression & suicidal thoughts in teens
o serotonin syndrome (potentially fatal)
Clinical guidelines
Mild depression no drugs
Moderate to severe depression antidepressants
Antidepressants have same efficacy but different side effects
SSRI is the preferred drug better tolerated, safer in OD
Take 2-6 weeks to have effect
Treatment should continue > 2 years
TREATMENT OF BIPOLAR DISORDER

MOOD STABILISING DRUGS FOR BIPOLAR

14

DRUGS IN AFFECTIVE DISORDERS 2

TREATMENT OF BIPOLAR DISORDER
Mood-stabilising drugs
o Lithium
o Antiepileptic drugs (e.g. carbamazepine)
Atypical antipsychotic drugs
o E.g. olanzapine, risperidone
Others
o Benzos
General principles
Given prophylactically to prevent mood swings
Given over long periods
3-4 weeks before drugs have effect
In an acute attack, effective only in reducing mania
o Exception: lithium
Lithium carbonate (LITHICARB)
Depresses manic behaviour
Modulates frequency and magnitude of mood swings
(manic and depressive)
Excreted by kidney
Lithium
Li+ enters cells through Nav channels accumulates
Inhibits IP3 (inositol triphosphate) formation in PI linked
receptors blocks receptor-mediated effects
Selective for brain and kidney (Na channels more active)
Unwanted effects:
o Narrow therapeutic index must monitor blood levels

15

HISTORY
Modern era started with sulfanilamide
Golden age began with penicillin (1941)
o Fleming, Florey & Chain won Nobel Prize in 45

ANTIBIOTICS
Tetracyclines
Block 30S subunit - tRNA cant bind
Milk and iron tablets interfere with absorption
o form complexes with drug

DEFINITIONS
Chemotherapy: use of chemicals to destroy infective agents
or malignant/cancerous cells
Antibiotics: substances produced by microorganisms that
kill/inhibit growth of other microorganisms
Selective toxicity: ability of drug to injure a target
cell/organism without injuring other cells/organisms
EFFECTS OF ANTIBIOTICS
Bactericidal action kill bacteria
Bacteriostatic action stop bacteria multiplying
CLASSIFICATION OF ANTIBIOTICS
By susceptible organisms
Narrow spectrum a few
Broad spectrum wide variety
By mechanism of action
Inhibit cell wall synthesis
Inhibit protein synthesis
Antimetabolites
Nucleic acid synthesis inhibitors
Disruptors of cell membrane
INHIBITORS OF CELL WALL SYNTHESIS
-lactam antibiotics penicillins, cephalosporins
Bind to proteins on cytoplasmic membrane
Inhibit transpeptidase (required for cross-linking
peptidoglycan chains final step in cell wall synthesis)
Also activate autolytic enzymes that destroy cell wall
Penicillin
Widely used antibiotic to treat non-resistant Gram +
Benzylpenicillin (Penicillin G) is prototype
Poor absorption must be injected (parenteral admin.)
Narrow spectrum, bactericidal
Side effects: least toxic of all antibiotics
o neurotoxic (seizures) when high blood level or given
intrathecally (into spine)
o allergic reactions (rashes, fever)
Cephalosporins
Second choice for many infections
1st gen attack Gram +ve
cefaclor, cephalothin
2nd gen attach Gram -ve, more resistant to -lactamases
cephamandole
3rd gen attack resistant Gram ve
cefotaxime, ceftriaxone
PROTEIN SYNTHESIS INHIBITORS
Mechanisms of protein synthesis in microorganisms different
to people drugs have selective toxicity
BUT high doses do reduce host protein synthesis

Aminoglycosides (end in cin)

Incorrect binding of tRNA at 30S subunit false proteins
Possible ototoxicity (toxic to ears)
gentamicin= drug of choice for hospital acquired Gram ve
Macrolides (end in thromycin)
Binds to 50S subunit to suppress ribosome advancement
Alternative to penicillins in allergic patients
ANTIMETABOLITES
Nucleic acid synthesis dependent on folic acid
Antimetabolites interfere with folic acid synthesis
Sulfonamides (resemble PABA)
o inhibit dihydropteroate synthetase
Trimethoprim (resemble folic acid)
o inhibits dihydrofolate reductase
Used to treat UTIs
NUCLEIC ACID SYNTHESIS INHIBITORS
Quinolines inhibit topoisomerase II (coils DNA)
o end in -floxacin
Antimycobacterial agents (e.g. rifampicin) inhibit RNA
polymerase
o Used to treat TB & leprosy
DISRUPTORS OF CELL MEMBRANE
Polymixins (polymixin B & E)
Act as detergents disrupt phospholipids in cell membrane
Increase cell membrane permeability cell death
Polymixin B used for topical treatment of eyes, ears, skin
MECHANISMS OF BACTERIAL RESISTANCE
Microbes have 4 mechanisms for resisting drugs:
1) reducing drug conc. and accumulation
2) producing enzymes that inactivate drug
3) altering drug target molecules
4) developing altered metabolic pathways
Causes of penicillin resistance
1) Difficult to penetrate outer membrane of Gram ve bacteria
2) Microbes produce -lactamases inactive penicillin
o Inhibitors of these enzymes (e.g. clavulanic acid) used
3) Microbes produce penicillin binding proteins with low
affinity for -lactam antibiotics
CHOOSING AN ANTIBIOTIC
Objective: maximal antimicrobial effects, least harm to host
3 principal factors affect choice:
1) identity of infecting organism
2) drug sensitivity of infecting organism
3) host factors (e.g. age, pregnancy, site of infection)

Chloramphenicol
Binds to 50S ribosomal subunit - inhibits peptidyl transferase
Reserved for life threatening infections (e.g. Salmonella)
Rare side effect: pancytopenia (reduced RBC, WBC)
Neonatal grey baby syndrome
Cannot be used with clindamycin and macrolide

16

ANTIFUNGALS
Adverse effects
FUNGI
>2,000 known species
Highly toxic and dangerous drug
Only ~400 cause disease in animals
Renal impairment
Even fewer cause significant human disease
Hypokalaemia (low K+)
Fungal infections becoming more common
Drug interactions:
o interact with nephrotoxic drugs risk to kidney
Patients with compromised immune systems are susceptible
o potentiate effect of flucytosine
Clinically important fungi
Nystatin
Yeasts
Has similar structure, same mechanism of action
(e.g. Cryptococcus neoformans)
Yeast-like fungi that produce structure resembling mycelium Administered orally or topically
Rx Candida infections of skin, mucous membranes, GI tract
(e.g. Candida albicans)
Filamentous fungi with true mycelium
Unwanted effects: nausea, vomiting, diarrhoea
(e.g. Aspergillus fumigatus)
Griseofulvin
Dimorphic fungi (can grow as yeasts or filamentous fungi)
(e.g. Histoplasma capsulatum)
Narrow spectrum
Isolated from cultures of Penicillium griseofulvum
FUNGAL INFECTIONS
Interferes with mitosis by binding to fungal microtubules
Used to treat filamentous fungi infections when local
Systemic fungal infections (systemic mycoses)
treatment ineffective has been superseded
Opportunistic infections immunocompromised hosts
Administered orally
(e.g. candidiasis)
Non-opportunistic infections any host, uncommon
Adverse effects
GI upsets
Superficial mycoses
Headaches
Caused by 2 groups:
Photosensitivity
1) Candida - occur in mucous membranes, most skins
Allergic reactions (rash, fever)
- risk factors: corticosteroid therapy, tight clothing,
Should not be given to pregnant women
oral contraceptives
2) Filamentous fungi - occur in skin, hair & nails
Echinocandins
Among most common infections in world
Newest class of antifungals
Candida albican infections
Can be systemic or superficial
Superficial oral thrush, vaginitis
Filamentous fungi ringworm and tinea
Tinea unguium: infection of finger & toe nails
Tine cruris: starts in groin area (jock itch)
Tinea capitis: ringworm of scalp and hair
TREATMENT IS CHALLENGING
Most fungi resistant to conventional antimicrobials
Few drugs available for treatment of systemic fungal disease
Primary drugs used in systemic infections
Primary drugs used in systemic infections:
o Amphotericin B
o Azoles:
- fluconazole
- itraconazole
- ketoconazole
- voriconazole
Selectively toxic to fungi interact/inhibit ergosterol
(a sterol unique to fungal cell membranes)
ANTIFUNGAL ANTIBIOTICS
Amphotericin B
Mix of substances derived from cultures of Streptomyces
Site of action: fungal cell membrane
Interferes with permeability and transport functions
o Forms large pores in the membrane
o Disturbs ion balance of cell (K+ lost)
Drug of choice for systemic mycoses (gold standard)
o Active against most fungi
Should only be used for progressive, serious infections
Administered intravenously

Disrupt the fungal cell wall

Inhibit synthesis of 1,3, -glucan
Caspofungin active against wide variety of fungi
Administered intravenously

SYNTHETIC ANTIFUNGAL DRUGS

Azoles
Synthetic fungistatic agents
Broad spectrum of activity
Alternative to amphotericin B for systemic fungal infections
o Lower toxicity
o Can be administered orally
Inhibit fungal cytochrome P450 3A enzyme
inhibit synthesis of ergosterol
Alters fluidity of membrane so fungi cant replicate
OTHER ANTIFUNGALS
Flucytosine (a pyrimidine analog)
Synthetic, orally active antifungal
Effective against limited range (mainly yeasts) of fungi
Disrupts DNA synthesis
Combined with amphotericin for severe systemic infections
Development of resistance during therapy is problem
Few unwanted effects
Ketaconazole
First azole given orally to treat systemic fungal infection
Adverse effects:
o liver toxicity (can be fatal)
o loss of libido
o gynaecomastia (man boobs)

17

ANTIVIRALS
Protease inhibitors (sanquinavir)
Inhibit cleavage of nascent viral protein into functional and
What are viruses
structural proteins
Infective agents w/ DNA or RNA enclosed in protein coat
Used in combination with reverse transcriptase inhibitors
Lack independent metabolism
Sanquinavir buccal (cheek) and mucosal ulceration
Can only replication within host cells
DRUGS FOR INFLUENZA
Replication of a DNA virus
1) Attachment to host cell
Amantadine
2) Penetration
Inhibits penetration into the host cell
3) Virus coat removed
Binds to viral M2 protein prevents uncoating of the virus
4) Early transcription into viral mRNA
Used as prophylactic against influenza A
5) Early translation of mRNA into enzymes for viral DNA
Not effective against influenza B
synthesis
Not used widely because of problems with resistance
6) Synthesis of viral DNA, late transcription of viral mRNA
7) Late translation of mRNA into viral structural proteins
Oseltamivir (Tamiflu) & Zanamivir
8) Assembly of virus particles in nucleus
Inhibit neuraminidases produced by influenza A & B
9) Release of virions
Prevent viral escape from infected cells stops spread
Neuraminidases help escape:
HIV/AIDS
breaking bonds between particle coat and host sialic acid
Since 1981, AIDS has become global epidemic
Decreased susceptibility to drugs due to mutations in viral
> 40 million infected
neuraminidase
> 25 million dead
Can be taken to treat or prevent influenza
INTRODUCTION

Pathophysiology
HIV is an RNA retrovirus
Two forms HIV-1 responsible for human AIDS
Virions infect CD4+ T cells
Transmitted by:
o sexual contact
o exposure to blood
o mother to child
Diagnosed by blood test
OVERVIEW OF ANTIVIRAL DRUGS
Most available antivirals were approved in last 20 years
Doubts about developing selective drugs erased
Most antivirals only effective while virus is replicating
ALL are virustatic rather than virucidal
o rely on host immunocompetence for cure
DRUGS FOR HIV
HAART: therapy using a number of (>3) antiviral drugs
Should monitor plasma virus load & CD4 count
Change regime if viral concentration increases
Reverse transcriptase inhibitors
Interfere with viral nucleic acid synthesis
Nucleoside (zidovudine, lamivudine)
Nucleoside analogues
Phosphorylated by host cell
Competitively inhibit reverse transcriptase
Terminate DNA chain elongation
Zidovudine treat HIV, prevent maternal-fetal transmission
Lamivudine treat HIV, hepatitis B
Non-nucleoside (delaviridine)
Chemically diverse
Bind to reverse transcriptase and inactivate it
Terminate DNA chain elongation
Delavirdine:
o drug interactions are major problem
- metabolised by CYP3A4 & 2D6
- its blood levels are altered by other drugs
- it alters blood levels of other drugs
o should be avoided in pregnancy teratogenic

DRUGS FOR HBV & HCV

HBV: agents are suppressive rather than curative
HCV: primary goal is viral eradication
INF-
Enhance the hosts defence
Bind to receptors on host cell membranes
Induce in host cell ribosomes the production of enzymes that
inhibit the translation of viral mRNA into viral proteins
stop viral replication
Used to treat HBV & HCV
o when used in combo with ribavirin, progression of acute
HCV to chronic HCV reduced
Ribavirin
Mechanism of action not known
o inhibits guanosine triphosphate formation
o prevents capping of viral mRNA
o can block RNA polymerases
Inhibits replication of wide range of DNA & RNA viruses
o influenza
o HIV
o HCV
Adverse effect: haemolytic anaemia, foetal development
problems
DRUGS FOR HERPES
Acyclovir
Phosphorylated in herpes-infected cells
o by viral thymidine kinase (rather than host kinase)
Triphosphate nucleotide form inhibits DNA polymerase
Terminates nucleotide chain
CMV is resistant to acyclovir no thymidine kinase
Ganciclovir
Similar action to acyclovir
o phosphorylated by different kinase
Reserved for severe CMV infections owing to toxicity
o CMV: cytomegalovirus
Adverse effects: neutropenia (low WBCs), carcinogenicity

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