To explain pathogenesis of Schizophrenia
To classify antipsychotic drugs
To describe mechanism of action of antipsychotics
To enlist side effects of antipsychotic drugs.
Atypical antipsychotics have mixtures of pharmacological properties.
Beyond antagonism of 5HT2A and D2 receptors, they interact with multiple other receptor subtypes for both dopamine and serotonin, and have effects on other neurotransmitter systems as well.
Some of these multiple pharmacological properties can contribute to the therapeutic effects of atypical antipsychotics (e.g., antidepressant, antimanic, and anxiolytic effects), whereas others can contribute to their side effects (e.g,. sedative-hypnotic and cardiometabolic effects).
No two atypical antipsychotics have identical binding properties, which probably helps to explain why they all have distinctive clinical properties.
complete explanation with amicable pictures regarding CNS stimulants and cognitive enhancers.useful for both UG and PG students.references from different books and authors
complete explanation with amicable pictures regarding CNS stimulants and cognitive enhancers.useful for both UG and PG students.references from different books and authors
In this presentation we will discuss Parkinsonism and other movement disorders, Pathophysiology of parkinsonism and its types, drugs used in Parkinsonism and their pharmacology and briefly discuss the drugs used to treat other movement disorders like tourettes syndrome, Huntington chorea etc.
Presentation is about different types of dopaminergic receptors, dopamiergic pathway, its different functions, agonists, antagonists and various disorders associated with it along with its treatment.
antipsychotics history, managment of psychosis,side effect of antipsychotics, mechanism of antipsychotics, atypical antipsychotics,2nd generation antipsychotics.
In this presentation we will discuss Parkinsonism and other movement disorders, Pathophysiology of parkinsonism and its types, drugs used in Parkinsonism and their pharmacology and briefly discuss the drugs used to treat other movement disorders like tourettes syndrome, Huntington chorea etc.
Presentation is about different types of dopaminergic receptors, dopamiergic pathway, its different functions, agonists, antagonists and various disorders associated with it along with its treatment.
antipsychotics history, managment of psychosis,side effect of antipsychotics, mechanism of antipsychotics, atypical antipsychotics,2nd generation antipsychotics.
You will find Dopamine, Parkinson, Mental Disorders, Antipsychotics, Antidepressants and Antimaniac drugs here with mechanism of drugs, uses, adverse drug reaction and diagrams explaining the mechanisms. In case, if there is any query or update regarding the information provided, your comments are welcomed.
Parkinson’s disease is a progressive disorder of the nervous system that, in the early stages, is characterized by mild signs that are often missed. These signs can be remembered by the mnemonic “SMART”
S = Shuffling-Gait
M = Mask-like Face
A = Akinesia
R = Rigidity
T = Tremor
Parkinsonism
It is an extra-pyramidal motor disorder characterized by rigidity, tremor and hypokinesia with secondary manifestations like defective posture and gait, mask-like face and sialorrhoea; dementia may accompany. If untreated the symptoms progress over several years to end-stage disease in which the patient is rigid, unable to move, unable to breathe properly; succumbs mostly to chest infections / embolism
Ovarian tumors are abnormal growths on the ovaries, the female reproductive organs that produce eggs. Ovarian tumors can be noncancerous (benign) or cancerous (malignant). Many things can make you more likely to develop an ovarian tumor.
Gestational trophoblastic disease (GTD) is a group of rare diseases in which abnormal trophoblast cells grow inside the uterus after conception. In gestational trophoblastic disease (GTD), a tumor develops inside the uterus from tissue that forms after conception (the joining of sperm and egg).
A number of medical conditions have high association with kidney stone disease. Any type of chronic diarrhea state (such as Crohn's disease, gastric bypass, inflammatory bowel disorder), primary hyperparathyroidism, obesity, gout, and even diabetes have all been linked to increased risk of kidney stone disease.
The lymph node examination is performed with circular motion, identifying pain, and swollen ganglia or induration. For the anterior cervical lymph node exam, palpate the lymph nodes in the neck using circular motion over the underlying tissues in each area.
Position patient supine, with the hand on the side you're examining behind their head.
Palpate the asymptomatic breast first.
Palpate using the flat palmar surface of your fingers.
Palpate using a systematic technique to ensure you examine all of the breast regions.
The abdominal examination consists of four basic components: inspection, palpation, percussion, and auscultation. It is important to begin with the general examination of the abdomen with the patient in a completely supine position. The presence of any of the following signs may indicate specific disorders.
The lymph node examination is performed with circular motion, identifying pain, and swollen ganglia or induration. For the anterior cervical lymph node exam, palpate the lymph nodes in the neck using circular motion over the underlying tissues in each area.
LOWER LIMB EXAMINATION ,INSPECTION,PALPATION,TONE ,POWER, The neurologic examination is typically divided into eight components: mental status; skull, spine and meninges; cranial nerves; motor examination; sensory examination; coordination; reflexes; and gait and station.
Opioids are substances that act on opioid receptors to produce morphine-like effects. Medically they are primarily used for pain relief, including anesthesia. Other medical uses include suppression of diarrhea, replacement therapy for opioid use disorder, reversing opioid overdose, and suppressing cough
Opioid analgesia is indicated for the treatment of moderate to severe pain. An opioid is a medication that relieves pain by binding to opioid receptors in the central nervous system spinal cord and peripheral nervous system.
Opioids are substances that act on opioid receptors to produce morphine-like effects. Medically they are primarily used for pain relief, including anesthesia. Other medical uses include suppression of diarrhea, replacement therapy for opioid use disorder, reversing opioid overdose, and suppressing cough
Opioid analgesia is indicated for the treatment of moderate to severe pain. An opioid is a medication that relieves pain by binding to opioid receptors in the central nervous system spinal cord and peripheral nervous system.
To explain pathogenesis of Bipolar Disorders
To classify drugs used for treatment of Bipolar Disorders
To describe mechanism of action of drugs used for treatment of Bipolar Disorders
To enlist side effects of drugs used for treatment of Bipolar Disorders.
Indications: Bipolar, cyclothymia, schizoaffective, impulse control and intermittent explosive disorders.
Classes: Lithium, anticonvulsants, antipsychotics
Which you select depends on what you are treating and again the side effect profile.
To explain pathogenesis of Depression
To describe the synthesis, degradation and reuptake mechanism of 5HT
To classify Antidepressant drugs
To describe mechanism of action of Antidepressants.
To enlist side effects of Antidepressants.
The symptoms of depression are feelings of sadness and hopelessness, s well as the inability to experience pleasure in usual activities, changes in sleep patterns and appetite, loss of energy, and suicidal thoughts. Mania is characterized by the opposite behavior: enthusiasm, anger, rapid thought and speech patterns, extreme self-confidence, and impaired judgment.
Learning Objectives:
After completing the topic, the student will be able to:
• Recognize the importance of hemostasis and thrombosis in health and disease.
• Describe the process that leads to platelet aggregation.
• Classify anti-platelets drugs and the mechanism by which they inhibit platelet
aggregation.
• Describe indications, contraindications, drug interactions & adverse effects of anti-
platelets drugs.
• Describe treatment recommendations for antiplatelet agents
Acetylsalicylic Acid (Aspirin)
• Irreversibly inhibits COX1 and, in higher doses, COX2.
• COX1 inhibition (main antithrombotic mechanism); the formation of prostaglandin H2 is blocked, thus
thromboxane A2 cannot be synthesized (TxA2 stimulates platelets aggregation).
Drug interactions
• Co-administration of non-selective COX1 inhibitors may impair its efficacy.
• About one-third of patients receiving aspirin manifest treatment failure (Thrombotic Complication or
Death).
Adverse Events
• Resulting from rebound thrombocyte activation after aspirin withdrawal.
• Single binding site and does not influence other thrombocyte receptors results in aspirin having less
antithrombotic effect than many other agents
Define Angina pectoris, its type and causes
Explain mechanism of action of Nitrates, calcium channel blockers and
Beta Blockers?
3. Describe the clinical uses and adverse effects of anti Anginal drugs
4. Explain why the combination of a nitrate with a beta blocker or a calcium blocker may be more effective than either alone
To be able to describe:
Hypertension: its prevalence, cardiovascular mortality risks & complications.
Anti hypertensive drugs: classification, mechanism of action & side effects
D) In collecting duct, sodium enters through sodium channels & transferred into interstitial fluid by sodium pump, while potassium is pumped in opposite direction and moves through potassium channels into tubular fluid. Aldosterone stimulates these processes by increasing synthesis of messenger RNA that encodes for sodium channel and sodium pump proteins. The potassium-sparing diuretics exert their effects via two mechanisms: amiloride and triamterene inhibit the entrance of sodium into the principal cells, whereas spironolactone blocks the mineralocorticoid receptor and thereby inhibits sodium reabsorption and potassium secretion.
To be able to describe:
Cholesterol synthesis, source & metabolism
Hyperlipidemia – definition & normal values.
Anti hyperlipidemic drugs: its classification, mechanism of action & side effects.
The natural history of atherosclerosis might involve coronary plaque rupture / erosion, thrombus formation and vessel lumen occlusion, clinically recognized as acute coronary syndrome (ACS). International guidelines strongly recommend early statin administration in patients admitted for ACS. In addition to lowering circulating levels of low-density lipoprotein cholesterol (LDL-c), statin treatment was shown to promote plaque stabilization or regression in several ways, including reduction in necrotic lipid core, anti-inflammatory effects and improvement in endothelial function.
Update on the efficacy of statin treatment in acute coronary syndromes by Rosa, Gian Marco; Carbone, Federico; Parodi, Antonello; Massimelli, Elena A; Brunelli, Claudio; Mach, François (more...) European journal of clinical investigation, 05/2014, Volume 44, Issue 5, 501 - 515
Currently, only one medication has been approved to treat COVID-19. No cure is available for COVID-19. Antibiotics aren't effective against viral infections such as COVID-19. Researchers are testing a variety of possible treatments.
The FDA has approved the antiviral drug remdesivir (Veklury) to treat COVID-19 in hospitalized adults and children who are age 12 and older in the hospital. Remdesivir may be prescribed for people who are hospitalized with COVID-19 and need supplemental oxygen or have a higher risk of serious illness. It's given through a needle in the skin (intravenously).
The FDA has authorized a drug called Paxlovid that includes nirmatrelvir – a drug that blocks the activity of a specific enzyme needed for the virus that causes COVID-19 to replicate – and an antiviral drug called ritonavir that helps slow the breakdown of nirmatrelvir. Paxlovid is authorized to treat mild to moderate COVID-19 in people age 12 and older who are at higher risk of serious illness. The medications are taken by mouth as pills.
The FDA has authorized another drug called molnupiravir to treat mild to moderate COVID-19 in adults who are at higher risk of serious illness and who aren't able to take other treatment options. The medication is taken by mouth as a pill.
The FDA has authorized the rheumatoid arthritis drug baricitinib (Olumiant) to treat COVID-19 in some cases. Baricitinib is a pill that seems to work against COVID-19 by reducing inflammation and having antiviral activity. Baricitinib may be used in people who are hospitalized with COVID-19 who are on mechanical ventilators or need supplemental oxygen.
The U.S. National Institutes of Health has recommended the corticosteroid dexamethasone for people hospitalized with severe COVID-19 who are on supplemental oxygen or need mechanical ventilation. Other corticosteroids, such as prednisone, methylprednisolone or hydrocortisone, may be used if dexamethasone isn't available.
In some cases, the drugs remdesivir, tocilizumab or baricitinib may be given with dexamethasone in hospitalized people who are on mechanical ventilation or need supplemental oxygen.
The FDA has also authorized convalescent plasma therapy with high antibody levels to treat COVID-19. Convalescent plasma is blood donated by people who've recovered from COVID-19. Convalescent plasma with high antibodies may be used to treat some hospitalized people ill with COVID-19 who are either early in their illness or who have weakened immune systems.
Monoclonal antibodies aren't effective against treating COVID-19 caused by the omicron variant. These drugs were previously used to treat mild to moderate COVID-19 in people who had a higher risk of developing serious illness due to COVID-19.
Many people with COVID-19 may have mild illness and can be treated with supportive care. Supportive care is aimed at relieving symptoms and may include:
Pain relievers (ibuprofen or acetaminophen)
Cough syrup or medication
Rest
Fluid intake.
At the end of the lecture, students should be able to:
▶ Classify Antihistamines
Define mechanism of action and uses of Antihistamines
Enlisting the adverse effects of Antihistamines.
Describe the Pharmacology of Expectorants and Mucolytics
Explain the mechanism of action ,clinical uses and toxicity of cough suppressants
▶ Histamine is a chemical messenger mostly generated
in mast cell that mediates a wide range of cellular responses, Including;
-Allergic and inflammatory reactions,
-Gastric acid secretion
- Neurotransmission in parts of the brain
▶ Histamine has no clinical application but antihistamines have important therapeutic applications.
Adverse effects are a significant issue in the treatment of both cytotoxic drugs and newer targeted therapies, leading to dose reductions, dose delays, and treatment discontinuation.
Toxicity can reduce quality of life, jeopardies treatment adherence, and necessitate dose reductions and dose delays, all of which can have a negative impact on treatment response and outcome.
More from FAZAIA RUTH PFAU MEDICAL COLLEGE ,KARACHI,PAKISTAN (20)
Francesca Gottschalk - How can education support child empowerment.pptxEduSkills OECD
Francesca Gottschalk from the OECD’s Centre for Educational Research and Innovation presents at the Ask an Expert Webinar: How can education support child empowerment?
Embracing GenAI - A Strategic ImperativePeter Windle
Artificial Intelligence (AI) technologies such as Generative AI, Image Generators and Large Language Models have had a dramatic impact on teaching, learning and assessment over the past 18 months. The most immediate threat AI posed was to Academic Integrity with Higher Education Institutes (HEIs) focusing their efforts on combating the use of GenAI in assessment. Guidelines were developed for staff and students, policies put in place too. Innovative educators have forged paths in the use of Generative AI for teaching, learning and assessments leading to pockets of transformation springing up across HEIs, often with little or no top-down guidance, support or direction.
This Gasta posits a strategic approach to integrating AI into HEIs to prepare staff, students and the curriculum for an evolving world and workplace. We will highlight the advantages of working with these technologies beyond the realm of teaching, learning and assessment by considering prompt engineering skills, industry impact, curriculum changes, and the need for staff upskilling. In contrast, not engaging strategically with Generative AI poses risks, including falling behind peers, missed opportunities and failing to ensure our graduates remain employable. The rapid evolution of AI technologies necessitates a proactive and strategic approach if we are to remain relevant.
Welcome to TechSoup New Member Orientation and Q&A (May 2024).pdfTechSoup
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The Roman Empire A Historical Colossus.pdfkaushalkr1407
The Roman Empire, a vast and enduring power, stands as one of history's most remarkable civilizations, leaving an indelible imprint on the world. It emerged from the Roman Republic, transitioning into an imperial powerhouse under the leadership of Augustus Caesar in 27 BCE. This transformation marked the beginning of an era defined by unprecedented territorial expansion, architectural marvels, and profound cultural influence.
The empire's roots lie in the city of Rome, founded, according to legend, by Romulus in 753 BCE. Over centuries, Rome evolved from a small settlement to a formidable republic, characterized by a complex political system with elected officials and checks on power. However, internal strife, class conflicts, and military ambitions paved the way for the end of the Republic. Julius Caesar’s dictatorship and subsequent assassination in 44 BCE created a power vacuum, leading to a civil war. Octavian, later Augustus, emerged victorious, heralding the Roman Empire’s birth.
Under Augustus, the empire experienced the Pax Romana, a 200-year period of relative peace and stability. Augustus reformed the military, established efficient administrative systems, and initiated grand construction projects. The empire's borders expanded, encompassing territories from Britain to Egypt and from Spain to the Euphrates. Roman legions, renowned for their discipline and engineering prowess, secured and maintained these vast territories, building roads, fortifications, and cities that facilitated control and integration.
The Roman Empire’s society was hierarchical, with a rigid class system. At the top were the patricians, wealthy elites who held significant political power. Below them were the plebeians, free citizens with limited political influence, and the vast numbers of slaves who formed the backbone of the economy. The family unit was central, governed by the paterfamilias, the male head who held absolute authority.
Culturally, the Romans were eclectic, absorbing and adapting elements from the civilizations they encountered, particularly the Greeks. Roman art, literature, and philosophy reflected this synthesis, creating a rich cultural tapestry. Latin, the Roman language, became the lingua franca of the Western world, influencing numerous modern languages.
Roman architecture and engineering achievements were monumental. They perfected the arch, vault, and dome, constructing enduring structures like the Colosseum, Pantheon, and aqueducts. These engineering marvels not only showcased Roman ingenuity but also served practical purposes, from public entertainment to water supply.
A Strategic Approach: GenAI in EducationPeter Windle
Artificial Intelligence (AI) technologies such as Generative AI, Image Generators and Large Language Models have had a dramatic impact on teaching, learning and assessment over the past 18 months. The most immediate threat AI posed was to Academic Integrity with Higher Education Institutes (HEIs) focusing their efforts on combating the use of GenAI in assessment. Guidelines were developed for staff and students, policies put in place too. Innovative educators have forged paths in the use of Generative AI for teaching, learning and assessments leading to pockets of transformation springing up across HEIs, often with little or no top-down guidance, support or direction.
This Gasta posits a strategic approach to integrating AI into HEIs to prepare staff, students and the curriculum for an evolving world and workplace. We will highlight the advantages of working with these technologies beyond the realm of teaching, learning and assessment by considering prompt engineering skills, industry impact, curriculum changes, and the need for staff upskilling. In contrast, not engaging strategically with Generative AI poses risks, including falling behind peers, missed opportunities and failing to ensure our graduates remain employable. The rapid evolution of AI technologies necessitates a proactive and strategic approach if we are to remain relevant.
Biological screening of herbal drugs: Introduction and Need for
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Macroeconomics- Movie Location
This will be used as part of your Personal Professional Portfolio once graded.
Objective:
Prepare a presentation or a paper using research, basic comparative analysis, data organization and application of economic information. You will make an informed assessment of an economic climate outside of the United States to accomplish an entertainment industry objective.
June 3, 2024 Anti-Semitism Letter Sent to MIT President Kornbluth and MIT Cor...Levi Shapiro
Letter from the Congress of the United States regarding Anti-Semitism sent June 3rd to MIT President Sally Kornbluth, MIT Corp Chair, Mark Gorenberg
Dear Dr. Kornbluth and Mr. Gorenberg,
The US House of Representatives is deeply concerned by ongoing and pervasive acts of antisemitic
harassment and intimidation at the Massachusetts Institute of Technology (MIT). Failing to act decisively to ensure a safe learning environment for all students would be a grave dereliction of your responsibilities as President of MIT and Chair of the MIT Corporation.
This Congress will not stand idly by and allow an environment hostile to Jewish students to persist. The House believes that your institution is in violation of Title VI of the Civil Rights Act, and the inability or
unwillingness to rectify this violation through action requires accountability.
Postsecondary education is a unique opportunity for students to learn and have their ideas and beliefs challenged. However, universities receiving hundreds of millions of federal funds annually have denied
students that opportunity and have been hijacked to become venues for the promotion of terrorism, antisemitic harassment and intimidation, unlawful encampments, and in some cases, assaults and riots.
The House of Representatives will not countenance the use of federal funds to indoctrinate students into hateful, antisemitic, anti-American supporters of terrorism. Investigations into campus antisemitism by the Committee on Education and the Workforce and the Committee on Ways and Means have been expanded into a Congress-wide probe across all relevant jurisdictions to address this national crisis. The undersigned Committees will conduct oversight into the use of federal funds at MIT and its learning environment under authorities granted to each Committee.
• The Committee on Education and the Workforce has been investigating your institution since December 7, 2023. The Committee has broad jurisdiction over postsecondary education, including its compliance with Title VI of the Civil Rights Act, campus safety concerns over disruptions to the learning environment, and the awarding of federal student aid under the Higher Education Act.
• The Committee on Oversight and Accountability is investigating the sources of funding and other support flowing to groups espousing pro-Hamas propaganda and engaged in antisemitic harassment and intimidation of students. The Committee on Oversight and Accountability is the principal oversight committee of the US House of Representatives and has broad authority to investigate “any matter” at “any time” under House Rule X.
• The Committee on Ways and Means has been investigating several universities since November 15, 2023, when the Committee held a hearing entitled From Ivory Towers to Dark Corners: Investigating the Nexus Between Antisemitism, Tax-Exempt Universities, and Terror Financing. The Committee followed the hearing with letters to those institutions on January 10, 202
2. Objectives:
To explain pathogenesis of Schizophrenia
To classify antipsychotic drugs
To describe mechanism of action of antipsychotics
To enlist side effects of antipsychotic drugs.
Fazaia Ruth
Pfau Medical
College
Department of Pharmacology 2
4. Typical & Atypical antipsychotics and D2 & 5HT2A
receptors
Atypical antipsychotic
drugs are effective at lower
occupancy of 30-50% -
because of concurrent high
occupancy of striatal 5HT2A
receptors.
Fazaia Ruth
Pfau Medical
College
Department of Pharmacology 4
EPS when
occupancy of
striatal D2
receptors reach
80% or more.
Typical Antipsychotics are
COMPETITIVE antagonists
D2 dopamine receptor
Typical antipsychotic
drugs must be given in
sufficient doses to
achieve 60% occupancy
of striatal D2 receptors.
6. D2 partial agonism render an
antipsychotic atypical - may stabilize
dopamine neurotransmission in a state
between silent antagonism and full
stimulation.
Partial agonists have the intrinsic ability
to bind receptors in a manner that
causes signal transduction from the
receptor to be intermediate between full
output and no output.
Thus, many degrees of partial agonism
are possible between two extremes.
Full agonists, antagonists, and partial
agonists may cause different changes
in receptor conformation.
Fazaia Ruth
Pfau Medical
College
Department of Pharmacology 6
Typical VS Atypical and diversity in Atypical
7. Atypical antipsychotics have mixtures of
pharmacological properties.
Beyond antagonism of 5HT2A and D2 receptors, they
interact with multiple other receptor subtypes for
both dopamine and serotonin, and have effects on
other neurotransmitter systems as well.
Some of these multiple pharmacological properties
can contribute to the therapeutic effects of atypical
antipsychotics (e.g., antidepressant, antimanic, and
anxiolytic effects), whereas others can contribute to
their side effects (e.g,. sedative-hypnotic and
cardiometabolic effects).
No two atypical antipsychotics have identical
binding properties, which probably helps to explain
why they all have distinctive clinical properties.
Atypical antipsychotic binding properties.
Serotonin and/or
norepinephrine reuptake
inhibition – quetiapine
has potency greater
than its D2 binding
Atypical antipsychotics
(aripiprazole & cariprazine) have
greater efficacy for nonpsychotic
mania.
Potent antihistamine actions
Clozapine, Quetiapine,
Olanzapine Fazaia Ruth
Pfau Medical
College
Department of Pharmacology 7
8. Fazaia Ruth
Pfau Medical
College
Department of Pharmacology 8
(3) Nigrostriatal pathway - Substantia Niagra to corpus
striatum, coordination of voluntary movements ,
accounts for 75% of Dopamine in brain, + D2 receptor blockade
is responsible for extra pyramidal symptoms. This pathway is
involved in movement regulation. Remember that
dopamine suppresses acetylcholine activity.
Dopamine hypoactivity can cause Parkinsonian
movements i.e. rigidity, bradykinesia, tremors),
akathisia and dystonia.
(1) Mesolimbic – Ventral tegmental
area to nucleus accumbens.
Increased activity in this pathway may
cause delusions, hallucinations, and
other so-called positive symptoms of
schizophrenia. Problem here in a
psychotic patient is there is too much
dopamine.
(2) Mesocortical pathway -
Ventral tegmental area to
cortex. Decreased activity in
can cause apathy,
withdrawal, lack of
motivation and pleasure,
and other so-called negative
symptoms of schizophrenia.
Mesocortical dysfunction also
disinhibits the mesolimbic
pathway. Problem here for a
psychotic patient, is too
little dopamine.
(4) Tuberoinfundibular system
- hypothalamus to pituitary
gland, inhibits prolactin secretion
from anterior pituitary.
Area postrema (to vomit centre in
reticular formation)
Incertohypothalamic pathway -
descending pathways originating in
hypothalamus
9. Fazaia Ruth
Pfau Medical
College
9
Administration of D2 antagonist - conventional
antipsychotic, blocks dopamine, which reduces
hyperactivity in this pathway and thereby reduces
positive symptoms.
SCHIZOPHRENIA
UNTREATED
TREATED
Mesolimbic dopamine pathway and D2 antagonists.
In untreated schizophrenia, mesolimbic
dopamine pathway is hyperactive.
This leads to positive symptoms such as
delusions and hallucinations.
Department of Pharmacology
10. If D2 receptors in mesolimbic
system are blocked, then it also
block reward mechanisms,
leaving patients apathetic,
anhedonic, lacking motivation,
interest, and joy from social
interactions, like negative
symptoms of schizophrenia.
Antipsychotics also block D2
receptors in meso-cortical DA
pathway where it is already
deficient in schizophrenia
This worsen negative and
cognitive symptoms.
Typical antipsychotics can cause
“neuroleptic induced deficit
syndrome” as it is like negative
symptoms produced by
schizophrenia.
Fazaia Ruth
Pfau Medical
College
Department of Pharmacology 10
11. In untreated schizophrenia, the mesocortical dopamine pathways to DLPFC and to VMPFC
are hypoactive resulting in cognitive symptoms of DLPFC, affective symptoms of VMPFC
AND negative symptoms due to both.
Administration of a D2 antagonist could further reduce activity in this pathway and thus
potentially worsen them.
Mesocortical dopamine pathway and D2 antagonists.
Dorsolateral prefrontal cortex Ventromedial prefrontal cortex
Fazaia Ruth
Pfau Medical
College
Department of Pharmacology 11
12. Fazaia Ruth Pfau Medical College
Department of Pharmacology
12
Blockade of D2 receptors with a conventional antipsychotic, prevents
dopamine from binding there and can cause motor side effects that
are often collectively termed extrapyramidal symptoms (EPS).
Nigrostriatal dopamine pathway and D2 antagonists.
This pathway is unaffected in untreated schizophrenia.
Long-term blockade of D2 receptors in
nigrostriatal dopamine pathway cause
upregulation of receptors, which lead
to a hyperkinetic motor condition -
tardive dyskinesia tongue
protrusions, facial grimaces, chewing
as well as quick, jerky limb
movements.
Tardive dyskinesia.
13. D2 antagonists reduce activity in
this pathway.
This causes prolactin levels to
rise, which is associated with
side effects such as
galactorrhea & irregular
menstrual periods.
Tuberoinfundibular dopamine pathway and D2 antagonists.
This pathway projects from
hypothalamus to pituitary
gland, is “normal” in
untreated schizophrenia.
Fazaia Ruth
Pfau Medical
College
Department of Pharmacology 13
14. Reciprocal relationship of Dopamine and Acetylcholine in the nigrostriatal dopamine pathway
Dopamine neurons make postsynaptic connections
with the dendrite of a cholinergic neuron.
Normally, dopamine suppresses acetylcholine
activity.
Antagonism of D2 receptors on the cholinergic
dendrite, results in acetylcholine excess.
This produces extrapyramidal symptoms (EPS) due
to relative dopamine deficiency and a relative
acetylcholine excess.
D2 antagonism and anticholinergic agents: Anticholinergics
overcome excess acetylcholine activity caused by removal of
dopamine inhibition when dopamine receptors are blocked by
conventional antipsychotics and reduces extrapyramidal symptoms
Fazaia Ruth
Pfau Medical
College
Department of Pharmacology 14
15. (1) Serotonin is released in the cortex and binds
to 5HT2A receptors on glutamatergic pyramidal
neurons, causing activation of those neurons.
(2) Activation of glutamatergic pyramidal neurons
leads to glutamate release in the brainstem,
which in turn stimulates GABA release. GABA
binds to dopaminergic neurons projecting
from the substantia nigra to the striatum,
inhibiting dopamine release.
Cortical 5HT2A receptors decrease dopamine release.
Their blocking will ↑ dopamine release
from substantia nigra into striatum.
5HT2A are located in many brain regions and are postsynaptic.
On cortical pyramidal neurons, they are excitatory & ↑
downstream glutamate release.
5HT2A receptors are the key to understand atypical antipsychotics.
5HT2A receptors are brakes on dopamine release in the Striatum. 5HT2A antagonism cuts this brake cable.
Fazaia Ruth
Pfau Medical
College
Department of Pharmacology 15
16. Nigral and striatal 5HT2A receptor stimulation decreases dopamine release
Blocking nigral and striatal 5HT2A
receptors increases dopamine
release.
5HT2A receptor stimulation by
serotonin at either end of
substantia nigra neurons
hypothetically blocks dopamine
release in the striatum
Fazaia Ruth
Pfau Medical
College
Department of Pharmacology 16
17. Cortical 5HT1A receptor stimulation
↑ dopamine release.
5HT projections from raphe nucleus to cortex
also make axoaxonic connections with
glutamatergic pyramidal neurons.
(1) Serotonin released at these synapses
can bind to 5HT1A receptors, which
causes inhibition of the glutamatergic
neuron.
(2) If glutamate is not released from
glutamatergic pyramidal neurons into
brainstem, then GABA release is not
stimulated and in turn cannot inhibit
dopamine release from substantia nigra
into striatum.
Cortical 5HT1A receptor stimulation is
functionally analogous to cortical 5HT2A
receptor blockade, in that both lead to
increased dopamine release in the
striatum.
Fazaia Ruth
Pfau Medical
College
Department of Pharmacology 17
18. Serotonin binding to 5HT1A receptors in
the raphe nucleus inhibits serotonin
release.
(1) In the striatum, reduced serotonin
release means that 5HT2A receptors on
GABAergic & dopaminergic neurons are
not stimulated, which in turn means that
dopamine release is not inhibited.
(2) Similarly, in the brainstem, reduced
serotonin release means that 5HT2A
receptors on GABAergic interneurons
are not stimulated and therefore GABA is
not released. Thus, dopamine can be
released into striatum.
Raphe 5HT1A receptor stimulation increases dopamine release.
Fazaia Ruth
Pfau Medical
College
Department of Pharmacology 18
19. Normally, 5HT inhibits DA release
Antagonist of 5HT2A receptor disinhibits
dopamine neuron, causing dopamine
release.
Thus dopamine compete with SDA for D2
receptor & reverse inhibition there. As D2
blockade is thereby reversed, SDAs cause
little or no extrapyramidal symptoms (EPS)
or tardive dyskinesia
5HT2A receptor antagonism
makes an antipsychotic
atypical: low EPS
Fazaia Ruth
Pfau Medical
College
Department of Pharmacology 19
20. Dopamine inhibits prolactin
release from pituitary gland when it
binds to D2 receptors (red circle).
Serotonin (5HT) stimulates prolactin
release from pituitary gland when it binds to
5HT2A receptors (red circle).
Conventional antipsychotic drugs are D2
antagonists and thus oppose dopamine’s
inhibitory role on prolactin secretion
As dopamine and serotonin have reciprocal
regulatory roles in the control of prolactin
secretion, one cancels the other. Thus,
stimulating 5HT2A receptors reverses the effects
of stimulating D2 receptors.
5HT2A receptor
antagonism makes
an atypical
antipsychotic : low
hyperprolactinemia
Fazaia Ruth
Pfau Medical
College
Department of Pharmacology 20
21. The mesolimbic and mesocortical pathways, which are
responsible for positive and negative symptoms, may
be involved in aggression and violence. Agents
targeting much more than 60% D2 receptor occupancy
in these pathways could reduce these symptoms.
Orbitofrontal cortex and amygdala play a role in
impulsive aggression, which could be relieved by
targeting much more than 60% D2 receptor occupancy.
Affective symptoms may contribute to violent behavior
are mediated by ventromedial prefrontal cortex and
could potentially be treated with mood stabilizers.
Finally, instrumental aggression and violent sociopathy
may be mediated by dorsolateral prefrontal cortex, and
may best be managed with behavioral strategies,
including seclusion and incarceration.
Psychopharmacologic targeting of circuits associated with violence.
Fazaia Ruth
Pfau Medical
College
Department of Pharmacology 21
22. NMDA receptors require presence of both
glutamate and a coagonist at glycine site in
order to be fully active. Hence agonists at
glycine coagonist site may enhance NMDA
functioning.
The glycine transporter 1 terminates actions of glycine at
NMDA receptors in glutamate synapse by transporting
glycine back up into glial cells as a reuptake pump.
Inhibitors at GlyT1 would increase availability of
synaptic glycine, enhancing activity at NMDA receptors.
Schizophrenia is linked to hypoactive NMDA receptors.
Glycine agonists OR GlyT1 inhibition may thus be promising future treatments for
negative and cognitive symptoms of schizophrenia without worsening positive symptoms.
Fazaia Ruth
Pfau Medical
College
Department of Pharmacology 22
23. Fazaia Ruth
Pfau Medical
College
Department of Pharmacology 23
AT FIRST anti
psychotic drugs
cause an
increase in
dopamine
synthesis,
release, and
metabolism.
A response to
acute blockade
of postsynaptic
dopamine
receptors.
Over time, continued
dopamine receptor
blockade leads to
inactivation of
dopaminergic neurons
which results in
reduced dopamine
release from
mesolimbic &
nigrostriatal neurons
and alleviate the
positive symptoms of
schizophrenia while
causing EPSs.
Lastly the reduction
in dopamine release
caused by
depolarization
blockade leads to
dopamine receptor
up-regulation and to
dopamine agonists.
This super sensitivity
may contribute to the
development of a
delayed type of EPS
called tardive
dyskinesia.
Whereas these receptors are blocked immediately when antipsychotic
drugs are first administered, therapeutic effects usually require
several weeks to fully develop.
This is because antipsychotic drugs produce three time-dependent
changes in dopamine neurotransmission.
Pharmacologic Effects
24. Mechanisms Responsible for the Therapeutic and Adverse Effects of Antipsychotic Drugs
* .
Fazaia Ruth
Pfau Medical
College
Department of Pharmacology 24
MECHANISM THERAPEUTIC EFFECTS ADVERSE EFFECTS
Blockade of α1 -adrenoceptors — Dizziness, orthostatic hypotension, and
reflex tachycardia
Blockade of dopamine D2 receptors Alleviation of positive symptoms of
schizophrenia
Extrapyramidal effects (akathisia,
dystonia, and pseudoparkinsonism) and
elevated serum prolactin levels
Blockade of dopamine D4 receptors Alleviation of negative symptoms of
schizophrenia and decrease in the
incidence of extrapyramidal side
effects
—
Blockade of histamine H1 receptors Sedation may be considered a
therapeutic effect with a typical
antipsychotic administered for acute
psychosis
Drowsiness and increase in appetite
and weight
Blockade of muscarinic receptors — Blurred vision, constipation, dry
mouth, and urinary retention
Blockade of serotonin 5-
HT2 receptors
Alleviation of negative symptoms of
schizophrenia and decrease in the
incidence of extrapyramidal side
effects
Anxiety and insomnia
25. Antipsychotic adverse effects
Tardive Dyskinesia (TD)-involuntary muscle movements that may not resolve
with drug discontinuation- risk approx. 5% per year
Neuroleptic Malignant Syndrome (NMS): Characterized by severe muscle
rigidity, fever, altered mental status, autonomic instability, elevated WBC,
CPK and fits. Potentially fatal.
Extrapyramidal side effects (EPS): Acute dystonia, Parkinson syndrome,
Akathisia
Effects due to
alpha adrenoceptors blockade.
muscuranic cholinoceptor blockade
endocrine & metabolic disturbances: galactorrhea, loss of libido &
gynaecomastia
Fazaia Ruth
Pfau Medical
College
Department of Pharmacology 25
26. Haloperidol
High potency & widely used.
Highly lipid soluble & protein bound (92-
99%). They have large volume of
distribution(usually more than 7 L/kg).
Extensively metabolized by liver -
bioavailability of about 65% after an oral
dose and excreted in urine.
Has longer clinical duration of action as is
evident from plasma half life.
It has fewer autonomic effects but greater
extra pyramidal effects
Clozapine (Clozaril)
First of the new generation of
antipsychotics. (Atypical)
Decreased risk of extra pyramidal effects &
effective for negative symptoms of
Schizophrenia.
Associated with agranulocytosis (0.5-2%)
and therefore requires weekly blood draws
x 6 months)
Associated with the most sedation, weight
gain and Increased liver enzymes
Fazaia Ruth
Pfau Medical
College
Department of Pharmacology 26
27. Risperidone (Risperdal)
Available in regular tabs, IM depot forms
and rapidly dissolving tablet
Functions more like atypical
antipsychotic.
Increased extrapyramidal side effects
(dose dependent)
Weight gain, less sedation & orthostatic
hypotension.
Most likely atypical to induce
hyperprolactinemia
It also lengthens QT interval and
predispose patients to cardiac
arrhythmias.
Quetiapine (Seroquel)
Available in a regular tablet form
only
May cause Increased level of liver
enzymes - 6% of all patients.
May be associated with weight gain,
though less than seen with
olanzapine
May cause hypertriglyceridemia,
hypercholesterolemia, hyperglycemia
(even without weight gain), however
less than olanzapine
Most likely to cause orthostatic
hypotension
Fazaia Ruth
Pfau Medical
College
Department of Pharmacology 27
28. Aripiprazole’s unique binding profile.
Aripiprazole differs from most other
antipsychotics in that it is a partial
agonist at D2 receptors rather than an
antagonist. Additionally it is 5HT2A
antagonist actions, 5HT1A partial agonist
actions, and 5HT7 antagonist actions.
Aripiprazole has weak binding
potency at receptors associated with
sedation & also lack associated with
weight gain and increased
cardiometabolic risk, such as
increasing fasting plasma
triglyceride levels or increasing
insulin resistance.
Fazaia Ruth
Pfau Medical
College
Department of Pharmacology 28
29. Monitoring on the metabolic highway.
First, increased appetite and weight gain can lead to
elevated body mass index (BMI) and ultimately
obesity.
Second, atypical antipsychotics can cause insulin
resistance by an unknown mechanism; this can be
detected by measuring fasting plasma triglyceride
levels.
Finally, atypical antipsychotics can cause sudden
onset of diabetic ketoacidosis (DKA) or
hyperglycemic hyperosmolar syndrome (HHS) by
unknown mechanisms, possibly including blockade
of M3-cholinergic receptors. This can be detected by
informing patients of the symptoms of DKA/HHS and
by measuring fasting glucose levels.
Fazaia Ruth
Pfau Medical
College
Department of Pharmacology 29
30. Take home points
Be clear on the diagnosis you are treating
and any comorbid diagnoses when you are
selecting an agent to treat- often can get 2
birds with 1 stone!
Select the agent based on patients history,
current symptom profile and the side effect
profile of the medication- there is no one
correct answer in most cases.
Monitor for efficacy and tolerance and
adjust as indicated.
If the patient does not improve step back,
rethink your diagnosis and treatment plan!
Keep an eye on drug-drug interactions
Sulaiman
AlRajhi
Colleges
Department of Pharmacology 30
1. Basic & Clinical Pharmacology by Katzung 13th
edition.
2. Rang & Dale Pharmacology 8th edition.
3. Pharmacology by Brenner 3rd edition.
4. Board review series Pharmacology 5th edition.
5. Netters Pharmacology.
6. Stahl’s Psychopharmacology 4th edition.
Editor's Notes
(1) In striatum, 5HT2A projections synapse indirectly via GABAergic neurons disinhibits GABA release, which in turn ↓ release of dopamine, AND when serotonin binds directly to 5HT2A receptors on dopamine neurons, this causes a ↓ in dopamine release.
(2) Serotonin can also decrease dopamine release in striatum via 5HT2A binding in brainstem. Serotonin released in raphe nucleus binds to 5HT2A receptors on GABAergic interneurons and causes GABA to be released onto dopaminergic neurons in substantia nigra, thus inhibiting dopamine release into striatum.