Pharmacology 2 Notes
Pharmacology 2 Notes
Pharmacology 2 Notes
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
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
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
Pharmacokinetics
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
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)
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
Pharmacokinetics
CANNABIS
Plant
Active ingredient
(cannabinoid):
9-tetrahydro-cannabinol
(THC)
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
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
Structure
Indole (6-ring + 5-ring)
Tetracyclic (4 rings)
D-LSD isomer has
psychoactive properties
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
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
CANDY FLIPPING
MDMA + LSD
Enhance effects
Reduce bad trips
Both potentially neurotoxic
Both increase release of
excitatory glutamate
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
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
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)
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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
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12
13
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
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
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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
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
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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
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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
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